tbuckley/cabot-search huggingface dataset:
Epigenetic priming prior to pembrolizumab in mismatch repair-proficient advanced colorectal cancer.
Authors: Adrian Gerard Murphy, Rosalind Walker, Eric R. Lutz, Rose Parkinson, Nita Ahuja, Lei Zheng, Elizabeth M. Jaffee, Nilofer Saba Azad
Journal: Journal of Clinical Oncology (2019)

591 Background: Pembrolizumab results in compelling responses in MMR-deficient CRC. However, most advanced CRC patients have MMR proficient (MMR-p) tumors resistant to PD1 blockade. DNA methyltransferases (DNMT) and histone deacetylases (HDAC) result in silencing of tumor suppressor genes. Preclinical combined HDAC/DNMT inhibition induces susceptibility to immune checkpoints and inhibit tumor growth by re-expressing silenced tumor suppressors. Methods: Single institution, open-label, randomized pilot study (NCT02512172) enrolling patients with advanced MMR-p CRC who progressed on ≥ 1 line of chemotherapy. Patients were randomized to A: oral 5-azacitidine (5AZA, CC486), B: romidepsin or C: combined 5AZA and romidepsin. Patients had pre-treatment biopsy, 14 days of epigenetic therapy with repeat biopsy. All groups began pembrolizumab 200 mg combined with epigenetic therapy until disease progression. Toxicity was assessed using CTCAE v4.0. Results: From 2016 to 2018, 24 patients enrolled with median age of 60 (range 40-69) and median treatment cycles was 3 (range 1-16). There were 2 deaths on study (1 acute kidney injury/ sepsis, 1 cardiac arrest, both unrelated to study drugs). The most common treatment-related hematological AEs in all arms were anemia (63%), lymphopenia (50%) and thrombocytopenia (29%). Most common treatment-related non-hematological AEs in arm A (n = 7) were diarrhea (86%), nausea (86%), fatigue (71%) and anorexia (71%); Arm B (n = 8) were fatigue (63%), dysgeusia (63%), anorexia (63%) and vomiting (63%); and Arm C (n = 9) were nausea (100%), vomiting (100%), fatigue (78%) and anorexia (67%). Treatment-related non-laboratory AEs ≥ grade 3 occurred in 0 patients in Arm A, 3 patients (38%) in Arm B and 3 patients (33%) in Arm C. The most common laboratory AEs in all arms were raised alkaline phosphatase (38%), increased ALT (33%), hyperglycemia (29%), and hypophosphatemia (29%). Conclusions: In this study, the combination of epigenetic agents 5-azacitidine and romidepsin with pembrolizumab is considered safe and generally tolerable in patients with advanced p-MMR colorectal cancer. Further comparison of pre- and post-treatment biopsies is required to determine predictors of response. Clinical trial information: NCT02512172.
Sudden Cardiac Death in Women
Authors: M. Anette E. Haukilahti, Lauri Holmström, Juha Vähätalo, Tuomas Kenttä, Jani Tikkanen, Lasse Pakanen, Marja-Leena Kortelainen, Juha Perkiömäki, Heikki Huikuri, Robert J. Myerburg, M. Juhani Junttila
Journal: Circulation (2019)

