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Showing 100 Latest Publications
TitleDate Created
Prevalence and impact of long-term use of nicotine replacement therapy in UK Stop-Smoking Services: findings from the ELONS study.Saturday, September 24, 2016
Shahab L, Dobbie F, Hiscock R, McNeill A, Bauld L,
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 24-Sep-2016
Little is known about the long-term effects of Nicotine Replacement Therapy (NRT). Given an increasing shift towards harm reduction in tobacco control, reducing the harm from combustible products by complete or partial substitution with non-combustible products, more data on long-term use are needed. This study shows that in the context of stop smoking services, clients rarely use products for up to a year and that NRT use does not affect users' stress response. Ex-smokers using NRT long-term can completely replace nicotine from cigarettes with nicotine from NRT; long-term NRT use by continuing smokers does not increase nicotine intake. Long-term NRT appears to be a safe and effective way to reduce exposure to combustible nicotine.
Doxorubicin-loaded nanocarriers: A comparative study of liposome and nanostructured lipid carrier as alternatives for cancer therapy.Saturday, September 24, 2016
Fernandes RS, Silva JO, Monteiro LO, Leite EA, Cassali GD, Rubello D, Cardoso VN, Ferreira LA, Oliveira MC, de Barros AL,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 21-Sep-2016
Nowadays cancer is one of the most common causes of deaths worldwide. Conventional antitumor agents still present various problems related to specificity for tumor cells often leading to therapeutic failure. Nanoscale particles are considered potential alternative to direct access of drugs into tumor cells, therefore increasing the drug accumulation and performance. The aim of this study was to evaluate the antitumor activity of doxorubicin (DOX)-loaded nanostructured lipid carriers (NLC) versus liposomes against a breast cancer animal experimental model. NLC-DOX and liposomes-DOX were successfully prepared and characterized. Tumor-bearing mice were divided into five groups (blank-NLC, blank-liposome, DOX, NLC-DOX, liposome-DOX). Each animal received by the tail vein four doses of antitumoral drugs (total dose, 16mg/kg), every 3 days. Antitumor efficacy was assessed by measuring 1) tumor volume, calculating the inhibitory ratio (TV-IR, see after) and 2) acquiring scintigraphic images of the tumor using doxorubicin radiolabeled with technetium-99m as an imaging tumor probe. Liposome-DOX and free DOX did not showed differences in the tumor mean volume, whereas NLC-DOX proved to be the best treatments in controlling the tumor growth. NLC-DOX showed an inhibition ration (TV-IR) of 73.5% while free DOX and liposome-DOX decreased TV-RI of 48.8% and 68.0%, respectively. Tumor was clearly visualized in controls, DOX, and liposome-DOX groups. Yet, regarding the NLC-DOX group, tumor was barely identified by the image, indicating antitumor efficacy. Moreover, both NLC and liposomes proved to be able to delay the occurrence of lung metastasis. In conclusion, results of this study indicated that NLC-DOX might be an alternative strategy to achieve an efficient antitumor activity.
Bronchiolitis: More Evidence, Fewer Interventions. Shifting paradigms with evidence based diagnostics.Saturday, September 24, 2016
Eltorki M, Rosenfield D,
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 24-Sep-2016
Young, non-verbal children presenting to the emergency department (ED) with non-specific complaints pose a significant diagnostic challenge to the emergency physician (EP). Given the paucity of pediatric research and clinical decision rules (CDR)(1) for many common conditions that present to the ED, this can lead to over-investigation, which can have negative consequences for the patient and families.(2) Traditionally, rigorous evidence requires derivation of a rule, testing and validating the rule in small contexts, and externally validating the CDR in multiple settings.(3) This article is protected by copyright. All rights reserved.
Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis.Saturday, September 24, 2016
Aoki H, Aoki M, Katsuta E, Ramanathan R, Idowu MO, Spiegel S, Takabe K,
The Journal of surgical research. Oct-2016
Our results raise an intriguing possibility that S1P generated by SphK1 in the host promotes pancreatic cancer PC progression by stimulation of proliferation of cancer cells.
Global microRNA profiling for diagnostic appraisal of melanocytic Spitz tumors.Saturday, September 24, 2016
Latchana N, Regan K, Howard JH, Aldrink JH, Ranalli MA, Peters SB, Zhang X, Gru A, Payne PR, Suarez-Kelly LP, Carson WE,
The Journal of surgical research. Oct-2016
Overall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.
Is the unbound concentration of Atazanavir of interest in Therapeutic Drug Monitoring?Saturday, September 24, 2016
Metsu D, Seraissol P, Delobel P, Cinq-Frais C, Cuzin L, Izopet J, Chatelut E, Gandia P,
Fundamental & clinical pharmacology. 24-Sep-2016
To date, therapeutic drug monitoring (TDM) is carried out with anti-retrovirals and is usually based on total concentrations (Ct). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (Cu) is the pharmacological active form, the aim of the study was to evaluate the value of Cu and the unbound fraction (fu, fu = Cu / Ct) for the TDM of ATV. The variability of Cu and the corresponding fu of ATV were explored in 43 patients treated with ATV for an average of 13.5 months. Cu was determined by coupling ultrafiltration and liquid-chromatography. As ATV is highly bound to alpha-1-acid glycoprotein (AAG), the correlation between fu and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough Cu and Ct were 37.9μg/L (InterQuartileRange (IQR) 20.6-94.9μg/L) and 628.6μg/L (IQR 362.7-1078.1μg/L), respectively. fu, Cu and Ct showed high variability, but the fu variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (p=0.21 and p=0.65 for Cu and fu, respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (rho), rho=0.22; p=0.17 for Cu). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than Ct. This article is protected by copyright. All rights reserved.
Economic viability of Stratified Medicine concepts: An investor perspective on drivers and conditions that favour using Stratified Medicine approaches in a cost-contained healthcare environment.Saturday, September 24, 2016
Fugel HJ, Nuijten M, Postma M,
New biotechnology. 21-Sep-2016
The article outlines the effects of development time and time to peak sales as key economic value drivers influencing profitability of SM interventions under specific conditions. If regulatory and reimbursement challenges can be solved, decreasing development time and enhancing early market penetration would most directly improve the economic attractiveness of SM interventions. Appropriate tailoring of highly differentiated patient subgroups is the prerequisite to leverage potential efficiency gains in the R&D process. Also, offering a better targeted and hence ultimately more cost-effective therapy at reimbursable prices will facilitate time to market access and allow increasing market share gains within the targeted populations.
Utilization of physiological and taxonomic fluorescent probes to study Lactobacilli cells and response to pH challenge.Saturday, September 24, 2016
Olszewska MA, Kocot AM, Nynca A, Łaniewska-Trokenheim Ł,
Microbiological research. Nov-2016
pH stress is recognized as an important feature for Lactobacillus in relation to lifestyle and commercial utility. Hence, this study aims to investigate the cell function of Lactobacilli cells subjected to pHs between 7.0 and 2.0. For this purpose, the Lactobacilli isolates of vegetable origin were first hybridized with fluorescent oligonucleotide rRNA probes for detecting Lactobacillus species. Then, cells were exposed to pH stress and labelled with fluorescent probes, carboxyfluorescein diacetate (CFDA) and propidium iodine (PI), which provided the insight into esterase activity and membrane integrity of cells. Among isolates, fluorescence in situ hybridization (FISH) enabled us to specifically detect L. plantarum and L. brevis. Interestingly, FCM analysis revealed that at pHs between 7.0 and 4.0 the cell membrane was intact, while after the exposure at pH 3.0, and 2.0 became perturbed or impaired. Finally, L. brevis and L. plantarum differed from each other in fluorescence labeling behaviour and culturability. However, the results showed that the same standard protocol for labeling enables discrimination of subpopulations of tested species. Depending on the species, the substantial culturability loss was observed at pH 3.0 and 2.0. These results suggest that the taxonomic and physiological fluorescent probes could be suitable for in situ detection of specific bacteria and rapid assessment of the physiological status of cells.
Impairment of Decision Making and Disruption of Synchrony between Basolateral Amygdala and Anterior Cingulate Cortex in the Maternally Separated Rat.Saturday, September 24, 2016
Cao B, Wang J, Zhang X, Yang X, Chun-Hei Poon D, Jelfs B, Chan RH, Che-Yuen Wu J, Li Y,
Neurobiology of learning and memory. 21-Sep-2016
There is considerable evidence to suggest early life experiences, such as maternal separation (MS), play a role in the prevalence of emotional dysregulation and cognitive impairment. At the same time, optimal decision making requires functional integrity between the amygdala and anterior cingulate cortex (ACC), and any dysfunction of this system is believed to induce decision-making deficits. However, the impact of MS on decision-making behavior and the underlying neurophysiological mechanisms have not been thoroughly studied. As such, we consider the impact of MS on the emotional and cognitive functions of rats by employing the open-field test, elevated plus-maze test, and rat gambling task (RGT). Using multi-channel recordings from freely behaving rats, we assessed the effects of MS on the large scale synchrony between the basolateral amygdala (BLA) and the ACC; while also characterizing the relationship between neural spiking activity and the ongoing oscillations in theta frequency band across the BLA and ACC. The results indicated that the MS rats demonstrated anxiety-like behavior. While the RGT showed a decrease in the percentage of good decision-makers, and an increase in the percentage of poor decision-makers. Electrophysiological data revealed an increase in the total power in the theta band of the LFP in the BLA and a decrease in theta power in the ACC in MS rats. MS was also found to disrupt the spike-field coherence of the ACC single unit spiking activity to the ongoing theta oscillations in the BLA and interrupt the synchrony in the BLA-ACC pathway. We provide specific evidence that MS leads to decision-making deficits that are accompanied by alteration of the theta band LFP in the BLA-ACC circuitries and disruption of the neural network integrity. These observations may help revise fundamental notions regarding neurophysiological biomarkers to treat cognitive impairment induced by early life stress.
Dosage Effects of Extracorporeal Shockwave Therapy in Early Hip Necrosis.Saturday, September 24, 2016
Wang CJ, Huang CC, Yip HK, Yang YJ,
International journal of surgery (London, England). 21-Sep-2016
High dosage ESWT is more effective in early stage ONFH. The systemic beneficial effects of ESWT may ultimately enhance angiogenesis with improvement of microcirculation of the peri-necrotic areas, that in turn, can improve subchondral bone remodeling and prevent femoral head collapse.
Targeted Next Generation Sequencing of CIC-DUX4 Soft Tissue Sarcomas Demonstrates Low Mutational Burden and Recurrent Chromosome 1p Loss.Saturday, September 24, 2016
de la Vega LL, Hovelson DH, Cani AK, Liu CJ, McHugh JB, Lucas DR, Thomas DG, Patel RM, Tomlins SA,
Human pathology. 21-Sep-2016
Gene fusions between CIC and DUX4 define a rare class of soft tissue sarcomas poorly understood at the molecular level. Previous karyotyping and fluorescence in situ hybridization studies support trisomy chromosome 8 as a recurrent alteration, however other driving alterations are largely unknown. Thus, we analyzed eleven formalin fixed paraffin embedded CIC-DUX4 sarcoma tissue samples (including three sample pairs) using targeted Ion Torrent based multiplexed polymerase chain reaction (PCR) next generation sequencing to characterize potential somatic driver alterations in 409 genes. Although we did not identify recurrent somatic mutations (point mutations or indels), copy number analysis showed recurrent, broad, copy number alterations, including gain of chromosome 8 and loss of 1p. In one sample pair (untreated primary and local recurrence resections), we identified similar copy number profiles and a somatic ARID1A R963X nonsense mutation exclusively in the local recurrence sample. In another sample pair (pre- and post-radiation treatment specimens), we observed single copy loss of chromosome 7q exclusively in the post-treatment recurrence sample, supporting it as an acquired event after radiation treatment. In the last sample pair (near concurrent, post-chemotherapy primary and distant metastasis), molecular profiles were highly concordant, consistent with limited inter-tumoral heterogeneity. In summary, next generation sequencing identified limited somatic driver mutations in CIC-DUX4 sarcomas. However, we identified novel, recurrent copy number alterations, including chromosome 1p, which is also the locus of ARID1A. Additional functional work and assessment of larger cohorts is needed to determine the biological and clinical significance of the alterations identified herein.
