tbuckley/cabot-search huggingface dataset:
TET2 deficiency leads to stem cell factor–dependent clonal expansion of dysfunctional erythroid progenitors
Authors: Xiaoli Qu, Shijie Zhang, Shihui Wang, Yaomei Wang, Wei Li, Yumin Huang, Huizhi Zhao, Xiuyun Wu, Chao An, Xinhua Guo, John Hale, Jie Li, Christopher D. Hillyer, Narla Mohandas, Jing Liu, Karina Yazdanbakhsh, Francesca Vinchi, Lixiang Chen, Qiaozhen Kang, Xiuli An
Journal: Blood (2018)
Development, Validation, and Comparative Assessment of an International Scoring System to Determine Risk of Upper Gastrointestinal Bleeding
Authors: Kathryn Oakland, Brennan C. Kahan, Leonardo Guizzetti, Myriam Martel, Robert V. Bryant, Mayur Brahmania, Siddharth Singh, Nam Quoc Nguyen, Michael Sai Lai Sey, Alan Barkun, Vipul Jairath
Journal: Clinical Gastroenterology and Hepatology (2018)
The Biomedical Use of Silk: Past, Present, Future
Authors: Chris Holland, Keiji Numata, Jelena Rnjak‐Kovacina, F. Philipp Seib
Journal: Advanced Healthcare Materials (2018)

Abstract Humans have long appreciated silk for its lustrous appeal and remarkable physical properties, yet as the mysteries of silk are unraveled, it becomes clear that this outstanding biopolymer is more than a high‐tech fiber. This progress report provides a critical but detailed insight into the biomedical use of silk. This journey begins with a historical perspective of silk and its uses, including the long‐standing desire to reverse engineer silk. Selected silk structure–function relationships are then examined to appreciate past and current silk challenges. From this, biocompatibility and biodegradation are reviewed with a specific focus of silk performance in humans. The current clinical uses of silk (e.g., sutures, surgical meshes, and fabrics) are discussed, as well as clinical trials (e.g., wound healing, tissue engineering) and emerging biomedical applications of silk across selected formats, such as silk solution, films, scaffolds, electrospun materials, hydrogels, and particles. The journey finishes with a look at the roadmap of next‐generation recombinant silks, especially the development pipeline of this new industry for clinical use.
Dramatic response to brentuximab vedotin in refractory nontransformed <scp>CD</scp> 30 <sup>–</sup> mycosis fungoides allowing allogeneic stem cell transplant and long‐term complete remission
Authors: T. Mahévas, C. Ram‐Wolff, M. Battistella, M.D.V. Pennamen, J. Rivet, P. Brice, M. Bagot
Journal: British Journal of Dermatology (2018)

The erythrodermic ulcerated form of mycosis fungoides (MF) is exceptional, and treatment of refractory cases is challenging. Brentuximab vedotin (BV) is a monoclonal antibody combined with monomethyl auristatin E, recently approved for the treatment of refractory CD30+ cutaneous T‐cell lymphoma. We report a case of refractory MF in a 56‐year‐old man with a long history of large‐plaque parapsoriasis, as revealed by psoriasiform erythroderma, treated initially with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) polychemotherapy, inducing a 2‐year complete response. After relapse, interferon and gemcitabine were unsuccessful. Finally, treatment with BV was decided upon, despite the absence of CD30 expression. After three infusions of BV 1·8 mg kg−1, we achieved a complete and stable response, allowing an allogeneic stem cell transplant. The patient is still in complete remission, 19 months after the graft. This case illustrates the possibility of using BV in refractory CD30– MF as a salvage therapy.
Genomic takeover by transposable elements in the Strawberry poison frog
Authors: Rebekah L Rogers, Long Zhou, Chong Chu, Roberto Márquez, Ammon Corl, Tyler Linderoth, Layla Freeborn, Matthew D MacManes, Zijun Xiong, Jiao Zheng, Chunxue Guo, Xu Xun, Marcus R Kronforst, Kyle Summers, Yufeng Wu, Huanming Yang, Corinne L Richards-Zawacki, Guojie Zhang, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2014)

