tbuckley/cabot-search huggingface dataset:
Abstract 357: Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury
Authors: Geoffrey W Cho, Min Xie, Yongli Kong, Dan L Li, Xiang L Luo, Francisco Altamirano, Cyndi Morales, Herman May, Gabriele Schiattarella, Jessica Medina, Nan Jiang, John Shelton, Anwarul Ferdous, Thomas G Gillette, Joseph A Hill
Journal: Circulation Research (2017)

Background: Reperfusion injury accounts for a significant portion of myocardial damage in acute coronary syndromes. Autophagy, a process of cell catabolism, plays a vital role in the heart’s response to stress. We have reported that re-induction of ischemia/reperfusion (I/R)-suppressed cardiomyocyte autophagy with histone deacetylase (HDAC) inhibitors affords significant cardioprotection. However, as HDACs govern many processes and may have off-target effects, we set out to modulate autophagy in a manner independent of HDAC activity. Here, we hypothesized that induction of autophagy with a novel agent, Tat-Beclin, at the time of reperfusion, will reduce I/R injury and rescue cardiac function. Methods: Wild type and ATG7 (protein required for autophagic flux) knockout mice were randomized among 3 treatment groups prior to surgical I/R injury [45 min LAD artery ligation; 24h reperfusion]: vehicle control (VC), Tat-Scrambled (TS), or Tat-Beclin (TB). Each agent was delivered at coronary reperfusion. To define molecular mechanisms, cultured adult and neonatal rat ventricular cardiomyocytes (ARVMs/NRVMs) were subjected to simulated I/R. Results: Induction of cardiomyocyte autophagy at reperfusion reduced infarct size 20.1% (±6.3%, n=23, p&lt;0.02 vs VC). This treatment was associated with improved systolic function (declines in fractional shortening: 19.8±3.7% VC; 18.7±2.1% TS; 8.5±1.7% TB, n=11, p&lt;0.01 vs VC). In NRVMs subjected to I/R injury, cell death was reduced 41% (±6%, n=12, p&lt;0.001 vs VC). Improvements correlated with increased autophagic flux measured by the marker LC3-II, particularly at the infarct border zone. Additional data suggested that autophagy rescues I/R injury through reduction of oxidative stress. ATG7 KO mice or NRVM depleted of ATG7 (RNAi) manifested significantly less cardioprotection. Conclusion: Direct induction of cardiomyocyte autophagy reduces infarct size and declines in contractile function. Autophagy rescues I/R injury in part through reduction of oxidative stress. Critically, this cardioprotection was observed when intervention occurred at the time of reperfusion, the clinically relevant context.
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1
Authors: Evangelia Loizou, Ana Banito, Geulah Livshits, Yu-Jui Ho, Richard P. Koche, Francisco J. Sánchez-Rivera, Allison Mayle, Chi-Chao Chen, Savvas Kinalis, Frederik O. Bagger, Edward R. Kastenhuber, Benjamin H. Durham, Scott W. Lowe
Journal: Cancer Discovery (2019)

Abstract Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer. Significance: Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types. This article is highlighted in the In This Issue feature, p. 813
Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells
Authors: Dean P J Kavanagh, Adam B Lokman, Georgiana Neag, Abigail Colley, Neena Kalia
Journal: Cardiovascular Research (2019)

Adequate microcirculatory perfusion, and not just opening of occluded arteries, is critical to salvage heart tissue following myocardial infarction. However, the degree of microvascular perfusion taking place is not known, limited primarily by an inability to directly image coronary microcirculation in a beating heart in vivo. Haematopoietic stem/progenitor cells (HSPCs) offer a potential therapy but little is known about their homing dynamics at a cellular level and whether they protect coronary microvessels. This study used intravital microscopy to image the anaesthetized mouse beating heart microcirculation following stabilization.A 3D-printed stabilizer was attached to the ischaemia-reperfusion injured (IRI) beating heart. The kinetics of neutrophil, platelet and HSPC recruitment, as well as functional capillary density (FCD), was imaged post-reperfusion. Laser speckle contrast imaging (LSCI) was used for the first time to monitor ventricular blood flow in beating hearts. Sustained hyperaemic responses were measured throughout reperfusion, initially indicating adequate flow resumption. Intravital microscopy confirmed large vessel perfusion but demonstrated poor transmission of flow to downstream coronary microvessels. Significant neutrophil adhesion and microthrombus formation occurred within capillaries with the latter occluding them, resulting in patchy perfusion and reduced FCD. Interestingly, 'patrolling' neutrophils were also observed in capillaries. Haematopoietic stem/progenitor cells readily trafficked through the heart but local retention was poor. Despite this, remarkable anti-thromboinflammatory effects were observed, consequently improving microvascular perfusion.We present a novel approach for imaging multiple microcirculatory perturbations in the beating heart with LSCI assessment of blood flow. Despite deceptive hyperaemic responses, increased microcirculatory flow heterogeneity was seen, with non-perfused areas interspersed with perfused areas. Microthrombi, rather than neutrophils, appeared to be the major causative factor. We further applied this technique to demonstrate local stem cell presence is not a pre-requisite to confer vasculoprotection. This is the first detailed in vivo characterization of coronary microcirculatory responses post-reperfusion injury.
Abstract P3-03-22: Prognostic impact of axillary lymph node status after neoadjuvant chemotherapy for patients with breast cancer
Authors: R Nakamura, N Yamamoto, T Miyaki, M Itami
Journal: Cancer Research (2019)

