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Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy.Monday, November 30, 2015
Borah A, Raveendran S, Rochani A, Maekawa T, Kumar DS,
Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction for future cancer therapy.
Differential modulation of claudin 4 expression and myosin light chain phosphorylation by thyroid function in lung injury.Monday, November 30, 2015
Masoumeh V, Naser P, Mohammad O, Naghibalhossaini F, Omrani GH,
The clinical respiratory journal. 30-Nov-2015
Our data suggest that thyroid function plays significant role in lung injury perhaps by modulating expression of the proteins involved in junctional tightness. Besides, they strongly support the idea that the tissue hypothyroid state may contribute to endothelial-epithelial barriers breakdown associated with trauma. This article is protected by copyright. All rights reserved.
Strategies for individualizing management of patients with metastatic melanoma: a managed care perspective.Monday, November 30, 2015
Goldstein DA, Zeichner SB,
The American journal of managed care. Sep-2015
The management of metastatic melanoma has been revolutionized in recent years with the development of both targeted therapy and immunotherapy. Although potentially extending the life expectancy for patients, these therapies also significantly increase the healthcare expenditure. In this paper, we review the monthly costs for drugs approved by the FDA since 2011. Additionally, factors that affect the cost, such as dosing strategies, biomarkers, combination therapies, and political/legislative issues, will be discussed.
Skin biomarkers for neurodegenerative disease: a future perspective.Monday, November 30, 2015
Castanedo-Cazares JP, Rodriguez-Leyva I,
Neurodegenerative disease management. 30-Nov-2015
The Polyunsaturated Fatty Acids Arachidonic Acid and Docosahexaenoic Acid Induce Mouse Dendritic Cells Maturation but Reduce T-Cell Responses In Vitro.Monday, November 30, 2015
Carlsson JA, Wold AE, Sandberg AS, Östman SM,
PloS one. 30-11-2015
Long-chain polyunsaturated fatty acids (PUFAs) might regulate T-cell activation and lineage commitment. Here, we measured the effects of omega-3 (n-3), n-6 and n-9 fatty acids on the interaction between dendritic cells (DCs) and naïve T cells. Spleen DCs from BALB/c mice were cultured in vitro with ovalbumin (OVA) with 50 μM fatty acids; α-linolenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid or oleic acid and thereafter OVA-specific DO11.10 T cells were added to the cultures. Fatty acids were taken up by the DCs, as shown by gas chromatography analysis. After culture with arachidonic acid or DHA CD11c+ CD11b+ and CD11c+ CD11bneg DCs expressed more CD40, CD80, CD83, CD86 and PDL-1, while IAd remained unchanged. However, fewer T cells co-cultured with these DCs proliferated (CellTrace Violetlow) and expressed CD69 or CD25, while more were necrotic (7AAD+). We noted an increased proportion of T cells with a regulatory T cell (Treg) phenotype, i.e., when gating on CD4+ FoxP3+ CTLA-4+, CD4+ FoxP3+ Helios+ or CD4+ FoxP3+ PD-1+, in co-cultures with arachidonic acid- or DHA-primed DCs relative to control cultures. The proportion of putative Tregs was inversely correlated to T-cell proliferation, indicating a suppressive function of these cells. With arachidonic acid DCs produced higher levels of prostaglandin E2 while T cells produced lower amounts of IL-10 and IFNγ. In conclusion arachidonic acid and DHA induced up-regulation of activation markers on DCs. However arachidonic acid- and DHA-primed DCs reduced T-cell proliferation and increased the proportion of T cells expressing FoxP3, indicating that these fatty acids can promote induction of regulatory T cells.
What the Erythrocytic Nuclear Alteration Frequencies Could Tell Us about Genotoxicity and Macrophage Iron Storage?Monday, November 30, 2015
Gomes JM, Ribeiro HJ, Procópio MS, Alvarenga BM, Castro AC, Dutra WO, da Silva JB, Corrêa Junior JD,
PloS one. 30-11-2015
Erythrocytic nuclear alterations have been considered as an indicative of organism's exposure to genotoxic agents. Due to their close relationship among their frequencies and DNA damages, they are considered excellent markers of exposure in eukaryotes. However, poor data has been found in literature concerning their genesis, differential occurrence and their life span. In this study, we use markers of cell viability; genotoxicity and cellular turn over in order to shed light to these events. Tilapia and their blood were exposed to cadmium in acute exposure and in vitro assays. They were analyzed using flow cytometry for oxidative stress and membrane disruption, optical microscopy for erythrocytic nuclear alteration, graphite furnace atomic absorption spectrometry for cadmium content in aquaria water, blood and cytochemical and analytical electron microscopy techniques for the hemocateretic aspects. The results showed a close relationship among the total nuclear alterations and cadmium content in the total blood and melanomacrophage centres area, mismatching reactive oxygen species and membrane damages. Moreover, nuclear alterations frequencies (vacuolated, condensed and blebbed) showed to be associated to cadmium exposure whereas others (lobed and bud) were associated to depuration period. Decrease on nuclear alterations frequencies was also associated with hemosiderin increase inside spleen and head kidney macrophages mainly during depurative processes. These data disclosure in temporal fashion the main processes that drive the nuclear alterations frequencies and their relationship with some cellular and systemic biomarkers.
CD99 correlates with low cyclin D1, high topoisomerase 2 status and triple negative molecular phenotype but is prognostically irrelevant in breast carcinoma.Monday, November 30, 2015
Czapiewski P, Wełnicka-Jaśkiewicz M, Seroczyńska B, Skokowski J, Sejda A, Szade J, Wiewiora C, Biernat W, Żaczek A,
Polish journal of pathology : official journal of the Polish Society of Pathologists. 30-11-2015
CD99 is a protein initially described in the Ewing sarcoma family of tumors, but growing evidence has shown its expression in other tumors of mesenchymal, hematopoietic and even epithelial origin. Some articles report CD99 in metaplastic carcinoma of the breast, a subtype of breast carcinoma (BC) with pronounced epithelial to mesenchymal (EMT) phenotype. Our aim was to analyse the potential relationship between CD99 and selected EMT (vimentin, E-cadherin, Twist) and proliferation markers (Ki-67, c-myc, cyclin D1, topoisomerase 2), molecular subtypes of BC, as well as overall survival (OS) and progression-free survival (PFS). In a group of 122 cases CD99 membrane expression was seen in 14 (11.5%) cases: strong in 11 (9%) and moderate in 3 (2.5%). Expression of CD99 correlated with low cyclin D1 index, high level of topoisomerase 2 expression and lack of progesterone receptor (PR) but not with EMT characteristics. Additionally, strong expression of CD99 correlated with triple negative molecular BC phenotype. CD99 was prognostically irrelevant for OS and PFS. CD99 correlates with selected proliferative markers and low ER/PR receptor status but not with patients' outcome in BC. Further studies are required to explain precisely its role in molecular pathogenesis of BC.
Relationship among mismatch repair deficiency, CDX2 loss, p53 and E-cadherin in colon carcinoma and suitability of using a double panel of mismatch repair proteins by immunohistochemistry.Monday, November 30, 2015
Sayar I, Akbas EM, Isik A, Gokce A, Peker K, Demirtas L, Gürbüzel M,
Polish journal of pathology : official journal of the Polish Society of Pathologists. 1-12-2015
Biomarkers such as mismatch repair proteins, CDX2, p53, and E-cadherin are blamed for colon cancers, but the relationships of these biomarkers with each other and with pathological risk factors in colon carcinoma are still not clear. The aim of this study was to evaluate the association of these biomarkers with each other by using immunohistochemical staining and to compare their expression with pathological risk factors for colonic adenocarcinoma. We also aimed to study the usability of a double panel of mismatch repair proteins. One hundred and eleven cases with colonic adenocarcinoma were examined. There was a statistically significant relationship between tumor histological differentiation and perineural invasion, vascular invasion, mismatch repair deficiency, p53, CDX2, and E-cadherin (p < 0.05). PMS2 and MSH6 loss covered 100% of cases with mismatch repair deficiency. Mismatch repair deficiency was correlated with CDX2 loss and E-cadherin expression (p < 0.05). It was also observed that cases with PMS2 loss covered all the cases with CDX2 loss. In conclusion, this double panel may be used instead of a quadruple panel for detecting mismatch repair deficiency. Association of CDX2 and PMS2 in the present study is necessary to conduct further genetic and pathological studies focusing on these two markers together.
Microsatellite instability in colorectal cancer: clinicopathological significance.Monday, November 30, 2015
Setaffy L, Langner C,
Polish journal of pathology : official journal of the Polish Society of Pathologists. 1-12-2015
Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.
Prognostic significance of Forkhead box M1 (FOXM1) expression and antitumor effect of FOXM1 inhibition in melanoma.Monday, November 30, 2015
Ito T, Kohashi K, Yamada Y, Maekawa A, Kuda M, Furue M, Oda Y,
Histopathology. 30-Nov-2015
We have shown the prognostic impact of FOXM1 on melanoma patients. FOXM1 inhibition may be a potential therapeutic option for advanced melanoma. This article is protected by copyright. All rights reserved.
The Differential Diagnosis of Sinonasal/Nasopharyngeal Neuroendocrine/Neuroectodermally Derived Tumors.Monday, November 30, 2015
Montone KT,
Archives of pathology & laboratory medicine. Dec-2015
Context .- The differential diagnosis of neuroendocrine neoplasms arising in the sinonasal tract is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. Objective .- To review the differential diagnosis of sinonasal neuroendocrine and neuroectodermally derived tumors. Data Sources .- The current literature was reviewed to provide updated information regarding the differential diagnosis and means for diagnosing neuroendocrine tumors including sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, malignant melanoma, paraganglioma, pituitary adenoma, and Ewing family of tumors. Conclusions .- The differential diagnosis of neoplasms with neuroendocrine differentiation in the sinonasal tract is broad, and diagnosis often includes not only histologic review but also immunohistochemical or molecular analysis.
Fine-Needle Aspiration Biopsy of Salivary Gland Lesions.Monday, November 30, 2015
Wang H, Fundakowski C, Khurana JS, Jhala N,
Archives of pathology & laboratory medicine. Dec-2015
Context .- Fine-needle aspiration (FNA) is a well-established diagnostic approach for salivary gland lesions; however, lack of a standard system of terminology for classification of salivary gland neoplasms collected by FNA and the relatively high frequency of uncertainty of diagnosis are likely partly responsible for current confusion in the interpretation of these FNA samples. Objective .- To propose a novel classification system for reporting salivary gland FNA samples and summarize recent progress in application of molecular and immunohistochemical markers in selected salivary gland neoplasms. Data Sources .- Literature review and authors' personal practice experience. Conclusions .- The new classification system provides a more succinct, standardized interpretation of results and will ultimately assist in communication between clinicians, clinical decision making, and preoperative patient counseling. Impressive advances have been made in recent years in the understanding of molecular pathogenesis of salivary gland tumors. With the newly acquired diagnostic tools, significant improvement in diagnostic accuracy of salivary gland FNA can certainly be expected.
Value of Molecular Tests in Cytologically Indeterminate Lesions of Thyroid.Monday, November 30, 2015
Zhang X,
Archives of pathology & laboratory medicine. Dec-2015
Context .- Fine-needle aspiration has been the initial step in the workup of thyroid nodular lesions and has successfully reduced the number of unnecessary surgeries and improved preoperative malignancy detection. However, up to one-third of cases fall in the diagnostically "indeterminate group," which poses a patient-management challenge. Objective .- To review the characteristics of molecular tests useful for stratifying the malignancy risk of indeterminate thyroid lesions, including their advantages and limitations. Data sources .- PubMed. Conclusions .- Molecular tests are useful for triage of indeterminate thyroid nodules initially diagnosed by using fine-needle aspiration. Immunocytochemistry is readily available with the shortest turnaround time among the molecular tests but suffers from poor reproducibility and low interpretation concordance. Gene mutation analysis is superior in detecting malignancies as a rule-in test, despite low specificity. Next-generation sequencing seems promising but needs more validations before widespread use. Gene expression profiling is more suitable for detecting benign lesions as a rule-out test to avoid unnecessary surgeries but is not reliable in excluding malignancies. MicroRNA profiling has great potential for both risk stratification and predicting prognosis but is limited by significant variations in sensitivity and specificity. Although many questions still need to be answered, taken together, molecular tests are a promising option for classifying cytologically indeterminate thyroid nodular lesions.
