tbuckley/cabot-search huggingface dataset:
Preoperative β-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial
Authors: Jonathan G. Hiller, Steven W. Cole, Elizabeth M. Crone, David J. Byrne, David M. Shackleford, Jia-Min B. Pang, Michael A. Henderson, Sophie S. Nightingale, Kwok M. Ho, Paul S. Myles, Stephen Fox, Bernhard Riedel, Erica K. Sloan
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by β-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative β-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. Patients and Methods: In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80–160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. Results: Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P &amp;lt; 0.01), and AP-1 (P &amp;lt; 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P &amp;lt; 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells. Conclusions: One week of β-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that β-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of β-blockade on cancer recurrence and survival. See related commentary by Blaes et al., p. 1781
First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas
Authors: Pieternella Lugtenburg, Rogier Mous, Michael Roost Clausen, Martine E.D. Chamuleau, Peter Johnson, Kim Linton, Simon Rule, Roberto S Oliveri, Dena DeMarco, Ida H Hiemstra, Guang Chen, Ada Azaryan, Manish Gupta, Tahamtan Ahmadi, Martin Hutchings
Journal: Blood (2019)
Abstract 1048: Chronic Heart Failure and Aging: Effects of Exercise Training on Left Ventricular Diastolic Dysfunction
Authors: Marcus Sandri, Stephan Gielen, Norman Mangner, Volker Adams, Robert Hollriegel, Sandra Erbs, Axel Linke, Sven Mobius-Winkler, Rainer Hambrecht, Gerhard Schuler
Journal: Circulation (2009)

BACKGROUND: Diastolic dysfunction (DD) may occur in both physiologic aging and chronic heart failure (CHF). It has, however, never been assessed, whether the degree of DD in CHF patients is age dep...
Romidepsin Plus Liposomal Doxorubicin Is Safe and Effective in Patients with Relapsed or Refractory T-Cell Lymphoma: Results of a Phase I Dose-Escalation Study
Authors: Khoan Vu, Chi-Heng Wu, Chen-Yen Yang, Aaron Zhan, Erika Cavallone, Wade Berry, Pamela Heeter, Laura Pincus, Matthew J. Wieduwilt, Basem M. William, Charalambos Andreadis, Lawrence K. Kaplan, Frank McCormick, Pierluigi Porcu, Jonathan E. Brammer, Weiyun Z. Ai
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL. Patients and Methods: Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days. Results: Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response. Conclusions: Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.
Blockchain vehicles for efficient Medical Record management
Authors: Anuraag A. Vazirani, Odhran O’Donoghue, David Brindley, Edward Meinert
Journal: npj Digital Medicine (2020)

Abstract The lack of interoperability in Britain’s medical records systems precludes the realisation of benefits generated by increased spending elsewhere in healthcare. Growing concerns regarding the security of online medical data following breaches, and regarding regulations governing data ownership, mandate strict parameters in the development of efficient methods to administrate medical records. Furthermore, consideration must be placed on the rise of connected devices, which vastly increase the amount of data that can be collected in order to improve a patient’s long-term health outcomes. Increasing numbers of healthcare systems are developing Blockchain-based systems to manage medical data. A Blockchain is a decentralised, continuously growing online ledger of records, validated by members of the network. Traditionally used to manage cryptocurrency records, distributed ledger technology can be applied to various aspects of healthcare. In this manuscript, we focus on how Electronic Medical Records in particular can be managed by Blockchain, and how the introduction of this novel technology can create a more efficient and interoperable infrastructure to manage records that leads to improved healthcare outcomes, while maintaining patient data ownership and without compromising privacy or security of sensitive data.
The Children's Hospital-Acquired Thrombosis (CHAT) Consortium Admission Risk-Assessment Models from Traditional Biostatistics and Machine Learning
Authors: Arash Mahajerin, Julie Jaffray, Amy Stillings, Emily Krava, Jemily Malvar, Lingyun Ji, Richard Sposto, John H. Fargo, James D. Cooper, Stacy E. Croteau, Michael Silvey, Nihal Bakeer, Ali Jalali, Hannah Lonsdale, Luis Ahumada, Neil A. Zakai, E Vince S Faustino, Neil A Goldenberg, Guy Young, Brian R. Branchford
Journal: Blood (2019)
A survey of palliative care clinicians’ weekly self-care practices.
Authors: Eduardo Bruera, Aimee Elizabeth Anderson, Janet L. Williams, Diane D. Liu
Journal: Journal of Clinical Oncology (2019)

