tbuckley/cabot-search huggingface dataset:
Prognostic factors in <i>KRAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts) treated with biweekly cetuximab (C) plus irinotecan, fluorouracil, and leucovorin (FOLFIRI): A phase II study.
Authors: Nicola Personeni, Lorenza Rimassa, Claudio Verusio, Sandro Barni, Annarita Destro, Carlotta Raschioni, Silvia Armenia, Irene Floriani, Chiara Gerardi, Marta Monteforte, Eugenio Villa, Silvia Bozzarelli, Massimo Roncalli, Valter Torri, Roberto Labianca, Armando Santoro
Journal: Journal of Clinical Oncology (2013)

e14611 Background: Retrospective studies showed that efficacy of C increases in molecularly-defined subsets of KRAS wt mCRC pts. In pretreated pts, biweekly C seems as effective as a weekly schedule. Aim of this field-practice study was to evaluate the efficacy of FOLFIRI plus biweekly C (C-FOLFIRI) as first-line treatment for mCRC and prospectively validate PTEN expression as a prognostic marker. Methods: Pts with previously untreated metastatic KRAS wt mCRC not suitable for curative-intent resection were eligible. Initially, pts were randomized to receive FOLFIRI alone or in combination with C (500 mg/m 2 every two weeks). After a protocol amendment, pts were assigned to receive only C-FOLFIRI, while the FOLFIRI alone arm was discontinued. Clinical outcome was assessed according to expression of PTEN and MET by immunohistochemistry (IHC), as well as to BRAF mutations. Results: From April, 2009 to June, 2012, a total of 89 pts were enrolled. 35 pts were randomly assigned to receive FOLFIRI alone, while 54 pts received C-FOLFIRI: 33 were treated in the random phase and 21 after protocol amendment. Median overall survival (OS) was 17.7 months for FOLFIRI and 23.3 months for C-FOLFIRI. Corresponding median progression-free survival was 8.2 and 6.8 months, respectively. Objective response rate was 52.0% for FOLFIRI and 52.3% for C-FOLFIRI. The toxicity profile of C-FOLFIRI was consistent with that expected from a weekly C schedule. 23/38 pts (61.0%) assessed for PTEN were positive for IHC expression, 8/39 pts (21.0%) had a MET high status, 6/45 pts (13.3%) had BRAF mutations. In pts treated with C-FOLFIRI, only BRAF mutations negatively affected OS (Hazard ratio mutations vs. wt: 4.77; 95%CI 1.41-16.13; p = 0.01). Conclusions: Safety, effectiveness and generalizability of C-FOLFIRI validate in field practice results gained with FOLFIRI plus a weekly C schedule. Despite the small sample size, analysis of BRAF mutations reaffirms the strong prognostic impact of this biomarker. The extended analysis of BRAF mutations, PTEN and MET expression on all pts is ongoing. Data will be presented. Clinical trial information: NCT01068132.
The relationship between metastatic status and exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC)
Authors: Brittany Case, Moh'd Khushman, Arun Bhardwaj, Girijesh Patel, Javier Laurini, Kelly Roveda, Robert Donnell, Kelley Sherling, Marcus Tan, Lee Thompson, Cindy Nelson, Mary Wyatt, Seema Singh, William Taylor, Ajay Singh
Journal: Annals of Oncology (2017)
Abstract P152: Cardiac mTOR Preserves Cardiac Function and Inhibits the Inflammatory Response After Transient Ischemia
Authors: Toshinori Aoyagi, Brendan T Inouye, Takashi Matsui
Journal: Circulation Research (2011)