Updates on Surgical and Molecular Pathology Concerning Head and Neck Diseases.Monday, November 30, 2015
Zhang L, LiVolsi VA,
Archives of pathology & laboratory medicine. Dec-2015
Cellular O-Glycome Reporter/Amplification to explore O-glycans of living cells.Monday, November 30, 2015
Kudelka MR, Antonopoulos A, Wang Y, Duong DM, Song X, Seyfried NT, Dell A, Haslam SM, Cummings RD, Ju T,
Nature methods. 30-Nov-2015
Protein O-glycosylation has key roles in many biological processes, but the repertoire of O-glycans synthesized by cells is difficult to determine. Here we describe an approach termed Cellular O-Glycome Reporter/Amplification (CORA), a sensitive method used to amplify and profile mucin-type O-glycans synthesized by living cells. Cells convert added peracetylated benzyl-α-N-acetylgalactosamine to a large variety of modified O-glycan derivatives that are secreted from cells, allowing for easy purification for analysis by HPLC and mass spectrometry (MS). Relative to conventional O-glycan analyses, CORA resulted in an ∼100-1,000-fold increase in sensitivity and identified a more complex repertoire of O-glycans in more than a dozen cell types from Homo sapiens and Mus musculus. Furthermore, when coupled with computational modeling, CORA can be used for predictions about the diversity of the human O-glycome and offers new opportunities to identify novel glycan biomarkers for human diseases.
Diagnostic Utility of Different Blood Components in Gene Expression Analysis of Sepsis.Monday, November 30, 2015
Maslove DM, Marshall JC,
Shock (Augusta, Ga.). 25-Nov-2015
Our results support the use of whole blood to derive gene expression data in sepsis studies investigating novel diagnostics and subtype discovery. This strategy has a number of practical advantages, and the resulting data also have potential utility in developing molecular classifications of sepsis syndromes.
Glioblastoma care in the elderly.Monday, November 30, 2015
Jordan JT, Gerstner ER, Batchelor TT, Cahill DP, Plotkin SR,
Cancer. 30-Nov-2015
Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2015. © 2015 American Cancer Society.
Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells.Monday, November 30, 2015
Nguyen LV, Pellacani D, Lefort S, Kannan N, Osako T, Makarem M, Cox CL, Kennedy W, Beer P, Carles A, Moksa M, Bilenky M, Balani S, Babovic S, Sun I, Rosin M, Aparicio S, Hirst M, Eaves CJ,
Nature. 2-Dec-2015
Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.
Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.Monday, November 30, 2015
Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Krogh Pedersen H, Arumugam M, Kristiansen K, Yvonne Voigt A, Vestergaard H, Hercog R, Igor Costea P, Roat Kultima J, Li J, Jørgensen T, Levenez F, Dore J, Bjørn Nielsen H, Brunak S, Raes J, Hansen T, Wang J, Dusko Ehrlich S, Bork P, Pedersen O,
Nature. 2-Dec-2015
In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.
miR-143 suppresses epithelial-mesenchymal transition and inhibits tumor growth of breast cancer through down-regulation of ERK5.Monday, November 30, 2015
Zhai L, Ma C, Li W, Yang S, Liu Z,
Molecular carcinogenesis. 30-Nov-2015
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer invasion and metastasis. Many studies have significantly enhanced the knowledge on EMT through the characterization of microRNAs (miRNAs) influencing the signaling pathways and downstream events that define EMT on a molecular level. In this study, we found that miR-143 suppressed EMT. Up-regulating miR-143 enhanced E-cadherin-mediated cell-cell adhesion ability, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-143 on tumor growth. Additionally, we demonstrated that up-regulating extracellular signal regulated kinase 5 (ERK5) was associated with poor prognosis of breast cancer patients. Moreover, we observed an inverse correlation between miR-143 and ERK5 in breast cancer tissues. miR-143 directly targeted seed sequences in the 3'-untranslated regions of ERK5. Furthermore, we revealed that the downstream molecules of glycogen synthase kinase 3 beta (GSK-3β)/Snail signaling were involved in EMT and modulated by ERK5. In summary, our findings demonstrated that miR-143 down-regulated its target ERK5, leading to the suppression of EMT induced by GSK-3β/Snail signaling of breast cancer. © 2015 Wiley Periodicals, Inc.
Orthotopic transplantation of a tissue engineered diaphragm in rats.Monday, November 30, 2015
Gubareva EA, Sjöqvist S, Gilevich IV, Sotnichenko AS, Kuevda EV, Lim ML, Feliu N, Lemon G, Danilenko KA, Nakokhov RZ, Gumenyuk IS, Grigoriev TE, Krasheninnikov SV, Pokhotko AG, Basov AA, Dzhimak SS, Gustafsson Y, Bautista G, Beltrán Rodríguez A, Pokrovsky VM, Jungebluth P, Chvalun SN, Holterman MJ, Taylor DA, Macchiarini P,
Biomaterials. 14-Nov-2015
The currently available surgical options to repair the diaphragm are associated with significant risks of defect recurrence, lack of growth potential and restored functionality. A tissue engineered diaphragm has the potential to improve surgical outcomes for patients with congenital or acquired disorders. Here we show that decellularized diaphragmatic tissue reseeded with bone marrow mesenchymal stromal cells (BM-MSCs) facilitates in situ regeneration of functional tissue. A novel bioreactor, using simultaneous perfusion and agitation, was used to rapidly decellularize rat diaphragms. The scaffolds retained architecture and mechanical properties and supported cell adhesion, proliferation and differentiation. Biocompatibility was further confirmed in vitro and in vivo. We replaced 80% of the left hemidiaphragm with reseeded diaphragmatic scaffolds. After three weeks, transplanted animals gained 32% weight, showed myography, spirometry parameters, and histological evaluations similar to native rats. In conclusion, our study suggested that reseeded decellularized diaphragmatic tissue appears to be a promising option for patients in need of diaphragmatic reconstruction.
Genome-Wide Microarray Analysis of Long Non-Coding RNAs in Eutopic Secretory Endometrium with Endometriosis.Monday, November 30, 2015
Wang Y, Li Y, Yang Z, Liu K, Wang D,
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 29-Nov-2015
These dysregulated lncRNAs might provide information for new biomarkers or novel therapeutic targets of endometriosis. AC002454.1 might induce cell cycle disorder by regulating CDK6 to participate in the pathogenesis of endometriosis.
Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype.Monday, November 30, 2015
Maletzki C, Huehns M, Knapp P, Waukosin N, Klar E, Prall F, Linnebacher M,
PloS one. 29-11-2015
Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53mut, KRASmut; 3/8 marker methylated; HROC43: APCmut, TP53mut, KRASmut; 4/8 marker methylated; HROC60: APCwt, TP53mut, KRASwt; 4/8 marker methylated; HROC183: APCmut, TP53mut, KRASmut; 6/8 marker methylated). Cell lines were of epithelial origin (EpCAM+) with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan). Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib). This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo-) therapeutics helps bringing forward the concept of personalized tumor therapy.
A direct high affinity interaction between Aβ42 and GSK3α stimulates hyperphosphorylation of tau. A new molecular link in Alzheimer's disease?Monday, November 30, 2015
Dunning CJ, McGauran G, Willén K, Gouras GK, O'Connell DJ, Linse S,
ACS chemical neuroscience. 30-Nov-2015
Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified co-localization of Aβ42 and GSK3α in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-Aβ42 and GSK3α in solution using thermophoresis. An even lower apparent KD was estimated between GSK3α and dextran-immobilized Aβ42 in surface plasmon resonance experiments. Parallel experiments with GSK3β also identified co-localization and high affinity binding to this isoform. GSK3α-mediated hyperphosphorylation of the protein tau, was found to be stimulated by Aβ42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Aβ42 and GSK3α, which opens an important avenue towards understanding the mechanism of Aβ42-mediated neuronal toxicity in Alzheimer's disease.
Aptamers: versatile molecular recognition probes for cancer detection.Monday, November 30, 2015
Sun H, Tan W, Zu Y,
The Analyst. 30-Nov-2015
In the past two decades, aptamers have emerged as a novel class of molecular recognition probes comprising uniquely-folded short RNA or single-stranded DNA oligonucleotides that bind to their cognate targets with high specificity and affinity. Aptamers, often referred to as "chemical antibodies", possess several highly desirable features for clinical use. They can be chemically synthesized and are easily conjugated to a wide range of reporters for different applications, and are able to rapidly penetrate tissues. These advantages significantly enhance their clinical applicability, and render them excellent alternatives to antibody-based probes in cancer diagnostics and therapeutics. Aptamer probes based on fluorescence, colorimetry, magnetism, electrochemistry, and in conjunction with nanomaterials (e.g., nanoparticles, quantum dots, single-walled carbon nanotubes, and magnetic nanoparticles) have provided novel ultrasensitive cancer diagnostic strategies and assays. Furthermore, promising aptamer targeted-multimodal tumor imaging probes have been recently developed in conjunction with fluorescence, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). The capabilities of the aptamer-based platforms described herein underscore the great potential they hold for the future of cancer detection. In this review, we highlight the most prominent recent developments in this rapidly advancing field.
Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer's Disease.Monday, November 30, 2015
Byun MS, Kim SE, Park J, Yi D, Choe YM, Sohn BK, Choi HJ, Baek H, Han JY, Woo JI, Lee DY,
PloS one. 30-11-2015
We aimed to identify and characterize subtypes of Alzheimer's disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer's Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the "both impaired" subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: "hippocampal atrophy only" (19.0%), "cortical atrophy only" (11.7%), and "both spared" (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β1-42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients.
Integrated genomic characterization of IDH1-mutant glioma malignant progression.Monday, November 30, 2015
Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M,
Nature genetics. 30-Nov-2015
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
ROS production and gene expression in alveolar macrophages exposed to PM2.5 from Baghdad, Iraq: Seasonal trends and impact of chemical composition.Monday, November 30, 2015
Hamad SH, Schauer JJ, Antkiewicz DS, Shafer MM, Kadhim AK,
The Science of the total environment. 24-Nov-2015
The objective of this study was to assess the impact of changes in atmospheric particulate matter (PM) composition on oxidative stress markers in an in-vitro alveolar macrophage (AM) model. Fifty-three PM2.5 samples were collected during a year-long PM sampling campaign in Baghdad, Iraq, a semi-arid region of the country. Monthly composites were analyzed for chemical composition and for biological activity using in-vitro measurements of ROS production and gene expression in the AM model. Twelve genes that were differentially expressed upon PM exposure were identified and their co-associations with the composition of PM2.5 were examined. Ten of those genes were up-regulated in January and April composites; samples which also exhibited high ROS activity and relatively high PM mass concentration. ROS production was statistically correlated with total PM2.5 mass, levoglucosan (a wood burning tracer) and several trace elements of the PM (especially V and Ni, which are associated with oil combustion). The expression of several cytokine genes was found to be moderately associated with PM mass, crustal materials (indication of dusty days or dust storms) and certain metals (e.g. V, Fe and Ni) in the PM. Thus, the ROS activity association with PM2.5, may, in part, be driven by redox-active metals. The antioxidant response genes (Nqo1 and Hmox1) were moderately associated with polyaromatic hydrocarbons (PAHs) and showed a good correlation (r-Pearson of >0.7) with metals linked to vehicle-related emissions (i.e. Cu, Zn and Sb). Examining these associations in a larger sample pool (e.g. daily samples) would improve the power of the analysis and may strengthen the implication of these chemicals in the oxidative stress of biological systems, which could aid in the development of new metrics of PM toxicity.
Diagnostic, Prognostic, and Predictive Molecular Biomarkers and the Utility of Molecular Imaging in Common Gastrointestinal Tumors.Monday, November 30, 2015
Idowu MO, Laudadio J, Rizzo K,
BioMed research international. 2015
Impact of Extracellular Matrix on Cellular Behavior: A Source of Molecular Targets in Disease.Monday, November 30, 2015
Skandalis SS, Dobra K, Götte M, Karousou E, Misra S,
BioMed research international. 2015
Enhanced Oxidative Stress and Other Potential Biomarkers for Retinopathy in Type 2 Diabetics: Beneficial Effects of the Nutraceutic Supplements.Monday, November 30, 2015
Roig-Revert MJ, Lleó-Pérez A, Zanón-Moreno V, Vivar-Llopis B, Marín-Montiel J, Dolz-Marco R, Alonso-Muñoz L, Albert-Fort M, López-Gálvez MI, Galarreta-Mira D, García-Esparza MF, Galbis-Estrada C, Marco-Ramirez C, Shoaie-Nia K, Sanz-González SM, Vila-Bou V, Bendala-Tufanisco E, García-Medina JJ, Nucci C, Gallego-Pinazo R, Arévalo JF, Pinazo-Durán MD, Valencia Study On Diabetic Retinopathy Vsdr
BioMed research international. 2015
We have studied the global risk of retinopathy in a Mediterranean population of type 2 diabetes mellitus (T2DM) patients, according to clinical, biochemical, and lifestyle biomarkers. The effects of the oral supplementation containing antioxidants/omega 3 fatty acids (A/ω3) were also evaluated. Suitable participants were distributed into two main groups: (1) T2DMG (with retinopathy (+DR) or without retinopathy (-DR)) and (2) controls (CG). Participants were randomly assigned (+A/ω3) or not (-A/ω3) to the oral supplementation with a daily pill of Nutrof Omega (R) for 18 months. Data collected including demographics, anthropometrics, characteristics/lifestyle, ophthalmic examination (best corrected visual acuity, ocular fundus photographs, and retinal thickness as assessed by optical coherence tomography), and blood parameters (glucose, glycosylated hemoglobin, triglycerides, malondialdehyde, and total antioxidant capacity) were registered, integrated, and statistically processed by the SPSS 15.0 program. Finally, 208 participants (130 diabetics (68 +DR/62 -DR) and 78 controls) completed the follow-up. Blood analyses confirmed that the T2DMG+DR patients had significantly higher oxidative stress (p < 0.05), inflammatory (p < 0.05), and vascular (p < 0.001) risk markers than the T2DMG-DR and the CG. Furthermore, the A/ω3 oral supplementation positively changed the baseline parameters, presumptively by inducing metabolic activation and ameliorating the ocular health after 18 months of supplementation.
