tbuckley/cabot-search huggingface dataset:
Comparison of 2-hydroxyglutarate (2HG) levels in tissue and serum of isocitrate dehydrogenase (IDH)-mutated (MUT) versus wild-type (WT) gliomas.
Authors: Hao-Wen Sim, Romina Nejad, Wenjiang Zhang, Warren P. Mason, Mark Bernstein, Ken Aldape, Gelareh Zadeh, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2017)

2037 Background: IDH mutations are common in low-grade gliomas and confer significantly improved prognosis. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, and subsequently to the oncometabolite 2HG. Mutant IDH leads to preferential accumulation of the R relative to the S enantiomer of 2HG. We analyzed the ratio of R to S enantiomers (rRS) in glioma tissues and matched serum samples, and correlated findings with IDH status, 1p19q codeletion status and survival. Methods: Fresh frozen glioma tissues and matched serum samples were obtained from the University of Toronto Brain Tumor Bank. IDH status was determined by immunohistochemistry and confirmed by 450K methylation profile or direct sequencing. 1p19q codeletion status was determined by loss-of-heterozygosity PCR analysis. R-2HG and S-2HG levels were quantified using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC column. Results: Glioma tissues from 70 patients were analyzed – 52 with IDH MUT and 18 WT. 30 had matched serum samples. Using glioma tissues, rRS clearly distinguished MUT vs WT (median 574 vs 1.3, p &lt; 1x10 -9 ) with only three outliers. In contrast, rRS was not elevated in serum samples (median 1.5 vs 1.2, p = 0.13). Overall survival (OS) was significantly longer for MUT vs WT (median 178 vs 33 months, p &lt; 1×10 -7 ). Stratifying MUT by tissue rRS, median OS was 197, 178, 178 and 122 months for lowest to highest quartiles of rRS respectively. 1p19q codeletion status and tumor latency did not explain this trend, given rRS was similar in codeleted vs non-codeleted MUT, and similar in MUT operated &lt; 3 vs ≥3 months from diagnosis. Progression-free survival results corresponded to OS. Conclusions: rRS from glioma tissues effectively differentiated MUT vs WT, whereas serum samples were unreliable. Unlike current methods, tissue rRS enables real-time determination of IDH status, and thus may guide clinical practice such as extent of surgical resection intraoperatively and upfront selection of adjuvant therapy. rRS potentially stratifies survival within MUT patients, providing detailed correlative information.
Abstract P131: An Akt-Phosphomimetic Sequence of the Cavb2 C-Terminal Region Protects L-Type Calcium Channels from Protein Degradation
Authors: Francesca Rusconi, Magali Cazade, Silvia Caprari, Fabio Polticelli, Jean Chemin, Gianluigi Condorelli, Daniele Catalucci
Journal: Circulation Research (2011)

Alteration in the density or function of L-Type Calcium Channels (LTCCs) has been related to cardiovascular diseases such as heart failure and diabetic cardiomyopathy. It could therefore be envisioned that increasing LTCC density may improve cardiac function in heart failure. Recently, we determined that the Ser-Thr kinase Akt plays a key role in regulating cardiac inotropism through the modulation of LTCC density and function. Specifically, we found that the LTCC pore-forming channel subunit Cava1.2 contains highly evolutionary conserved PEST sequences (signals for rapid proteolytic degradation) that are responsible for direct Cava1.2 protein degradation. Phosphorylation of the C-terminal coiled coil of the Cavb2 chaperone subunit enhances LTCC protein stability by preventing PEST-mediated Cava1.2 degradation. The aim of this study was to further dissect this Akt-dependent fine-tuning mechanism regulating LTCC density, searching for potential Akt-phosphomimetic (APM) molecules that could enhance LTCC density. Using yeast two-hybrid screening, we found that APM Cavb2 sequences interact with the globular domain of Cavb2 itself in a solvent-exposed region that we named Tail Interacting Domain (TID). Biochemical and functional assays as well as site-specific mutagenesis in TID identified the minimal aminoacid sequence responsible for the TID-tail interaction. In addition, through an approach comprising western blot analyses, fluorescent-based calcium assays, calcium current (ICaL) measurements, molecular modeling and peptide arrays, we identified the minimal APMs that efficiently protects Cava1.2 from protein degradation. Based on our in vitro results, we suggest that the identified APM sequence/peptide could be used as a “therapeutic approach”; for increasing or reestablishing impaired cardiac contractility in mouse models of cardiomyopathy in which the LTCC density is altered, thus enhancing inotropism.
Abstract 312: Troponin I Phosphorylation Crosstalk
Authors: Brandon J Biesiadecki, Benjamin R Nixon, Sean C Little, Elizabeth A Brundage, Jonathan P Davis
Journal: Circulation Research (2012)