Responses to crizotinib can occur in high level MET-amplified non-small cell lung cancer independent of MET exon 14 alterations: A brief report.Saturday, September 24, 2016
Caparica R, Yen CT, Coudry R, Ignatius Ou SH, Varella-Garcia M, Camidge DR, de Castro G,
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 21-Sep-2016
MET activation highly sensitive to MET inhibition has recently been described in non-small cell lung cancer (NSCLC) through two mechanisms: high-level amplification of the MET gene (usually expressed relative to the centromere on chromosome 7 when using fluorescence in-situ hybridization) and exon 14 alterations. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other, or if both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor sensitive NSCLC harboring exon 14 alterations without co-incident amplification have already been described. Here we report two cases of MET inhibitor-sensitive NSCLC harboring high level MET amplification (MET:CEP7 ≥5) without co-incident exon 14 alterations, suggesting that these two methods of MET activation can produce independent MET-addicted states in NSCLC. Molecular profiling designed to capture all potentially MET-addicted NSCLC cases should address both activation mechanisms.
Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities.Saturday, September 24, 2016
Rekvig OP, Thiyagarajan D, Pedersen HL, Horvei KD, Seredkina N,
The American journal of pathology. 21-Sep-2016
Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti-double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed.
Going from darkness to gray zones of knowledge: The role of biomarkers on Major Adverse Cardiovascular Events after Carotid Interventions.Saturday, September 24, 2016
Patelis N, Moris D, Schizas D, Georgopoulos S, Liakakos T,
Annals of vascular surgery. 21-Sep-2016
PhIP/DSS-induced Colon Carcinogenesis in CYP1A-humanized Mice and the Possible Role of Lgr5+ Stem Cells.Saturday, September 24, 2016
Chen JX, Wang H, Liu A, Zhang L, Reuhl K, Yang CS,
Toxicological sciences : an official journal of the Society of Toxicology. 23-Sep-2016
In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, recently developed a colon carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. The resulting colon tumors shared many histologic and molecular features of human colon cancer. In the present study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (i.e., days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5+ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-EGFP-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this dietary carcinogen-induced, inflammation-promoted colon carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced colon carcinogenesis is likely initiated by dominant active Ctnnb1/β-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma.
Quantum dots-labeled strip biosensor for rapid and sensitive detection of microRNA based on target-recycled nonenzymatic amplification strategy.Saturday, September 24, 2016
Deng H, Liu Q, Wang X, Huang R, Liu H, Lin Q, Zhou X, Xing D,
Biosensors & bioelectronics. 12-Sep-2016
MicroRNAs (miRNAs) have been proved to be potential biomarkers in early cancer diagnosis. It is of great significance for rapid and sensitive detection of miRNAs, particularly with point-of-care (POC) diagnosis. Herein, it is the first time to construct quantum dots (QDs)-labeled strip biosensor based on target-recycled nonenzymatic amplification strategy for miRNA detection. In the system, QDs were served as bright, photostable signal labels, which endow this biosensor with good detection efficiency. Moreover, a target-recycled amplification strategy relies on sequence-specific hairpins strand displacement process without the assistance of enzymes, was introduced to further improve the sensitivity. Meanwhile eliminating the requirement of environment-susceptible enzyme protein makes it easy to preserve and enhances the stability and reproducibility of this sensor. Benefiting from these outstanding characteristics, this platform exhibited a good detection sensitivity range from 2fmol to 200fmol with a limit of 200amol, using only 20μL of sample within 80min. The assay was also 10-fold more sensitive than that with a conventional colloidal gold-based test strip for miRNA detection. Additionally, the analysis of miRNA in various tumor cell extracts was in accordance with the performance of quantitative realtime polymerase chain reaction (qRT-PCR). Clinical tumor samples were also tested, and 16 of 20 samples gave out positive signals, which demonstrated the practical application capacity of the biosensor. Therefore, the proposed biosensor holds great promise for potential POC applications and early cancer diagnosis.
Rapid biosensing tools for cancer biomarkers.Saturday, September 24, 2016
Ranjan R, Esimbekova EN, Kratasyuk VA,
Biosensors & bioelectronics. 18-Sep-2016
The present review critically discusses the latest developments in the field of smart diagnostic systems for cancer biomarkers. A wide coverage of recent biosensing approaches involving aptamers, enzymes, DNA probes, fluorescent probes, interacting proteins and antibodies in vicinity to transducers such as electrochemical, optical and piezoelectric is presented. Recent advanced developments in biosensing approaches for cancer biomarker owes much credit to functionalized nanomaterials due to their unique opto-electronic properties and enhanced surface to volume ratio. Biosensing methods for a plenty of cancer biomarkers has been summarized emphasizing the key principles involved.
Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy.Saturday, September 24, 2016
Calvo E, Schmidinger M, Heng DY, Grünwald V, Escudier B,
Cancer treatment reviews. 10-Sep-2016
Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.
Improving outcomes for older women with gynaecological malignancies.Saturday, September 24, 2016
Dumas L, Ring A, Butler J, Kalsi T, Harari D, Banerjee S,
Cancer treatment reviews. 29-Aug-2016
The incidence of most gynaecological malignancies rises significantly with increasing age. With an ageing population, the proportion of women over the age of 65 with cancer is expected to rise substantially over the next decade. Unfortunately, survival outcomes are much poorer in older patients and evidence suggests that older women with gynaecological cancers are less likely to receive current standard of care treatment options. Despite this, older women are under-represented in practice changing clinical studies. The evidence for efficacy and tolerability is therefore extrapolated from a younger; often more fit population and applied to in every day clinical practice to older patients with co-morbidities. There has been significant progress in the development of geriatric assessment in oncology to predict treatment outcomes and tolerability however there is still no clear evidence that undertaking a geriatric assessment improves patient outcomes. Clinical trials focusing on treating older patients are urgently required. In this review, we discuss the evidence for treatment of gynaecological cancers as well as methods of assessing older patients for therapy. Potential biomarkers of ageing are also summarised.
Systemic treatment and management approaches for medullary thyroid cancer.Saturday, September 24, 2016
Ernani V, Kumar M, Chen AY, Owonikoko TK,
Cancer treatment reviews. 10-Sep-2016
Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.
Erroneous HbA1c results in a patient with elevated HbC and HbF.Saturday, September 24, 2016
Adekanmbi J, Higgins T, Rodriguez-Capote K, Thomas D, Winterstein J, Dixon T, Gifford JL, Krause R, Venner AA, Clarke G, Estey MP,
Clinica chimica acta; international journal of clinical chemistry. 21-Sep-2016
Reliable HbA1c results may be unobtainable in the presence of some hemoglobinopathies. HPLC and capillary electrophoresis alerted the laboratory to the presence of an unusual hemoglobinopathy. Immunoassays generated falsely low results without warning, which could lead to missed diagnoses and under treatment of patients with DM.
Molecular typing of isolates obtained from aborted foetuses in Brucella-free Holstein dairy cattle herd after immunisation with Brucella abortus RB51 vaccine in Egypt.Saturday, September 24, 2016
Wareth G, Melzer F, Böttcher D, El-Diasty M, El-Beskawy M, Rasheed N, Schmoock G, Roesler U, Sprague LD, Neubauer H,
Acta tropica. 21-Sep-2016
Bovine brucellosis is endemic in Egypt in spite of application of surveillance and control measures. An increase of abortions was reported in a Holstein dairy cattle herd with 600 animals in Damietta governorate in Egypt after immunisation with Brucella (B.) abortus RB51 vaccine. Twenty one (10.6%) of 197 vaccinated cows aborted after 3 months. All aborted cows had been tested seronegative for brucellosis in the past 3 years. B. abortus was isolated from four foetuses. Conventional biochemical and bacteriological identification and polymerase chain reaction (PCR) confirmed two B. abortus biovars (bv.) 1 smooth and two B. abortus rough strains. None of the B. abortus isolates were identified as RB51. Genotyping analysis by multiple locus of variable number tandem repeats analysis based on 16 markers (MLVA-16) revealed two different profiles with low genetic diversity. B. abortus bv1 was introduced in the herd and caused abortions.
Exosomal proteins as prostate cancer biomarkers in urine: From mass spectrometry discovery to immunoassay-based validation.Saturday, September 24, 2016
Wang L, Skotland T, Berge V, Sandvig K, Llorente A,
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 21-Sep-2016
Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumor-specific molecules can be found in exosomes isolated from biological fluids. We have previously analyzed the proteome of urinary exosomes by mass spectrometry, and identified proteins differentially expressed in prostate cancer patients compared to healthy males. Since mass spectrometry is so far not commonly used in clinical laboratories, we have here investigated whether antibody-based methods such as Western blot or ELISA can be used to validate the use of the identified proteins as prostate cancer biomarkers. Western blot experiments designed to detect flotillin 2, TMEM256, Rab3B and LAMTOR1 showed that the level of these proteins was higher in urinary exosomes from prostate cancer patients compared to healthy males. Furthermore, a receiver operating characteristic curve of flotillin 2 in samples from 16 controls and 16 patients showed an area under the curve of 0.91, and 88% sensitivity at a threshold set to give 94% specificity. In addition, ELISA-based detection of flotillin 2 and PARK7 showed that the combination of these proteins was able to distinguish prostate cancer patients and healthy controls with 68% sensitivity and 93% specificity. Several promising biomarkers identified by mass spectrometry could not be evaluated by Western blot or ELISA due their low exosomal amount and/or lack of good antibodies. In conclusion, our results show that several urinary exosomal proteins identified as prostate cancer biomarkers by mass spectrometry have a high diagnostic value also when analyzed by immunology-based methods, thus bringing these biomarkers closer to a potential clinical use.
Accuracy of faecal Calprotectin and neutrophil gelatinase B-associated lipocalin in Evaluating sub-clinical inflammation in UlceRaTIVE Colitis - ACERTIVE study.Saturday, September 24, 2016
Magro F, Lopes S, Coelho R, Cotter J, de Castro FD, de Sousa HT, Salgado M, Andrade P, Vieira AI, Figueiredo P, Caldeira P, Sousa A, Duarte MA, Ávila F, Silva J, Moleiro J, Mendes S, Giestas S, Ministro P, Sousa P, Gonçalves R, Gonçalves B, Oliveira A, Chagas C, Torres J, Dias CC, Lopes J, Borralho P, Afonso J, Geboes K, Carneiro F,
Journal of Crohn's & colitis. 23-Sep-2016
Faecal calprotectin and neutrophil gelatinase B-associated lipocalin levels are a valuable addition to assess disease activity in asymptomatic ulcerative colitis patients. Biological levels of the analysed biomarkers below the proposed thresholds can rule out the presence of macroscopic and microscopic lesions with a probability of 75% to 93%. However, caution should be applied whenever interpreting positive results, as these biomarkers present consistently low positive predictive values.