Enzymatic antioxidant system in vascular inflammation and coronary artery disease.Monday, November 30, 2015
Lubrano V, Balzan S,
World journal of experimental medicine. 20-Nov-2015
In biological systems there is a balance between the production and neutralization of reactive oxygen species (ROS). This balance is maintained by the presence of natural antioxidants and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. The enhancement of lipid peroxidation or the decrease of antioxidant protection present in metabolic diseases or bad lifestyle can induce endothelial dysfunction and atherosclerosis. Clinical studies have shown that oxidative stress can increase ROS reducing the formation of antioxidant defences, especially in subjects with coronary artery disease (CAD). Some observation indicated that in the early stages of the disease there is a homeostatic up-regulation of the antioxidant enzyme system in response to increased free radicals to prevent vascular damage. As soon as free radicals get to chronically elevated levels, this compensation ceases. Therefore, SOD and the other enzymes may represent a good therapeutic target against ROS, but they are not useful markers for the diagnosis of CAD. In conclusion antioxidant enzymes are reduced in presence of metabolic disease and CAD. However the existence of genes that promote their enzymatic activity could contribute to create new drugs for the treatment of damage caused by metabolic diseases or lifestyle that increases the plasma ROS levels.
An evolving computational platform for biological mass spectrometry: workflows, statistics and data mining with MASSyPup64.Monday, November 30, 2015
Winkler R,
PeerJ. 20-11-2015
In biological mass spectrometry, crude instrumental data need to be converted into meaningful theoretical models. Several data processing and data evaluation steps are required to come to the final results. These operations are often difficult to reproduce, because of too specific computing platforms. This effect, known as 'workflow decay', can be diminished by using a standardized informatic infrastructure. Thus, we compiled an integrated platform, which contains ready-to-use tools and workflows for mass spectrometry data analysis. Apart from general unit operations, such as peak picking and identification of proteins and metabolites, we put a strong emphasis on the statistical validation of results and Data Mining. MASSyPup64 includes e.g., the OpenMS/TOPPAS framework, the Trans-Proteomic-Pipeline programs, the ProteoWizard tools, X!Tandem, Comet and SpiderMass. The statistical computing language R is installed with packages for MS data analyses, such as XCMS/metaXCMS and MetabR. The R package Rattle provides a user-friendly access to multiple Data Mining methods. Further, we added the non-conventional spreadsheet program teapot for editing large data sets and a command line tool for transposing large matrices. Individual programs, console commands and modules can be integrated using the Workflow Management System (WMS) taverna. We explain the useful combination of the tools by practical examples: (1) A workflow for protein identification and validation, with subsequent Association Analysis of peptides, (2) Cluster analysis and Data Mining in targeted Metabolomics, and (3) Raw data processing, Data Mining and identification of metabolites in untargeted Metabolomics. Association Analyses reveal relationships between variables across different sample sets. We present its application for finding co-occurring peptides, which can be used for target proteomics, the discovery of alternative biomarkers and protein-protein interactions. Data Mining derived models displayed a higher robustness and accuracy for classifying sample groups in targeted Metabolomics than cluster analyses. Random Forest models do not only provide predictive models, which can be deployed for new data sets, but also the variable importance. We demonstrate that the later is especially useful for tracking down significant signals and affected pathways in untargeted Metabolomics. Thus, Random Forest modeling supports the unbiased search for relevant biological features in Metabolomics. Our results clearly manifest the importance of Data Mining methods to disclose non-obvious information in biological mass spectrometry . The application of a Workflow Management System and the integration of all required programs and data in a consistent platform makes the presented data analyses strategies reproducible for non-expert users. The simple remastering process and the Open Source licenses of MASSyPup64 ( enable the continuous improvement of the system.
Infectious Uveitis.Monday, November 30, 2015
Lin P,
Current ophthalmology reports. Sep-2015
Infectious uveitis is one of the most common and visually devastating causes of uveitis in the US and worldwide. This review provides a summary of the identification, treatment, and complications associated with certain forms of viral, bacterial, fungal, helminthic, and parasitic uveitis. In particular, this article reviews the literature on identification and treatment of acute retinal necrosis due to herpes simplex virus, varicella virus, and cytomegalovirus. While no agreed-upon treatment has been identified, the characteristics of Ebola virus panuveitis is also reviewed. In addition, forms of parasitic infection such as Toxoplasmosis and Toxocariasis are summarized, as well as spirochetal uveitis. Syphilitic retinitis is reviewed given its increase in prevalence over the last decade. The importance of early identification and treatment of infectious uveitis is emphasized. Early identification can be achieved with a combination of maintaining a high suspicion, recognizing certain clinical features, utilizing multi-modal imaging, and obtaining specimens for molecular diagnostic testing.
Overexpression of miR-1260b in Non-small Cell Lung Cancer is Associated with Lymph Node Metastasis.Monday, November 30, 2015
Xu L, Li L, Li J, Li H, Shen Q, Ping J, Ma Z, Zhong J, Dai L,
Aging and disease. Nov-2015
Lymph node (LN) metastasis is often an early event in the progression of malignant tumors and it contributes to the majority of cancer mortalities. MiRNAs play key roles in tumor metastasis. This study aimed to investigate the specific miRNAs as putative indicators of metastasis early diagnosis for non-small cell lung cancer (NSCLC). In this study, five NSCLC cases with LN metastasis and four cases without metastasis (NLN) were enrolled for Agilent Human miRNA array. The interested differentially expressed miRNA was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in the LN metastasis (n = 46) and NLN (n = 39) groups. The microarray results revealed that three miRNAs (miR-1260b, miR-423-3p, miR-23a-5p) were differentially expressed in LN metastasis group compared with NLN group. The expression of miR-1260b was tested by qRT-PCR and the mean relative expression fold change (2(-ΔΔCt)) in LN metastasis was significantly higher than that in the NLN group (3.942, 1.743 respectively, P = 1.179E-04). The patients with tumor-node-metastasis (TNM) stage III were identified more frequently in LN metastasis group (P = 1.772E-11) and with a higher expression level of miR-1260b (5.126, P = 1.147E-06). In addition, the LN metastasis cases were associated with a poorly differentiated degree (P = 0.007). The overexpression of miR-1260b in NSCLC with LN metastasis can be regarded as a specific signature for early progression and prognosis of NSCLC.
Low Cerebral Glucose Metabolism: A Potential Predictor for the Severity of Vascular Parkinsonism and Parkinson's Disease.Monday, November 30, 2015
Xu Y, Wei X, Liu X, Liao J, Lin J, Zhu C, Meng X, Xie D, Chao D, Fenoy AJ, Cheng M, Tang B, Zhang Z, Xia Y, Wang Q,
Aging and disease. Nov-2015
This study explored the association between cerebral metabolic rates of glucose (CMRGlc) and the severity of Vascular Parkinsonism (VP) and Parkinson's disease (PD). A cross-sectional study was performed to compare CMRGlc in normal subjects vs. VP and PD patients. Twelve normal subjects, 22 VP, and 11 PD patients were evaluated with the H&Y and MMSE, and underwent 18F-FDG measurements. Pearson's correlations were used to identify potential associations between the severity of VP/PD and CMRGlc. A pronounced reduction of CMRGlc in the frontal lobe and caudate putamen was detected in patients with VP and PD when compared with normal subjects. The VP patients displayed a slight CMRGlc decrease in the caudate putamen and frontal lobe in comparison with PD patients. These decreases in CMRGlc in the frontal lobe and caudate putamen were significantly correlated with the VP patients' H&Y, UPDRS II, UPDRS III, MMSE, cardiovascular, and attention/memory scores. Similarly, significant correlations were observed in patients with PD. This is the first clinical study finding strong evidence for an association between low cerebral glucose metabolism and the severity of VP and PD. Our findings suggest that these changes in glucose metabolism in the frontal lobe and caudate putamen may underlie the pathophysiological mechanisms of VP and PD. As the scramble to find imaging biomarkers or predictors of the disease intensifies, a better understanding of the roles of cerebral glucose metabolism may give us insight into the pathogenesis of VP and PD.
Erratum: Signaling pathway and molecular subgroups of medulloblastoma.Monday, November 30, 2015
Li KK, Lau KM, Ng HK,
International journal of clinical and experimental pathology. 17-11-2015
Medulloblastoma (MB) is the most common malignant brain tumor in children. Although multimodality treatment regimens including surgery, radiotherapy and chemotherapy have greatly improved disease outcome, about one-third of MB patient remains incurable, and many long-term survivors are suffered from deleterious effects due to aggressive treatment. Understanding the signaling pathways and the genetic mechanisms contributed to MB development would be the key to develop novel therapeutic treatment strategies for improving survival and outcome of MB. In this review, we discuss the biological signaling pathways involved in MB pathogenesis. We also go through the current international consensus of four core MB subgroups namely, SHH, WNT, Group 3 and Group 4. This is adopted based on the knowledge of genomic complexity of MB as analyzed by recent high-throughput genomic technology. We talk about immunohistochemistry assays established to determine molecular subgroup affiliation. In the last part of review, we discuss how identification of molecular subgroups is going to change our routine disease diagnosis and clinical management.[This corrects the article on p. 1211 in vol. 6, PMID: 23826403.].
Essentials of oral cancer.Monday, November 30, 2015
Rivera C,
International journal of clinical and experimental pathology. 2015
Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor prognosis, without specific biomarkers for the disease and expensive therapeutic alternatives. This review aims to present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC), moving from its definition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malignant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challenges. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical sciences and dentistry in particular are likely to improve their poor clinical indicators.
Beta-3 adrenergic receptors could be significant factors for overactive bladder-related symptoms.Monday, November 30, 2015
Yamamichi F, Shigemura K, Behnsawy HM, Yamashita M, Shirakawa T, Fujisawa M,
International journal of clinical and experimental pathology. 2015
The treatment failure often happens in overactive bladder (OAB) partly owing to its unknown pathogenesis. The purpose of this study is to find significant receptors or biological markers for OAB-related symptoms for establishment of potential order-made therapeutic strategies. The overactive bladder symptom scores (OABSS) and international prostate symptom scores (IPSS)/quality of life (QOL) were questioned in all the 18 patients with OAB diagnosis. Their bladder mucosal tissues were taken from the random biopsy of bladder cancer suspected patients without any finding such as inflammation or carcinoma in situ. They were investigated quantitatively by immunohistochemical (IHC) stainings for inflammatory or immune-system (Interleukin (IL)-6 and cyclooxygenase-2 (Cox-2)), Caspase-3 apoptosis markers, angiogenesis (CD-31), epithelial-mesenchymal transition (E-cadherin) and muscarinic receptor (Muscarine-2 (M)-2), adrenergic receptors (ARs) (alpha 1-d (α1-d) and beta-3 (β-3)). The statistical correlation between the expressions of these 5 markers and 3 receptors and these symptom scores were examined under the comparison between OAB patients and control patients who had urgency score with less than 2 in OABSS. The OABSS and IPSS/QOL was 7.39 ± 2.69 and 21.2 ± 6.59/4.33 ± 1.33, respectively but those of control patients were 2.00 ± 1.41 and 10.1 ± 9.52/2.14 ± 1.46, respectively (P<0.05). Regarding the correlation of those markers' expressions and symptom scores, in OAB patients, OABSS total significantly correlated with β-3 AR expressions (P=0.0457). IPSS post-voiding significantly correlated with β-3 AR expressions (P=0.0308) but no significant relationship in control patients (P>0.05). In conclusion, this study demonstrated that β-3 AR in our tested 8 markers or receptors was correlated strongly with OAB-related symptoms. These data may help elucidate the pathophysiology of OAB and offer possible strategy for its order-made therapies.