The troponin (Tn) complex is a critical regulatory and integrative hub for myofilament post-translational modifications that regulate cardiac contraction. Beta-adrenergic-induced protein kinase A (PKA) phosphorylation of cardiac troponin I (cTnI) at Ser-23/24 is a major myofilament cardiac contractile modulator. In addition to this PKA-induced phosphorylation, cTnI can be simultaneously phosphorylated at a number of other residues. To fully understand the molecular mechanisms that underlie cardiac muscle regulation at the myofilament level, cTnI phosphorylations must be studied as integrated events. As an initial step towards understanding the integration of these events, we employed a phosphomimetic approach to investigate the effect of cTnI Ser-150 pseudo-phosphorylation (TnI-S150D) on cTnI PKA pseudo-phosphorylation (TnI-S23/24D) function within the thin filament. The combinatorial effect of these phosphorylation events were determined by measuring the binding of calcium to troponin C in thin filaments reconstituted with human Tn. The steady-state calcium sensitivity of TnC was increased ∼2.3 fold in thin filaments reconstituted with TnI-S150D containing Tn, while TnI-S23/24D containing filaments exhibited an ∼3.9 fold decrease of calcium sensitivity. Importantly, in the presence of both cTnI pseudo-phosphorylations (TnI-S23/24/150D) calcium binding was not different from that of wild-type. Likewise, calcium dissociation from thin filaments reconstituted with TnI-S23/24D was increased by ∼3.5 fold, while TnI-S150D containing filaments demonstrated a decrease in calcium dissociation of ∼2.3 fold compared to wild-type filaments. Interestingly the combined pseudo-phosphorylations of TnI-S23/24/150D only blunted TnI-23/24D calcium dissociation kinetics to ∼1.2 fold of the TnI-S23/24D filaments alone. These findings demonstrate the integrated effects of cTnI site-specific phosphorylation crosstalk to affect the function of cTnI PKA-induced phosphorylation. These data further highlight the importance of understanding the integrated role of Tn phosphorylation crosstalk on cardiac contractile regulation.
Is epicardial fat thickness a novel parameter for cardiovascular disease in estrogen receptor-positive breast cancer?
Authors: Bilge Aktas, Murat Sunbul, Gulce Celik, Reshad Rzayev, Umit Mustafa Ugurlu, Sina Mokhtare, Rahib Hasanov, Mehmet Besiroglu, Metin Kanitez, Nazim S. Turhal, Faysal Dane, Fulden Perran Yumuk
Journal: Journal of Clinical Oncology (2016)