Background: Despite recent progress in profiling of risk for sudden cardiac death (SCD) and prevention and intervention of cardiac diseases, SCD remains a major cause of death. Among women, the incidence of SCD is significant, but lower than in men, particularly in the premenopausal and early postmenopausal years. Possibly, as a consequence of the difference in population burden, the mechanisms and risk markers of SCD are not as well defined for women. The aim of this study was to determine the autopsy findings and causes of death among women in a large SCD population. Additionally, we sought to classify prior ECG characteristics in male and female subjects with SCD. Methods: The Fingesture study has systematically collected clinical and autopsy data from subjects with SCD in Northern Finland between 1998 and 2017. The cohort consists of 5869 subjects with SCD. Previously recorded ECGs were available and analyzed in 1101 subjects (18.8% of total population; and in 25.3% of women). Results: Female subjects with SCD were significantly older than men: 70.1±13.1 years versus 63.5±11.8 years (mean ± standard deviation, P &lt;0.001). The most frequently identified cause of death was ischemic heart disease in both sexes: 71.7% among women versus 75.7% among men, P =0.005. In contrast, women were more likely to have nonischemic cause of SCD than men (28.3% versus 24.3%, P =0.005). The prevalence of primary myocardial fibrosis was higher among women (5.2%, n=64) than in men (2.6%, n=120; P &lt;0.001). Female subjects with SCD were more likely to have normal prior ECG tracings (22.2% versus 15.3% in men, P &lt;0.001). A normal ECG was even more common among nonischemic female subjects with SCD (27.8% versus 16.2% in men, P =0.009). However, ECG markers of left ventricular hypertrophy, with or without repolarization abnormalities, were more common among women (8.2%; 17.9%) than in men (4.9%; 10.6%, P =0.036; P &lt;0.001, respectively). Conclusions: Women were considerably older at the time of SCD and more commonly had nonischemic causes. Women were also more likely to have a prior normal ECG than men, but an increased marker for SCD risk based on ECG criteria for left ventricular hypertrophy with repolarization abnormalities was more commonly observed in women.
Impact of clostridium difficile infection on gastrointestinal malignancies.
Authors: Stuthi Perimbeti, Rishi Shrivastav, Prateeth Pati, Kristine Marie Ward, Michael Styler, Maneesh Rajiv Jain, Neilanjan Nandi
Journal: Journal of Clinical Oncology (2019)

170 Background: According to the Centers for Disease Control and Prevention, there were half a million documented cases with 83,000 re-infections and 29,000 deaths due to Clostridium Difficile Infection(CDI) in the year 2011. The influence of CDI on outcomes in gastrointestinal(GI) malignancies is not well described, although the incidence is known to be higher in this subgroup of patients. Methods: National Inpatient Sample 1999-2014 was analyzed to identify adult admissions (&gt;18 years of age) using ICD-9-CM codes with a primary diagnosis of esophageal(EC), Gastric(GC), Colorectal(CRC), Small intestinal(SIC), Hepatobiliary(HCC) and Pancreatic(PC) cancers. ICD-9 code 00845 was used to stratify these for the presence of CDI. We performed Chi-Square test to determine the in-hospital mortality percentage, and Cox Proportional Hazard model to control for confounders and determine the Hazard Ratio(HR) of death within 30 days of admission during hospitalization in patients with and without CDI. Results: See table. Conclusions: Despite controlling for potential confounders, patients with GI cancers and CDI are at an increased risk of death compared to those without CDI. Taking the more detrimental effects of CDI in this subgroup of patients into consideration, healthcare professionals should strive to avoid the inordinate use of antibiotics and strictly maintain current guidelines designed to prevent spread. It may be prudent to treat these patients as severe CDI, even if current criteria are not met. More scientific research is warranted in analyzing the specific outcomes of CDI in GI cancer patients and if more aggressive therapy for CDI is warranted, considering the limitations of this study. [Table: see text]
Intervention to Prevent Major Depression in Primary Care
Authors: Juan Ángel Bellón, Sonia Conejo-Cerón, Patricia Moreno-Peral, Michael King, Irwin Nazareth, Carlos Martín-Pérez, Carmen Fernández-Alonso, Antonina Rodríguez-Bayón, Anna Fernández, José María Aiarzaguena, Carmen Montón-Franco, Inmaculada Ibanez-Casas, Emiliano Rodríguez-Sánchez, María Isabel Ballesta-Rodríguez, Antoni Serrano-Blanco, María Cruz Gómez, Pilar LaFuente, María del Mar Muñoz-García, Pilar Mínguez-Gonzalo, Luz Araujo, Diego Palao, Paola Bully, Fernando Zubiaga, Desirée Navas-Campaña, Juan Mendive, Jose Manuel Aranda-Regules, Alberto Rodriguez-Morejón, Luis Salvador-Carulla, Juan de Dios Luna
Journal: Annals of Internal Medicine (2016)