Mixed epithelial and stromal tumor of the kidney: report of a rare case and review of literature.Monday, November 30, 2015
Wang Y, Yuan J, Wang J, Fu Q,
International journal of clinical and experimental pathology. 2015
Mixed epithelial and stromal tumor of the kidney (MESTK) is a rare benign tumor composed of epithelial and stromal cells. We report a rare male case with detailed clinicopathological data and follow-up information. The patient presented with gross hematuria. Computed tomography (CT) and magnetic resonance imaging study showed a 60 mm×40 mm cystic lesion with thickened septa and minimal contrast enhancement at the lower pole of the right kidney. The patient underwent nephron sparing surgery (NSS). Intraoperative frozen section showed benign histological features without significant cytologic atypia and mitosis. By additional immunohistochemistry investigations, the epithelial component was positive for cytokeratin-7, high molecular weight cytokeratin, and PAX-8. The stromal component showed strong positivity for vimentin and smooth-muscle actin. This case emphasizes that it is difficult to establish a precise diagnosis of MESTK preoperatively due to lack of any typical radiological features. Thus, intraoperative frozen section is of great clinical significance for NSS with preservation of kidney function. Additionally, regular follow-up is necessary for the MESTK with malignant potential.
A case of gastric cancer with heterogeneous components of EB virus (+)/TP53 (+) and EB virus (-)/TP53 (-).Monday, November 30, 2015
Matsuda I, Kan K, Doi S, Motoki Y, Onodera M, Hirota S,
International journal of clinical and experimental pathology. 2015
Epstein-Barr virus (EBV)-associated gastric adenocarcinoma is a histological subtype of gastric adenocarcinoma, in which all of the carcinoma cells are basically positive for EBV-encoded small RNA (EBER) by in situ hybridization. Although its typical histology has some overlap with gastric carcinoma with lymphoid stroma, absence of massive lymphoid infiltrate is sometimes observed either in whole or in part. EBV-associated adenocarcinoma is one of the four representative molecular pathological subtypes recently identified by comprehensive genomic analysis of gastric adenocarcinomas. According to the analysis, typical EBV-associated gastric adenocarcinoma constitutes an independent molecular pathological subgroup, which is mutually exclusive to TP53-mutated adenocarcinoma with chromosomal instability, another molecular pathological subtype in gastric adenocarcinomas. Here, we report a rare case of gastric cancer heterogeneously composed of EBER (+)/TP53 (+) and EBER (-)/TP53 (-) portions. The EBER (+)/TP53 (+) component with massive lymphoid infiltrate surrounded the EBER (-)/TP53 (-) component showing well to moderately differentiated tubular adenocarcinoma. Although collision of two independent gastric cancers could be the simplest and most possible explanation for this situation, we discussed another possibility. In the case of gastric collision tumors, concurrent development of EBER (+) gastric adenocarcinomas and EBER (-) gastric adenocarcinomas in a single stomach is a rare incident. Since presence of the EBER (+)/TP53 (+) tumor component is atypical in itself, we also discussed the mechanism of development of the clone.
Discordant intracellular and plasma D-2-hydroxyglutarate levels in a patient with IDH2 mutated angioimmunoblastic T-cell lymphoma.Monday, November 30, 2015
Churchill H, Naina H, Boriack R, Rakheja D, Chen W,
International journal of clinical and experimental pathology. 2015
While our case suggests that circulating D-2HG is not a reliable marker of IDH mutation in AITL, more cases need to be studied to arrive at a definite conclusion.
Cysts in angiomyolipoma with epithelial cysts may be consisted of entrapped and dilated renal tubules: report of a case with additional immunohistochemical evidence to the pre-existing literature.Monday, November 30, 2015
Tajima S, Yamada Y,
International journal of clinical and experimental pathology. 2015
Angiomyolipoma with epithelial cysts (AMLEC) is a distinctive variant of angiomyolipoma characterized by grossly apparent epithelial cysts and a cellular, müllerian-like subepithelial stroma. Some authors suspect that the epithelial cysts mainly represent dilated entrapped native renal collecting duct epithelium, while other authors think that they represented true epithelial differentiation of the AML. Recently, it has been reported that obvious immunolabeling of melanocytic markers such as Melan A and HMB45, which are often immunolabeled in classical angiomyolipoma, are present in epithelial cysts in cases of AMLEC. Here, we report the case of a 43-year-old Japanese woman with AMLEC, and attempt to elucidate the significance of melanocytic marker immunolabeling in the cyst's epithelium. In the present case, Melan A was labeled in the cyst's epithelium, and was thought to reflect its labeling in renal tubules existing in the renal parenchyma outside the tumor. This finding may indicate that the cyst epithelium is derived from entrapped renal tubules inside the AML. Non-immunolabeling of the estrogen and progesterone receptors in the cyst epithelium may also suggest that the cyst epithelium is not neoplastic, in contrast to their labeling in neoplastic cells existing in cyst wall. Further examination, such as molecular analysis, is needed to determine whether these epithelial cysts is neoplastic or non-neoplastic.
Pattern of nodal involvement in papillary thyroid cancer: a challenge of quantitative analysis.Monday, November 30, 2015
Fama F, Cicciù M, Giudice GL, Sindoni A, Palella J, Piquard A, Saint-Marc O, Benvenga S, Bramanti E, Cervino G, Florio MG,
International journal of clinical and experimental pathology. 2015
We suppose, notwithstanding the limited number of patients, that the number of lymph nodes harvested to achieve an optimal cervical dissection may be superior to 8 and 11 in central and lateral compartments, and 6 and 10 in contralateral ones, respectively. Moreover we recommend the bilateral dissection of central nodes compartment in presence of tumour localised in the isthmus.
Association of NER pathway gene polymorphisms with susceptibility to laryngeal cancer in a Chinese population.Monday, November 30, 2015
Sun Y, Tan L, Li H, Qin X, Liu J,
International journal of clinical and experimental pathology. 2015
We systematically analyzed the association of nine SNPs of seven key NER pathway genes with the development of laryngeal cancer patients, and investigated whether NER pathway polymorphisms could serve as potential biomarkers for laryngeal cancer risk. 271 patients with pathologically proven laryngeal cancer and 271 control subjects were included in our study. Genotyping of ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs50871, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs2094258, XPA rs2808668 and XPC rs2228001 were analyzed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying the TT genotype of ERCC1 rs11615 were correlated with an increased risk of larynx cancer when compared with the CC genotype (OR=1.89, 95% CI=1.07-3.37; P value=0.02). Moreover, individuals with the GG genotype of ERCC2 rs50871 were associated with an elevated risk of larynx cancer when compare with the TT genotype (OR=2.03, 95% CI=1.15-3.63; P value=0.01). We found a significant interaction between ERCC2 rs50871 polymorphism and tobacco smoking in the risk of larynx cancer (P for interaction <0.05). In conclusion, our study showed that ERCC1 rs11615 and ERCC2 rs50871 polymorphisms could influence the risk of larynx cancer in Chinese population, particularly among smokers.
CCND1 G870A polymorphism is associated with toxicity of methotrexate in childhood acute lymphoblastic leukemia.Monday, November 30, 2015
Xue Y, Rong L, Tong N, Wang M, Zhang Z, Fang Y,
International journal of clinical and experimental pathology. 2015
CCND1 plays a key role in cell cycle progression and may cause methotrexate (MTX) resistance, as well as its cytotoxicity. CCND1 870A variant allele is associated with altered transcripts of this gene. We hypothesized that this polymorphism may contribute to the elimination rate and hepatotoxicity of MTX in childhood acute lymphoblastic leukemia (ALL). We genotyped the CCND1 G870A polymorphism in 125 childhood ALL patients treated with HDMTX. We found no notable associations between G870A polymorphism and the risk of delayed MTX elimination. However, this polymorphism was significantly associated with an increased risk of MTX hepatotoxicity [adjusted odds ratio (OR) = 4.44, 95% confidence interval (CI) = 1.35-14.63 for AG versus GG and adjusted OR = 6.39, 95% CI = 1.82-22.43 for AA versus GG]. Our results indicated that the CCND1 G870A polymorphism may be involved in the hepatotoxicity of MTX and act as a biological marker.
Serum cytokine, chemokine and hormone levels in Saudi adults with pre-diabetes: a one-year prospective study.Monday, November 30, 2015
Al-Daghri NM, Al-Ajlan AS, Alfawaz H, Yakout SM, Aljohani N, Kumar S, Alokail MS,
International journal of clinical and experimental pathology. 2015
Approximately 5-10% of subjects with pre-diabetes eventually progress to diabetes every year. While inflammation is thought to be involved in the development of obesity-related type 2 diabetes mellitus (T2DM), the relation between inflammation and pre-diabetes remains largely unexplored. In this study we examined a comprehensive panel of 10 serum biomarkers involved in overweight and obese subjects with pre-diabetes. A total of 98 subjects (23 males, 75 females) were advised to reduce total intake of fat, increase fiber intake and physical activity. Serum cytokines, MCP and other hormones were assessed by multiplex cytokine profiling. Results show that CRP, IL-6, leptin, IL-10, MCP, resistin, serpin, and TNF-α were significantly lower after 12-months than baseline. Serum concentrations of other adipocytokines, including adipsin and leptin were modestly lower in the 12-month follow-up than baseline, but failed to reach statistical significance. Changes in HbA1c was found to be positively correlated with adipsin, CRP, IL-6, IL-10, resistin, serpin, and TNF-α. The results suggest that promotion of lifestyle changes for one year among overweight and obese subjects modestly changes several circulating inflammatory biomarkers which maybe favorable in reducing risk for T2DM progression.
TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline.Monday, November 30, 2015
Sun ZL, Chan AK, Chen LC, Tang C, Zhang ZY, Ding XJ, Wang Y, Sun CR, Ng HK, Yao Y, Zhou LF,
International journal of clinical and experimental pathology. 2015
The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas.
Down-regulation of PAX6 by promoter methylation is associated with poor prognosis in non small cell lung cancer.Monday, November 30, 2015
Zhang X, Yang X, Wang J, Liang T, Gu Y, Yang D,
International journal of clinical and experimental pathology. 2015
We found that PAX6 gene was specifically methylated in NSCLC, and demonstrated the effect of promoter methylation of PAX6 gene on clinical outcome in NSCLC, indicating the methylated PAX6 may be useful biomarkers for prognostic evaluation in NSCLC.
Role of GPER1, EGFR and CXCR1 in differentiating between malignant follicular thyroid carcinoma and benign follicular thyroid adenoma.Monday, November 30, 2015
Zhao L, Zhu XY, Jiang R, Xu M, Wang N, Chen GG, Liu ZM,
International journal of clinical and experimental pathology. 2015
It is extremely difficult to discriminate between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA) before surgery, because the morphologies of carcinoma cells and adenoma cells obtained by fine needle aspiration biopsy (FNAB) are similar. Molecular markers may be helpful on this issue. The purpose of this study was to assess the role of GPER1, EGFR and CXCR1 in differential diagnosis between FTC and FTA. GPER1, EGFR and CXCR1 mRNA expression levels were examined in 15 FTCs and 10 FTAs using real-time RT-PCR. FTC showed to have significantly increased mRNA levels of the three molecules compared to FTA (P < 0.001 for all the three molecules). GPER1, EGFR and CXCR1 protein expression in 106 FTCs and 128 FTAs were analyzed using immunohistochemistry. The rates of GPER1, EGFR and CXCR1 high expression were 73.6%, 72.6% and 70.8% in FTC and 30.5%, 28.1% and 27.3% in FTA, respectively. Statistical analysis showed that GPER1, EGFR and CXCR1 protein expression were correlated with one another in FTC and concomitant high expression of the three molecules had stronger correlation with the occurrence of FTC than did each alone. The positive predictive values (PPV) for concomitant high expression of the three molecules for discriminating between FTC and FTA were 91.0% for GPER1/EGFR, 93.8% for GPER1/CXCR1, 92.3% for EGFR/CXCR1 and 98.2% for GPER1/EGFR/CXCR1, respectively. These results indicated that the evaluation of GPER1, EGFR and CXCR1 concomitant high expression may be helpful in differential diagnosis between FTC and FTA.
SP-D, KL-6, and HTI-56 levels in children with mycoplasma pneumoniae pneumonia.Monday, November 30, 2015
Shu LH, Lu Q, Han LY, Dong GH,
International journal of clinical and experimental pathology. 2015
The high levels of SP-D, KL-6, and HTI-56 in infected bronchoalveolar lavage fluid samples may reflect the injury of alveolar epithelium caused by M. pneumoniae. Instead of SP-D in uninfected bronchoalveolar lavage fluid samples obtained by invasive bronchoscopy, serum SP-D may serve as a convenient medium to distinguish lung infection caused by M. pneumoniae.