We sequenced the genome of the strawberry poison frog, Oophaga pumilio, at a depth of 127.5× using variable insert size libraries. The total genome size is estimated to be 6.76 Gb, of which 4.76 Gb are from high copy number repetitive elements with low differentiation across copies. These repeats encompass DNA transposons, RNA transposons, and LTR retrotransposons, including at least 0.4 and 1.0 Gb of Mariner/Tc1 and Gypsy elements, respectively. Expression data indicate high levels of gypsy and Mariner/Tc1 expression in ova of O. pumilio compared with Xenopus laevis. We further observe phylogenetic evidence for horizontal transfer (HT) of Mariner elements, possibly between fish and frogs. The elements affected by HT are present in high copy number and are highly expressed, suggesting ongoing proliferation after HT. Our results suggest that the large amphibian genome sizes, at least partially, can be explained by a process of repeated invasion of new transposable elements that are not yet suppressed in the germline. We also find changes in the spliceosome that we hypothesize are related to permissiveness of O. pumilio to increases in intron length due to transposon proliferation. Finally, we identify the complement of ion channels in the first genomic sequenced poison frog and discuss its relation to the evolution of autoresistance to toxins sequestered in the skin.
Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer
Authors: Matthew S. Alexander, Justin G. Wilkes, Samuel R. Schroeder, Garry R. Buettner, Brett A. Wagner, Juan Du, Katherine Gibson-Corley, Brianne R. O’Leary, Douglas R. Spitz, John M. Buatti, Daniel J. Berg, Kellie L. Bodeker, Sandy Vollstedt, Heather A. Brown, Bryan G. Allen, Joseph J. Cullen
Journal: Cancer Research (2018)

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.
Sustaining positive outcomes with a progressive upright mobility program protocol in cancer patients.
Authors: Paul Gehringer
Journal: Journal of Clinical Oncology (2018)

126 Background: Critical illness associated with immobility leads to significant morbidity including increased intensive care unit (ICU) days, hospital lengths of stay (LOS), and prolonged deconditioning. Several prior studies have demonstrated improvements in LOS and ventilator days when early institution of mobility programs are utilized; however, malignancy and a short expected life span have been exclusions from all prior studies. The purpose of this retrospective investigation was to examine the safety and effectiveness of a progressive upright mobility program (PUM) in critically ill ventilated cancer patients. Methods: After twelve months of baseline data was collected investigating ventilator days, ICU LOS and hospital LOS, a stepwise multidisciplinary PUM protocol was developed and followed in all mechanically ventilated patients admitted to a single subspecialty cancer hospital ICU. Exclusions to protocol included hemodynamic instability, the need for continuous sedation, and neuromuscular blockade. Data from control period (pre) was compared to twelve-month post-intervention (post) data. To determine sustainability, an additional twelve months of data was collected and compared to the pre and post intervention groups. Compared data included demographics, severity of illness, ventilator days, and LOS. Results: Statistical analysis of the data included comparison of means and analysis of variance (ANOVA). The post protocol implementation group demonstrated statistically significant outcomes in the three areas measured; ventilator days reduced from 6.3 to 3.7 (p = 0.001755), ICU LOS 10.2 to 7.5 (p = 0.011016), and hospital LOS 20.9 to 14.1 (p = 0.000364). Conclusions: Despite oncology patients having a high severity of illness and likely functional decline, the patients continue to benefit from early mobilization as previously studied groups. The results reflect consistencies with current literature supporting the absence of complications in early mobilization of patients in the ICU. To our knowledge, this has been the first mobilization study conducted in an oncology critical care setting.
Surgical Universal euGlycemic Attainment during Recovery (SUGAR) Initiative.
Authors: Jolyn Sharpe Taylor, Katherine Cain, Terri Earles, Melinda Harris, Deepthi James, Cheryl Hubbs, Joseph Dottino, Katherine Ikard Stewart, Leon McGrew, Christine Siebel, Ahmed Enbaya, Maria Iniesta, Shital Vachhani, Javier Lasala, Sonali Thosani, Conor Best, Sunil Kumar Sahai, Kathleen M. Schmeler, Pedro T Ramirez, Larissa Meyer
Journal: Journal of Clinical Oncology (2018)