Depression is common. Current practice is to treat depression after it develops, but some clinicians believe that it can be prevented. These researchers developed a way to predict which persons are...
GPs should consider offering statins to all patients aged over 75, researchers say
Authors: Ingrid Torjesen
Journal: BMJ (2019)

Statins should be considered for everyone over 75 according to the authors of a large meta-analysis, published in the Lancet ,1 which found the drugs reduced major vascular events, such as heart attacks and strokes, in patients of all ages.

Only a third of the 5.5 million over 75s in the UK take statins and up to 8000 deaths per year could be prevented if all took them, said Colin Baigent, director of the Medical Research Council Population Health Research Unit at the University of Oxford, which conducted the research. He was speaking at a press conference to launch the study on 30 January. Thousands of elderly patients also become disabled after strokes and heart attacks, greatly affecting their quality of life.

Statins would not be appropriate for all over-75s, nor might all want to take …
Abstract 18596: RelationsBetween Plasma microRNAS, Echocardiographic Markers of Atrial Remodeling, andAtrial Fibrillation: Data From the Framingham Offspring Study
Authors: Aditya Vaze, Kahraman Tanriverdi, Darleen Lessard, Eric Mick, Emelia J Benjamin, Vasan S Ramachandran, Daniel Levy, Jane E Freedman, David D McManus
Journal: Circulation (2017)

Introduction: MicroRNAs (miRs) are detectable in circulation and play a role in gene regulation. Secretion of cardiac-specific or enriched miRs may reflect pathological cardiac remodeling and enhan...
FENOTEROL AND FATAL ASTHMA
Authors: T.V. O'Donnell, H.H. Rea, P.E. Holst, M.R. Sears, A.Sonia Buist, PeterG.J. Burney, AlvanR. Feinstein, RalphI. Horwitz, StephanF. Lanes, AnthonyS. Rebuck, WalterO. Spitzer
Journal: The Lancet (1989)
Abstract 19907: The Biomimetic Cardiac Tissue Model Differentiates Encapsulated Cardiac Progenitors by Reproducing the Hemodynamics Seen During Cardiogenesis
Authors: Aaron J Rogers, Vladimir Fast, Palaniappan Sethu
Journal: Circulation (2016)

Introduction: Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) provide a source of human cardiomyocytes for disease modeling and regenerative medicine. However, current iPSC-CMs are immature and lack vital structural and functional components such as ion channels, t-tubules and calcium handling mechanisms. Studies of avian and rodent heart development confirm that mechanical stimuli are critical to normal heart development and even small alterations in blood flow or hemodynamic loads results in congenital defects and impaired heart function. These studies conflict with current iPSC-CM differentiation protocols, which are accomplished in static environments in the absence of hemodynamic loading. Hypothesis: We tested the hypothesis that differentiation of cardiac progenitors under hemodynamic loads as seen in cardiogenesis is necessary to attain functional maturation of iPSC-CMs. Methods: In order to recreate the hemodynamic environment seen during cardiogenesis the Biomimetic Cardiac Tissue...
Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer—Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis
Authors: Marlon Perera, Nathan Papa, Matthew Roberts, Michael Williams, Cristian Udovicich, Ian Vela, Daniel Christidis, Damien Bolton, Michael S. Hofman, Nathan Lawrentschuk, Declan G. Murphy
Journal: European Urology (2019)
Analysis of Clonal Evolution/Heterogeneity of MDS By Simultaneous Detection of Both Mutation and Gene Expression By Single Cell Sequencing
Authors: Masahiro Marshall Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Lanying Zhao, Yutaka Kuroda, June Takeda, Xingxing Qi, Akinori Yoda, Ayana Kon, Hisashi Tsurumi, Hideki Makishima, Shuichi Matsuda, Seishi Ogawa
Journal: Blood (2018)
Abstract 18705: The Association of Body Mass Index With Coronary Artery Calcium and Subsequent Mortality: The Coronary Artery Calcium Consortium
Authors: Joseph C Jensen, Zeina Dardari, Michael J Blaha, Susan White, Leslee J Shaw, John Rumberger, Alan Rozanski, Daniel S Berman, Matthew J Budoff, Michael D Miedema
Journal: Circulation (2017)