e12014 Background: The prevalence of cardiovascular disease (CVD) is unexpectedly high and suboptimally managed in cancer. Increased epicardial fat thickness (EFT) is associated with subclinical atherosclerosis and plays an important role in the pathogenesis of CVD. The primary objective of this study was to evaluate EFT in early stage breast cancer patients for clarification of CVD risk before treatment. Methods: 25 early stage breast cancer patients were eligible for EFT evaluation by echocardiography. This cross-sectional controlled study was conducted between January 2013 to December 2015 at Marmara University Medical Oncology Clinics, Istanbul, Turkey. The study population was consisted of ER-positive, ER-negative and control groups. We evaluated anthropometric, metabolic parameters and left ventricular ejection fraction (LVEF) in cardiovascular risk free patients. Results: Out of 25 patients, 5 had stage I, 9 had stage II and 11 had stage III tumor. Fifteen patients were postmenopausal. 15 ER-positive (15 ER-positive and PR-positive), 10 ER-negative (5 ER-negative and PR-positive, 5 ER-negative and PR-negative) breast cancer and 15 control subjects were enrolled. Median age were 47.7±13.8, 54.8±12.3 and 47.9±5.5 years in ER-positive, ER-negative and control groups respectively(p = 0.224). Body Mass Index(BMI) was less than obesity levels and LVEF was at normal range in all groups. ER-positive patients showed higher EFT than ER-negative patients and controls (34.2±5.5 mm vs 27.9±7.2 mm vs 23.2±2.6 , p < 0.001)(Table 1). Conclusions: EFT appears to be a novel parameter that may enable the detection of the subclinical atherosclerosis and CVD risk in early stage ER-positive breast cancer compared to ER-negative and control groups. Prospective, randomized, double-blind, and large-scale clinical trials are needed. Epicardial fat thickness (EFT) in ER-positive breast cancer compared to ER-negative tumors. ER (+) and PR (+) (n = 15) ER (-) and PR (+/-) (n = 10) Controls (n = 15) p LVEF 63.7±5.9 64.7±7.1 65.8±3.3 0.558 EFT 34.2±5.5 27.9±7.2 23.2±2.6 < 0.001* Age (years) 47.7±13.8 54.8±12.3 47.9±5.5 0.224 BMI 27.8±4.4 25.7±4.3 25.4±4.5 0.351 *p < 0.05 for ER-positive and ER-negative
Effect of miRNA-205 on VEGFA and FGF2 and on resistance to chemotherapeutics in breast cancer.
Authors: Yunhui Hu, Rong Guo, Jiayang Wei, Jing Zhao, Jingjing Liu, Jin Zhang
Journal: Journal of Clinical Oncology (2016)

1028 Background: Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). miR-205 has been reported to be negatively correlated with proliferation and metastasis of many types of cancer, while mechanism of chemoresistance mediated by miR-205 in breast cancer have not been fully elucidated. Methods: Taqman RT-PCR analysis was utilized to examine miR-205 expression in tumor tissues from the breast cancer patients before neoadjuvant chemotherapy treatment, as well as in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by lentiviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related protein cleaved PARP and cleaved caspase 3 by western blot. miR target was studied using transient transfection of luciferase constructs with the 3’UTR of target mRNAs. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. Results: miR-205 expression is positively correlated with neo-adjuvant chemotherapy sensitivity of breast cancer patients. miR-205 is down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-205 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-205 binds VEGFA and FGF2 simultaneously. Adding VEGFA and FGF2 exogenously to chemosensitive breast cancer cells and chemoresistant cells with miR-205 overexpressed, which in turn lead to drug resistance. In addition, resensitization to doxorubicin was also observed in mouse tumor xenografts from cells over-expressing miR-205. Conclusions: miR-205 is involved in the development of MDR in breast cancer cells via targeting VEGFA and FGF2 simultaneously and leading to evasion of apoptosis. Targeting miR-205 may thus provide a potential strategy for reversing drug resistance in breast cancer.
L'oesophagite à éosinophiles de l'adulte: une entité émergente
Authors: H Lamouliatte, L Message, F Zerbib
Journal: Endoscopy (2005)

Parmi les causes peu fréquentes de dysphagie chronique et/ou de sténose oesophagienne, l'oesophagite à éosinophiles de l'adulte (OEA), décrite en 1978 par Landres et al, est encore souvent méconnue malgré un regain d'intérêt récent. Le but de cette étude était de préciser les aspects cliniques et endoscopiques des EOA.
Molecular classification of difficult to diagnose metastatic cancers and characterization of young patients: Clinical experience with the 92-gene assay in &gt;22,000 cases.
Authors: F Anthony Greco, David R. Spigel, Theresa N. Operana, Brock Schroeder, Junmei Liu, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2016)