252 Background: Surgical site infections (SSI) are infections of the surgical incision or organ space within 30 days of surgery and are associated with increased morbidity, mortality and healthcare expenditures. Diabetic patients undergoing laparotomy are at high risk. Prior studies have shown SSI reduction by avoiding hyperglycemia. The aim of our Quality Improvement (QI) initiative is to reduce the SSI rate among diabetic patients undergoing laparotomy by 40% within 2 years compared to the baseline (2/2015-8/2017) rate of 16%. Methods: We formed a multi-disciplinary QI team including physicians, nurses and advanced care providers from Gynecologic Oncology, Pharmacy, Nutrition, Endocrinology, Internal Medicine and Anesthesiology. The intervention began 2/2018 in our main center and 5 satellite sites including: screening gynecologic cancer patients undergoing laparotomy with hemoglobin A1C, intra-operative glucose monitoring with goal of &lt; 180mg/dL, creation and use of a standardized basal-bolus insulin order set for post-operative care, and endocrine and nutritional consultation. The following variables were assessed: age, race, ethnicity, BMI, cancer type, comorbidities, smoking status, surgical procedure, receipt of antibiotic prophylaxis, hemoglobin A1C, post-operative glucose values, intervention compliance, intra-operative complications, post-operative complications including SSI, hospital readmissions, reoperation and mortality. Results: Since 2/2018, 39 gynecologic cancer patients have undergone laparotomy. Overall compliance with HgA1c screening is 64% (25/39), which has improved from 42% in 2/2018 to 70% in 3/2018 and 83% in 4/2018. Causes of non-compliance included unplanned conversion to laparotomy and need for additional education. Five of 39 (13%) patients were diabetic, including one newly diagnosed through this initiative. The post-intervention diabetic SSI rate is 0% (0/5) with all post-intervention glucose values &lt; 180mg/dL. There have been no safety adverse events resulting in patient harm. Conclusions: Implementing a QI initiative to standardize management of diabetic patients undergoing surgery is both safe and feasible. Effectiveness data will continue to be collected.
The impact of financial toxicity on quality of life in older patients with cancer: Baseline data from the University of Rochester NCI Community Oncology Research Program (NCORP).
Authors: Asad Arastu, Joseph Ciminelli, Eva Culakova, Lianlian Lei, Huiwen Xu, David W. Dougherty, Mostafa Refaat Mohamed, Megan Wells, Paul Duberstein, Marie Anne Flannery, Gary R. Morrow, Charles Stewart Kamen, Chintan Pandya, Jeffrey L. Berenberg, Valerie Aarne, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2018)

87 Background: Financial toxicity (FT), or the stress and strain patients (pts) experience as a result of paying for cancer care, can have profound negative impacts on pts’ overall quality of life (QoL). This study examined associations of FT with anxiety, depression, and QoL in older pts with advanced cancer. Methods: This is a secondary analysis of baseline data from a Geriatric Assessment intervention study conducted by UR NCORP across 31 practice sites (PI: Mohile). Pts were categorized as experiencing FT if they reported any one of the following: delaying medications due to cost, insufficient income in a typical month for food and housing, or insufficient income in a typical month for other basic needs. Pts also completed the Generalized Anxiety Disorder-7 (GAD7, score 0-21) to evaluate anxiety, the Geriatric Depression Scale (GDS, score 0-15) to assess depression, and the Functional Assessment of Cancer Therapy- Generation (FACT-G, score 0-108), to measure overall QoL. Associations of FT with anxiety, depression, and QoL were assessed in separate multivariate linear regression models controlling for covariates at p &lt; 0.1. Results: Among 542 pts (mean age 77; range 70-96, 49% female), 18% (98 pts) experienced FT. In separate regression analysis, FT was significantly associated with all 3 outcome measures. On average, pts experiencing FT scored 1.76 higher (p &lt; 0.01) on the GAD7 (indicating greater anxiety severity), 0.76 points higher (p = 0.02) on the GDS (indicating greater depression severity), and 5.16 points lower (p &lt; 0.01) on the FACT-G (indicating lower QoL). Conclusions: Older pts with advanced cancer who experience income and cost-related barriers to quality cancer care reported worse anxiety, depression, and QoL than those without FT. Given the association between FT and these outcomes, these 3 FT questions may help identify vulnerable older pts and allow providers to intervene sooner and thereby enhance the quality of care pts receive.
Creating an optimal care coordination model for patients with lung cancer on Medicaid.
Authors: Amy Marbaugh, Thomas Asfeldt, Amanda Kramar, Lorna Lucas
Journal: Journal of Clinical Oncology (2018)