Introduction: Obesity is associated with multiple CVD risk factors as well as coronary artery calcium (CAC). CAC is a strong predictor of CHD and CVD mortality. It would then seem intuitive that an elevated BMI would be associated with higher risk for mortality but studies evaluating this association have frequently shown paradoxical results. Methods: The CAC Consortium is a multi-centered cohort of 66,636 individuals free of established CVD who underwent non-contrast cardiac-gated CAC testing for clinical indications. We included patients with data available to calculate BMI at the baseline assessment. Mortality was assessed through linkage to the Social Security Death Index and cause of death was obtained from the National Death Index. Multivariable logistic regression was used to determine odds ratios (OR) for CAC according to clinically relevant BMI categories. Cox proportional hazards regression modeling was be used to determine hazard ratios (HR) to assess the relationship between BMI and CHD, CVD, ...
Omadacycline for Acute Bacterial Skin and Skin-Structure Infections
Authors: William O’Riordan, Sinikka Green, J. Scott Overcash, Ivan Puljiz, Symeon Metallidis, J. Gardovskis, Lynne Garrity-Ryan, Anita F. Das, Evan Tzanis, Paul B. Eckburg, Amy Manley, Stephen A. Villano, Judith N. Steenbergen, Evan Loh
Journal: New England Journal of Medicine (2019)

Acute bacterial skin and skin-structure infections are associated with substantial morbidity and health care costs. Omadacycline, an aminomethylcycline antibiotic that can be administered once daily either orally or intravenously, is active against pathogens that commonly cause such infections, including antibiotic-resistant strains.In this double-blind trial, we randomly assigned adults with acute bacterial skin and skin-structure infections (in a 1:1 ratio) to receive omadacycline (100 mg given intravenously every 12 hours for two doses, then 100 mg given intravenously every 24 hours) or linezolid (600 mg given intravenously every 12 hours). A transition to oral omadacycline (300 mg every 24 hours) or oral linezolid (600 mg every 12 hours) was allowed after 3 days; the total treatment duration was 7 to 14 days. The primary end point was an early clinical response at 48 to 72 hours, defined as survival with a reduction in lesion size of at least 20% without rescue antibacterial therapy. A secondary end point was an investigator-assessed clinical response at the post-treatment evaluation 7 to 14 days after the last dose, with clinical response defined as survival with resolution or improvement in signs or symptoms of infection to the extent that further antibacterial therapy was unnecessary. For both end points, the noninferiority margin was 10 percentage points.In the modified intention-to-treat population, omadacycline (316 patients) was noninferior to linezolid (311 patients) with respect to early clinical response (rate of response, 84.8% and 85.5%, respectively; difference, -0.7 percentage points; 95% confidence interval [CI], -6.3 to 4.9). Omadacycline also was noninferior to linezolid with respect to investigator-assessed clinical response at the post-treatment evaluation in the modified intention-to-treat population (rate of response, 86.1% and 83.6%, respectively; difference, 2.5 percentage points; 95% CI, -3.2 to 8.2) and in the clinical per-protocol population (96.3% and 93.5%, respectively; difference, 2.8 percentage points; 95% CI, -1.0 to 6.9). In both groups, the efficacy of the trial drug was similar for methicillin-susceptible and methicillin-resistant Staphylococcus aureus infections. Adverse events were reported in 48.3% of the patients in the omadacycline group and in 45.7% of those in the linezolid group; the most frequent adverse events in both groups were gastrointestinal (in 18.0% and 15.8% of the patients in the respective groups).Omadacycline was noninferior to linezolid for the treatment of acute bacterial skin and skin-structure infections and had a similar safety profile. (Funded by Paratek Pharmaceuticals; OASIS-1 ClinicalTrials.gov number, NCT02378480 .).
Immunotherapy response evaluation with MR elastography (MRE) in advanced HCC.
Authors: Aliya Qayyum, Rony Avritscher, Ajaykumar Morani, Jia Sun, Priya Bhosale, Ken-Pin Hwang, Jason Stafford, Yehia I. Abugabal, Jingfei Ma, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2019)