Circadian gene expression predicts patient response to neoadjuvant chemoradiation therapy for rectal cancer.Monday, November 30, 2015
Lu H, Chu Q, Xie G, Han H, Chen Z, Xu B, Yue Z,
International journal of clinical and experimental pathology. 2015
Preoperative neoadjuvant chemoradiation therapy may be useful in patients with operable rectal cancer, but treatment responses are variable. We examined whether expression levels of circadian clock genes could be used as biomarkers to predict treatment response. We retrospectively analyzed clinical data from 250 patients with rectal cancer, treated with neoadjuvant chemoradiation therapy in a single institute between 2011 and 2013. Gene expression analysis (RT-PCR) was performed in tissue samples from 20 patients showing pathological complete regression (pCR) and 20 showing non-pCR. The genes analyzed included six core clock genes (Clock, Per1, Per2, Cry1, Cry2 and Bmal1) and three downstream target genes (Wee1, Chk2 and c-Myc). Patient responses were analyzed through contrast-enhanced pelvic MRI and endorectal ultrasound, and verified by histological assessment. pCR was defined histologically as an absence of tumor cells. Among the 250 included patients, 70.8% showed regression of tumor size, and 18% showed pCR. Clock, Cry2 and Per2 expressions were significantly higher in the pCR group than in the non-pCR group (P<0.05), whereas Per1, Cry1 and Bmal1 expressions did not differ significantly between groups. Among the downstream genes involved in cell cycle regulation, c-Myc showed significantly higher expression in the pCR group (P<0.05), whereas Wee1 and Chk2 expression did not differ significantly between groups. Circadian genes are potential biomarkers for predicting whether a patient with rectal cancer would benefit from neoadjuvant chemoradiation therapy.
Correlation between congenital heart disease complicated with pulmonary artery hypertension and circulating endothelial cells as well as endothelin-1.Monday, November 30, 2015
Li X, Qiu J, Pan M, Zheng D, Su Y, Wei M, Kong X, Sun W, Zhu J,
International journal of clinical and experimental pathology. 2015
CHD complicated with PAH is associated with increased CEC counts and ET-1 production. This study suggests that CECs and ET-1 could be used as clinical biomarkers to define medical strategies for control of PAH.
Variation in the expression levels of predictive chemotherapy biomarkers in histological subtypes of lung adenocarcinoma: an immunohistochemical study of tissue samples.Monday, November 30, 2015
Fujimoto Y, Togo S, Tulafu M, Shimizu K, Hayashi T, Uekusa T, Honma Y, Namba Y, Takamochi K, Oh S, Suzuki K, Takahashi K,
International journal of clinical and experimental pathology. 2015
Immunohistochemical H-scores of the predictive chemotherapy biomarkers were strongly associated with histological subtype. The presence of a solid subtype, which was associated with poor outcomes, might be assessed by measuring these biomarkers in mixed subtype adenocarcinomas.
Perfluorooctanoic acid enhances colorectal cancer DLD-1 cells invasiveness through activating NF-κB mediated matrix metalloproteinase-2/-9 expression.Monday, November 30, 2015
Miao C, Ma J, Zhang Y, Chu Y, Li J, Kuai R, Wang S, Peng H,
International journal of clinical and experimental pathology. 2015
Our study confirmed that PFOA could induce colorectal cancer cell DLD-1 invasive ability and MMP-2/-9 expression through activating NF-κB, which deserves more concerns on environmental pollutant-resulted public health risk.
Trefoil factor 1 elevates the malignant phenotype of mucinous ovarian cancer cell through Wnt/β-catenin signaling.Monday, November 30, 2015
Zhao S, Ma Y, Huang X,
International journal of clinical and experimental pathology. 2015
Mucinous ovarian cancer accounts for almost 10% of epithelial ovarian cancer, though patients in the early stage have an excellent prognosis, patients with advanced disease have a poor outcome and the molecular mechanism remains unclear. In this study, we retrieved database and found a secretory protein TFF1, which plays a tumor suppressor role in gastric cancer, is highly expressed in mucinous ovarian cancer, not serous or any other kind of ovarian cancer. Furthermore, the highly expressed TFF1 indicates a poor clinical outcome. Further biological function analysis revealed that TFF1 not only promotes cell proliferation but also invasion and chemoresistance, and these oncogenic effects might through regulating the activity of Wnt/β-catenin signaling and the level of Twist. Taken together, we found TFF1 plays an oncogenic role in mucinous ovarian cancer, unlike its suppressive role in gastric cancer.
MicroRNA-101 regulates the viability and invasion of cervical cancer cells.Monday, November 30, 2015
Lin C, Huang F, Shen G, Yiming A,
International journal of clinical and experimental pathology. 2015
MiR-101 likely acts as a tumor suppressor in cervical cancer. Overexpression of miR-101 decreased expression of its target gene Cox-2 and inhibited proliferation and invasion, and promoted apoptosis to suppress tumorigenicity. MiR-101 is a promising new target for the development of therapeutic strategies for the clinical treatment of cervical cancer.
Ectopic expressed long non-coding RNA H19 contributes to malignant cell behavior of ovarian cancer.Monday, November 30, 2015
Zhu Z, Song L, He J, Sun Y, Liu X, Zou X,
International journal of clinical and experimental pathology. 2015
Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in ovarian cancer (OC) remains largely unknown. In the present study, we focused on lncRNAH19 and investigated the expression and functional role of H19 in OC. H19 expression was measured in 70 pairs of ovarian cancer tissue samplescompared with normal controls by real-time quantitative RT-PCR. The effects of H19 on ovarian cancer cells were studied by RNA interference approach. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using cell counting Kit-8. Our results demonstrated that that H19 silencing inhibited OV90 and SKOV3 OC cell proliferation in vitro. Further investigation into the mechanisms responsible for the growth inhibitory effects by H19 silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, our data suggest that LncRNAH19 plays an important role in OC cell proliferation and contributes to a better understanding of the importance of dysregulated lncRNAs in OC progression.
Impairment of mesenchymal stem cells derived from oral leukoplakia.Monday, November 30, 2015
Zhang Z, Song J, Han Y, Mu D, Su S, Ji X, Liu H,
International journal of clinical and experimental pathology. 2015
Oral leukoplakia is one of the common precancerous lesions in oral mucosa. To compare the biological characteristics and regenerative capacities of mesenchymal stem cells (MSCs) from oral leukoplakia (epithelial hyperplasia and dysplasia) and normal oral mucosa, MSCs were isolated by enzyme digestion. Then these cells were identified by the expression of MSC related markers, STRO-1, CD105 and CD90, with the absent for the hematopoietic stem cell marker CD34 by flow cytometric detection. The self-renewal ability of MSCs from oral leukoplakia was enhanced, while the multipotent differentiation was descended, compared with MSCs from normal oral mucosa. Fibrin gel was used as a carrier for MSCs transplanted into immunocompromised mice to detect their regenerative capacity. The regenerative capacities of MSCs from oral leukoplakia became impaired partly. Collagen IV (Col IV) and matrix metalloproteinases-9 (MMP-9) were selected to analyze the potential mechanism for the functional changes of MSCs from oral leukoplakia by immunochemical and western blot analysis. The expression of Col IV was decreased and that of MMP-9 was increased by MSCs with the progression of oral leukoplakia, especially in MSCs from epithelial dysplasia. The imbalance between regenerative and metabolic self-regulatory functions of MSCs from oral leukoplakia may be related to the progression of this premalignant disorder.
Niflumic acid exhibits anti-tumor activity in nasopharyngeal carcinoma cells through affecting the expression of ERK1/2 and the activity of MMP2 and MMP9.Monday, November 30, 2015
Luo S, Huang G, Wang Z, Wan Z, Chen H, Liao D, Chen C, Li H, Li B, Chen L, Huang Z, He Z,
International journal of clinical and experimental pathology. 2015
Niflumic acid (NFA) was known to inhibit cell proliferation or migration in several types of cancer. However, the function of NFA in human nasopharyngeal carcinoma (NPC) cells was not clarified. The proliferation of NPC cell line CNE-2Z cells with NFA treatment was detected using the cell counting kit-8 method and transwell assay was employed to assess the effect of NFA on the CNE-2Z cell migration and invasion. The activity of MMP2 and MMP9 was detected by Gelatin Zymography. Cell cycle distribution and apoptosis were detected using flow cytometry. In vitro pull-down assay, western blot, and computational technique were applied to investigate the NFA regulating signaling pathway. Our results indicated that the growth capacity and colony formation potential of CNE-2Z cells in soft agar were significantly suppressed by treatment with NFA. NFA inhibited the proliferation of CNE-2Z cells in a concentration and time-dependent manner. NFA exerted an S phase arrest on the CNE-2Z cells in a concentration-dependent manner, while promoting apoptosis in a dose-dependent manner. Migration and invasion potential of CNE-2Z cells were decreased by NFA treatment in vitro. In vitro pull-down assay and molecular modeling indicated that NFA directly bound with early respond kinase 1 (ERK1). Finally, the anti-tumor effect of NFA was suggested to be mediated by inhibiting early respond kinases (ERK) expression and the MMP2 and MMP9 activities. NFA has proliferation-inhibiting, invasion-suppressing, cell cycle-blocking and apoptosis-promoting effects on CNE-2Z cells through regulation of ERK/MAPK and our results indicates that NFA may serve as a candidate of anticancer drug for NPC.
Proteomic analysis of synovial fluid as an analytical tool to detect candidate biomarkers for knee osteoarthritis.Monday, November 30, 2015
Liao W, Li Z, Zhang H, Li J, Wang K, Yang Y,
International journal of clinical and experimental pathology. 2015
We conducted research to detect the proteomic profiles in synovial fluid (SF) from knee osteoarthritis (OA) patients to better understand the pathogenesis and aetiology of OA. Our long-term goal is to identify reliable candidate biomarkers for OA in SF. The SF proteins obtained from 10 knee OA patients and 10 non-OA patients (9 of whom were patients with a meniscus injury in the knee; 1 had a discoid meniscus in the knee, and all exhibited intact articular cartilage) were separated by two-dimensional electrophoresis (2-DE). The repeatability of the obtained protein spots regarding their intensity was tested via triplicate 2-DE of selected samples. The observed protein expression patterns were subjected to statistical analysis, and differentially expressed protein spots were identified via matrix-assisted laser desorption/ionisation-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Our analyses showed low intrasample variability and clear intersample variation. Among the protein spots observed on the gels, there were 29 significant differences, of which 22 corresponded to upregulation and 7 to downregulation in the OA group. One of the upregulated protein spots was confirmed to be haptoglobin by mass spectrometry, and the levels of haptoglobin in SF are positively correlated with the severity of OA (r = 0.89, P < 0.001). This study showed that 2-DE could be used under standard conditions to screen SF samples and identify a small subset of proteins in SF that are potential markers associated with OA. Spots of interest identified by mass spectrometry, such as haptoglobin, may be associated with OA severity.
Up-regulation of AKAP13 and MAGT1 on cytoplasmic membrane in progressive hepatocellular carcinoma: a novel target for prognosis.Monday, November 30, 2015
Molee P, Adisakwattana P, Reamtong O, Petmitr S, Sricharunrat T, Suwandittakul N, Chaisri U,
International journal of clinical and experimental pathology. 2015
Hepatocellular carcinoma (HCC) is one of the most common cancers and is associated with high mortality worldwide. The current gold standards for HCC surveillance are detection of serum α-fetoprotein (AFP) and ultrasonography; however, non-specificity of AFP and ultrasonography has frequently been reported. Therefore, alternative tools, especially novel specific tumor markers, are required. In this study, cytoplasmic membrane proteins were isolated from phorbol 12-myristate 13-acetate (PMA)-induced invasive HepG2 cells and identified using nano-scale liquid chromatographic tandem mass spectrometry (NLC-MS/MS) with comparison to non-treated controls. The results showed that two proteins, magnesium transporter protein 1 (MAGT1) and A-kinase anchor protein 13 (AKAP13), were highly expressed in PMA-treated HepG2 cells. This up-regulation was confirmed by real-time RT-PCR, western blot analysis, and immunofluorescent staining studies. Furthermore, evaluation of MAGT1 and AKAP13 expression in clinical HCC tissues by immunohistochemistry suggested that both proteins were strongly expressed in tumor tissues with significantly higher average immunoreactive scores of Remmele and Stegner (IRS) than in non-tumor tissues (P ≤ 0.005). In conclusion, the expression levels of MAGT1 and AKAP13 in HCC may be potential biomarkers for the diagnosis and prognosis of this cancer.