273 Background: The Association of Community Cancer Centers (ACCC) created an Optimal Care Coordination Model (OCCM), which provides a comprehensive self-assessment tool designed to orient cancer programs to achieving patient-centered, multidisciplinary care. The OCCM is designed to help cancer programs, regardless of resources, location, or population, improve care for lung cancer patients, especially those on Medicaid. Methods: An environmental scan was conducted in early 2016 with a focus on coordination of care after lung cancer diagnosis to improve experiences and outcomes for Medicaid beneficiaries. Five ACCC Cancer Program Members each hosted 2-day site visits in mid-2016. Interview sessions were conducted to explore effective practices and current care models for patients with lung cancer insured by Medicaid. Key problems in care coordination were identified, as well as local solutions that had been put in place to overcome these barriers. The NCI Community Cancer Centers Program’s (NCCCP) Multidisciplinary Care (MDC) Assessment Tool was the foundational template to create the OCCM. The MDC Tool included 7 assessment areas that were identified as impactful to establishing multidisciplinary care and includes a Level 1-5 evaluation matrix. Results: The beta version of the OCCM was created in early 2017. The number of Assessment Areas was expanded to better capture current care coordination philosophies; (1) Patient Access to Care; (2) Prospective Multidisciplinary Case Planning; (3) Financial, Transportation, and Housing; (4) Management of Comorbid Conditions; (5) Care Coordination; (6) Treatment Team Integration; (7) Electronic Health Records (EHR) and Patient Access to Information; (8) Survivorship Care; (9) Supportive Care; (10) Tobacco Cessation; (11) Clinical Trials; (12) Physician Engagement; (13) Quality Measurement and Improvement. Conclusions: Seven ACCC Cancer Program Members are currently validating the model by each implementing at least one program-specific quality improvement project focused on an Assessment Area over a 12-month time period. All programs are collecting extensive data to determine the extent their program improved within an assessment area. Final results will be available for dissemination in 2019.
HCV core antigen as an alternative to HCV RNA testing in the era of direct-acting antivirals: retrospective screening and diagnostic cohort studies
Authors: Marjolein van Tilborg, Saeed H Al Marzooqi, William W L Wong, Raoel Maan, Johannes Vermehren, Benjamin Maasoumy, Tony Mazzulli, Shelly Bolotin, Gary Garber, Fiona Guerra, Christopher R Flud, Matthew Kowgier, Harry L Janssen, Robert J de Knegt, Jean-Michel Pawlotsky, Gavin A Cloherty, Andres Duarte-Rojo, Christoph Sarrazin, Heiner Wedemeyer, Jordan J Feld
Journal: The Lancet. Gastroenterology & hepatology (2018)
Abstract 15183: Circulating MicroRNA-210 Levels Are Increased in Patients With Moderate to Severe Aortic Stenosis and Provide Independent Prognostic Information Regarding Mortality
Authors: Helge Røsjø, Mai Britt Dahl, Anja Bye, Johanna Andreassen, Marit Jørgensen, Ulrik Wisløff, Geir Christensen, Thor Edvardsen, Torbjørn Omland
Journal: Circulation (2013)

Background: Micro-RNA(miR)-210 production is increased by cellular hypoxia, and circulating miR-210 levels have been found inversely correlated to maximal oxygen uptake. As poor physical capacity is an established risk factor in patients with aortic stenosis (AS), we hypothesized that circulating miR-210 levels are increased in patients with AS and associated with a poor prognosis. Methods: Circulating miR-210 levels were measured by RT-qPCR in 57 patients with moderate to severe AS and in 10 age- and gender-matched healthy controls. MiR-210 levels were normalized to miR-425 levels, and RNA extraction was controlled by measuring the spike-in control cel-miR-39. Myocardial structure and function were characterized by echocardiography and the prognostic utility of miR-210 was compared to established risk indices. Results: All patients and control subjects had miR-210 levels within the range of detection (Cp<35). The coefficient of variation (CV) for the samples run in triplet was 0.6% for both AS patients a...
Real-world comparison of biosimilar filgrastim and reference filgrastim in cancer patients receiving chemotherapy.
Authors: Xiaoxue Chen, John Barron, Abiy Agiro, David Joseph Debono, Michael Jordan Fisch
Journal: Journal of Clinical Oncology (2018)