Extracellular vesicles are present in mouse lymph and their level differs in atherosclerosis.Saturday, September 24, 2016
Milasan A, Tessandier N, Tan S, Brisson A, Boilard E, Martel C,
Journal of extracellular vesicles. 2016
The lymphatic system works in close collaboration with the cardiovascular system to preserve fluid balance throughout the body and is essential for the trafficking of antigen-presenting cells and lymphocytes to lymphoid organs. Recent findings have associated lymphatic dysfunction with the pathogenesis of cardiovascular-related diseases such as atherosclerosis, inflammation and obesity. Whether lymphatic dysfunction is a cause or a consequence of these diseases, as well as how, is under intensive investigation. Extracellular vesicles (EVs) are submicron vesicles released by diverse cell types upon activation or apoptosis and are considered important biomarkers for several inflammatory diseases. Thus, it is critical to characterize the presence of EVs in various biological tissues and fluids to delineate their origins and, subsequently, their functions. In the past few years, new techniques allowing the quantitative and qualitative analysis of EVs have emerged, thus facilitating the onset of studies bridging these vesicles to the lymphatic system. Using several state-of-the-art approaches, this article reports the presence of diverse EVs inclusively derived from red blood cells and platelets in lymph of healthy animals. Our results suggest that lymph from atherosclerotic mice displays a higher concentration of EVs, bringing forward the concept that EVs contained in lymph could either be a biomarker for lymphatic dysfunction or, conversely, for inflammatory disease progression.
The Role of Long Non-Coding RNAs in Ovarian Cancer.Saturday, September 24, 2016
Nikpayam E, Tasharrofi B, Sarrafzadeh S, Ghafouri-Fard S,
Iranian biomedical journal. 24-Sep-2016
Expression profiling as well as methylation analysis of lncRNAs in ovarian cancer may lead to the identification of novel biomarkers that can help in the classification of patients based on prognosis and treatment response.
Trends in Laboratory Rotavirus Detection: 2003 to 2014.Saturday, September 24, 2016
Kaufman HW, Chen Z,
Pediatrics. 23-Sep-2016
Our findings show a marked reduction in rotavirus detection throughout the nation after vaccine licensure, consistent with herd immunity. Postvaccine effectiveness may wane with aging. Seasons appear to be longer in the postvaccine period.
Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis.Saturday, September 24, 2016
Khalfallah O, Jarjat M, Davidovic L, Nottet N, Cestèle S, Mantegazza M, Bardoni B,
Stem cells (Dayton, Ohio). 24-Sep-2016
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, βIII-tubulin, p27(kip1) , NeuN and NeuroD1 were up-regulated, leading to an accelerated neuronal differentiation, that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout (KO) mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. This article is protected by copyright. All rights reserved.
Three-base periodicity of sites of sequence variation in Pseudomonas aeruginosa and Staphylococcus aureus core genomes.Saturday, September 24, 2016
Morán Losada P, Fischer S, Chouvarine P, Tümmler B,
FEBS letters. 24-Sep-2016
The three-base periodicity property is characteristic of protein-coding sequences. Here we report on three-base periodicity of sequence variation in the core genome of bacteria. Single nucleotide polymorphism (SNP) syntenies were extracted from pairwise genome alignments of 41 Staphylococcus aureus or 20 Pseudomonas aeruginosa strains. The length of fragment pairs with identical nucleotides at all SNP positions showed a length-dependent overrepresentation of multiples of three nucleotides at corresponding codon positions of the AT-rich S. aureus and the GC-rich P. aeruginosa. Three-base SNP periodicity seems to be a characteristic feature of the tightly arranged bacterial core genome. This article is protected by copyright. All rights reserved.
Shigellosis murine model established by intraperitoneal and intranasal route of administration: A comparative comprehension overview.Saturday, September 24, 2016
Sharma D, Yagnik B, Baksi R, Desai N, Padh H, Desai P,
Microbes and infection / Institut Pasteur. 20-Sep-2016
Shigellosis, a major cause of mortality and morbidity, requires development of effective intervention strategy for which animal model mimicking human pathology is essential. Among various animal models for shigellosis, mice being more convenient have been used wherein intraperitoneal and intranasal routes are preferred. With the aim to comprehend the comparative pathophysiological indicators, we have examined relatively high and low dose of S. flexneri administered through intraperitoneal and intranasal routes in mice. Characterization of these two models along with the resulting pathophysiology of shigellosis adds to our understanding and offers suitable models appropriate to the objectives of the study.
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism.Saturday, September 24, 2016
Lützen U, Zhao Y, Lucht K, Zuhayra M, Marx M, Cascorbi I, Culman J,
Naunyn-Schmiedeberg's archives of pharmacology. 23-Sep-2016
The peroxisome proliferator-activated receptor γ (PPARγ) agonists, thiazolidinediones, including pioglitazone (PIO) exhibit anti-tumour activities in cancer cells. The present study investigates the effects of PIO on cell proliferation and apoptosis in SK-UT-1 cells, a human uterine leiomyosarcoma cell line, and human uterine smooth muscle cells (HUtSMC). The proliferation and viability of SK-UT-1 cells treated with vehicle or PIO were assessed by cell counting and WST-1 assay. The activity of MEK/ERK and p38 MAPK signalling pathways and the expression of p53, the cyclin-dependent kinase inhibitor, p21, Bax, Bad and Bim proteins and cleaved caspase-3 were analysed by Western blotting. Quiescent SK-UT-1 cells intensively proliferate and display high levels of phosphorylated, activated MEK1/2, ERK1/2 and p38 MAPK. PIO (10 or 25 μM) induced time- and dose-dependently cell-growth arrest, reduced the cell numbers and effectively suppressed the over-activated MEK/ERK and p38 MAPK signalling pathways as evidenced by the abolished levels of phosphorylated MEK1/2, ERK1/2 and p38 MAPK. PIO activated the intrinsic apoptotic pathway, i.e. up-regulated the p53, p21, Bax and Bad proteins and cleaved caspase-3. PIO also reduced cell numbers of highly proliferative SK-UT-1 cells cultured in growth medium. The anti-proliferative and pro-apoptotic actions of PIO were not PPARγ dependent and exclusive for SK-UT-1 cells as PIO did not interfere with the proliferation of HUtSMC. The pronounced anti-tumorigenic effects of PIO in SK-UT-1 cells address an important issue about the relevance of the PPARγ agonist in the treatment of the human uterine leiomyosarcoma.
Mutant IDH1 and thrombosis in gliomas.Saturday, September 24, 2016
Unruh D, Schwarze SR, Khoury L, Thomas C, Wu M, Chen L, Chen R, Liu Y, Schwartz MA, Amidei C, Kumthekar P, Benjamin CG, Song K, Dawson C, Rispoli JM, Fatterpekar G, Golfinos JG, Kondziolka D, Karajannis M, Pacione D, Zagzag D, McIntyre T, Snuderl M, Horbinski C,
Acta neuropathologica. 23-Sep-2016
Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.
Attachment, Development, and Mental Health in Abused and Neglected Preschool Children in Foster Care: A Meta-Analysis.Saturday, September 24, 2016
Vasileva M, Petermann F,
Trauma, violence & abuse. 22-Sep-2016
A proper preparation for foster parents to care for abused and neglected children includes effective training and initial diagnostics in order to plan individual treatment. Hence, a basic knowledge about the main psychosocial and developmental problems associated with abuse and neglect and their prevalence in foster children is needed. For this purpose, a systematical literature review and a series of meta-analyses were conducted. A total of 25 studies reporting data on development (n = 4,033), mental health (n = 726), and attachment (n = 255) of foster children in preschool age met the inclusion criteria. The meta-analyses indicated prevalence rates of approximately 40% for developmental, mental health problems, and insecure attachment. Rates of disorganized attachment were estimated to 22%. These findings outline the necessity of an initial trauma-oriented diagnostics and trainings for foster parents that address foster children's development, mental health, and disorganized attachment.
The Inherited p53 Mutation in the Brazilian Population.Saturday, September 24, 2016
Achatz MI, Zambetti GP,
Cold Spring Harbor perspectives in medicine. 23-Sep-2016
A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ∼15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ∼100 million. Moreover, it has been determined that carriers of this founder mutation display variable tumor susceptibility, ranging from isolated cases of pediatric ACC to Li-Fraumeni or Li-Fraumeni-like (LFL) syndromes, thus representing a significant medical issue for this country. Studying the biochemical and molecular consequences of this mutation on p53 tumor-suppressor activity, as well as the putative additional genetic alterations that cooperate with this mutation, is advancing our understanding of how p53 functions in tumor suppression in general. These studies, which originated with a rare childhood tumor, are providing important information for guiding genetic counselors and physicians in treating their patients and are already providing clinical benefit.
Novel regional age-associated DNA methylation changes within human common disease-associated loci.Saturday, September 24, 2016
Bell CG, Xia Y, Yuan W, Gao F, Ward K, Roos L, Mangino M, Hysi PG, Bell J, Wang J, Spector TD,
Genome biology. 23-9-2016
By analysing the functionally enriched disease and trait-associated regions of the human genome, we identify novel epigenetic ageing changes, which could be useful biomarkers or provide mechanistic insights into age-related common diseases.
Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections.Saturday, September 24, 2016
Williams KA, Swedo SE, Farmer CA, Grantz H, Grant PJ, D'Souza P, Hommer R, Katsovich L, King RA, Leckman JF,
Journal of the American Academy of Child and Adolescent Psychiatry. Oct-2016
IVIG was safe and well tolerated. Between-group differences were smaller than anticipated, and the double-blind comparison failed to demonstrate superiority of IVIG over placebo. The observed open-label improvements indicate that future trials would benefit from larger sample sizes designed in part to aid in the identification of biomarkers predictive of a positive response to immunotherapy. Future investigations focused on the natural history of PANDAS are also warranted. Clinical trial registration information-Intravenous Immunoglobulin for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections);; NCT01281969ZIAMH002666.
Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance.Saturday, September 24, 2016
Jeong Y, Hoang NT, Lovejoy A, Stehr H, Newman AM, Gentles AJ, Kong W, Truong D, Martin S, Chaudhuri A, Heiser D, Zhou L, Say C, Carter JN, Hiniker SM, Loo BW, West RB, Beachy P, Alizadeh AA, Diehn M,
Cancer discovery. 23-Sep-2016
Lung squamous cell carcinomas (LSCC) pathogenesis remains incompletely understood and biomarkers predicting treatment response remain lacking. Here we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histological and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in non-small lung cancer (NSCLC) patients and could be non-invasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.