230 Background: To determine changes in MRE HCC stiffness as predictor of immunotherapy response in patients with advanced HCC. Methods: This was a prospective, Institutional Review Board approved study of 15 patients with biopsy proven advanced HCC (not amenable to curative therapy), who were to be treated with Pembrolizumab. Eligible patients were &gt; 18 years old with radiographic disease progression/intolerance to sorafenib. All patients had liver MRI with MR Elastography (MRE) and liver biopsy at baseline and at 9 weeks of therapy. HCC stiffness (kilopascals, kPa) was measured on liver MRE elastograms (stiffness maps). Change in HCC stiffness on MRE was compared with overall survival, time to disease progression, and total number of lymphocytes on targeted liver biopsy. Data cutoff date was September 1st 2018. Analysis was performed using descriptive statistics including Spearman correlation ( R), Cox regression, Wilcoxon rank sum test and Fisher’s exact test. Results: Of the initial 15 patients, 4 withdrew from therapy, 1 patient did not undergo MRE scan, and 1 patient had MRE failure. The final 9 patients included 6 men. Median age was 70 years (range, 54-78). Etiology of liver disease was HCV (n = 4) and NASH (n = 5). HCC was moderately differentiated in 8 of 9 patients and well-differentiated in 1 patient. Median overall survival and time to progression were 52 weeks (range, 16-112) and 18 weeks (range, 9-48), respectively. Average non-tumorous liver stiffness was 3.2 kPa (range, 2.1-4.3). No significant change in non-tumor liver stiffness was seen at 9 weeks (p = 0.12). Median baseline tumor stiffness was 4.5 kPa (range, 2.4-7.5). Increase in HCC stiffness at 9 weeks was seen in 5 patients, decrease in 3 patients and no change in 1. Change in HCC stiffness at 9 weeks correlated significantly with overall survival ( R = 0.83), and time to progression ( R = 0.96), (p &lt; 0.05). Nine patients had liver biopsy at baseline and 7 had biopsy at 9 weeks. HCC T lymphocytes on biopsy (n/mm2) significantly correlated with HCC stiffness ( R = 0.79), (p &lt; 0.01). Conclusions: Our pilot data suggests early change in tumor stiffness may help predict better immunotherapy response in patients with advanced HCC.
Loss of patellofemoral cartilage thickness over 5 years following ACL injury depends on the initial treatment strategy: results from the KANON trial
Authors: Adam G Culvenor, Felix Eckstein, Wolfgang Wirth, L Stefan Lohmander, Richard Frobell
Journal: British Journal of Sports Medicine (2019)