11554 Background: Patients with metastatic cancers are at risk of suboptimal treatment and outcomes if tumor type/subtype are not definitively determined by standard clinicopathologic evaluation. Molecular classification has been incorporated into clinical algorithms for patients with metastatic cancers of unknown/uncertain origin, and may aid in optimizing treatment; particularly in younger patients where specialized treatment challenges or opportunities can arise. In this study, 92-gene assay results from patients with unclear diagnoses were characterized. Methods: Consecutive biopsies from patients (N = 22,428) submitted for testing with the 92-gene assay (CancerTYPE ID) were investigated. Patient demographics and distribution of molecular diagnoses were analyzed. Subset analysis was performed in young patients ( < 40y). Results: Mean age was 65y (54% female). The most common tumor types predicted were pancreaticobiliary (n = 4495, 20%); squamous cell carcinoma including lung, head & neck, and skin (n = 2142, 9.6%); lung adenocarcinoma (n = 1814, 8.1%); and intestine (n = 1538, 6.9%). Young patients accounted for 3% (n = 731, 61% female) with a mean age of 32y. In these patients, the most common tumor types were pancreaticobiliary (n = 145, 19.8%), intestine (n = 68, 9.3%), sarcoma (n = 61, 8.3%), and neuroendocrine (n = 53, 7.3%). Tumors with higher frequency in young patients were intestine, sarcoma, germ cell, melanoma, thyroid, adrenal, and sex cord stromal tumor; while squamous cell carcinoma and urinary bladder cancer were predicted at lower frequency ( P < 0.05, all comparisons). 55% and 54% of patients ≥ 40y and < 40y, respectively, had tumor types associated with moderate to excellent responsiveness to standard site directed therapies, and 54% and 55% would potentially be eligible for molecularly targeted treatments or immunotherapy. Conclusions: This large series of patient biopsies tested with the 92-gene assay demonstrated significant differences in the distribution of predicted tumor types by age, and highlight its potential to aid in treatment optimization, particularly in young patients with difficult to diagnose cancer.
Measuring patient-reported outcomes (PROs/PROMs) in people with Achilles tendinopathy: how useful is the VISA-A?
Authors: Adrian Mallows, Chris Littlewood, Peter Malliaras
Journal: British Journal of Sports Medicine (2017)

It is important for clinicians and researchers to measure outcomes. Patient-reported outcome measures (PROMs) are short questionnaires, which are self-reported and designed to capture a person’s perceptions of specified aspects of their health status.1 Conceptually, PROMs can be viewed either as a ‘tool for evaluation’ or as a ‘mechanism for improvement’ suited to the many factors that characterise a person’s health status that cannot be observed, measured with a device or analysed with even the most sophisticated imaging methods.2 Such questionnaires are ideally suited to areas such as tendinopathy where disease impact does not correlate consistently with biomarkers.

The Victorian Institute of Sport Assessment - Achilles (VISA-A) Questionnaire is a widely used PROM for Achilles tendinopathy and is available in seven different languages (figure 1). The ability of the VISA-A to improve decision making is determined by its reliability, validity and responsiveness to change, as these are essential psychometric properties for any measure.3 4 Here we critically …
Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing
Authors: Miguel Crespo, Eduardo Vilar, Su-Yi Tsai, Kyle Chang, Sadaf Amin, Tara Srinivasan, Tuo Zhang, Nina H Pipalia, Huanhuan Joyce Chen, Mavee Witherspoon, Miriam Gordillo, Jenny Zhaoying Xiang, Frederick R Maxfield, Steven Lipkin, Todd Evans, Shuibing Chen
Journal: Nature Medicine (2017)
Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice
Authors: A.D. Cohen, J.J. Wu, L. Puig, S. Chimenti, R. Vender, M. Rajagopalan, R. Romiti, C. de la Cruz, L. Skov, C. Zachariae, H.S. Young, P. Foley, J.M. van der Walt, L. Naldi, E.P. Prens, A. Blauvelt
Journal: British Journal of Dermatology (2017)

The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of 'big data' should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies.
Authors’ reply to Dib
Authors: Adrian Stanley, Stig Laursen
Journal: BMJ (2017)

Pre-endoscopy scoring systems do not take into account whether bleeding is from varices because that is unknown before endoscopy. Several risk scoring systems, however, such as the Glasgow Blatchford score and admission Rockall score include underlying liver disease (and other comorbidities) as variables. In addition, and as Dib notes,1 the AIMS65 score includes albumin and international normalised ratio, which are often altered in patients …
Abstract 409: Role of the Mitochondrial AAA+ Lon Protease in Cardioprotection
Authors: Min Li, Sundararajan Venkatesh, Eman Rashad, Toshiro Saito, Junichi Sadoshima, Carolyn K Suzuki
Journal: Circulation Research (2015)