What are the structural features that drive partitioning of proteins in aqueous two-phase systems?Saturday, September 24, 2016
Wu Z, Hu G, Wang K, Zaslavsky BY, Kurgan L, Uversky VN,
Biochimica et biophysica acta. 21-Sep-2016
Protein partitioning in aqueous two-phase systems (ATPSs) represents a convenient, inexpensive, and easy to scale-up protein separation technique. Since partition behavior of a protein dramatically depends on an ATPS composition, it would be highly beneficial to have reliable means for (even qualitative) prediction of partitioning of a target protein under different conditions. Our aim was to understand which structural features of proteins contribute to partitioning of a query protein in a given ATPS. We undertook a systematic empirical analysis of relations between 57 numerical structural descriptors derived from the corresponding amino acid sequences and crystal structures of 10 well-characterized proteins and the partition behavior of these proteins in 29 different ATPSs. This analysis revealed that just a few structural characteristics of proteins can accurately determine behavior of these proteins in a given ATPS. However, partition behavior of proteins in different ATPSs relies on different structural features. In other words, we could not find a unique set of protein structural features derived from their crystal structures that could be used for the description of the protein partition behavior of all proteins in all ATPSs analyzed in this study. We likely need to gain better insight into relationships between protein-solvent interactions and protein structure peculiarities, in particular given limitations of the used here crystal structures, to be able to construct a model that accurately predicts protein partition behavior across all ATPSs.
Proteomic study of hepatocellular carcinoma using a novel modified aptamer-based array (SOMAscan™) platform.Saturday, September 24, 2016
Qiao Z, Pan X, Parlayan C, Ojima H, Kondo T,
Biochimica et biophysica acta. 20-Sep-2016
Vascular invasion is a pathological hallmark of hepatocellular carcinoma (HCC), associated with poor prognosis; it is strongly related to the early recurrence and poor survival after curative resection. In order to determine the proteomic backgrounds of HCC carcinogenesis and vascular invasion, we employed a novel modified aptamer-based array (SOMAscan) platform. SOMAscan is based on the Slow Off-rate Modified Aptamers (SOMAmers), which rely on the natural 3D folding of single-stranded DNA-based protein affinity reagents. Currently, the expression level of 1129 proteins can be assessed quantitatively. Correlation matrix analysis showed that the overall proteomic features captured by SOMAscan differ between tumor and non-tumor tissues. Non-tumor tissues were shown to have more homogeneous proteome backgrounds than tumor tissues. A comparative study identified 68 proteins with differential expression between tumor and non-tumor tissues, together with eight proteins associated with vascular invasion. Gene Ontology analysis showed that the extracellular space and extracellular region proteins were predominantly detected. Network analysis revealed the linkage of seven proteins, AKT1, MDM2, PTEN, FGF1, MAPK8, PRKCB, and FN1, which were categorized as the components of "Pathways in cancer" in pathway analysis. The results of SOMAscan analysis were not concordant with those obtained by western blotting; only the determined FN1 levels were concordant between the two platforms. We demonstrated that the proteome captured by SOMAscan includes the proteins relevant to carcinogenesis and vascular invasion in HCC. The identified proteins may serve as candidates for the future studies of disease mechanisms and clinical applications.
Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer.Saturday, September 24, 2016
Kitahara M, Hazama S, Tsunedomi R, Takenouchi H, Kanekiyo S, Inoue Y, Nakajima M, Tomochika S, Tokuhisa Y, Iida M, Sakamoto K, Suzuki N, Takeda S, Ueno T, Yamamoto S, Yoshino S, Nagano H,
Cancer science. 24-Sep-2016
We previously reported a phase II study of a cancer vaccine using five novel peptides recognized by HLA-A*2402-restricted CTLs in combination with oxaliplatin-containing chemotherapy (FXV study) as first-line therapy for patients with metastatic colorectal cancer (mCRC) and demonstrated the safety and promising potential of our five-peptide cocktail. The objective of this analysis was to identify predictive biomarkers for identifying patients who are likely to receive a clinical benefit from immunochemotherapy. Circulating cell-free DNA (cfDNA) in plasma has been reported to be a candidate molecular biomarker for the efficacy of anticancer therapy. Unlike uniformly truncated small-sized DNA released from apoptotic normal cells, DNA released from necrotic cancer cells varies in size. The integrity of plasma cfDNA, i.e., the ratio of longer fragments (400 bp) to shorter fragments (100 bp) of cfDNA, may be clinically useful for detecting colorectal cancer progression. We assessed plasma samples collected from 93 patients prior to receiving immunochemotherapy. The cfDNA levels and integrity were analyzed by semi-quantitative real-time polymerase chain reaction. Progression-free survival was significantly better in patients with a low plasma cfDNA integrity value than in those with a high value (p = 0.0027). Surprisingly, in the HLA-A*2402-matched group, patients with a low plasma cfDNA integrity value had significantly better progression-free survival than those with a high value (p = 0.0015). This difference was not observed in the HLA-A*2402-unmatched group. In conclusion, the integrity of plasma cfDNA may provide important clinical information and may be a useful predictive biomarker of the outcome of immunotherapy in mCRC. This article is protected by copyright. All rights reserved.
RIFM fragrance ingredient safety assessment, 3,7-dimethyl-1,6-nonadien-3-ol, CAS Registry Number 10339-55-6.Saturday, September 24, 2016
Api AM, Belsito D, Bhatia S, Bruze M, Calow P, Dagli ML, Dekant W, Fryer AD, Kromidas L, La Cava S, Lalko JF, Lapczynski A, Liebler DC, Miyachi Y, Politano VT, Ritacco G, Salvito D, Schultz TW, Shen J, Sipes IG, Wall B, Wilcox DK,
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 20-Sep-2016
The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analog linalool (CAS # 78-70-6) show that this material is not genotoxic nor does it have skin sensitization potential and also provided a MOE > 100 for the local respiratory endpoint. The repeated dose, developmental and reproductive toxicity endpoints were completed using nerolidol (isomer unspecified, CAS # 7212-44-4) as a suitable read across analog, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.
The chromatin binding protein Smyd1 restricts adult mammalian heart growth.Saturday, September 24, 2016
Franklin S, Kimball T, Rasmussen TL, Rosa Garrido M, Chen H, Tran T, Miller MR, Gray R, Jiang S, Ren S, Wang Y, Tucker HO, Vondriska TM,
American journal of physiology. Heart and circulatory physiology. 23-Sep-2016
All terminally differentiated organs face two challenges: maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical importance to organismal development and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in humans and animals models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood-insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified up-regulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathologic cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1.
Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan.Saturday, September 24, 2016
Yu JS, Chen YT, Chiang WF, Hsiao YC, Chu LJ, See LC, Wu CS, Tu HT, Chen HW, Chen CC, Liao WC, Chang YT, Wu CC, Lin CY, Liu SY, Chiou ST, Chia SL, Chang KP, Chien CY, Chang SW, Chang CJ, Young JD, Pao CC, Chang YS, Hartwell LH,
Proceedings of the National Academy of Sciences of the United States of America. 23-Sep-2016
Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan's Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.
Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature.Saturday, September 24, 2016
Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, Gunther C, Ritchie D, Gale DP, Kanwar YS, Challis R, Buist H, Overell J, Weller B, Flossmann O, Blunden M, Meyer EP, Krucker T, Evans SJ, Campbell IL, Jackson AP, Chandran S, Hunt DP,
Blood. 23-Sep-2016
Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular TMA has been reported in association with recombinant type I interferon therapies, with recent concern regarding the use of interferon in multiple sclerosis patients. However a causal association has yet to be demonstrated. Here we adopt a combined clinical and experimental approach to provide evidence of a such an association between type I interferon and TMA. We show the clinical phenotype of cases referred to a national centre is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of interferon toxicity. This includes specific microvascular pathological changes seen in patient biopsies, and is dependent on transcriptional activation of the interferon response through the type I interferon receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I interferon and thrombotic microangiopathy. As such, recombinant type I interferon therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.
Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop.Saturday, September 24, 2016
Aigner A, Buesen R, Gant T, Gooderham N, Greim H, Hackermüller J, Hubesch B, Laffont M, Marczylo E, Meister G, Petrick JS, Rasoulpour RJ, Sauer UG, Schmidt K, Seitz H, Slack F, Sukata T, van der Vies SM, Verhaert J, Witwer KW, Poole A,
Regulatory toxicology and pharmacology : RTP. 20-Sep-2016
The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies. (2) Develop consensus on how to conduct ncRNA expression profiling in a toxicological context. (3) Conduct experimental projects, including, e.g., rat (90-day) oral toxicity studies, to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. Thereby, physiological ncRNA expression profiles should be established, including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be dose-dependently linked with substance-induced apical effects. Applying a holistic approach, knowledge on ncRNAs, 'omics and epigenetics technologies should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context.
Human biomonitoring in Israel: Recent results and lessons learned.Saturday, September 24, 2016
Berman T, Goldsmith R, Levine H, Grotto I,
International journal of hygiene and environmental health. 16-Sep-2016
The use of human biomonitoring (HBM) as a tool for environmental health policy and research is developing rapidly in Israel. Despite challenges in securing political and financial support for HBM, the Ministry of Health has initiated national HBM studies and has utilized HBM data in environmental health policy decision making. Currently, the Ministry of Health is collecting urine samples from children and adults in the framework of the National Health and Nutrition Study (MABAT), with the goal of ongoing surveillance of population exposure to pesticides and environmental tobacco smoke, and of combining HBM data with data on diet and health behavior. In academic research studies in Israel, biomarkers are used increasingly in environmental epidemiology, including in three active birth cohort studies on adverse health effects of phthalates, brominated flame retardants, and organophosphate pesticides. Future Ministry of Health goals include establishing HBM analytical capabilities, developing a long term national HBM plan for Israel and participating in the proposed HBM4EU project in order to improve data harmonization. One of the lessons learned in Israel is that even in the absence of a formal HBM program, it is possible to collect meaningful HBM data and use it in an ad hoc fashion to support environmental health policy.
Overexpression of functional SLC6A3 in clear cell renal cell carcinoma.Saturday, September 24, 2016
Hansson J, Lindgren D, Nilsson H, Johansson E, Johansson M, Gustavsson L, Axelson H,
Clinical cancer research : an official journal of the American Association for Cancer Research. 23-Sep-2016
We conclude that the dopamine transporter SLC6A3 constitute a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC.
Alternative lengthening of telomeres in primary pancreatic neuroendocrine neoplasms is associated with aggressive clinical behavior and poor survival.Saturday, September 24, 2016
Kim JY, Brosnan-Cashman JA, An S, Kim SJ, Song KB, Kim MS, Kim MJ, Hwang DW, Meeker AK, Yu E, Kim SC, Hruban RH, Heaphy CM, Hong SM,
Clinical cancer research : an official journal of the American Association for Cancer Research. 23-Sep-2016
Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease.
Thioflavones as novel neuroprotective agents.Saturday, September 24, 2016
Ravishankar D, Corona G, Hogan SM, Spencer JP, Greco F, Osborn HM,
Bioorganic & medicinal chemistry. 6-Sep-2016
Oxidative stress is associated with the pathology of neurodegenerative diseases. Identification of small molecules capable of protecting against oxidative stress is therefore of significant importance. In this context, a library of 76 hydroxy flavones, methoxy flavones and their 4-thio analogues has been evaluated for neuroprotection against H2O2-induced oxidative stress. This revealed the synthetic 7,8-dihydroxy 4-thioflavones as neuroprotective compounds, with 14d and 18d showing highest neuroprotective effects at lower concentrations (0.3μM). Neuroprotection was found to be mediated via activation of the anti-apoptotic cell survival proteins of the ERK1/2 and PI3K/Akt pathways. Structure-activity relationship analysis revealed the B-ring phenyl group as essential for greater neuroprotection. Replacing the 4-CO moiety with a 4-CS moiety also generally enhanced neuroprotection.
Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.Saturday, September 24, 2016
Alexander GS, Palmer JD, Tuluc M, Lin J, Dicker AP, Bar-Ad V, Harshyne LA, Louie J, Shaw CM, Hooper DC, Lu B,
Journal of hematology & oncology. 6-9-2016
An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771 .
BCL-2 system analysis identifies high-risk colorectal cancer patients.Saturday, September 24, 2016
Lindner AU, Salvucci M, Morgan C, Monsefi N, Resler AJ, Cremona M, Curry S, Toomey S, O'Byrne R, Bacon O, Stühler M, Flanagan L, Wilson R, Johnston PG, Salto-Tellez M, Camilleri-Broët S, McNamara DA, Kay EW, Hennessy BT, Laurent-Puig P, Van Schaeybroeck S, Prehn JH,
Gut. 23-Sep-2016
DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.
Pharmacodynamic endpoints as clinical trial objectives to answer important questions in oncology drug development.Saturday, September 24, 2016
Parchment RE, Doroshow JH,
Seminars in oncology. Aug-2016
Analyzing the molecular interplay between malignancies and therapeutic agents is rarely a straightforward process, but we hope that this special issue of Seminars has highlighted the clinical value of such endeavors as well as the relevant theoretical and practical considerations. Here, we conclude with both an overview of the various high-value applications of clinical pharmacodynamics (PD) in developmental therapeutics and an outline of the framework for incorporating PD analyses into the design of clinical trials. Given the increasingly recognized importance of determining and administering the biologically effective dose (BED) and schedule of targeted agents, we explain how clinical PD biomarkers specific to the agent mechanism of action (MOA) can be used for the development of pharmacodynamics-guided biologically effective dosage regimens (PD-BEDR) to maximize the efficacy and minimize the toxicity of targeted therapies. In addition, we discuss how MOA-based PD biomarker analyses can be used both as patient selection diagnostic tools and for designing novel drug combinations targeting the specific mutational signature of a given malignancy. We also describe the role of PD analyses in clinical trials, including for MOA confirmation and dosage regimen optimization during phase 0 trials as well as for correlating molecular changes with clinical efficacy when establishing proof-of-concept in phase I/II trials. Finally, we outline the critical technological developments that are needed to enhance the quality and quantity of future clinical PD data collection, broaden the types of molecular questions that can be answered in the clinic, and, ultimately, improve patient outcomes.
Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations.Saturday, September 24, 2016
Parchment RE, Voth AR, Doroshow JH, Berzofsky JA,
Seminars in oncology. Aug-2016
Immunotherapy has become a major modality of cancer treatment, with multiple new classes of immunotherapeutics recently entering the clinic and obtaining market approval from regulatory agencies. While the promise of these therapies is great, so is the number of possible combinations not only with each other but also with small molecule therapeutics. Furthermore, the observation of unusual dose-response relationships suggests a critical dependency of drug effectiveness on the dosage regimen (dose and schedule). Clinical pharmacodynamic (PD) biomarkers will be useful endpoints for confirming drug mechanism of action, evaluating combination therapies for synergy or antagonism, and identifying optimal dosage regimens. In contrast to conventional PD in which drug action occurs entirely within a single target cell (ie, is self-contained within the malignant cell), immunotherapy involves a complex mechanism of action with sequential steps that propagate through multiple cell types, both normal and malignant. Its intercellular pharmacology begins with molecular target engagement either on an immune effector cell or a malignant cell, followed by stimulatory biochemical and biological signals in immune effector cells, and then finally ends with activation of cell death mechanisms in malignant cells lying within a certain distance from the activated effector cells (immune cell-tumor cell proximity). Evaluating such "trans-cellular pharmacology," in which different steps of drug action are distributed across multiple cell types, requires novel microscopy and image analysis tools capable of quantifying PD-biomarker responses, mapping the responses onto the cellular geography of the tumor using phenotypic biomarkers to identify specific cell types, and finally analyzing the spatial relationships between biomarkers in the context of each cell's biological role. We have termed this form of nearest neighbor image analysis of drug action "proximity PD microscopy," to indicate the importance of the location of the PD-biomarker response within the cellular landscape of a tumor specimen. We discuss herein the major modes of immunotherapy, and lay out a blueprint for using PD assessment to optimize dosage regimens of single agents and guide development of combination immunotherapy regimens, using PD1/PD-L1 immune checkpoint inhibition as a case study.
The root causes of pharmacodynamic assay failure.Saturday, September 24, 2016
Ferry-Galow KV, Makhlouf HR, Wilsker DF, Lawrence SM, Pfister TD, Marrero AM, Bigelow KM, Yutzy WH, Ji JJ, Butcher DO, Gouker BA, Kummar S, Chen AP, Kinders RJ, Parchment RE, Doroshow JH,
Seminars in oncology. Aug-2016
Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.
Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells.Saturday, September 24, 2016
Wang L, Balasubramanian P, Chen AP, Kummar S, Evrard YA, Kinders RJ,
Seminars in oncology. Aug-2016
Circulating tumor cells (CTCs), which are captured from blood with anti-epithelial cell adhesion molecule (EpCAM) antibodies, have established prognostic value in specific epithelial cancers, but less is known about their utility for assessing patient response to molecularly targeted agents via measurement of pharmacodynamic (PD) endpoints. We discuss the use of CellSearch (Janssen Diagnostics, LLC, Raritan, NJ) CTC isolation technology for monitoring PD response in early phase trials. We present representative data from three clinical trials with the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects. However, while often leading to hypothesis-generating information, our experience points to the difficulty in obtaining sufficient EpCAM-expressing CTCs from patients with advanced disease to reach statistically significant conclusions about PD effects from each trial. Overall, the level of phenotypic heterogeneity observed in specimens from patients with advanced carcinomas suggests caution in the use of cell-surface differentiation marker-based methods for isolating CTCs.
Translating pharmacodynamic biomarkers from bench to bedside: analytical validation and fit-for-purpose studies to qualify multiplex immunofluorescent assays for use on clinical core biopsy specimens.Saturday, September 24, 2016
Marrero A, Lawrence S, Wilsker D, Voth AR, Kinders RJ,
Seminars in oncology. Aug-2016
Multiplex pharmacodynamic (PD) assays have the potential to increase sensitivity of biomarker-based reporting for new targeted agents, as well as revealing significantly more information about target and pathway activation than single-biomarker PD assays. Stringent methodology is required to ensure reliable and reproducible results. Common to all PD assays is the importance of reagent validation, assay and instrument calibration, and the determination of suitable response calibrators; however, multiplex assays, particularly those performed on paraffin specimens from tissue blocks, bring format-specific challenges adding a layer of complexity to assay development. We discuss existing multiplex approaches and the development of a multiplex immunofluorescence assay measuring DNA damage and DNA repair enzymes in response to anti-cancer therapeutics and describe how our novel method addresses known issues.
Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials.Saturday, September 24, 2016
Kummar S, Do K, Coyne GO, Chen A, Ji J, Rubinstein L, Doroshow JH,
Seminars in oncology. Aug-2016
Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. Assessing target modulation in paired tumor biopsies in patients with solid tumors presents multiple challenges, including procedural issues such as patient safety, ethical considerations, and logistics of sample handling and processing. In addition, the availability of qualified biomarker assay technologies, resources to conduct such studies, and real-time analysis of samples to detect inter-species differences that may affect the determination of optimal sampling time points must be taken into account. This article provides a discussion of the challenges that confront the practical application of pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.
Critical parameters in targeted drug development: the pharmacological audit trail.Saturday, September 24, 2016
Banerji U, Workman P,
Seminars in oncology. Aug-2016
The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. The questions asked in the PhAT should be viewed as a continuum and not used in isolation. Different drug development programmes derive different types of benefit from these questions. The PhAT is critical in making go-no-go decisions in the development of currently studied drugs and will continue to be relevant to discovery and development of future generations of anticancer agents.
Inhibiting poly-ADP ribosylation increases fatty acid oxidation and protects against fatty liver disease.Saturday, September 24, 2016
Gariani K, Ryu D, Menzies K, Yi HS, Stein S, Zhang H, Perino A, Lemos V, Katsyuba E, Jha P, Vijgen S, Rubbia-Brandt L, Kim YK, Kim JT, Kim KS, Shong M, Schoonjans K, Auwerx J,
Journal of hepatology. 20-Sep-2016
Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies.
Modulating Immunosuppression in the Intrapleural Space of Malignant Pleural Mesothelioma and Predictive Biomarkers to Guide Treatment Decisions.Saturday, September 24, 2016
Wong RM,
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. Oct-2016
Salivary DNA methylation panel to diagnose HPV-positive and HPV-negative head and neck cancers.Saturday, September 24, 2016
Lim Y, Wan Y, Vagenas D, Ovchinnikov DA, Perry CF, Davis MJ, Punyadeera C,
BMC cancer. 26-7-2016
Salivary DNA tumour-suppressor methylation gene panel has the potential to detect early-stage tumours in HPV-negative HNSCC patients. HPV infection was found to deregulate the methylation levels in HPV-positive HNSCC patients. Large-scale double-blinded clinical trials are crucial before this panel can potentially be integrated into a clinical setting.
Major influence of repetitive elements on disease-associated copy number variants (CNVs).Saturday, September 24, 2016
Cardoso AR, Oliveira M, Amorim A, Azevedo L,
Human genomics. 23-9-2016
Copy number variants (CNVs) are important contributors to the human pathogenic genetic diversity as demonstrated by a number of cases reported in the literature. The high homology between repetitive elements may guide genomic stability which will give rise to CNVs either by non-allelic homologous recombination (NAHR) or non-homologous end joining (NHEJ). Here, we present a short guide based on previously documented cases of disease-associated CNVs in order to provide a general view on the impact of repeated elements on the stability of the genomic sequence and consequently in the origin of the human pathogenic variome.
[Update on molecular classifications and new histological classification of bladder cancer].Saturday, September 24, 2016
Varinot J, Furudoï A, Roupret M, Compérat E,
Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie. 20-Sep-2016
The molecular biology and classifications allow a better understanding of bladder cancer and could complete in near future histological data to improve patient management.
Precision and improving outcomes in acute kidney injury: Personalizing the approach.Saturday, September 24, 2016
Forni LG, Chawla L, Ronco C,
Journal of critical care. 13-Sep-2016
It is now well over a decade since attempts at harmonization of acute renal failure into a definable entity termed acute kidney injury. This has led to several landmark studies outlining the epidemiology of acute kidney injury, particularly in the critically ill, as well as providing insights into the long-term effects of the syndrome. Despite the introduction of consensus definitions and improvement in recognition, this has not been translated into outcome benefits as yet. The introduction of novel biomarkers associated with renal damage was primarily aimed at aiding early recognition of acute kidney injury. We argue that, in the future, using biomarkers may not only alert to acute kidney injury but may direct therapy in a personalized fashion rather than a one-size-fits-all approach.
