tbuckley/cabot-search huggingface dataset:
Minimal Residual Disease Status Predicts Progression-Free Survival in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (KRd)
Authors: Jagoda Jasielec, Dominik Dytfeld, Kent A. Griffith, Kathryn McDonnell, Daniel Lebovic, Malathi Kandarpa, Tara Anderson, Melissa Mietzel, Malek Faham, Liana Lee, Joan Levy, Mattina Alonge, Shaun Rosebeck, Mark Kaminski, Andrzej Jakubowiak
Journal: Blood (2014)
A Diet Low in Fermentable Oligo-, Di-, and Monosaccharides and Polyols Improves Quality of Life and Reduces Activity Impairment in Patients With Irritable Bowel Syndrome and Diarrhea
Authors: Shanti Eswaran, William D. Chey, Kenya Jackson, Sivaram Pillai, Samuel W. Chey, Theresa Han-Markey
Journal: Clinical Gastroenterology and Hepatology (2017)
Abstract 111: NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Regulates Atypical Neddylation and Protects Against Myocardial Ischemia-reperfusion Injury
Authors: Jie Li, Wenxia Ma, Huizhong Li, Ning Hou, Xuejun Wang, Il-man Kim, Faqian Li, Huabo Su
Journal: Circulation Research (2015)

Neddylation is a ubiquitination-like pathway that covalently conjugates NEDD8 to target proteins and involves in diverse cellular processes. Under stress conditions, NEDD8 forms a chain or mixes with ubiquitin to modify protein substrates in NEDD8 conjugating enzymes-independent manner (atypical neddylation). The functional consequence of atypical neddylation remains unexplored in any cell types including cardiomyocytes. Here we report that increased neddylated proteins were observed in desmin-related cardiomyopathic (DRC) mouse hearts, mouse hearts subjected to myocardial ischemia-reperfusion (I/R) and human failing hearts. In cultured cardiomyocytes, multiple cellular stresses induced atypical neddylation, which was attenuated by NUB1L overexpression but exaggerated by loss of NUB1L, revealing NUB1L as a negative regulator of atypical neddylation. Activation of atypical neddylation by forced expression of NEDD8 accumulated a proteasome surrogate substrate GFPu, while suppression of atypical neddylation by NUB1L overexpression enhanced the degradation of GFPu and a DRC-linking misfolded protein. NUB1L is necessary and sufficient to protect cardiomyocytes against proteotoxic stress-induced cell injury. In vivo, cardiac-specific overexpression of NUB1L (NUB1L-O/E) in mice dose-dependently reduced neddylated proteins and facilitated the degradation of the proteasome surrogate substrate. NUB1L-O/E mice displayed no discernible cardiac structural and functional abnormality at baseline, but exihibted reduced apoptotic cardiomyocytes, limited infarct sizes and preserved cardiac function in response to I/R. We therefore conclude that NUB1L suppresses atypical neddylation, enhances proteasome proteolytic function and protects against myocardial I/R injury. Targeting atypical neddylation could be a novel therapeutic strategy to treat cardiac ischemic cardiomyopathy.
Re: Weighing the Risks and Benefits of Tamoxifen Treatment for Preventing Breast Cancer
Authors: J. Norsigian
Journal: JNCI Journal of the National Cancer Institute (2000)

In April 1998, the Breast Cancer Prevention Trial (P-1) was halted 14 months early because of a 45% reduction in breast cancer among those patients receiving tamoxifen. At that time, all of the major networks and newspapers made a lead story out of the National Cancer Institute’s announcement of this finding. Many of the media reports repeated the investigators’ contention that the trial’s entry criteria identified women who are potentially eligible for tamoxifen therapy, e.g., all women over the age of 60 years (1). Now, 11⁄2 years later, the Journal has published a special article entitled “Weighing the Risks and Benefits of Tamoxifen Treatment for Preventing Breast Cancer” (2). Its authors assessed the data from the Breast Cancer Prevention Trial P-1 (3) and estimate that the benefits of taking tamoxifen substantially outweigh the risks only for younger high-risk women; conversely, the risks might outweigh the benefits for most black women older than 60 years of age and most white women older than 60 years with a uterus. In other words, tamoxifen therapy is an appropriate consideration for a much smaller subset of high-risk women than was originally thought. The Journal special article (2) states that the risk/benefit assessment grew out of a National Cancer Institute-sponsored workshop held in July 1998. Why did it take so long to get this assessment into print? By contrast, results of the P-1 trial were published by the Journal less than 6 months after the trial ended. Until this assessment was published, it was not known which women are at enough of a high risk to make tamoxifen’s potentially fatal side effects worth its potential benefits. Yet as early as October 1998, tamoxifen received U.S. Food and Drug Administration (FDA) approval
Amplification of the Topoisomerase 2a Gene Occurs in Colorectal Cancer and is Associated with more Aggressive Disease
Authors: A Coss, K Sheahan, S Sullivan, E Fox, J Hyland, D O'Donoghue, D Leahy, H Mulcahy, J O'Sullivan
Journal: Endoscopy (2006)