Immune-phenotypical markers for the differential diagnosis of melanocytic lesions.Monday, November 30, 2015
Botti G, Marra L, Anniciello A, Scognamiglio G, Gigantino V, Cantile M,
International journal of clinical and experimental pathology. 2015
For specific subsets of melanocytic proliferations, there are morphologic limitations in the histological diagnosis, especially for borderline melanocytic tumors. In particular, Spitzoid proliferations can be difficult to diagnose. For these reasons, in the last years, clinic research has focusedattention on discovery of new diagnostic markers. Published gene expression and proteomic profiling data indicate new candidate molecules involved in melanoma pathogenesis, and useful in differential diagnosis of difficult melanocytic lesions. Recently, the diagnostic power of galectin-3 was demonstrated in series of melanocytic lesions, with a strong increasing of expression in malignant lesions compared with benign lesions. Similarly, the accumulation of Collagen XVII antibody was detected in vertical melanoma fronts and associated with invasive phenotype. Moreover, overexpression of cyclin D1 and p21 was detected in Spitz nevi compared with non-spitzoid melanomas; Ki-67 appears highly expressed in deep areas of non-spitzoid melanomas. In this review,werealizedan overviewofthe main molecular markersthat canbe a usefultoolfor the differential diagnosisofbenign, borderlineand malignant melanocytic lesions, related to their biological behavior, useful also for predicting the evolutionof the disease.
HTRF: a technology tailored for biomarker determination-novel analytical detection system suitable for detection of specific autoimmune antibodies as biomarkers in nanogram level in different body fluids.Monday, November 30, 2015
Einhorn L, Krapfenbauer K,
The EPMA journal. 01-09-2015
The aim of this work is to describe the development and establishment of this novel HTRF system that allows the very fast detection and quantification of biomarkers in different human body fluids. Furthermore, a specific antibody combination that assures a specific binding of the correct refolded autoimmune IgG is evaluated.
Genome-wide predictors of NF-κB recruitment and transcriptional activity.Monday, November 30, 2015
Cieślik M, Bekiranov S,
BioData mining. 27-11-2015
We provide evidence of NF-κB binding within genomic regions that lack classical marks of activity. These pioneer binding events are relatively often associated with transcriptional regulation. Further, our predictive models indicate that specific combinations of epigenetic marks and transcription factors predetermine the NF-κB cistrome, supporting the feasibility of using statistical approaches to identify "histone codes".
Recovery Potential After Acute Stroke.Monday, November 30, 2015
Seitz RJ, Donnan GA,
Frontiers in neurology. 26-11-2015
In acute stroke, the major factor for recovery is the early use of thrombolysis aimed at arterial recanalization and reperfusion of ischemic brain tissue. Subsequently, neurorehabilitative training critically improves clinical recovery due to augmention of postlesional plasticity. Neuroimaging and electrophysiology studies have revealed that the location and volume of the stroke lesion, the affection of nerve fiber tracts, as well as functional and structural changes in the perilesional tissue and in large-scale bihemispheric networks are relevant biomarkers of post-stroke recovery. However, associated disorders, such as mood disorders, epilepsy, and neurodegenerative diseases, may induce secondary cerebral changes or aggravate the functional deficits and, thereby, compromise the potential for recovery.
Plasma 24-metabolite Panel Predicts Preclinical Transition to Clinical Stages of Alzheimer's Disease.Monday, November 30, 2015
Fiandaca MS, Zhong X, Cheema AK, Orquiza MH, Chidambaram S, Tan MT, Gresenz CR, FitzGerald KT, Nalls MA, Singleton AB, Mapstone M, Federoff HJ,
Frontiers in neurology. 11-11-2015
We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer's disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n = 28) and a matched set of cognitively normal subjects (n = 73), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0-1.0, and 0.981-1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD.
Joint Coupling of Awake EEG Frequency Activity and MRI Gray Matter Volumes in the Psychosis Dimension: A BSNIP Study.Monday, November 30, 2015
Soh P, Narayanan B, Khadka S, Calhoun VD, Keshavan MS, Tamminga CA, Sweeney JA, Clementz BA, Pearlson GD,
Frontiers in psychiatry. 12-11-2015
Our data suggest that a joint EEG and GMV model yielded a biomarker specific to SZ, not abnormal in PBP or SZA. Alpha activity was related to both increased and decreased volume in different cortical structures. Additionally, the joint model failed to identify endophenotypes across psychotic disorders.
Apolipoprotein A-I and Cancer.Monday, November 30, 2015
Zamanian-Daryoush M, DiDonato JA,
Frontiers in pharmacology. 09-11-2015
High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), the predominant protein in plasma HDL, have long been the focus of intense studies in the field of atherosclerosis and cardiovascular disease. ApoA-I, in large part, is responsible for HDL assembly and its main atheroprotective function, that of shuttling excess cholesterol from peripheral tissues to the liver for excretion (reverse cholesterol transport). Recently, a protective role for HDL in cancer was suggested from several large clinical studies where an inverse relationship between plasma HDL-cholesterol (HDL-C) levels and risk of developing cancer was noted. This notion has now been tested and found to be supported in mouse tumor studies, where increasing levels of apoA-I/HDL were discovered to protect against tumor development and provision of human apoA-I was therapeutic against established tumors. This mini-review discusses the emerging role of apoA-I in tumor biology and its potential as cancer therapeutic.
Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics.Monday, November 30, 2015
Li J, Zhang Z, Liu X, Wang Y, Mao F, Mao J, Lu X, Jiang D, Wan Y, Lv JY, Cao G, Zhang J, Zhao N, Atkinson M, Greiner DL, Prud'homme GJ, Jiao Z, Li Y, Wang Q,
Frontiers in pharmacology. 12-11-2015
Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes.
Neuroinflammation is not a Prerequisite for Diabetes-induced Tau Phosphorylation.Monday, November 30, 2015
van der Harg JM, Eggels L, Ruigrok SR, Hoozemans JJ, la Fleur SE, Scheper W,
Frontiers in neuroscience. 10-11-2015
Abnormal phosphorylation and aggregation of tau is a key hallmark of Alzheimer's disease (AD). AD is a multifactorial neurodegenerative disorder for which Diabetes Mellitus (DM) is a risk factor. In animal models for DM, the phosphorylation and aggregation of tau is induced or exacerbated, however the underlying mechanism is unknown. In addition to the metabolic dysfunction, DM is characterized by chronic low-grade inflammation. This was reported to be associated with a neuroinflammatory response in the hypothalamus of DM animal models. Neuroinflammation is also implicated in the development and progression of AD. It is unknown whether DM also induces neuroinflammation in brain areas affected in AD, the cortex and hippocampus. Here we investigated whether neuroinflammation could be the mechanistic trigger to induce tau phosphorylation in the brain of DM animals. Two distinct diabetic animal models were used; rats on free-choice high-fat high-sugar (fcHFHS) diet that are insulin resistant and streptozotocin-treated rats that are insulin deficient. The streptozotocin-treated animals demonstrated increased tau phosphorylation in the brain as expected, whereas the fcHFHS diet fed animals did not. Remarkably, neither of the diabetic animal models showed reactive microglia or increased GFAP and COX-2 levels in the cortex or hippocampus. From this, we conclude: 1. DM does not induce neuroinflammation in brain regions affected in AD, and 2. Neuroinflammation is not a prerequisite for tau phosphorylation. Neuroinflammation is therefore not the mechanism that explains the close connection between DM and AD.
Treatment Individualization in Colorectal Cancer.Monday, November 30, 2015
van Geel RM, Beijnen JH, Bernards R, Schellens JH,
Current colorectal cancer reports. 09-11-2015
Colorectal cancer has been characterized as a genetically heterogeneous disease, with a large diversity in molecular pathogenesis resulting in differential responses to therapy. However, the currently available validated biomarkers KRAS, BRAF, and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment. Recent studies have focused on novel targets and rationally designed combination strategies. Furthermore, a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance. Accordingly, patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer.
Differential abundance analysis of mesocarp protein from high- and low-yielding oil palms associates non-oil biosynthetic enzymes to lipid biosynthesis.Monday, November 30, 2015
Ooi TE, Yeap WC, Daim LD, Ng BZ, Lee FC, Othman AM, Appleton DR, Chew FT, Kulaveerasingam H,
Proteome science. 26-8-2015
Forty-one proteins in several important biological pathways were identified as exhibiting differential in abundance at critical oil production stages. These confirm that oil yield is a complex trait involving the regulation of genes in multiple biological pathways. The results also provide insights into key control points of lipid biosynthesis in oil palm and can assist in the development of genetic markers for use in oil palm breeding programmes.
Red clover (Trifolium pratense L.) draft genome provides a platform for trait improvement.Monday, November 30, 2015
De Vega JJ, Ayling S, Hegarty M, Kudrna D, Goicoechea JL, Ergon Å, Rognli OA, Jones C, Swain M, Geurts R, Lang C, Mayer KF, Rössner S, Yates S, Webb KJ, Donnison IS, Oldroyd GE, Wing RA, Caccamo M, Powell W, Abberton MT, Skøt L,
Scientific reports. 2015
Red clover (Trifolium pratense L.) is a globally significant forage legume in pastoral livestock farming systems. It is an attractive component of grassland farming, because of its high yield and protein content, nutritional value and ability to fix atmospheric nitrogen. Enhancing its role further in sustainable agriculture requires genetic improvement of persistency, disease resistance, and tolerance to grazing. To help address these challenges, we have assembled a chromosome-scale reference genome for red clover. We observed large blocks of conserved synteny with Medicago truncatula and estimated that the two species diverged ~23 million years ago. Among the 40,868 annotated genes, we identified gene clusters involved in biochemical pathways of importance for forage quality and livestock nutrition. Genotyping by sequencing of a synthetic population of 86 genotypes show that the number of markers required for genomics-based breeding approaches is tractable, making red clover a suitable candidate for association studies and genomic selection.
Development of germ cell neoplasia in situ in chinchilla rabbits.Monday, November 30, 2015
Vigueras-Villaseñor RM, Montelongo Solís P, Chávez-Saldaña M, Gutiérrez-Pérez O, Cortés Trujillo L, Rojas-Castañeda JC,
Histology and histopathology. 30-Nov-2015
The present study was designed to describe the development of germ cell neoplasia in situ in Chinchilla rabbit by administration of estradiol. The study was performed in rabbits distributed into two groups: control and 17 β-estradiol. The determination of histological alterations and POU5F1 and c-kit proteins employed as biomarkers for the diagnosis of this neoplasia was carried out. Testicular descent and complete spermatogenesis were observed in the control group. The protein biomarkers were negative. However, in the rabbits treated with estradiol, the testes remained undescended with the gonocytes undifferentiated to spermatogonia. There were histological lesions owing to germ cell neoplasia in situ and positive to POU5F1 and c-kit proteins. These findings indicate that the chinchilla rabbit is an ideal model to study this neoplasia in which the histological characteristics and biomarkers of the disease could be clearly observed. Using this model we suggested that the persisting gonocytes could be responsible for the development of germ cell neoplasia in situ.
Intratumor molecular heterogeneity in pleomorphic adenoma of the salivary glands.Monday, November 30, 2015
Gomes CC, Galvão CF, do Carmo AC, Pereira NB, Gomez RS,
Oral surgery, oral medicine, oral pathology and oral radiology. 16-Sep-2015
Our findings point to the existence of intratumor molecular heterogeneity in salivary gland PA. This is an advance in the efforts to clarify PA molecular pathogenesis, showing that this characteristic is not exclusive to malignant solid tumors.
Evaluation of Two Lyophilized Molecular Assays to Rapidly Detect Foot-and-Mouth Disease Virus Directly from Clinical Samples in Field Settings.Monday, November 30, 2015
Howson EL, Armson B, Madi M, Kasanga CJ, Kandusi S, Sallu R, Chepkwony E, Siddle A, Martin P, Wood J, Mioulet V, King DP, Lembo T, Cleaveland S, Fowler VL,
Transboundary and emerging diseases. 30-Nov-2015
Accurate, timely diagnosis is essential for the control, monitoring and eradication of foot-and-mouth disease (FMD). Clinical samples from suspect cases are normally tested at reference laboratories. However, transport of samples to these centralized facilities can be a lengthy process that can impose delays on critical decision making. These concerns have motivated work to evaluate simple-to-use technologies, including molecular-based diagnostic platforms, that can be deployed closer to suspect cases of FMD. In this context, FMD virus (FMDV)-specific reverse transcription loop-mediated isothermal amplification (RT-LAMP) and real-time RT-PCR (rRT-PCR) assays, compatible with simple sample preparation methods and in situ visualization, have been developed which share equivalent analytical sensitivity with laboratory-based rRT-PCR. However, the lack of robust 'ready-to-use kits' that utilize stabilized reagents limits the deployment of these tests into field settings. To address this gap, this study describes the performance of lyophilized rRT-PCR and RT-LAMP assays to detect FMDV. Both of these assays are compatible with the use of fluorescence to monitor amplification in real-time, and for the RT-LAMP assays end point detection could also be achieved using molecular lateral flow devices. Lyophilization of reagents did not adversely affect the performance of the assays. Importantly, when these assays were deployed into challenging laboratory and field settings within East Africa they proved to be reliable in their ability to detect FMDV in a range of clinical samples from acutely infected as well as convalescent cattle. These data support the use of highly sensitive molecular assays into field settings for simple and rapid detection of FMDV.