Two patients with Ehlers-Danlos syndrome type VIII with unexpected hoarseness.Saturday, September 24, 2016
George SM, Vandersteen A, Nigar E, Ferguson DJ, Topham EJ, Pope FM,
Clinical and experimental dermatology. Oct-2016
Ehlers-Danlos syndrome (EDS) encompasses a genetically and clinically heterogeneous group of connective tissue disorders, characterized by joint hypermobility, skin hyperextensibility and tissue fragility. It is a rare condition, and inheritance is either autosomal dominant or recessive. Previously grouped into 11 different subtypes, with increasing knowledge of the underlying molecular defects, it was reclassified in 1997 into 6 major groups, with type VIII excluded from this classification. Type VIII EDS is a very rare subtype, characterized by severe, early-onset periodontitis, skin fragility and abnormal scarring. Voice abnormalities have occasionally been described in other forms of the condition, and may be due to defects in the collagen of the vocal ligament. We report two cases of patients with EDS type VIII and hoarseness.
[The quest for immunotherapy response biomarkers still goes on].Saturday, September 24, 2016
Rodrigues MJ,
Bulletin du cancer. 20-Sep-2016
Immune checkpoint status in penile squamous cell carcinoma: A North American Cohort.Saturday, September 24, 2016
Cocks M, Taheri D, Ball MW, Bezerra SM, Del Carmen Rodriguez M, Ricardo BF, Bivalacqua TJ, Sharma RB, Meeker A, Chaux A, Burnett AL, Netto GJ,
Human pathology. 20-Sep-2016
Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic disease require a multidisciplinary treatment approach. However, mortality and morbidity remain high and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays (TMAs). TMAs were stained with immunohistochemistry (IHC) for PD-L1, FOXP3, CD8 and Ki-67. PD-L1 was investigated using rabbit monoclonal anti PD-L1 antibody (Cell Signaling, E1L3N, 1:100). Overall 21/53 (40%) of penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. 44% (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion or tumor grade. FOXP3 expression in tumoral immune cells was found in 26/53 (49%) of cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P=.0086). The ratio of CD8:FOXP3 was >1 in 62% of tumor-infiltrating immune cells and 34% of stromal immune cells samples. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC.
Muscle MRI of facioscapulohumeral dystrophy (FSHD): A growing demand and a promising approach.Saturday, September 24, 2016
Fatehi F, Salort-Campana E, Le Troter A, Bendahan D, Attarian S,
Revue neurologique. 20-Sep-2016
Facioscapulohumeral muscular dystrophy (FSHD), an inherited and progressive muscle disorder, is among the most common hereditary muscle disorders. From a clinical vantage point, FSHD is characterized by weakness of the facial, shoulder (often with scapular winging), arm (including biceps and triceps) and abdominal muscles. Forearm muscles are usually spared and weakness is usually asymmetrical. Over the past few decades, muscle magnetic resonance imaging (MRI) has become established as a reliable and accurate noninvasive tool for the diagnosis and assessment of progression in neuromuscular diseases, showing specific patterns of muscle involvement for a number of myopathies. More recently, MRI has been used to noninvasively identify quantitative biomarkers, allowing evaluation of the natural progression of disease and assessment of therapeutic interventions. In the present review, the intention was to present the most significant MRI developments related to diagnosis and pattern recognition in FSHD and to discuss its capacity to provide outcome measures.
Production and Characterization of Neutralizing Antibodies against Bungarus multicinctus Snake Venom.Saturday, September 24, 2016
Lee CH, Lee YC, Leu SJ, Lin LT, Chiang JR, Hsu WJ, Yang YY,
Applied and environmental microbiology. 23-Sep-2016
Snake envenomation is one of global medical issues in concern. Horse-derived antivenin is an effective way to treat snakebites but it is costly and occasionally causes severe side effects. In this study, we first generated and characterized IgY antibodies with neutralization activity in chickens. Subsequently, we generated a panel of monoclonal scFv antibodies using phage display antibody technology. Mixture of scFv antibodies was able to partially inhibit the lethal effect in mice injected with lethal dosage of venom proteins and prolong their survival time. We believe the chicken-derived IgY and scFv antibodies have great potential to develop diagnostic agents for wound exudates and therapeutic agents against snake envenomation in the future.
Insulin Exhibits an Antiproliferative and Hypertrophic Effect in First Trimester Human Extravillous Trophoblasts.Saturday, September 24, 2016
Silva C, Nunes C, Correia-Branco A, Araújo JR, Martel F,
Reproductive sciences (Thousand Oaks, Calif.). 22-Sep-2016
Our aim was to investigate the effect of high levels of glucose, insulin, leptin, and tumor necrosis factor alpha, biomarkers of diabetes in pregnancy, in the process of placentation, using as a cell model a first trimester extravillous human trophoblast cell line (HTR8/SVneo cells). Exposure of HTR8/SVneo cells for 24 hours to either glucose (20 mmol/L) or leptin (25-100 ng/mL) did not cause significant changes in cell proliferation and viability. Tumor necrosis factor alpha (24 hours; 10-100 ng/L) caused a small decrease (10%) in cell proliferation and an increase (9%) in cell viability; however, both effects disappeared when exposure time was increased. Insulin (24 hours; 1-10 nmol/L) caused a concentration- and time-dependent decrease (10%-20%) in cell proliferation; the effect of insulin (10 nmol/L) was more pronounced after a 48 hours exposure (35%). In contrast, exposure to insulin (10 nmol/L; 48 hours) showed no significant effect on cell viability, apoptosis, and migration capacity. Insulin appears to cause hypertrophy of HTR8/SVneo cells as it reduces the cell mitotic index while increasing the culture protein content. The antiproliferative effect of insulin seems to involve activation of mammalian target of rapamycin, phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase. Finally, simvastatin and the polyphenol quercetin potentiated the antiproliferative effect of insulin; on the contrary, the polyphenol resveratrol, the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids, and folic acid were not able to change it. In conclusion, we show that insulin has an antiproliferative and hypertrophic effect on a first trimester extravillous human trophoblast cell line. So insulin might affect the process of placentation.
Implementation of a Multicenter Biobanking Collaboration for Next-Generation Sequencing-Based Biomarker Discovery Based on Fresh Frozen Pretreatment Tumor Tissue Biopsies.Saturday, September 24, 2016
Bins S, Cirkel GA, Gadellaa-van Hooijdonk CG, Weeber F, Nijman IJ, Bruggink AH, van Diest PJ, Willems SM, Veldhuis WB, van den Heuvel MM, de Knegt RJ, Koudijs MJ, van Werkhoven E, Mathijssen RH, Cuppen E, Sleijfer S, Schellens JH, Voest EE, Langenberg MH, de Jonge MJ, Steeghs N, Lolkema MP,
The oncologist. 23-Sep-2016
This study shows that it is safe to perform image-guided biopsy procedures to obtain fresh frozen tumor samples and that it is feasible to use these biopsies for biomarker discovery purposes in a Dutch multicenter collaboration. From the majority of the samples, sufficient DNA could be yielded to perform next-generation sequencing. These results indicate that the way is paved for consortia to prospectively collect fresh frozen tumor tissue.
DNA in serum extracellular vesicles is stable under different storage conditions.Saturday, September 24, 2016
Jin Y, Chen K, Wang Z, Wang Y, Liu J, Lin L, Shao Y, Gao L, Yin H, Cui C, Tan Z, Liu L, Zhao C, Zhang G, Jia R, Du L, Chen Y, Liu R, Xu J, Hu X, Wang Y,
BMC cancer. 23-9-2016
Serum EVs and EVs DNA can remain stable under different environments, which is the premise that EVs could serve as a novel means for genetic tumor detection and potential biomarkers for cancer diagnostics and prognostics.
Interlaboratory analytical comparison of fatty acid concentrations in serum or plasma.Saturday, September 24, 2016
Schantz MM, Powers CD, Schleicher RL, Betz JM, Wise SA,
Clinica chimica acta; international journal of clinical chemistry. 20-Sep-2016
The results from the first two exercises indicate the need for additional assessment of the comparability among laboratories doing these measurements. Future studies will be conducted with the goals of increasing the number of participating laboratories, increasing awareness of the need to use control materials, and improving the comparability among laboratories.
Altered Circulating T Follicular Helper Cell Subsets in Patients with Psoriasis Vulgaris.Saturday, September 24, 2016
Wang Y, Wang L, Shi Y, Wang F, Yang H, Han S, Bai Y,
Immunology letters. 20-Sep-2016
Circulating T follicular helper (Tfh) cells in the blood are counterparts to conventional Tfh cells in germinal centres. Similarly to conventional Tfh cells, circulating Tfh cells provide helpful signals for B cells. Circulating Tfh cells can be divided into three subpopulations, including Tfh17 (CXCR3-CCR6+), Tfh1 (CXCR3+CCR6-), and Tfh2 (CXCR3-CCR6-) cells, based on differences in CXCR3 and CCR6 expression. Recent studies have demonstrated that alterations in circulating Tfh cell subsets have significant effects on the progression of numerous autoimmune diseases. To address the role of circulating Tfh cells in psoriasis, we used flow cytometry to analyse frequencies of circulating Tfh cell subsets and levels of IL-21 receptor (IL-21R) expression on B cells in 32 patients with psoriasis vulgaris and 13 sex- and age-matched healthy controls. We observed dynamic changes in Tfh17 cell frequency and disease severity in 10 psoriasis patients during a 6-month treatment. Our results demonstrate that the frequency of Tfh17 cells was significantly increased in psoriasis patients and was positively correlated with psoriasis area and severity index (PASI) score, a marker of disease severity (P<0.05). During the follow-up period, the frequencies of Tfh17 cells decreased, and reductions in PASI scores were observed. Moreover, IL-21R expression on B cells was significantly increased in patients with psoriasis vulgaris (P<0.05). Interestingly, IL-21R levels on B cells were correlated with both PASI score and the frequency of Tfh17 cells (P<0.05). In conclusion, this study is the first investigation of the distribution of circulating Tfh subsets in psoriasis. These results deepen our understanding of the immune state of psoriasis patients. Our data also indicate that Tfh17 cells may not be good biomarkers for diagnosing psoriasis but may be potential biomarkers of disease severity in psoriasis.
Identification and characterization of isomeric N-glycans of human alfa-acid-glycoprotein by stable isotope labelling and ZIC-HILIC-MS in combination with exoglycosidase digestion.Saturday, September 24, 2016
Mancera-Arteu M, Giménez E, Barbosa J, Sanz-Nebot V,
Analytica chimica acta. 12-Oct-2016
In this study, a ZIC-HILIC-MS methodology for the analysis of N-glycan isomers was optimized to obtain greater detection sensitivity and thus identify more glycan structures in hAGP. In a second step, this method was combined with glycan reductive isotope labelling (GRIL) through [(12)C6]/[(13)C6]-aniline and exoglycosidase digestion to characterize the different glycan isomers. The GRIL method allows the peak areas resulting from two different labelled samples to be compared, since neither retention time shifts nor variations in the ionization of glycans between these samples are obtained. First, sialic acid linkage assignations were performed for most hAGP glycan isomers with α2-3 sialidase digestion. Bi-, tri- and tetraantennary glycan isomers with different terminal sialic acid linkages to galactose (α2-3 or α2-6) were assigned, and the potential of this technique for the structural characterization of isobaric isomers was therefore demonstrated. Furthermore, fucose linkage isomers of hAGP glycans were also characterized using this isotope-labelling approach in combination with α1-3,4 fucosidase and β1-4 galactosidase digestion. α1-3 antennary fucoses and α1-6 core fucosylation were detected in hAGP fucosylated glycans. These established methodologies can be extremely useful for patho-glycomic studies to characterize glycoproteins of biomedical interest and find novel glycan isomers that could be used as biomarkers in cancer research.