Mitochondrial Lon is an ATP-powered proteolytic machine that selectively degrades regulatory proteins as well as misfolded, unassembled and damaged proteins. Lon is a key mediator of mitochondrial quality control, adapting mitochondrial metabolism to hypoxic, oxidative, and proteotoxic stresses. Although studies imply that up-regulating Lon in the failing or ageing heart is ameliorative, there is little detailed in vivo data about its importance in cardiovascular health and disease. To test the hypothesis that Lon protects the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of Lon under the control of the alpha-MHC promoter (Tg-Lon). Lon was specifically overexpressed in heart with no change in the levels of endogenous substrates TFAM or mitochondrial aconitase, or the mitochondrial ClpXP protease. Baseline analysis of 2-11 month old mice showed no significant difference in body or heart weight or ventricular weight/tibial length. At 2-3 months, no significant difference was observed by echocardiography or histology. However, Tg-Lon mice showed significantly reduced cardiac injury in response to ischemia reperfusion (I/R)- ischemia (45 min)/reperfusion (24 hr). At 6-9 months Tg-Lon, infarct size/area at risk (AAR) was 32%±2.3 SEM versus NTg that was 51%±3.2 SEM (p-value&lt;0.003, n=9, n=4). At 3-5 months the infarct size/AAR for Tg-Lon was 37%±2.9 SEM versus NTg 51%±1.6 SEM, p&lt;0.009, n=4, n=4); and at 3 months, Tg-Lon was 37%±2.0 SEM versus NTg 47% ± 1.4 SEM, p&lt;0.008, n=3, n=4). In all cases, there was no change in AAR/left ventricle (AAR/LV), and no difference in LV/body weight (LV/BW). At baseline, mitochondria isolated from Tg-Lon hearts showed lower oxygen consumption rates (OCR, pmoles O2/min) as compared to NTg. Average OCR for Tg-Lon was 12,997±708 SD AUC (1 μg), by contrast to NTg that was 32,042±320 (1 μg) (p&lt;0.001, n=5, n=5). Associated with lower OCR of Tg-Lon, was a significant reduction of Complex I subunit NDUFB8 of NADH dehydrogenase, which was reduced 2.2 fold (p&lt;0.001) as compared to NTg in LV extracts as well as in isolated heart mitochondria. These data demonstrate that Lon overexpression promotes cardioprotection, and that this effect may be linked to a reduction in basal mitochondrial oxygen consumption.
Germline mutation in the KLRC2 gene to inform intrinsic resistance and inferior responses to trastuzumab in breast cancer.
Authors: Fengrui Xu, Li Bian, Yujuan Zhou, Ge Du, Jianbin Li, Tao Wang, Shaohua Zhang, Santai Song, Zefei Jiang
Journal: Journal of Clinical Oncology (2016)

e12078 Background: Trastuzumab elicit high response rates among individuals with HER2 positive breast cancer. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic variation affecting an individual’s response to trastuzumab. Although cancers used be classified according to their somatically acquired driver mutations, germline alterations can also directly modulate the responses of such cancers to targeted therapies and can strongly influence clinical outcomes. To correlate the variable clinical features of HER2 positive breast cancer with germline alterations, we studied the whole genome of 22 patients. Methods: All the 22 patients have been treated by trastuzumab within second-line salvage treatment, in which 16 patients received trastuzumab as first-line treatment. Among them,11 patients keep continuous benefit from trastuzumab while the others showed intrinsic resistance (we called intrinsic resistance as getting progression within 16 weeks during the treatment of trastuzumab). The whole genome from periheral neutrophils were detected by Illuminal sequencing platform and Pathway analysis was performed with KEGG and GeneGo Metacore. Results: A significant SNP in KLCR2 gene (chr12:10583431C > T, rs61917664) were detected in 8/11 patients of the trastuzumab-intrinsic resistance group but no patients in the trastuzumab-senstive group. KLRC2 is one of NKG2 family genes and encodes transmembrane proteins for natural killer cells. In the pathway analysis, we find that KLRC2 belongs to the natural killer cell mediated cytotoxicity pathway, and there were another 5 genes showed similar tendency as KLRC2 in this pathway. Conclusions: We use the NGS technology to reveal how germline variants and mutations may be associated with cancer. This study identified the trastuzumab resistance-related KLRC2 germline mutation in breast cancer, and informed that the natural killer cell mediated cytotoxicity pathway may play an important role in trastuzumab-intrinsic resistance mechanism. However, we need some more studies in vitro or in vivo to verify our finds.