Notch in T Cell Differentiation: All Things Considered.Monday, November 30, 2015
Amsen D, Helbig C, Backer RA,
Trends in immunology. 23-Nov-2015
Differentiation of naïve T cells into effector cells is required for optimal protection against different classes of microbial pathogen and for the development of immune memory. Recent findings have revealed important roles for the Notch signaling pathway in T cell differentiation into all known effector subsets, raising the question of how this pathway controls such diverse differentiation programs. Studies in preclinical models support the therapeutic potential of manipulating the Notch pathway to alleviate immune pathology, highlighting the importance of understanding the mechanisms through which Notch regulates T cell differentiation and function. We review these findings here, and outline both unifying principles involved in Notch-mediated T cell fate decisions and cell type- and context-specific differences that may present the most suitable points for therapeutic intervention.
Association of bacteria in diabetic and non-diabetic foot infection - An investigation in patients from Bangladesh.Monday, November 30, 2015
Karmaker M, Sanyal SK, Sultana M, Hossain MA,
Journal of infection and public health. 23-Nov-2015
The microbial community on a host relies on its immune status and pathophysiological condition. Diabetes mellitus is a metabolic disorder associated with a 25% increased risk of developing foot infection. The pathophysiological differences between diabetic foot infection (DFI) and non-DFI patients may alter the microbial composition in infections. The present study aims to comparatively analyze the microbes colonized in DFI and non-DFI patients in Bangladesh. Pus specimens were collected from 67 DFI and 12 non-DFI patients to investigate the bacteria associated with foot infection. For this investigation, an array of microbiological, molecular biological and immunological approaches were performed. Common bacteria detected in both DFI/non-DFI samples were Pseudomonas spp. (22/29%), Bacillus spp. (12/3%), Enterobacter spp. (22/7%), Staphylococcus spp. (13/13%) and Acinetobacter spp. (10/10%). Enterococcus spp. (9%) and Klebsiella spp. (8%) occurred only in DFI patients, whereas Citrobacter spp. (29%) was only detected in non-DFI samples. The rate of occurrence of three organisms, namely, Enterococcus spp. |Z|=2.2125, Klebsiella spp. |Z|=1.732, Bacillus spp. |Z|=1.9034, were also statistically significant. Most of the isolates from DFI patients were commonly resistant to the cephalosporin (Ceftazidime, Ceftriazone, Cefurozime) and monobactam (Aztreonam) groups of antibiotics. DFI patients had comparatively higher C-reactive protein (CRP) levels than non-DFI patients, and a positive correlation was observed between multi-antibiotic resistance and CRP levels (one of the markers of chronic subclinical inflammation). The present investigation implicated a complex association of the bacterial population in DFI compared with non-DFI with different antimicrobial resistance properties, which was linked with CRP levels.
Biomarkers for Allergen Immunotherapy: A "Panoromic" View.Monday, November 30, 2015
Moingeon P,
Immunology and allergy clinics of North America. Feb-2016
Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials.
Baked Milk and Egg Diets for Milk and Egg Allergy Management.Monday, November 30, 2015
Leonard SA, Nowak-Węgrzyn AH,
Immunology and allergy clinics of North America. Feb-2016
In baked form, cow's milk and egg are less allergenic and are tolerated by most milk- and egg-allergic children. Not only may including baked milk and egg in the diets of children who are tolerant improve nutrition and promote more social inclusion but there is also evidence that inclusion may accelerate the resolution of unheated milk and egg allergy. Further research is needed on biomarkers that can predict baked milk or egg reactivity; however, data suggest casein- and ovomucoid-specific immunoglobulin E levels may be useful. Physician-supervised introduction of baked milk and egg is recommended because anaphylaxis has occurred.
Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy.Monday, November 30, 2015
Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA,
Immunology and allergy clinics of North America. Feb-2016
Allergen immunotherapy (AIT) is an effective way to treat allergic disorders, targeting the underlying mechanisms and altering the disease course by inducing a long-lasting clinical and immune tolerance to allergens. Although sublingual and subcutaneous routes are used in daily practice, many novel ways to decrease side effects and duration and increase efficacy have been pursued. Further studies are needed to develop biomarkers for the identification of AIT responder patients and also to use the developed knowledge in allergy prevention studies. Future directions in AIT include treatments for autoimmune diseases, chronic infections, organ transplantation, and breaking immune tolerance to cancer cells.
Extracellular vesicles: pharmacological modulators of the peripheral and central signals governing obesity.Monday, November 30, 2015
Milbank E, Martinez MC, Andriantsitohaina R,
Pharmacology & therapeutics. 23-Nov-2015
Obesity and its metabolic resultant dysfunctions such as insulin resistance, hyperglycemia, dyslipidemia and hypertension, grouped as the "metabolic syndrome", are chronic inflammatory disorders that represent one of the most severe epidemic health problems. The imbalance between energy intake and expenditure, leading to an excess of body fat and an increase of cardiovascular and diabetes risks, is regulated by the interaction between central nervous system (CNS) and peripheral signals in order to regulate behavior and finally, the metabolism of peripheral organs. At the present, pharmacological treatment of obesity comprises actions in both CNS and peripheral organs. In the last decades, the extracellular vesicles have emerged as participants in many pathophysiological regulation processes. Whether used as biomarkers, targets or even tools, extracellular vesicles provided some promising effects in the treatment of a large variety of diseases. Extracellular vesicles are released by cells from the plasma membrane (microvesicles) or from multivesicular bodies (exosomes) and contain lipids, proteins and nucleic acids, such as DNA, protein coding, and non-coding RNAs. Owing to their composition, extracellular vesicles can (i) activate receptors at the target cell and then, the subsequent intracellular pathway associated to the specific receptor; (ii) transfer molecules to the target cells and thereby change their phenotype and (iii) be used as shuttle of drugs and, thus, to carry specific molecules towards specific cells. Herein, we review the impact of extracellular vesicles in modulating the central and peripheral signals governing obesity.
Contemporary Breast Radiotherapy and Cardiac Toxicity.Monday, November 30, 2015
Yeboa DN, Evans SB,
Seminars in radiation oncology. Jan-2016
Long-term cardiac effects are an important component of survivorship after breast radiotherapy. The pathophysiology of cardiotoxicity, history of breast radiotherapy, current methods of cardiac avoidance, modern outcomes, context of historical outcomes, quantifying cardiac effects, and future directions are reviewed in this article. Radiation-induced oxidative stress induces proinflammatory cytokines and is a process that potentiates late effects of fibrosis and intimal proliferation in endothelial vasculature. Breast radiation therapy has changed substantially in recent decades. Several modern technologies exist to improve cardiac avoidance such as deep inspiration breath hold, gating, accelerated partial breast irradiation, and use of modern 3-dimensional planning. Modern outcomes may vary notably from historical long-term cardiac outcomes given the differences in cardiac dose with modern techniques. Methods of quantifying radiation-related cardiotoxicity that correlate with future cardiac risks are needed with current data exploring techniques such as measuring computed tomography coronary artery calcium score, single-photon emission computed tomography imaging, and biomarkers. Placing historical data, dosimetric correlations, and relative cardiac risk in context are key when weighing the benefits of radiotherapy in breast cancer control and survival. Estimating present day cardiac risk in the modern treatment era includes challenges in length of follow-up and the use of confounding cardiotoxic agents such as evolving systemic chemotherapy and targeted therapies. Future directions in both multidisciplinary management and advancing technology in radiation oncology may provide further improvements in patient risk reduction and breast cancer survivorship.
Molecular Phenotype, Multigene Assays, and the Locoregional Management of Breast Cancer.Monday, November 30, 2015
Braunstein LZ, Taghian AG,
Seminars in radiation oncology. Jan-2016
Molecular profiling has revealed that breast cancer is not a single disease entity, but rather a class of heterogeneous subtypes, each with its own inherent biology and natural history. As a result, different treatment approaches have been optimized for the various subtypes and, in turn, the ability to identify subtypes has become a critical element in the management of breast cancer. Comprehensive transcriptional profiling studies have revealed at least 4 principal subtypes that, in practice, are often distinguished by immunohistochemical staining of the estrogen receptor (ER), progesterone receptor (PR), and HER2, along with a determination of histologic grade or Ki-67 staining: luminal A (ER+/HER2-/grade 1 or 2), luminal B (ER+/HER2-/grade 3), HER2 enriched (any HER2+ tumor), and basal like (ER-/PR-/HER2-). Although these immunohistochemically derived subtypes show robust prognostic and predictive ability, there remain many cases that demand profiling that more closely approximates the original transcriptionally derived definitions of the intrinsic subtypes. The need for improved prognostication and risk stratification has led to the development of several multigene assays in breast cancer. Although there is little molecular overlap between current assays, they all rely heavily on quantifying the transcriptional output of ER signaling and proliferation-related genes. These data are typically then used in multivariate prediction models that incorporate other canonical risk factors such as the tumor size, lymph node involvement, and patient demographic parameters, among others. Indeed, the advent of scalable molecular profiling technologies has brought a number of assays into routine clinical use for optimizing risk prediction and treatment assignment. The landscape of these assays and the clinical utility of contemporary molecular profiles are the main focus of this overview. In addition to the clinical advances in transcriptional subtyping, recent reports have characterized the most common genomic and epigenomic alterations that are likely to drive certain breast cancers. The identification of these "driver" lesions has heralded an era of precision medicine in which vulnerable oncogenic pathways may be targeted to disrupt the etiologic lesion(s) of a specific tumor. A number of such early targeted approaches have yielded success in treating breast cancer, demonstrating the critical need for molecular diagnostics in this disease.
Innate and adaptive immune response in stroke: Focus on epigenetic regulation.Monday, November 30, 2015
Picascia A, Grimaldi V, Iannone C, Soricelli A, Napoli C,
Journal of neuroimmunology. 15-Dec-2015
Inflammation and immune response play a pivotal role in the pathophysiology of ischemic stroke giving their contribution to tissue damage and repair. Emerging evidence supports the involvement of epigenetic mechanisms such as methylation, histone modification and miRNAs in the pathogenesis of stroke. Interestingly, epigenetics can influence the molecular events involved in ischemic injury by controlling the switch from pro- to anti-inflammatory response, however, this is still a field to be fully explored. The knowledge of epigenetic processes could to allow for the discovery of more sensitive and specific biomarkers for risk, onset, and progression of disease as well as further novel tools to be used in both primary prevention and therapy of stroke. Indeed, studies performed in vitro and in small animal models seem to suggest a neuroprotective role of HDAC inhibitors (e.g. valproic acid) and antagomir (e.g. anti-miR-181a) in ischemic condition by modulation of both immune and inflammatory pathways. Thus, the clinical implications of altered epigenetic mechanisms for the prevention of stroke are very promising but clinical prospective studies and translational approaches are still warranted.
ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.Monday, November 30, 2015
Debruyne DN, Bhatnagar N, Sharma B, Luther W, Moore NF, Cheung NK, Gray NS, George RE,
Oncogene. 30-Nov-2015
The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.Oncogene advance online publication, 30 November 2015; doi:10.1038/onc.2015.434.