Recent reports strongly suggested that the mammalian target of rapamycin (mTOR) is necessary for cardiomyocyte survival in pathological cardiac hypertrophy. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg), we reported that cardiac mTOR is sufficient to protect the heart against heart failure in pathological hypertrophy, accompanied by a decrease in production of proinflammatory cytokines. However, the role of cardiac mTOR in ischemic cardiac injury remains undefined. To assess the effects of cardiac mTOR in cardiac ischemia, we studied the response of hearts from mTOR-Tg mice to global ischemia-reperfusion injury (IRI) (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. mTOR-Tg mice demonstrated improved functional recovery compared with littermate control (WT) mice [percent recovery of LV developed pressure (LVDP); 44.6±7.3 vs. 24.7±5.3 %, mTOR-Tg vs. WT, n=9 each, p&lt;0.05]. Biochemical analyses demonstrated that the level of mTOR protein decreased under IRI stress in WT while the level of mTOR protein in post-IRI mTOR-Tg mice was comparable to non-ischemic control mice. Both mTORC1 (p70S6K) and mTORC2 (Akt) activation in mTOR-Tg mice were increased by IRI, while these were not changed in WT mice after IRI. Quantitative RT-PCR demonstrated that expression of proinflammatory cytokines in mTOR-Tg mice after IRI was significantly lower than WT mice (IL-6, 7.1±1.5 vs. 14.6±1.6, p&lt;0.005; TNF-alpha, 2.1±0.4 vs. 5.1±0.8, p&lt;0.01; post-IRI mTOR-Tg mice vs. WT mice, fold change over non-ischemic control WT mice, n=9 each). To further characterize the inflammatory response, we measured cytokine in the effluent samples by ELISA. We observed that secretion of IL-6 in post-IRI mTOR-Tg mice was significantly lower than that in WT mice (50.1±11.5 vs. 95.6±23.8 pg/ml, post-IRI mTOR mice vs. post-IRI WT mice, n=9 each, p&lt;0.05). IL-6 is known as a strong prognostic predictor in patients with heart failure. Taken together, these findings suggest that cardiac mTOR is sufficient to substantially preserve cardiac function and prevent the inflammatory response, which may have relevance for settings in heart failure.
FoundationOne as a relevant tool for comprehensive genomic profiling and assessment of tumor mutation burden in the era of precision oncology in India.
Authors: Amit Verma, Nitesh Rohatgi, Pramod Kumar Julka, Meenu Walia, Ankur Bahl, Ramandeep Singh Arora, Harit Chaturvedi, Anil Kumar Anand, Ranga Rao, Laurie M. Gay, Jatinder Kaur
Journal: Journal of Clinical Oncology (2017)

e23096 Background: Comprehensive genomic profiling (CGP) is gaining acceptability globally, but clinical experience in developing countries like India is limited. CGP identifies genomic alterations (GA), with tumor mutation burden (TMB) and microsatellite status (MSI), revealing therapeutic options such as targeted inhibitors and immunotherapies. We sought to evaluate the mutation frequency and actionability across tumors. Methods: Metastatic and/or refractory patients (referred to Personalized Cancer Medicine Clinic) underwent CGP analysis, including calculation of TMB and MSI, using a targeted NGS panel (FoundationOne, 53 samples; FoundationOne Heme, 4 samples). This panel detects all relevant classes of GA: base substitutions, small indels, rearrangements and copy number changes. Mutation frequencies were compared with the larger Foundation database. TMB status was reported as low (≤5 mutations/Mb), intermediate (6-19 mut/Mb) or high (≥20 mut/Mb). Results: The most common tumor types were lung (23%), breast (14%) and sarcoma (12%); other tumor types, including unknown primary constituted the rest (51%). Most samples were from metastatic sites (60%). Oncogenic GA were found in 131 genes across all tumor subtypes and affected major pathways: apoptosis/cell cycle (31%), PI3K (14%), transcriptional regulation (13%), and receptor tyrosine kinases (10%). Among these GA, 38 were considered actionable and were distributed across 43 (75%) samples. Therapies with FDA approval for the tumor type analyzed were indicated for 18 samples; an additional 25 samples had GA associated with therapies FDA approved for another indication. More than 1 actionable GA was identified in 24/43 (56%). TMB status was low in 36 (63%), intermediate in 19 (33%) and high in 2 (3.5%). High TMB status correlated with high MSI status (p &lt; 0.001). Trend observed in the mutation frequency was comparable with the larger Foundation database. Conclusions: This is the first study in India showing CGP identified actionable targets associated with FDA approved therapies in approx. 32% of cases. TMB status identified 2/57 samples with high mutation burden for whom immunotherapy might be relevant.
Abstract P007: Cardiomyocyte Damage-Released Extracellular S100A1 Protein Promotes Regeneration of Infarcted Myocardium by Modulating Cardiac Fibroblast Function
Authors: David Rohde, Gang Qiu, Nicole Herzog, Hugo A Katus, Angelika Bierhaus, Karsten Peppel, Patrick Most
Journal: Circulation Research (2011)