Background: Topoisomerase 2a (TOP2A) is a key enzyme involved in DNA replication and is frequently co-amplified with HER2 in breast cancer. However, limited data are available on its role in colorectal cancer (CRC), and amplification of the TOP2A gene in this disease has not been investigated. Previously, using microarray-based comparative genomic hybridisation (array CGH), we identified amplifications of the TOP2A gene in CRC tissue.
3' Untranslated Region (UTR) Alterations Are Frequently Targeted By MM-Related Mirnas and Affects the Clinical Outcome
Authors: Mehmet K. Samur, Irtisha Singh, Lee Shih-Han, Adam Samuel Sperling, Mariateresa Fulciniti, Yu-Tzu Tai, Giovanni Parmigiani, Christina S. Leslie, Christine Mayr, Nikhil C Munshi
Journal: Blood (2016)
Abstract P188: Suppression of MK2 Signaling Protects Against Pressure Overload-Induced Cardiac Dysfunction
Authors: Maya Khairallah, Dharmendra Dingar, Ramzi J Khairallah, George Vaniotis, Yanfen Shi, Matthias Gaestel, William C Stanley, Jean C Tardif, Bruce G Allen
Journal: Circulation Research (2011)

p38 mitogen-activated protein kinases (MAPKs) regulate a broad range of cellular activities but have been implicated in the pathogenesis of cardiovascular diseases. The mechanisms whereby p38 exerts divergent effects are unknown. Current p38 inhibitors both produce serious side effects and loose efficacy with chronic use. Hence, a better understanding of the downstream targets of p38, i.e. MAPK-activated protein kinases (MKs), is essential. We hypothesized that inhibition of MK2 activity (MK2-/-) during chronic pressure overload is cardioprotective. Twelve-week-old MK2-/- and littermate control (MK2+/+) mice were subjected to transverse aortic constriction (2 wks, n=8). MK2-/- mice showed a ∼20% reduced increase in heart weight-to-tibia length ratio (Fig A) despite similar increases in mean blood pressure and ANP expression. Compared to controls, banded MK2-/- hearts also showed preserved left ventricular: (i) fractional shortening, (ii) ejection fraction (preserved at 72.5 ± 2.2% after banding for MK2-/- but decreased from 67.9 ± 3.6% to 58.8 ± 3.4% in MK2+/+, p&lt;0.05, Fig B), and (iii) diastolic function evidenced by the ratio of transmitral and myocardial early diastolic velocities (E/Em preserved after banding in MK2-/- but increased by 78.8 ± 11.1% in MK2+/+, p&lt;0.01). MK2 deficiency did not reduce interstitial fibrosis. For equivalent respiration rates, mitochondria from MK2-/- hearts showed a significant decrease in Ca2+-sensitivity for mitochondrial permeability transition pore opening (p&lt;0.05, Fig C). Overall, these results suggest that MK2 mediates part of the detrimental remodeling evoked by chronic pressure overload-induced activation of p38.
John Kenneth Oyston
Authors: John Oyston
Journal: BMJ (2017)

In a home movie taken in 1955, John Kenneth Oyston (“Ken”) appears happy, relaxed, and self possessed, as he sails a wooden boat around the west coast of Scotland with four colleagues. He is a handsome young man, with wavy black hair and a pronounced dimple in his chin. His life was full of promise. He had recently turned 30, and he had just passed his fellowship of the Royal College of Surgeons, so the academic grind was behind him. He was planning to marry Audrey Wilkinson, a stunning redheaded sister on the plastics ward at the Royal Victoria Infirmary in Newcastle, and he was contemplating a career as an orthopaedic surgeon …
Lower haemoglobin may be the result rather than the cause of larger fetuses
Authors: D. Howe
Journal: BMJ (1995)

tional leaflet published by the National Society for the Prevention of Cruelty to Children and the Department of Health, Handle with Care, is a starting point for educating parents and other carers.This leaflet can be used by midwives and health visitors as a basis for individual work with parents, particularly targeting those considered to be most at risk.We stated that shaking a baby is dangerous, and this is recognised by paediatricians.The purpose of the editorial and the campaign by the National Society for the Prevention of Cruelty to Children was to alert carers to the dangers of shaking infants
Abstract 109: Regulation of TNF-α Signaling in Cardiomyocytes via a Novel Interaction Between TNF-α Receptor and RASSF1A
Authors: Tamer M Mohamed, Min Zi, Arfa Maqsood, Sukhpal Prehar, Ludwig Neyses, Delvac Oceandy
Journal: Circulation Research (2012)

Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that plays key roles in the pathogenesis of heart failure. Cardiomyocytes express the TNF-α receptor (TNFR), however, the mechanism of TNF-α signal transmission in cardiomyocytes is not completely understood. Recent studies showed that in cancer cells TNFR is regulated by Ras-association domain family 1 isoformA (RASSF1A). Therefore, we investigated whether RASSF1A modulates TNF-α signalling in cardiomyocytes. We used RASSF1A knockout (KO) mice and wild type (WT) controls and stimulated them with TNF-α (10µg/kg i.v.). In WT mice acute treatment with low dose of TNF-α increased cardiac contractility as indicated by the change in end systolic elastance (Ees) (baseline Ees (mmHg/μl), 3.3±0.5; Ees after TNF-α stimulation, 5.7±0.8, P&lt;0.05) which is consistent with previously published data (Circulation 2004; 109:406–411). However, KO mice showed a blunted contractile response following acute TNF-α treatment (baseline Ees: 3.05±0.4 vs Ees after TNF-α: 2.54±0.3). Consistently, isolated cardiomyocytes from WT mice showed 40% increase in calcium transient amplitude in response to TNF-α (10 ng/ml) stimulation (n=24 cells, p&lt;0.05). However, KO cardiomyocytes showed no significant increase in calcium transient amplitude following the same stimulation (n=24 cells). We also found that RASSF1A formed a molecular complex with TNF-α receptor in cardiomyocytes and this interaction was essential in the recruitment of TRADD and TRAF2, the major downstream effectors of TNF-α signalling. By mapping the interaction domain we found that the C-terminal region of RASSF1A was responsible for the formation of TNF-α receptor complex. Furthermore, using an adenoviral-mediated shRNA construct we found that cardiomyocytes lacking RASSF1A exhibited reduced activation of NFkB, a downstream target of TNF-α. Overall, our data indicate an essential role of RASSF1A in regulating TNF-α signalling in cardiomyocytes, with RASSF1A being key in the formation of TNF receptor complex and in the signal transmission to the downstream targets.
Allogeneic Hematopoietic Cell Transplantation for Lymphoma: Baseline and Post-Transplant Prognostic Factors
Authors: Sun-Hye Ko, Jung-Hee Lee, Je-Hwan Lee, Han-Seung Park, Eun-Ji Choi, Young-Shin Lee, Young-Ah Kang, Kyoo-Hyung Lee
Journal: Blood (2016)
Epigenetic resensitization to platinum in recurrent, platinum-resistant ovarian cancer (OC) using guadecitabine (SGI-110), a novel hypomethylating agent (HMA): Results of a randomized phase II study.
Authors: Ursula A. Matulonis, Amit M. Oza, Angeles Alvarez Secord, Lynda D. Roman, Sarah Patricia Blagden, Susana N. Banerjee, J C Elkas, John J. Nemunaitis, Sharad A. Ghamande, Gini F. Fleming, Merry Jennifer Markham, Hal W. Hirte, Diane M. Provencher, Bristi Basu, Rebecca Sophie Kristeleit, Sue Naim, Yong Hao, Harold N. Keer, Mohammad Azab, Daniela Matei
Journal: Journal of Clinical Oncology (2016)