Detecting Alzheimer's disease biomarkers: From antibodies to new bio-mimetic receptors and their application to established and emerging bioanalytical platforms - A critical review.Saturday, September 24, 2016
Scarano S, Lisi S, Ravelet C, Peyrin E, Minunni M,
Analytica chimica acta. 12-Oct-2016
The failure of therapeutic treatment of Alzheimer's disease (AD) patients can be related to the late onset of symptoms and, consequently, to a delayed pharmacological aid to counteract neurodegenerative progression. This is coupled to the fact that the diagnosis based on clinical criteria alone introduces high misdiagnosis rate. The availability of assessed biomarkers is therefore of crucial importance not only to counteract late diagnosis, but also to manage patients at high risk of AD development eligible for novel therapies. At the present time, amyloid-β peptides (Aβ1-40 and Aβ1-42 isoforms), alone or in combination with Tau protein (total and phosphorylated forms (p-tau)) constitute reliable AD biomarkers and result highly predictive of progression to AD dementia in patients with mild cognitive impairment (MCI), the earliest clinical presentation of AD. Improvement of existing diagnostic tools must take advantage of innovative bioanalytical approaches. In this review, starting from commercially available diagnostic platforms based on antibodies as recognition elements, we intended to provide a double point of view on the issue: 1) progresses achieved on innovative bioanalytical platforms (mainly sensors and biosensors) by using antibodies as consolidated receptors; 2) advance on promising bio-mimetic receptors alternative to antibodies in AD research, and their applications on conventional or innovative analytical platforms. In particular, we first focused on optical- (Propagating and Localized Surface Plasmon Resonance, named here SPR and LSPR) and electrochemical (voltammetric and impedimetric) transduction principles. Together with bioanalytical assays for AD biomarkers quantification, works aimed to investigate and understand their behavior, characteristics, and roles will also be considered in the discussion. An increasing interest in new emerging biomimetic receptors for AD diagnosis, as a promising alternative to antibodies is noticed, thus the description of peptides, peptoids, nanobodies, aptamers, and molecularly imprinted polymers and their role as recognition elements in different bioanalytical platforms is also reviewed. Features and limits are discussed, together with potentialities and perspectives of their further applicability to clinical routine AD analysis.
Grp94 in complexes with IgG is a soluble diagnostic marker of gastrointestinal tumors and displays immune-stimulating activity on peripheral blood immune cells.Friday, September 23, 2016
Tramentozzi E, Ruli E, Angriman I, Bardini R, Campora M, Guzzardo V, Zamarchi R, Rossi E, Rugge M, Finotti P,
Oncotarget. 20-Sep-2016
Glucose-regulated protein94 (Grp94), the most represented endoplasmic reticulum (ER)-resident heat shock protein (HSP), is a tumor antigen shared by different types of solid and hematological tumors. The tumor-specific feature of Grp94 is its translocation from the ER to the cell surface where it displays pro-oncogenic functions. This un-physiological location has important implications for both the tumor pathology and anti-tumor therapy. We wanted to address the question of whether Grp94 could be measured as liquid marker in cancer patients in order to make predictions of diagnostic and therapeutic relevance for the tumor. To this aim, we performed an in-depth investigation on patients with primary tumors of the gastrointestinal (GI) tract, using different methodological approaches to detect Grp94 in tumor tissues, plasma and peripheral blood mononuclear cells (PBMCs). Results indicate that Grp94 is not only the antigen highly expressed in any tumor tissue and in cells of tumor infiltrates, mostly B lymphocytes, but it is also found in the circulation. However, the only form in which Grp94 was detected in the plasma of any patients and in B lymphocytes induced to proliferate, was that of stable complexes with Immunoglobulin (Ig)G. Using a specific immune-enzyme assay to measure plasma Grp94-IgG complexes, we showed that Grp94-IgG complexes were significantly increased in cancer patients compared to healthy control subjects, serving as diagnostic tumor biomarker. Results also demonstrate that the stimulation of patient PBMCs with Grp94-IgG complexes led to an increased secretion of inflammatory cytokines that might drive a potentially beneficial anti-tumor effect.
Genomic characterization of liver metastases from colorectal cancer patients.Friday, September 23, 2016
Sayagués JM, Corchete LA, Gutiérrez ML, Sarasquete ME, Del Mar Abad M, Bengoechea O, Fermiñán E, Anduaga MF, Del Carmen S, Iglesias M, Esteban C, Angoso M, Alcazar JA, García J, Orfao A, Muñoz-Bellvis L,
Oncotarget. 20-Sep-2016
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice.Friday, September 23, 2016
Puchalapalli M, Zeng X, Mu L, Anderson A, Hix Glickman L, Zhang M, Sayyad MR, Mosticone Wangensteen S, Clevenger CV, Koblinski JE,
PloS one. 20-9-2016
Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model.
High-Grade Salivary-Gland Involvement, Assessed by Histology or Ultrasonography, Is Associated with a Poor Response to a Single Rituximab Course in Primary Sjögren's Syndrome: Data from the TEARS Randomized Trial.Friday, September 23, 2016
Cornec D, Jousse-Joulin S, Costa S, Marhadour T, Marcorelles P, Berthelot JM, Hachulla E, Hatron PY, Goeb V, Vittecoq O, Nowak E, Pers JO, Devauchelle-Pensec V, Saraux A,
PloS one. 23-9-2016
In patients with pSS, the highest SGUS grade or a high histological focus score is associated with absence of a response to a single rituximab course after 6 months. Further studies, including more patients and different treatment strategies, are required to confirm the clinical utility of these potential biomarkers in pSS.
Monocyte subsets in blood correlate with obesity related response of macrophages to biomaterials in vitro.Friday, September 23, 2016
Boersema GS, Utomo L, Bayon Y, Kops N, van der Harst E, Lange JF, Bastiaansen-Jenniskens YM,
Biomaterials. 13-Sep-2016
Macrophages play a key role in the foreign body response. In this study it was investigated whether obesity affects the acute response of macrophages to biomaterials in vitro and whether this response is associated with biomarkers in blood. CD14 (+) monocytes were isolated from blood from obese and age and gender matched lean persons. Monocyte subsets were determined based on CD14 and CD16 on their surface. C-reactive protein (CRP) was measured in peripheral blood. The response of monocyte-derived macrophages to polypropylene (PP), polylactic acid (PLA), polyethylene terephthalate (PET) monofilament, and PET-multifilament (mPET) in culture was based on cytokine production. More IL-6 (for PET), less CCL18 (all materials) and IL-1ra (for PLA) was produced by macrophages from obese patients than lean subjects. Body mass index, serum CRP and to a lesser extend percentages of monocyte subtypes correlated with IL-6, TNFα, CCL18, and IL-1ra production. Taken together, monocyte-derived macrophages of obese patients respond more pro-inflammatory and less anti-inflammatory to biomaterials than macrophages from lean subjects, depending on the material. These results are a step towards personalized medicine for the development of a model or even a blood test to decide which biomaterial might be suitable for each patient.
Reactivation of SIV reservoirs in the brain of virally suppressed macaques.Friday, September 23, 2016
Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, Pate KA, Wietgrefe SW, O'connor SL, Pianowski L, Haase AT, Van Lint C, Siliciano RF, Clements JE, Authors D,
AIDS (London, England). 20-Sep-2016
The CNS harbors latent SIV genomes after long-term viral suppression by ART indicating that the brain represents a potential viral reservoir and should be seriously considered during AIDS cure strategies.
Anti-Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres.Friday, September 23, 2016
Kaushik V, Yakisich JS, Azad N, Kulkarni Y, Venkatadri R, Wright C, Rojanasakul Y, Iyer AK,
Journal of cellular physiology. 23-Sep-2016
Lung cancer is a leading cause of cancer-related death in the United States. While several drugs have been developed that target individual biomarkers, their success has been limited due to intrinsic or acquired resistance for the specific targets of such drugs. A more effective approach is to target multiple pathways that dictate cancer progression. Cardiac glycosides demonstrate such multimodal effects on cancer cell survival, and our aim was to evaluate the effect of two naturally occurring monosaccaridic cardiac glycosides - Convallatoxin and Peruvoside on lung cancer cells. While both drugs had significant anti-proliferative effects on H460 and Calu-3 lung cancer cells, Convallatoxin demonstrated two-fold higher activity as compared to Peruvoside using both viability and colony forming assays, suggesting a role for the aglycone region in dictating drug potency. The tumor suppressor p53 was found to be important for action of both drugs - p53-underexpressing cells were less sensitive as compared to p53-positive H460 cells. Further assessment of p53-underexpressing H460 cells showed that drugs were able to arrest cells in the G0/G1 phase of the cell cycle in a dose-dependent manner. Both drugs significantly inhibited migration and invasion of cancer cells and decreased the viability of floating tumorspheres. An assessment of intracellular pathways indicated that both drugs were able to modulate proteins that are involved in apoptosis, autophagy, cell cycle, proliferation and EMT. Our data suggests a promising role for cardiac glycosides in lung cancer treatment, and provides impetus for further investigation of the anti-cancer potential of this class of drugs. This article is protected by copyright. All rights reserved.
Mapping US commercial payers' coverage policies for medical interventions.Saturday, September 24, 2016
Chambers JD, Chenoweth MD, Neumann PJ,
The American journal of managed care. 2016
Coverage of medical interventions varies across US private payers. Payers often report reviewing different evidence when formulating coverage policies, but do not report considering input directly from patients in evidence assessments.
TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma.Friday, September 23, 2016
Lettini G, Sisinni L, Condelli V, Matassa DS, Simeon V, Maddalena F, Gemei M, Lopes E, Vita G, Del Vecchio L, Esposito F, Landriscina M,
Cell death and differentiation. 23-Sep-2016
Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem cell markers was observed in stem cells located at the bottom of intestinal crypts and in CSCs sorted from CRC cell lines. Noteworthy, TRAP1 knockdown reduced the expression of stem cell markers and impaired colony formation, being the CSC phenotype and the anchorage-independent growth conserved in TRAP1-rich cancer cells. Consistently, the gene expression profiling of HCT116 cells showed that TRAP1 silencing results in the loss of the stem-like signature with acquisition of a more-differentiated phenotype and the downregulation of genes encoding for activating ligands and target proteins of Wnt/β-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/β-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of β-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of β-catenin and several Wnt/β-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of β-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/β-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics.Cell Death and Differentiation advance online publication, 23 September 2016; doi:10.1038/cdd.2016.67.
FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration.Friday, September 23, 2016
Yu C, Kim BS, Kim E,
Cell death and differentiation. 23-Sep-2016
Cumulative damage caused by oxidative stress results in diverse pathological conditions. Therefore, elucidating the molecular mechanisms underlying cell death following oxidative stress is important. Here, we describe a novel role for Fas-associated factor 1 (FAF1) as a crucial regulator of necrotic cell death elicited by hydrogen peroxide. Upon oxidative insult, FAF1 translocated from the cytoplasm to the nucleus and promoted the catalytic activation of poly(ADP-ribose) polymerase 1 (PARP1) through physical interaction. Moreover, FAF1 depletion prevented PARP1-linked downstream events involved in the triggering of cell death, including energetic collapse, mitochondrial depolarization and nuclear translocation of apoptosis-inducing factor (AIF), implying that FAF1 has a key role in PARP1-dependent necrosis in response to oxidative stress. We further investigated whether FAF1 might contribute to the pathogenesis of Parkinson's disease through excessive PARP1 activation. Indeed, the overexpression of FAF1 using a recombinant adeno-associated virus system in the mouse ventral midbrain promoted PARP1 activation and dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Collectively, our data demonstrate the presence of an FAF1-PARP1 axis that is involved in oxidative stress-induced necrosis and in the pathology of Parkinson's disease.Cell Death and Differentiation advance online publication, 23 September 2016; doi:10.1038/cdd.2016.99.
Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team.Friday, September 23, 2016
Arnerić SP, Batrla-Utermann R, Beckett L, Bittner T, Blennow K, Carter L, Dean R, Engelborghs S, Genius J, Gordon MF, Hitchcock J, Kaplow J, Luthman J, Meibach R, Raunig D, Romero K, Samtani MN, Savage M, Shaw L, Stephenson D, Umek RM, Vanderstichele H, Willis B, Yule S,
Journal of Alzheimer's disease : JAD. 21-Sep-2016
Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.
Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy.Friday, September 23, 2016
de Wit NM, Snkhchyan H, den Hoedt S, Wattimena D, de Vos R, Mulder MT, Walter J, Martinez-Martinez P, Hoozemans JJ, Rozemuller AJ, de Vries HE,
Journal of Alzheimer's disease : JAD. 21-Sep-2016
Here we provide evidence of a deregulated SL balance in capCAA. The increased levels of ASM and ceramide in activated glia cells suggest that the SL pathway is involved in the neuroinflammatory response in capCAA pathogenesis. Future research is needed to elucidate the role of S1P in capCAA.
Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium.Friday, September 23, 2016
Idland AV, Wyller TB, Støen R, Eri LM, Frihagen F, Ræder J, Chaudhry FA, Hansson O, Zetterberg H, Blennow K, Bogdanovic N, Brækhus A, Watne LO,
Journal of Alzheimer's disease : JAD. 20-Sep-2016
The reduction in CSF Aβ42, indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.
Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.Friday, September 23, 2016
Lewczuk P, Lelental N, Lachmann I, Holzer M, Flach K, Brandner S, Engelborghs S, Teunissen CE, Zetterberg H, Molinuevo JL, Mroczko B, Blennow K, Popp J, Parnetti L, Chiasserini D, Perret-Liaudet A, Spitzer P, Maler JM, Kornhuber J,
Journal of Alzheimer's disease : JAD. 20-Sep-2016
For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.
Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study.Friday, September 23, 2016
Kuiperij HB, Versleijen AA, Beenes M, Verwey NA, Benussi L, Paterlini A, Binetti G, Teunissen CE, Raaphorst J, Schelhaas HJ, Küsters B, Pijnenburg YA, Ghidoni R, Verbeek MM,
Journal of Alzheimer's disease : JAD. 23-Sep-2016
We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.
Spatial Patterns of Longitudinal Gray Matter Change as Predictors of Concurrent Cognitive Decline in Amyloid Positive Healthy Subjects.Friday, September 23, 2016
Caballero MÁ, Klöppel S, Dichgans M, Ewers M,
Journal of Alzheimer's disease : JAD. 21-Sep-2016
A substantial proportion of cognitively healthy elders (HC) show abnormally high amyloid-β (Aβ) deposition, a major pathology of Alzheimer's disease (AD). These subjects are at increased risk of Alzheimer's disease (AD) dementia, and biomarkers are needed to predict their cognitive deterioration. Here we used relevance vector regression (RVR), a pattern-recognition method, to predict concurrent cognitive decline on the basis of longitudinal gray matter (GM) changes, within two a priori, meta-analytically defined functional networks subserving episodic memory and executive function. Ninety-six HC subjects were assessed annually for three years with structural MRI and cognitive tests within the Alzheimer's Disease Neuroimaging Initiative. Presence of abnormal biomarker values of Aβ (Aβ+) were determined with cerebrospinal fluid and amyloid-PET (HC-Aβ+, n=30; with n=66 for normal HC-Aβ-). Using leave-one-out cross-validation, we found that in HC-Aβ+ patterns of GM changes within both networks predicted decline in episodic memory (r=0.61, p<0.001; r=0.40, p=0.03), but not executive function. In HC-Aβ-, GM changes within the executive function network predicted decline in executive function (r=0.44, p<0.001). Previously established region-of-interest (ROI)-based predictors such as changes in hippocampal volume, within an AD-signature multi-ROI, or total GM volume were not predictive of cognitive decline in any group or cognitive domain. RVR analyses unrestricted to the a priori networks yielded compatible results with the restricted case. In conclusion, RVR-derived patterns of subtle cortical GM changes are biomarker candidates of concurrent cognitive decline in aging and subjects at risk for AD.
Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.Friday, September 23, 2016
Darst BF, Koscik RL, Racine AM, Oh JM, Krause RA, Carlsson CM, Zetterberg H, Blennow K, Christian BT, Bendlin BB, Okonkwo OC, Hogan KJ, Hermann BP, Sager MA, Asthana S, Johnson SC, Engelman CD,
Journal of Alzheimer's disease : JAD. 21-Sep-2016
Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.
Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop.Friday, September 23, 2016
Cointe S, Judicone C, Robert S, Mooberry MJ, Poncelet P, Wauben M, Nieuwland R, Key NS, Dignat-George F, Lacroix R,
Journal of thrombosis and haemostasis : JTH. 23-Sep-2016
Despite remaining limitations, this study is the first to demonstrate a real potential of bead-based strategies for standardization of MP enumeration across different FCM platforms. Additional standardization efforts are still mandatory to evaluate MP clinical relevance at a multicenter level. This article is protected by copyright. All rights reserved.
Synthetic Biology-Based Point-of-Care Diagnostics for Infectious Disease.Saturday, September 24, 2016
Wei TY, Cheng CM,
Cell chemical biology. 22-Sep-2016
Infectious diseases outpace all other causes of death in low-income countries, posing global health risks, laying stress on healthcare systems and societies, and taking an avoidable human toll. One solution to this crisis is early diagnosis of infectious disease, which represents a powerful way to optimize treatment, increase patient survival rate, and decrease healthcare costs. However, conventional early diagnosis methods take a long time to generate results, lack accuracy, and are known to seriously underperform with regard to fungal and viral infections. Synthetic biology offers a fast and highly accurate alternative to conventional infectious disease diagnosis. In this review, we outline obstacles to infectious disease diagnostics and discuss two emerging alternatives: synthetic viral diagnostic systems and biosensors. We argue that these synthetic biology-based approaches may overcome diagnostic obstacles in infectious disease and improve health outcomes.
MED28 Regulates Epithelial-Mesenchymal Transition through NFκB in Human Breast Cancer Cells.Friday, September 23, 2016
Huang CY, Hsieh NT, Li CI, Weng YT, Liu HS, Lee MF,
Journal of cellular physiology. 23-Sep-2016
MED28, a mammalian Mediator subunit, was found highly expressed in several types of malignancy, including breast cancer. Recently, we have identified a role of MED28 in regulating both cell growth and migration in human breast cancer cells. In epithelium-derived solid tumor, migration and invasion are preceded by the progression of epithelial-mesenchymal transition (EMT) which calls for downregulation of epithelial markers as well as upregulation of mesenchymal markers, among other features. The objective of this study was to investigate a putative role of MED28 in the progression of EMT in human breast cancer cells. In fibroblast-like MDA-MB-231 cells, suppression of MED28 attenuated the mesenchymal morphology, concomitantly with a reduction of several mesenchymal biomarkers and Snail, a transcriptional repressor of E-cadherin. The suppression effect was also accompanied by downregulation of p-NFκB/p65. However, overexpression of MED28 exhibited in an opposite manner. In epithelial MCF7 cells, administration of Adriamycin®, an experimental EMT induction system, led to a mesenchyme-like appearance correlated with increased expression of MED28, p-p65, and Snail, and a reciprocal change of epithelial and mesenchymal markers. Furthermore, suppression of MED28 attenuated the experimental EMT effect and restored the original expression status of E-cadherin and MMP9 in MCF7 cell. Our data indicate that MED28 modulates the development of EMT through NFκB in human breast cancer cells, further reinforcing the significance of MED28 in the progression of breast cancer on top of its role in cell growth and migration. This article is protected by copyright. All rights reserved.
IL6-174 G>C Polymorphism (rs1800795) Association with Late Effects of Low Dose Radiation Exposure in the Portuguese Tinea Capitis Cohort.Friday, September 23, 2016
Boaventura P, Durães C, Mendes A, Costa NR, Chora I, Ferreira S, Araújo E, Lopes P, Rosa G, Marques P, Bettencourt P, Oliveira I, Costa F, Ramos I, Teles MJ, Guimarães JT, Sobrinho-Simões M, Soares P,
PloS one. 23-9-2016
Head and neck cancers, and cardiovascular disease have been described as late effects of low dose radiation (LDR) exposure, namely in tinea capitis cohorts. In addition to radiation dose, gender and younger age at exposure, the genetic background might be involved in the susceptibility to LDR late effects. The -174 G>C (rs1800795) SNP in IL6 has been associated with cancer and cardiovascular disease, nevertheless this association is still controversial. We assessed the association of the IL6-174 G>C SNP with LDR effects such as thyroid carcinoma, basal cell carcinoma and carotid atherosclerosis in the Portuguese tinea capitis cohort. The IL6-174 G>C SNP was genotyped in 1269 individuals formerly irradiated for tinea capitis. This sampling group included thyroid cancer (n = 36), basal cell carcinoma (n = 113) and cases without thyroid or basal cell carcinoma (1120). A subgroup was assessed for atherosclerosis by ultrasonography (n = 379) and included matched controls (n = 222). Genotypes were discriminated by real-time PCR using a TaqMan SNP genotyping assay. In the irradiated group, we observed that the CC genotype was significantly associated with carotid plaque risk, both in the genotypic (OR = 3.57, CI = 1.60-7.95, p-value = 0.002) and in the recessive (OR = 3.02, CI = 1.42-6.42, p-value = 0.004) models. Irradiation alone was not a risk factor for carotid atherosclerosis. We did not find a significant association of the IL6-174 C allele with thyroid carcinoma or basal cell carcinoma risk. The IL6-174 CC genotype confers a three-fold risk for carotid atherosclerotic disease suggesting it may represent a genetic susceptibility factor in the LDR context.
Recent developments in epigenetics of pediatric asthma.Friday, September 23, 2016
Harb H, Alhamwe BA, Garn H, Renz H, Potaczek DP,
Current opinion in pediatrics. 21-Sep-2016
The results of our systematic literature search provide a strong support for the role of epigenetic mechanisms in (mediating the effects of environmental exposure on) pediatric asthma. This knowledge may possibly be translated into diagnostic and/or therapeutic approaches.
Differential expression, localization and activity of MARCKS between mantle cell lymphoma and chronic lymphocytic leukemia.Friday, September 23, 2016
Vargova J, Vargova K, Dusilkova N, Kulvait V, Pospisil V, Zavadil J, Trneny M, Klener P, Stopka T,
Blood cancer journal. 21-9-2016
Number and type of TET2 mutations in chronic myelomonocytic leukemia and their clinical relevance.Friday, September 23, 2016
Patnaik MM, Zahid MF, Lasho TL, Finke C, Ketterling RL, Gangat N, Robertson KD, Hanson CA, Tefferi A,
Blood cancer journal. 23-9-2016
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