59 Background: Recent evidence suggests that clinician burnout exceeds the national average in the Palliative Care workforce. MD Anderson’s Palliative Care service has therefore implemented measures to reduce stress and burnout and support engagement and health, including a 13-item, evidence-based Palliative Clinician Self Care Checklist. To improve the checklist, we conducted a survey to understand clinicians’ perception of the list and its items, and the frequency with which clinicians were able to achieve each item. Methods: The survey was administered electronically to Palliative Care medical professionals, including physicians, advanced practice providers, and counsellors. We collected demographic information in addition to survey items. We asked respondents to rate their perception of the usefulness of each of the 13 items, and how often they achieved each item. We also asked participants to rate their satisfaction with their professional life, and to respond to questions related to burnout. Results: The response rate to the survey was 32/39 providers contacted (82.0%), including 15 physicians, 10 APPs, and 7 counsellors. Items most often rated as useful or very useful were meeting with friends (93.7%), achieving a personal self-care goal (90.7%), and meeting with family (90.3%). Items least often rated as useful or very useful were visual arts (46.9%), reading literature (59.4%), and art, movies, or theater (65.7%). Items most reported as achieved most weeks or every week were meeting with friends (84.4%), achieving a personalized self-care goal (81%), and avoiding a personal item of maladaptive coping (81%). Visual arts (28.1%), art, movies, or theater (37.6%), and literature (43.8%) were least reported to be achieved most weeks or every week. All respondents reported some degree of satisfaction with their professional life. However, 25% of respondents reported feeling burned out once a week or more. Conclusions: While checklist items that respondents achieved least frequently were those that they perceived as least useful, some items perceived as most useful were not achieved as frequently. Future studies will focus on measures to facilitate providers’ ability to practice and access self-care measures.
Abstract 14734: Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle-Aged Adults
Authors: Rebecca Angoff, Jayandra J Himali, Vasan S Ramachandran, Sudha Seshadri, Alexa Beiser, Connie W Tsao
Journal: Circulation (2019)

Introduction: The relations of metabolic health and obesity with brain health, particularly in young to middle-aged adults, are not well defined. Hypothesis: Greater metabolic risk factors and obes...
Use of medical cannabis in treating anorexia and nausea in elderly cancer patients.
Authors: Rachel Andrea Nathan, Charles Tonderai Mupamombe, Michelle Walter, Amy Allen Case, Eric Hansen
Journal: Journal of Clinical Oncology (2019)

124 Background: The use of medical cannabis (MC) in cancer symptom treatment has been increasing. Since its legalization is limited to select states, there are few clinical trials that have studied the effectiveness and safety of MC, and even fewer studies in the elderly patient population. Given this, we aimed to evaluate the effects of MC on nausea, appetite, and body mass index (BMI) of elderly cancer patients. Methods: We conducted a retrospective chart review of patients age 65 and older prescribed MC in the year 2018 in an outpatient palliative care clinic at a comprehensive cancer center. Nausea and appetite were measured by numerical rating (0-10) and BMI was recorded with data collected at consecutive clinic visits before and after MC use. Results: Eight-three patients aged 65 and over were included in our analysis. Half of patients were age 65-70, while 12% were age 76 or older. More than half were male (58%) and Caucasian (92%). For patients with anorexia or nausea, 58% had previously used cannabis. For nausea, 58% were prescribed ondansetron, 53% were prescribed prochlorperazine or metoclopramide, and 20% were prescribed olanzapine. For anorexia, 24% were prescribed mirtazapine, 6% were prescribed dronabinol, and 1% were prescribed megestrol. The majority of patients used oil (64%), with one-third using vape (33%) and fewer using pill (17%) and powder (5%). Patients primarily used high THC (50%) or equal THC:CBD (45%) formulations initially, with only 7% using high CBD products. The median nausea and anorexia trended towards improvement, though neither was significant (delta nausea = 0.1, p = 0.81) nor anorexia score (delta anorexia = 0.7, p = 0.69). BMI worsened despite MC use (delta BMI 1.9, p &lt; 0.001). Conclusions: In this study of elderly patients with cancer prescribed MC, more than half had previously used cannabis. Two-thirds of patients with anorexia were using MC first-line for appetite stimulation. The majority of patients used oil, with vape next most commonly used, and the vast majority of patients using high THC or equal THC:CBD initially. Use of MC was not associated with a significant improvement in nausea nor anorexia, and BMI significantly decreased despite MC use.
Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine
Authors: Yalong Wang, Wanlu Song, Jilian Wang, Ting Wang, Xiaochen Xiong, Zhen Qi, Wei Fu, Xuerui Yang, Ye-Guang Chen
Journal: The Journal of Experimental Medicine (2019)

The intestine plays an important role in nutrient digestion and absorption, microbe defense, and hormone secretion. Although major cell types have been identified in the mouse intestinal epithelium, cell type–specific markers and functional assignments are largely unavailable for human intestine. Here, our single-cell RNA-seq analyses of 14,537 epithelial cells from human ileum, colon, and rectum reveal different nutrient absorption preferences in the small and large intestine, suggest the existence of Paneth-like cells in the large intestine, and identify potential new marker genes for human transient-amplifying cells and goblet cells. We have validated some of these insights by quantitative PCR, immunofluorescence, and functional analyses. Furthermore, we show both common and differential features of the cellular landscapes between the human and mouse ilea. Therefore, our data provide the basis for detailed characterization of human intestine cell constitution and functions, which would be helpful for a better understanding of human intestine disorders, such as inflammatory bowel disease and intestinal tumorigenesis.
Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity
Authors: Stefano Angiari, Marah C. Runtsch, Caroline E. Sutton, Eva M. Palsson-McDermott, Beth Kelly, Nisha Rana, Harry Kane, Gina Papadopoulou, Erika L. Pearce, Kingston H.G. Mills, Luke A.J. O'Neill
Journal: Cell Metabolism (2019)

Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4
Psychology and the economics of invention
Authors: Robert C Allen
Journal: Behavioral and Brain Sciences (2019)

Abstract Invention is an investment in which the costs of the Research and Development (R&amp;D) project balance future returns. Those returns depend on objective factors like wage and capital costs but also on subjective factors because they are future projections. The more optimistic the inventor, the higher are the projected returns. Baumard uses Life History Theory (LHT) to relate optimism to the affluence of inventors and their societies.
Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response
Authors: Elaine R. Mardis
Journal: Genome Medicine (2019)

Abstract The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique ‘non-self’ peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.
B cell-derived anti-beta 2 glycoprotein I antibody contributes to hyperhomocysteinaemia-aggravated abdominal aortic aneurysm
Authors: Fangyu Shao, Yutong Miao, Yan Zhang, Lulu Han, Xiaolong Ma, Jiacheng Deng, Changtao Jiang, Wei Kong, Qingbo Xu, Juan Feng, Xian Wang
Journal: Cardiovascular Research (2019)

Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinaemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation.ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-β2GPI) antibody from B cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by liquid chromatography-tandem mass spectrometry, which contributed to elevated anti-β2GPI IgG secretion. By using the toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO4-induced AAA in male BALB/c mice, which was prevented in μMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into μMT mice, which were subsequently subjected to elastase- or CaPO4-induced AAA. Compared with μMT mice that received plasma IgG from control mice, μMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-β2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining.Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-β2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation.
A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome
Authors: Andrew H. Wei, Jacqueline S Garcia, Uma Borate, Chun Yew Fong, Maria R. Baer, Florian Nolte, Pierre Peterlin, Joseph G. Jurcic, Guillermo Garcia-Manero, Wan-Jen Hong, Uwe Platzbecker, Olatoyosi Odenike, Martin Dunbar, Ying Zhou, Jason Harb, Poonam Tanwani, Johannes E. Wolff, Meagan Jacoby
Journal: Blood (2019)
Activity of afatinib in patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC and baseline brain metastases: Pooled analysis of three large phase IIIb trials
Authors: M. Gottfried, F. de Marinis, H. Tu, K.K. Laktionov, J. Feng, A. Poltoratskiy, J. Zhao, E.-H. Tan, V. Lee, D. Kowalski, C.-T. Yang, B. Srinivasa, A. Passaro, L. Clementi, W. Tang, D.C.-L. Huang, A. Cseh, K. Park, C. Zhou, Y.-L. Wu
Journal: Annals of Oncology (2019)
Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice
Authors: Iuliia M. Gilchuk, Sandhya Bangaru, Pavlo Gilchuk, Ryan P. Irving, Nurgun Kose, Robin G. Bombardi, Natalie J. Thornburg, C. Buddy Creech, Kathryn M. Edwards, Sheng Li, Hannah L. Turner, Wenli Yu, Xueyong Zhu, Ian A. Wilson, Andrew B. Ward, James E. Crowe
Journal: Cell Host & Microbe (2019)
Diagnosis of Alzheimer's disease
Authors: E J. Byrne
Journal: BMJ (1991)

Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site <i>N</i>-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic; therefore, a thorough investigation of pathways responsible for metabolism is required. In the present study, the major drug-metabolizing enzyme responsible for oprozomib metabolism was identified in vitro. A diol of oprozomib was found to be the predominant metabolite in human hepatocytes, which formed via direct epoxide hydrolysis. Using recombinant epoxide hydrolases (EHs) and selective EH inhibitors in liver microsomes, microsomal EH (mEH) but not soluble EH (sEH) was found to be responsible for oprozomib diol formation. Coincubation with 2-nonylsulfanyl-propionamide, a selective mEH inhibitor, resulted in a significant decrease in oprozomib disappearance (&gt;80%) with concurrent complete blockage of diol formation in human hepatocytes. On the contrary, a selective sEH inhibitor did not affect oprozomib metabolism. Pretreatment of hepatocytes with the <i>pan</i>-cytochrome P450 (P450) inhibitor 1-aminobenzotriazole resulted in a modest reduction (∼20%) of oprozomib metabolism. These findings indicated that mEH plays a predominant role in oprozomib metabolism. Further studies may be warranted to determine whether drugs that are mEH inhibitors cause clinically significant DDIs with oprozomib. On the other hand, pharmacokinetics of oprozomib is unlikely to be affected by coadministered P450 and sEH inhibitors and/or inducers.
Drastic action is needed to reverse falling GP numbers, says RCGP
Authors: Abi Rimmer
Journal: BMJ (2019)

The number of full time equivalent GPs in England has fallen by 1.2% in a year, while the number of GP partners has fallen by 5%, data from NHS Digital show.1

Martin Marshall, chair of the Royal College of General Practitioners, said that “drastic action” needed to be taken to reverse the trend.

The figures show that there were 340 fewer full time equivalent GPs in September 2019 than in September 2018 (28 315 versus 28 655). The number of GP partners fell from 19 262 in September 2018 to …