5547 Background: Development of resistance to platinum (P) is fatal in OC and epigenetic changes are linked to this process; a previous phase II study demonstrated efficacy of decitabine and carboplatin (C) in P-resistant OC. A phase I trial established the safety of guadecitabine (G), a 2nd-generation, subcutaneously (SC) administered HMA in combination with C. Here we present clinical results of a randomized study comparing G+C to treatment choice (TC) chemotherapy. Methods: This was an open-label, randomized, controlled study in which subjects with recurrent P-resistant high grade serous OC, no limits on prior therapy, measurable (RECIST or CA125) disease, ECOG 0-1, and normal organ function were randomized 1:1 to receive 28-day cycles of G+C vs. TC (pegylated liposomal doxorubicin, topotecan, paclitaxel or gemcitabine). Tumor assessments were performed every 8 weeks. TC pts could crossover to G+C at progression. The primary endpoint was PFS; secondary endpoints were RECIST and CA-125 response rate, 6-month PFS, and OS. Results: Subjects (51 G+C/49 TC) were balanced for age (62/62.1 y), ECOG PS 1 (65%/51%), prior taxanes (94%/ 98%) and heavy pre-treatment (78%/73% receiving ≥ 3 prior regimens) for G+C and TC, respectively. PFS (investigator reported) analysis favored G+C (16.3 vs. 10.9 weeks, HR 0.74, log rank p = 0.17) as did PFS rates at 6 months (37% vs. 15%). Response rates (10%) were similar between groups. OS estimates with censoring of crossover subjects favored G+C vs TC (11.0 vs. 7.4 months, HR 0.81, NS). Treatment was reasonably tolerated with 5.9% and 4.1% of patients in G+C and TC respectively discontinuing treatment due to an adverse event. Conclusions: This study suggests that G can resensitize OC patients to P with efficacy endpoints favoring G+C over TC of established salvage chemotherapy with comparable safety. This is the first randomized study demonstrating the value of the HMA guadecitabine as a priming or resensitizing agent in the treatment of solid tumors. The results support further development of the strategy and identification of predictive markers of clinical benefit. Clinical trial information: NCT01696032.
Peginterferon-alpha-2a and ribavirin combination therapy in chronic hepatitis C infection
Authors: A Qasim, A Grogan, B Hynes, H Irish, D Kevans, A Zaheer, N Mahmud, S McKeirnan, S Norris
Journal: Endoscopy (2006)

Background: Peginterferon/ribavirin combination remains standard antiviral therapy for hepatitis C infection.
Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes Predicts Poor Long-term Glycemic Control
Authors: Lindsey M. Duca, Bing Wang, Marian Rewers, Arleta Rewers
Journal: Diabetes Care (2017)

OBJECTIVE This study tested the hypothesis that diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in children predicts poor long-term glycemic control independently of established risk factors. RESEARCH DESIGN AND METHODS This was a prospective cohort study of 3,364 Colorado residents diagnosed with type 1 diabetes before 18 years of age, in 1998–2012, and monitored for up to 15 years. Of those, 1,297 (39%) had DKA at diagnosis (blood glucose &amp;gt;250 mg/dL, and venous pH &amp;lt;7.3 or bicarbonate &amp;lt;15 mEq/L). Severity of DKA was further classified as mild/moderate (pH 7.10–7.29 or bicarbonate 5–14 mEq/L) or severe (pH &amp;lt;7.10 or bicarbonate &amp;lt;5 mEq/L). HbA1c levels were measured an average of 2.8 times/year (median 20 HbA1c values/patient). A linear mixed model was used to examine the effect of DKA on long-term HbA1c levels, adjusting for age, race/ethnicity, sex, family history of diabetes, health insurance, and insulin pump use. RESULTS DKA at diagnosis predicted persistently elevated HbA1c levels. Compared with children without DKA, HbA1c tracked 1.4% (15.3 mmol/mol) higher in those with severe DKA (P &amp;lt; 0.0001) and 0.9% (9.8 mmol/mol) higher in those with mild/moderate DKA at diagnosis (P &amp;lt; 0.0001). These effects were independent of ethnic minority status or lack of health insurance at diagnosis that predicted higher HbA1c by 0.5% (5.5 mmol/mol; P &amp;lt; 0.0001) and 0.2% (2.2 mmol/mol; P &amp;lt; 0.0001), respectively. Insulin pump use or having a parent or sibling with type 1 diabetes predicted lower long-term HbA1c by, respectively, 0.4% (4.4 mmol/mol; P &amp;lt; 0.0001) and 0.2% (2.2 mmol/mol; P = 0.01). CONCLUSIONS DKA at diagnosis of type 1 diabetes in children predicts poor long-term glycemic control, independent of demographic and socioeconomic factors.
Non-coding regulatory variations: the dark matter of pancreatic cancer genomics
Authors: Aldo Scarpa, Andrea Mafficini
Journal: Gut (2017)

Pancreatic ductal adenocarcinoma (PDAC) is the seventh cause of death for cancer worldwide and the third in the USA, where it is expected to become the second by year 2030. Unlike other cancers, little progress has been made when it comes to therapeutic options other than surgery, which is possible only for a small fraction (~20%) of patients presenting with localised disease.1 2 

For the above reasons, large efforts have been undertaken to get a deeper understanding of the molecular alterations and their effects on cancer cells and tumour microenvironment, by exploiting both innovative disease models and high-throughput studies for genomic and transcriptomic profiling of PDAC.3 4 In the meanwhile, genome-wide association studies, and the study of familial pancreatic cancer, have been looking for and found genetic variations associated to PDAC onset and outcome.5 6 