Background: Similar to heart muscle-specific creatinkinase (CK-MB), S100A1 protein is released from damaged human cardiomyocytes in response to myocardial infarction (MI). Since S100A1-knock out (SKO) mice display rapid post-MI onset of adverse myocardial remodeling and accelerated transition to heart failure, we assessed the hypothesis that ischemia-related release of S100A1 protein modulates myocardial regeneration. Methods and Results: After LAD ligation in C57/B6 mice, S100A1 serum levels peaked at 10 µg/ml 8 hours post-MI, precisely mirroring the time course previously observed in MI patients. RT-PCR analyses in post-MI whole heart samples revealed significantly lower I-CAM (−50%) and IL-10 (−75%) mRNA abundance as well as heightened Collagen-1 (+40%) and VEGF (+80%) expression in SKO vs. WT mice (p&lt;0.05, n=6 in each group). Interestingly, injection of an S100A1-neutralizing antibody prior to MI in WT mice mimicked the abnormalities observed in post-ischemic SKO animals. To further elucidate extracellular S100A1 biological activity, cardiomyocytes, cardiac fibroblasts (CF), endothelial and smooth muscle cells were exposed to S100A1 in vitro . A rapid internalization of S100A1 was exclusively found in CF, resulting in a phosphorylation of ERK1/2, JNK, and p38 with subsequent activation of NF-kappaB as assessed by Western Blot (WB) and EMSA. RT-PCR and WB analyses revealed significant alterations in CF gene expression in response to S100A1, including an increase in I-CAM (3,5-fold) and IL-10 (20-fold) mRNA levels and diminished Col-1 (−80%) expression. Similar effects were observed after direct injection of S100A1 protein into the left ventricular apical region of WT mice in vivo (S100A1- vs. PBS-injection, n=6). In SKO mice, intraperitoneal application of S100A1 prior to MI largely normalized the adverse gene expression pattern towards WT animals. Conclusions: Our study provides first evidence for cardiomyocyte damage-released S100A1 to act as an endogenous mediator of post-MI inflammation and tissue repair. Considering today's unability to manipulate these molecular mechanisms, extracellular S100A1 might represent a promising target for future therapies of MI.
INJURIES IN GERMAN MEŃS PROFESSIONAL ICE HOCKEY
Authors: Hendrik Bloch, Christian Klein, Patrick Luig
Journal: British Journal of Sports Medicine (2017)

Background Injury incidences during international major ice hockey events are high, but information about ice hockey injuries in Germany, particularly in regular league play, is lacking. Objective Analysis of injury characteristics in German professional ice hockey. Design Prospective observational cohort study. Setting Two highest German professional leagues in men's ice hockey. Participants All first and second division ice hockey players who played at least in one competitive club match during the season 2014/15 season (n=812). Assessment of Risk Factors Analysis of all injuries of these players that were registered by clubs or physicians with the VBG as a part of the occupational accident reporting and that either led to the player's short-term disability (time-loss) and/or to medical treatment costs (medical-attention). Main Outcome Measurements Injury prevalence and incidence, injured body parts, type of injury, medical treatment costs, days of absence. Results A total of 2.045 injuries were recorded. 76.7% of all players were injured at least once. In mean each player had 2.52 injuries per season. Incidence rate in the first division (2.7 injuries/season) was significantly higher than in second division (2.3 injuries/season). The majority of injuries (69.1%) occurred during matches with a match incidence of 136.8 injuries per 1000 h. Nearly one third (30.7%) of all training injuries occurred during the pre-season. The head (17.9%), the shoulder (10.7%) and the thigh (10.1%) were the body parts most frequently affected. Shoulder injuries lead to the highest share of overall time-loss (20.5%) and medical treatment costs (22.0%). Goalkeeper had significant lower overall risk of injury (1.5 injuries/season), but higher risk of knee and thigh injuries. Conclusions Injury Risk in German professional ice hockey is high, especially during match play. Preventive measures should aim at sport- and position-specific risk factors. Special focus should be laid on player preparedness after off-season break.
Registry Data as an “Alert” System for Detection of Occupational Lung Cancer Risk
Authors: Robert H. Depue, Jr.
Journal: JNCI Journal of the National Cancer Institute (1980)

Journal Article Registry Data as an “Alert” System for Detection of Occupational Lung Cancer Risk Get access Robert H. Depue, Jr. Robert H. Depue, Jr. Division of Cancer Cause and Prevention National Cancer Institute, Bethesda, Maryland 20205 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 65, Issue 3, September 1980, Pages 495–496, https://doi.org/10.1093/jnci/65.3.495 Published: 01 September 1980
The reaction of cinnamaldehyde and cinnam(o)yl derivatives with thiols
Authors: Alessandro Autelitano, Alberto Minassi, Alberto Pagani, Orazio Taglialatela-Scafati, Giovanni Appendino
Journal: Acta Pharmaceutica Sinica B (2017)

Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the "native" reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of simple thiols and reactive protein thiols that can benefit from iminium ion catalysis in Michael reactions. Cinnamoyl esters and amides, as well as cinnamyl ketones and oximes, did not show any reactivity with the two probe thiols, while cinnamaldehyde (1a) reacted with cysteamine to afford a mixture of a thiazoline derivative and compounds of multiple addition, and with aliphatic thiols to give a single bis-dithioacetal (6). Chalchones and their vinylogous C5-curcuminoid derivatives were the only cinnamoyl derivatives that gave a thia-Michael reaction. From a mechanistic standpoint, loss of conjugation in the adduct might underlie the lack of a native Michael reactivity. This property is restored by the presence of another conjugating group on the carbonyl, as in chalcones and C5-curcuminoids. A critical mechanistic revision of the chemical and biomedical literature on cinnamaldehyde and related compounds seems therefore required.
Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics
Authors: Yuanqing Yan, Ruli Gao, Thao L.P. Trinh, Maria B. Grant
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Pancreatic adenocarcinomas (PAAD) often are not diagnosed until their late stages, leaving no effective treatments. Currently, immunotherapy provides a promising treatment option against this malignancy. However, a set of immunotherapy agents benefit patients with many types of cancer, but not PAAD. Sharing the origin in the same organ, diabetes and PAAD tend to occur concurrently. We aimed to identify the impact of diabetes on immunotherapy of PAAD by conducting a comparative genomics analysis. Experimental Design: We analyzed level 3 PAAD genomics data (RNAseq, miRNAseq, DNA methylation, somatic copy number, and somatic mutation) from The Cancer Genome Atlas (TCGA) and Firehose. The differential molecular profiles in PAAD with/out diabetes were performed by the differential gene expression, pathway analysis, epigenetic regulation, somatic copy-number alteration, and somatic gene mutation. Results: Differential gene expression analysis revealed a strong enrichment of immunogenic signature genes in diabetic individuals, including PD-1 and CTLA4, that were currently targetable for immunotherapy. Pathway analysis further implied that diabetic individuals were defective in immune modulation genes. Somatic copy-number aberration (SCNA) analysis showed a higher frequency of amplification and deletion occurred in the cohort without diabetes. Integrative analysis revealed strong association between differential gene expression, and epigenetic regulations, however, seemed not affected by SCNAs. Importantly, our somatic mutation analysis showed that the occurrence of diabetes in PAAD was associated with a large set of gene mutations encoding genes participating in immune modulation. Conclusions: Our analysis reveals the impact of diabetes on immunodeficiency in PAAD patients and provides novel insights into new therapeutic opportunities. Clin Cancer Res; 23(20); 6363–73. ©2017 AACR.
Pan-Hematopoietic Cancer Gene Expression Analysis Identifies Immunologically Active Acute Myeloid Leukemia Subtypes
Authors: Olli Dufva, Petri Pölönen, Mikko A Keränen, Thomas Liuksiala, Jake Lin, Juha Mehtonen, Sergei Häyrynen, Kirsi Granberg, Matti Nykter, Olli Lohi, Merja Heinäniemi, Satu Mustjoki
Journal: Blood (2016)
Experiences of rosacea and its treatment: an interpretative phenomenological analysis
Authors: S.A. Johnston, M. Krasuska, A. Millings, A.C. Lavda, A.R. Thompson
Journal: British Journal of Dermatology (2017)

While rosacea is a chronic skin condition, it can often have a large psychosocial impact on the individual. There is therefore a need to understand the experience of living with rosacea from the patient perspective.To examine the experience of living with rosacea and the experience of seeking and receiving treatment.Nine participants took part in semistructured interviews, which were analysed using interpretative phenomenological analysis.Three superordinate themes were identified within the data: 'self-consciousness', which focused on the fear of others assigning blame to participants for having caused symptoms; 'avoidance, concealment and hiding emotions', referring to the coping strategies participants employed in response to rosacea; and 'inconsistencies in general practitioner treatment and guidance', which focused on the need for medical professionals to assess the psychosocial well-being of patients with rosacea.Rosacea can have a negative impact on the daily life of people with the condition, contributing to lowered self-esteem, embarrassment and feelings of shame. Engaging in emotion-focused and behavioural/avoidant-focused coping strategies increased participants' confidence and reduced their avoidance of social situations. However, such strategies might still serve to maintain underlying unhelpful cognitive processes. Consequently, it is important for medical professionals to assess for the presence of cognitive factors that might contribute to maintaining distress in patients with rosacea, and where unhelpful thoughts or beliefs are reported, patients may need to be referred for psychological support.
Abstract 340: From Stem Cells to Cardiomyocytes: HDAC1 Induces Cardiovascular Differentiation by Regulating SOX17-BMP2 Expression in Early Development.
Authors: Eneda Hoxha, Erin Lambers, Veronica Ramirez, Prasanna Krishnamurthy, Suresh Verma, Melissa Thal, Raj Kishore
Journal: Circulation Research (2012)