Objectives To evaluate changes in patellofemoral cartilage thickness over 5 years after anterior cruciate ligament (ACL) injury and to determine the impact of treatment strategy. Methods 121 adults (ages 18–35 years, 26% women) had an ACL injury and participated in the KANON randomised controlled trial. Of those, 117 had available MRIs at baseline (&lt;4 weeks post-ACL rupture) and at least one follow-up measurement (2, 5 years). Patellofemoral cartilage thickness was analysed by manual segmentation (blinded to acquisition order). Patellar, trochlear and total patellofemoral cartilage thickness changes were compared between as-randomised (rehabilitation+early ACL reconstruction (ACLR) (n=59) vs rehabilitation+optional delayed ACLR (n=58)) and as-treated groups (rehabilitation+early ACLR (n=59) vs rehabilitation +delayed ACLR (n=29) vs rehabilitation alone (n=29)). Results Patellofemoral cartilage thickness decreased −58 µm (95% CI −104 to –11 µm) over 5 years post-ACL rupture, with the greatest loss observed in trochlea during the first 2 years. Participants randomised to rehabilitation+early ACLR had significantly greater loss of patellar cartilage thickness compared with participants randomised to rehabilitation+optional delayed ACLR over the first 2 years (−25 µm (−52, 1 µm) vs +14 µm (−6 to 34 µm), p=0.02) as well as over 5 years (−36 µm (−78 to 5 µm) vs +18 µm (−7, 42 µm), p=0.02). There were no statistically significant differences in patellofemoral cartilage thickness changes between as-treated groups. Conclusion Patellofemoral (particularly trochlear) cartilage thickness loss was observed in young adults following acute ACL rupture. Early ACLR was associated with greater patellofemoral (particularly patellar) cartilage thickness loss over 5 years compared with optional delayed ACLR, indicating that early surgical intervention may be associated with greater short-term structural patellofemoral cartilage deterioration compared with optional delayed surgery. Trial registration number ISRCTN84752559 ; Post-results.
Pre-existing atopy protects against a lethal respiratory viral infection in an IgE independent fashion
Authors: Jenny Resiliac, Michelle Rohlfing, Jennifer L. Santoro, Syed-Rehan A. Hussain, Mitchell H. Grayson
Journal: Journal of Allergy and Clinical Immunology (2019)

During the 2009 influenza pandemic hospitalized asthma patients had lower mortality (4%) than those hospitalized without asthma (10%; p=0.04;BMC Infectious Diseases 2013,13:57), suggesting an atopic survival advantage. Using our well-characterized mouse model of paramyxoviral (Sendai virus, SeV) infection, we determined whether pre-existing atopy protects against lethal viral infection, and whether this requires IgE. Wild-type (WT) and IgE deficient (IgE-/-) B6 mice were sensitized and challenged with either ovalbumin (OVA; 40μg i.p. OVA/Alum 1:1, d1 and d7, then 30μg OVA i.n. daily d14-16), house dust mite (HDM; 1μg HDM i.n. d -5, then 10μg HDM i.n. daily d12-16), or PBS. All groups were inoculated with a lethal dose (2 x106pfu) of SeV and survival determined. In surviving mice, airway hyper-reactivity (AHR) and lung mucous cell metaplasia (MCM) was determined on d19-21 post-viral inoculation. All WT and IgE–/–mice in OVA and HDM groups survived, while all control mice died (p=0.0002 WT and p=0.0003 IgE–/–, n=3-10 mice/group). In surviving mice, AHR was elevated in the OVA, but not HDM groups compared to naive mice; n=8 OVA, p<0.0001; n=3 HDM, p>0.05). Compared to B6 uninfected, MCM was significantly elevated in the OVA but not HDM group (5.6+/-1.6 OVA, p=0.028; 2.1+/-0.74 HDM, p>0.05; 0.1+/-0.06 B6 uninfected mice, mean+/-SEM Muc5AC+cells/mmBM). Pre-existing atopy protects against a lethal SeV infection independent of IgE. OVA, but not HDM, led to atopic disease post infection. Future studies will examine differences in mechanisms of survival and post-viral atopic disease in these two models.
CD55 and CD59 Can Limit the Anti-Tumor Efficacy of Daratumumab in Natural Killer/T-Cell Lymphoma
Authors: Nurulhuda Mustafa, Adina Huey Fang Nee, Jing Yuan Chooi, Sabrina Hui Min Toh, Yan Ting Hee, Viknesvaran Selvarajan, Longen Zhou, Jennifer Yang, Wee Joo Chng
Journal: Blood (2018)