85 Background: The approval pathway for biosimilars was established in 2010 to facilitate drug competition and generate cost savings. Biosimilar filgrastim products (filgrastim-sndz or tbo-filgrastim) were the first approved biosimilars in the US. This study examined study outcomes (incidence of febrile neutropenia (FN), growth factor related adverse events (AE) and filgrastim treatment cost) between users of biosimilar and reference filgrastim drugs among the commercially-insured US population. Methods: A retrospective observational design was used to analyze administrative claims data on adults with cancer treated with chemotherapy between 09/01/2012 - 4/30/2017. The population was grouped into biosimilar filgrastim users (B) and filgrastim users (F) according to the earliest filgrastim use (index date). FN risk factors were assessed within 6 months prior to the index date. Study outcomes were assessed within 21 days post index date using multivariable regression modelling. Results: Among 1,694 biosimilar users and 10,460 filgrastim users, no meaningful differences in baseline FN risk factors were observed. In adjusted results, no difference in incidence of FN was observed between the two groups (B: 13.3%; F: 11.0%; odds ratio [OR]: 1.17; 95% confidence intervals [CI] 0.99-1.38; p = 0.06). Rates of AE were similar between the two groups (B: 6.9%; F: 6.4%; OR: 1.04; 95% CI: 0.84-1.29, p = 0.72). The mean number of filgrastim doses administered was 3.4 in both groups (Relative difference: 0.01; 95% CI: -0.02-0.04; p = 0.53). The mean filgrastim drug costs were similar between the two groups (B: $2,491; F: $2,510, Cost Ratio [CR]: 0.96; 95% CI: 0.91-1.01; p = 0.12). However, the mean filgrastim drug cost was 6.7% less for filgrastim-sndz when compared to reference filgrastim (sndz: $2,342; CR: 0.91; 95% CI: 0.84-0.99; p = 0.04); but not for tbo ($2,549; CR: 0.97; 95% CI: 0.91-1.04; p = 0.40). Conclusions: Biosimilar filgrastim is similar to the reference filgrastim in drug safety and effectiveness. The early adoption and saving impact of biosimilar filgrastim has been modest, which highlights the structural and regulatory challenges to biosimilar uptake.
Pseudogenes Provide Evolutionary Evidence for the Competitive Endogenous RNA Hypothesis
Authors: Cian Glenfield, Aoife McLysaght
Journal: Molecular Biology and Evolution (2018)

The competitive endogenous RNA (ceRNA) hypothesis is an attractively simple model to explain the biological role of many putatively functionless noncoding RNAs. Under this model, there exist transcripts in the cell whose role is to titrate out microRNAs such that the expression level of another target sequence is altered. That it is logistically possible for expression of one microRNA recognition element (MRE)-containing transcript to affect another is seen in the multiple examples of pathogenic effects of inappropriate expression of MRE-containing RNAs. However, the role, if any, of ceRNAs in normal biological processes and at physiological levels is disputed. By comparison of parent genes and pseudogenes we show, both for a specific example and genome-wide, that the pseudo-3' untranslated regions (3'UTRs) of expressed pseudogenes are frequently retained and are under selective constraint in mammalian genomes. We found that the pseudo-3'UTR of BRAFP1, a previously described oncogenic ceRNA, has reduced substitutions relative to its pseudo-coding sequence, and we show sequence constraint on MREs shared between the parent gene, BRAF, and the pseudogene. Investigation of RNA-seq data reveals expression of BRAFP1 in normal somatic tissues in human and in other primates, consistent with biological ceRNA functionality of this pseudogene in nonpathogenic cellular contexts. Furthermore, we find that on a genome-wide scale pseudo-3'UTRs of mammalian pseudogenes (n = 1,629) are under stronger selective constraint than their pseudo-coding sequence counterparts, and are more often retained and expressed. Our results suggest that many human pseudogenes, often considered nonfunctional, may have an evolutionarily constrained role, consistent with the ceRNA hypothesis.