At the genomic level, mutations in the coding region of several genes have been consistently identified, together with disruptive structural alterations whose effect has been linked to the altered functionality (eg, KRAS, TP53 ) or loss (eg, CDNK2A , SMAD4, ARID1A, ROBO2, BRCA1/2 ) of the respective gene products. Frequent and rare alterations identified converge in specific pathways, such as Wnt/Notch, Hedgehog, axon guidance, transforming growth factor beta, SWI/SNF (SWItch/sucrose non-fermentable) and DNA damage repair.3 RNA expression profiles, on the other …
Clofibrate and Niacin in Coronary Heart Disease
Journal: JAMA (1975)

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Randomized phase II study of WT1 peptide vaccine plus gemcitabine for advanced pancreatic ductal adenocarcinoma (PDAC): Clinical efficacy and immune response.
Authors: Sumiyuki Nishida, Takeshi Ishikawa, Satoshi Kokura, Shinichi Egawa, Shigeo Koido, Hiroaki Yasuda, Hiroaki Yanagimoto, Jun Ishii, Yoshihide Kanno, Mari Saito Oba, Maho Sato, Soyoko Morimoto, Hidetoshi Eguchi, Hiroaki Nagano, Sadamu Homma, Yoshihiro Oka, Satoshi Morita, Haruo Sugiyama
Journal: Journal of Clinical Oncology (2016)

3085 Background: Wilms’ tumor gene (WT1) is overexpressed in almost all malignancies including PDAC, and is supposed to be most promising tumor-associated antigen in cancer immunotherapies. To investigate superiority of WT1 vaccine in combination with gemcitabine (GEMWT1) compared to GEM alone (GEM) for patients (pts) with advanced PDAC, we designed the randomized phase II trial. Methods: HLA-A*02:01 and/or A*24:02-positive pts with locally advanced or metastatic PDAC without prior treatment, or recurrence after surgery were enrolled. Pts were randomly assigned at a ratio of 1:1 to GEMWT1 or GEM. Pts in GEM were allowed to receive GEM + WT1 vaccine after disease progression. The primary end point was overall survival (OS) rate at 1 year. Secondary end points were progression free survival (PFS), WT1-specific immunogenic response, and safety. WT1 vaccine, which was composed of HLA-restricted 9-mer WT1 peptide (3mg/body) and Montanide ISA51 adjuvant, was intradermally injected on days 1 and 15, and GEM was administrated at 1,000 mg/m2 on days 1, 8, and 15 in a 28-day cycle until disease progression. Results: A total of 91 pts were enrolled and 85 evaluable finally (GEMWT1, n = 42; GEM, n = 43). GEMWT1 improved 1-yr OS rate and prolonged PFS compared to GEM (Table). These were remarkable in pts with metastatic PDAC. WT1-specific immunity was assessed with delayed-typed hypersensitivity (DTH) to WT1 peptide and tetramer assay of WT1-specific cytotoxic lymphocytes (WT1-CTLs). Median PFS was 195, 102, and 100 days for DTH(+), DTH(-), and GEM, respectively [HR (90% CI), 0.51 (0.31 to 0.85), 0.80 (0.50 to 1.28), and 1]. WT1-CTLs increased in almost all DTH(+) pts. Conclusions: GEM + WT1 vaccine prolonged PFS in pts with advanced PDAC. Clinical efficacy of this combination therapy was associated with the induction of WT1-CTL responses. Clinical trial information: UMIN000005248. Total Metastatic GEM+WT1 n = 42 GEM n = 43 GEM+WT1 n = 35 GEM n = 34 1-yr OS, % [90% CI] 34.2 [22.4-46.3] 21.5 [12.2-32.6] 26.5 [15.1-39.4] 12.2 [4.8-23.3] PFS, median (days) [90% CI] 157 [102-193] 100 [57-141] 133 [87-166] 76 [54-106] PFS, HR [90% CI] 0.66 [0.44 – 0.99] p = 0.089 0.48 [0.30 – 0.77] p = 0.008
Performance d un cholangiopancréatoscope mono-opérateur digital à usage unique
Journal: Endoscopy (2017)

Les auteurs rapportent les résultats d’une étude rétrospective multicentrique de février 2015 à avril 2015, étudiant 108 malades consécutifs ayant eu une intraductale cholangioscopie ou pancréatoscopie (IDCP) porteurs de: sténoses inexpliquées suspectes, dilatations canalaires ou de volumineux calculs necessitant une lithotritie par laser ou hydroelectrique. Les endoscopistes pratiquaient tous l’IDCP optique depuis plusieurs années. Le but de ce travail était d’évaluer la qualité des examens avec le nouveau système digital Spyglass DS, Boston Scientific inc.