MicroRNA expression profiling in peritoneal fibrosis.Monday, November 30, 2015
Morishita Y, Yoshizawa H, Watanabe M, Imai R, Imai T, Hirahara I, Akimoto T, Ookawara S, Muto S, Nagata D,
Translational research : the journal of laboratory and clinical medicine. 5-Nov-2015
Peritoneal fibrosis (PF) is an intractable complication leading to peritoneal membrane failure in peritoneal dialysis (PD). The aim of this study was to identify microRNAs (miRNAs) involved in PF. Peritoneal tissue from a PF rat model was screened for miRNA expression using microarray analysis. The expression levels of differentially expressed miRNAs were evaluated in serum and drained dialysate and associated with peritoneal membrane functions, as measured by the peritoneal equilibration test in 33 PD patients. Furthermore, an miRNA inhibitor (anti-miRNA-21-5p locked nucleic acid (LNA): anti-miRNA-21-LNA) was intraperitoneally injected to PF model mice to investigate its effects on PF. The initial profiling study of PF rat peritoneal tissue identified 6 miRNAs (miRNA-142-3p, miRNA-21-5p, miRNA-221-3p, miRNA-223-3p, miRNA-34a-5p, and miRNA-327) whose expression was increased more than 2-fold and no miRNAs whose expression was decreased more than half. Among them, serum levels of miRNA-21-5p, miRNA-221-3p, and miRNA-327 and drained dialysate levels of miRNA-221-3p and miRNA-34a-5p were significantly correlated with peritoneal membrane functions in PD patients. Anti-miRNA-21-LNA significantly inhibited miRNA-21-5p expression in the PF mouse peritoneum, inhibited peritoneal fibrous thickening, and maintained peritoneal membrane functions. These results suggest that several miRNAs are involved in PF and that they may be useful as novel diagnostic biomarkers and therapeutic targets for PF.
[Research progress of Lgr4 in gastrointestinal carcinomas].Monday, November 30, 2015
Xiao Y, Chen L,
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery. 25-Nov-2015
Gastrointestinal carcinomas, whose incidence increases in recent years, are among the malignancies with highest morbidity and mortality. Many patients are always advanced stages when having diagnosis. So far, there are no any reliable tumor biomarkers which are able to screen people with high risk of developing cancer. Studies have shown that the expression level of Lgr4 is high in gastrointestinal carcinomas and Lgr4 is useful in diagnosis, differential diagnosis and prognosis judgment of these carcinomas. Lgr4 belongs to the G-protein-coupled receptors family. Its function is to potentiate Wnt signaling and plays an important role in the development of multiple organs. Recent studies find that Lgr4 has close relationship with the development of many gastrointestinal carcinomas, such as gastric cancer and colorectal cancer(CRC). In this article we review recent progress in understanding the relationship between Lgr4 and gastrointestinal carcinomas.
Anthropogenic waste indicators (AWIs), particularly PAHs and LABs, in Malaysian sediments: Application of aquatic environment for identifying anthropogenic pollution.Monday, November 30, 2015
Masood N, Zakaria MP, Halimoon N, Aris AZ, Magam SM, Kannan N, Mustafa S, Ali MM, Keshavarzifard M, Vaezzadeh V, Alkhadher SA, Al-Odaini NA,
Marine pollution bulletin. 23-Nov-2015
Polycyclic aromatic hydrocarbons (PAHs) and linear alkylbenzenes (LABs) were used as anthropogenic markers of organic chemical pollution of sediments in the Selangor River, Peninsular Malaysia. This study was conducted on sediment samples from the beginning of the estuary to the upstream river during dry and rainy seasons. The concentrations of ƩPAHs and ƩLABs ranged from 203 to 964 and from 23 to 113ngg(-1) dry weight (dw), respectively. In particular, the Selangor River was found to have higher sedimentary levels of PAHs and LABs during the wet season than in the dry season, which was primarily associated with the intensity of domestic wastewater discharge and high amounts of urban runoff washing the pollutants from the surrounding area. The concentrations of the toxic contaminants were determined according to the Sediment Quality Guidelines (SQGs). The PAH levels in the Selangor River did not exceed the SQGs, for example, the effects range low (ERL) value, indicating that they cannot exert adverse biological effects.
Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes.Monday, November 30, 2015
Wang Q,
Acta pharmacologica Sinica. 30-Nov-2015
Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy.
Genetic and phylogenetic characterization of novel bocaparvovirus infecting chimpanzee.Monday, November 30, 2015
Brožová K, Hrazdilová K, Slaninková E, Modrý D, Černý J, Celer V,
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 23-Nov-2015
Primate bocaparvoviruses were first described in 2005, since then further human and gorilla bocaparvoviruses have been identified. To uncover diversity of non-human primates' bocaparvoviruses, their phylogenetic relationship and potential to cross the host species barrier, we tested 153 fecal samples from 17 captive primate species. The only one captive female of central chimpanzee (coded CPZh2) has been identified as bocaparvovirus positive. Based on the full genome phylogenetic analyses, CPZh2 strain shows close relationship to HBoV3 and GBoV. Further recombination analysis confirmed expected mosaic origin of CPZh2 strain. According the phylogenetic position, following the ICTV recommendations, we propose a novel genotype within the Primate bocaparvovirus 1 species infecting chimpanzee.
Elements that Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome.Monday, November 30, 2015
Iyama T, Wilson DM,
Journal of molecular biology. 23-Nov-2015
Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration, and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts, and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage, and is most rapid and robust as follows: ICLs>DSBs>monoadducts>oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB, and in particular its ubiquitin-binding domain, were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts, but not oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS.
Evaluation of the first oral rabies vaccination campaign of the red foxes in Greece.Monday, November 30, 2015
Korou LM, Tasioudi KE, Tzani M, Konstantinidis A, Plevraki A, Iliadou P, Kostoglou P, Kaimaras D, Doudounakis S, Mangana-Vougiouka O,
Vaccine. 23-Nov-2015
Following the late 2012 recurrence of rabies in wild foxes (Vulpes vulpes) in central and north-western Greece, the first oral fox vaccination campaign co-financed by the European Union (EU) and the Greek state budget, was implemented. Initially, it involved 24 regional units of the Greek territory during the period October-December 2013. Vaccine-baits were aerially distributed by fixed-wing aircrafts. Vaccines were scattered along parallel flight paths 500m apart in order to optimize aerial missions and achieve homogeneous distribution. A geographical information system was used to objectively evaluate bait distribution. This system identified areas of inadequate bait density that would require additional flights. A total number of 1,504,821 baits were distributed covering an area of 54,584.29km(2). To assess the effectiveness of oral vaccination campaign a monitoring program was introduced, which entailed examination of serum samples and canine teeth derived from red foxes collected in the field. The laboratory analysis revealed 60% seropositivity and detection of tetracycline biomarker in 70% of the foxes tested.
Tempol prevents chronic sleep-deprivation induced memory impairment.Monday, November 30, 2015
Alzoubi KH, Khabour OF, Albawaana AS, Alhashimi FH, Athamneh RY,
Brain research bulletin. 23-Nov-2015
Sleep deprivation is associated with oxidative stress that causes learning and memory impairment. Tempol is a nitroxide compound that promotes the metabolism of many reactive oxygen species (ROS) and has antioxidant and neuroprotective effect. The current study investigated whether chronic administration of tempol can overcome oxidative stress and prevent learning and memory impairment induced by sleep deprivation. Sleep deprivation was induced in rats using multiple platform model. Tempol was administered to rats via oral gavages. Behavioral studies were conducted to test the spatial learning and memory using radial arm water maze. The hippocampus was dissected; antioxidant biomarkers (GSH, GSSG, GSH/GSSG ratio, GPx, SOD, and catalase) were assessed. The result of this project revealed that chronic sleep deprivation impaired both short and long term memory (P<0.05), while tempol treatment prevented such effect. Furthermore, tempol normalized chronic sleep deprivation induced reduction in the hippocampus activity of catalase, GPx, and SOD (P<0.05). Tempol also enhanced the ratio of GSH/GSSG in chronically sleep deprived rats treated with tempol as compared with only sleep deprived rats (P<0.05). In conclusion chronic sleep deprivation induced memory impairment, and treatment with tempol prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus.
IGFBP-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis.Monday, November 30, 2015
Ding H, Kharboutli M, Saxena R, Wu T,
Clinical and experimental immunology. 30-Nov-2015
Lupus nephritis is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the golden standard for the diagnosis and management of LN. The objective of this study is to validate serum IGFBP-2 as a novel biomarker for clinical disease and renal pathology in LN. 85 biopsy-proven lupus nephritis patients, 18 CKD patients and 20 healthy controls were recruited for ELISA testing of serum IGFBP-2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP-2 levels were significantly elevated in LN patients. Serum IGFBP-2 was able to discriminate LN patients from the other two groups of patients (AUC: 0.65 [95% CI: 0.52 to 0.78; P = 0.043] for LN vs CKD; 0.97 [95% CI: 0.93 to 1.00; P < 0.0001] for LN vs healthy controls). Serum IGFBP-2 was a potential indicator of both global disease activity and renal disease activity in LN patients, with correlation to serum creatinine levels (r = 0.658, P < 0.001, n = 85), urine protein-to-creatinine levels (r = 0.397, P < 0.001, n = 85). More importantly, in 19 concurrent patients' samples, serum IGFBP-2 correlate with the chronicity index of renal pathology (r = 0.576, P = 0.01, n=19) but not renal pathological classification. In conclusion, serum IGFBP-2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology. This article is protected by copyright. All rights reserved.
Evaluation of the antiproliferative, proapoptotic, and antiangiogenic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of leiomyoma.Monday, November 30, 2015
García-Pascual CM, Ferrero H, Juarez I, Martínez J, Villanueva A, Pozuelo-Rubio M, Soengas M, Tormo D, Simón C, Gómez R, Pellicer A,
Fertility and sterility. 23-Nov-2015
We hypothesize that the antiangiogenic and apoptotic effects exerted by [pIC(PEI)] might lead to a decrease in lesion size in this animal model if the compound is administered for longer periods of time. This study provides promising data on [pIC(PEI)] as a potential novel therapeutic agent against human leiomyoma.
Angiotensin II type 2 receptor is expressed in human sperm cells and is involved in sperm motility.Monday, November 30, 2015
Gianzo M, Muñoa I, Urizar I, Larreategui Z, Quintana F, Garrido N, Subirán N, Irazusta J,
Fertility and sterility. 23-Nov-2015
Angiotensin II type 2 receptor is present in human semen and may be involved in the control of sperm motility. In-depth understanding of the proteins involved in sperm motility can help to elucidate the role of these proteins in male infertility as well as to establish new biomarkers for male infertility.
Genetic dosage and position effect of small supernumerary marker chromosome (sSMC) in human sperm nuclei in infertile male patient.Monday, November 30, 2015
Olszewska M, Wanowska E, Kishore A, Huleyuk N, Georgiadis AP, Yatsenko AN, Mikula M, Zastavna D, Wiland E, Kurpisz M,
Scientific reports. 2015
Chromosomes occupy specific distinct areas in the nucleus of the sperm cell that may be altered in males with disrupted spermatogenesis. Here, we present alterations in the positioning of the human chromosomes 15, 18, X and Y between spermatozoa with the small supernumerary marker chromosome (sSMC; sSMC(+)) and spermatozoa with normal chromosome complement (sSMC(-)), for the first time described in the same ejaculate of an infertile, phenotypically normal male patient. Using classical and confocal fluorescent microscopy, the nuclear colocalization of chromosomes 15 and sSMC was analyzed. The molecular cytogenetic characteristics of sSMC delineated the karyotype as 47,XY,+der(15)(pter->p11.2::q11.1->q11.2::p11.2->pter)mat. Analysis of meiotic segregation showed a 1:1 ratio of sSMC(+) to sSMC(-) spermatozoa, while evaluation of sperm aneuploidy status indicated an increased level of chromosome 13, 18, 21 and 22 disomy, up to 7 × (2.7 - 15.1). Sperm chromatin integrity assessment did not reveal any increase in deprotamination in the patient's sperm chromatin. Importantly, we found significant repositioning of chromosomes X and Y towards the nuclear periphery, where both chromosomes were localized in close proximity to the sSMC. This suggests the possible influence of sSMC/XY colocalization on meiotic chromosome division, resulting in abnormal chromosome segregation, and leading to male infertility in the patient.
Mass spectrometry (ms)-based translational proteomics for biomarker discovery and application in colorectal cancer.Monday, November 30, 2015
Ma H, Chen G, Guo M,
Proteomics. Clinical applications. 30-Nov-2015
Colorectal cancer (CRC) is a leading cause of cancer-related death in the world. Clinically, early detection of the disease is the most effective approach to tackle this tough challenge. Discovery and development of reliable and effective diagnostic tools for the assessment of prognosis and prediction of response to drug therapy are urgently needed for personalized therapies and better treatment outcomes. Among many ongoing efforts in search for potential CRC biomarkers, mass spectrometry based translational proteomics provides a unique opportunity for the discovery and application of protein biomarkers towards better CRC early detection and treatment. This review updates most recent studies that use preclinical models and clinical materials for the identification of colorectal cancer related protein markers. Some new advances in the development of CRC protein markers, such as colorectal cancer stem cell related protein markers, selected and/or multiple reaction monitoring mass spectrometry (SRM/MRM-MS) and mass spectrometry cytometry (MSC) approaches are also discussed in order to address future directions and challenges from bench translational research to bedside clinical application of CRC biomarkers. This article is protected by copyright. All rights reserved.
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