Cardiomyocytes derived from embryonic and induced pluripotent stem cells (ES/iPS) provide an excellent source for cell replacement therapies following myocardial ischemia. However, some of the obstacles in the realization of the full potential of iPS/ES cells arise from incomplete and poorly understood molecular mechanisms and epigenetic modifications that govern their cardiovascular specific differentiation. We identified Histone Deacetylase 1 (HDAC1) as a crucial regulator in early differentiation of mES and iPS cells. We propose a novel pathway in which HDAC1 regulates cardiovascular differentiation by regulating SOX17 which in turn regulates BMP2 signaling in differentiating pluripotent cells. Utilizing stable HDAC1 knock-down (HDAC1-KD) cell lines, we report an essential role for HDAC1 in deacetylating regulatory regions of pluripotency-associated genes during early cardiovascular differentiation. HDAC1-KD cells show severely repressed cardiomyocyte differentiation potential. We propose a novel HDAC1-BMP2-SOX17 dependent pathway through which deacetylation of pluripotency associated genes leads to their suppression and allows for early cardiovascular-associated genes to be expressed and differentiation to occur. Furthermore, we show that HDAC1 affects DNA methylation both during pluripotency and differentiation and plays a crucial, non-redundant role in cardiovascular specific differentiation and cardiomyocyte maturation. Our data elucidates important differences between ES and iPS HDAC1-KD cells that affect their ability to differentiate into cardiovascular lineages. As varying levels of chromatin modifying enzymes are likely to exist in patient derived iPS cells, understanding the molecular circuitry of these enzymes in ES and iPS cells is critical for their potential therapeutic applications in regenerative medicine. Further research in the molecular mechanisms involved in this process will greatly aid our understanding of the epigenetic circuitry of pluripotency and differentiation in pluripotent cells.
Hand-foot skin reaction (HFSR) and outcomes in the phase 3 CORRECT trial of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Axel Grothey, Liping Huang, Andrea Wagner, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2017)

3551 Background: Cutaneous toxicity is a known adverse effect of multikinase inhibitors and has been associated with clinical outcomes (Granito 2016). In the phase 3 CORRECT trial (NCT01103323), the multikinase inhibitor regorafenib significantly improved overall survival (OS) vs placebo in patients with mCRC (hazard ratio [HR] 0.77, 95% CI 0.64, 0.94; 1-sided P = 0.0052). This retrospective analysis explored whether HFSR was associated with outcomes in CORRECT. Methods: Patients randomized to receive regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS and progression-free survival (PFS) (95% CI) were calculated using the Kaplan–Meier method. Patients who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of the 505 randomized patients, 500 received at least one dose of regorafenib. Among the treated patients, 47% (n = 235) had HFSR of any grade and 17% (n = 83) had HFSR grade 3. Of the patients who had HFSR, 69% (n = 162) had their first HFSR event (any grade) during the first treatment cycle. There was some imbalance in baseline characteristics between groups (Table). Survival was improved in patients who had HFSR at any time vs those who did not (Table). The OS benefit was also observed in patients who had the first HFSR event during Cycle 1 vs those who did not (median OS 7.2 vs 5.7 months; HR 0.66, 95% CI 0.51, 0.87). Conclusions: This post-hoc exploratory analysis suggests that patients who had HFSR had a greater treatment benefit from regorafenib. Since HFSR and survival are post-baseline assessments, results may be confounded by baseline factors or other unknown factors. Clinical trial information: NCT01103323. [Table: see text]
A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients
Authors: D Beck, J A I Thoms, C Palu, T Herold, A Shah, J Olivier, L Boelen, Y Huang, D Chacon, A Brown, M Babic, C Hahn, M Perugini, X Zhou, B J Huntly, A Schwarzer, J-H Klusmann, W E Berdel, B Wörmann, T Büchner, W Hiddemann, S K Bohlander, L B To, H S Scott, I D Lewis, R J D'Andrea, J W H Wong, J E Pimanda
Journal: Leukemia (2017)