Abstract BACKGROUND: Patients were stratified by final pathological axillary status: ypN0, ypN1, pN0 or pN1. The prognostic impact of lymph node involvement after neoadjuvant chemotherapy (NAC) for breast cancer is not straightforward. The aim of this study was to compare overall survival (OS) between pathologically node-positive T1,T2 T3 breast cancer patients treated with NAC, with ypN0 or ypN1 and those treated without NAC with pN0 or pN1. METHODS: A total of 3903 consecutive patients with operable breast cancer were prospectively identified at our institution between April 2006 and December 2017. Patients with suspicious axillary LN of breast cancer were assessed using preoperative imaging, underwent fine-needle aspiration cytology or core needle biopsy. The patients in this study were divided into four groups as follows: the ER(+), the ER(+)/HER2(+) , the HER2(+) and the Triple negative (TN) group. We evaluate the prognostic impact of the ypN0, ypN1 (with one to three positive lymph nodes after NAC), pN0 and pN1 with no NAC. The main outcome measures DFS and OS were analyzed using Kaplan–Meier survival analysis. Result A number of 270 and 3633 patients were included for NAC and non NAC, respectively. Pathologic nodal status was ypN0 in 58%, ypN1 in 42% for NAC and pN0 in 76%, pN1 in 24% of patients for non NAC. Overall, 10-year DFS and OS was 81%, 93% in ypN0, 67%, 80% in ypN1, in 90%, 97%, in pN0 and 83%, 94% in pN1 (p &amp;lt;0.001). In subgroup analysis, 10-year DFS of ypN0, ypN1, pN0 and pN1 was 86%,77%,95% and 80% in the ER group, 91%,56%,93%,and 76% in the ER/HER2 group,89%,55%,91% and 80% in the HER2 group, 85%,59%,92% and 80% in the TN group. 10 years DFS for the ER group were significantly different between ypN0 and pN0 (HR, 2.42 (1.03–4.86, p = 0.04) but were not significantly different between ypN0 and pN0 for the ER/HER2 group (HR 3.58 (0.2–6.88, p = 0.66), for the HER2 group (HR 2.6 (0.78–7.65, p = 0.10) and for the TN group (HR 1.22(0.56–2.38, p = 0.58), respectively). In all group, DFS for ypN1 was inferior to ypN0. Conclusions In the ER group treated with NAC, DFS for ypN0 be inferior to pN0 with adjuvant treatment. In the HER2, the ERHER2 and the TN group treated with NAC, ypN0 is similar to pN0 with adjuvant chemotherapy. Axillary nodal status ypN1 in each subgroup is associated with a less favorable prognosis compared to ypN0. In conclusion, the HER2 or TN group is highest for predicting ypN0, shown to be most prognostic of long-term survival similar to the patients with pN0. They could be omitted the axillary dissection. Citation Format: Nakamura R, Yamamoto N, Miyaki T, Itami M. Prognostic impact of axillary lymph node status after neoadjuvant chemotherapy for patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-22.
Controversies in care
Authors: Isobel Weinberg
Journal: BMJ (2013)

“Hospitals bribed to put patients on pathway to death,” screamed one recent Daily Mail headline. “Now sick babies go on death pathway,” was another. The “death pathway” in question is the Liverpool care pathway (LCP), a clinical tool for caring for dying patients. It offers a framework for suspending unnecessary treatment and prioritising the patient’s comfort. But the Daily Mail has claimed that the doctors in the UK are killing patients to meet targets by using the pathway to withdraw feeding. “Euthanasia by the back door,” they have termed it. Our article on p …
P043 Infection with citrullinating porphyromonas gingivalis can induce autoimmunity to human ribosomal proteins
Authors: M Jenning, B Marklein, Z Konthur, U Nonhoff, G-R Burmester, K Skriner
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Young investigator. <h3>Introduction</h3> Porphyromonas gingivalis (P g.) is involved in triggering self-reactive immune responses when citrullinating bacterial or human proteins. However, first evidence to link anti-ribosomal T and B cells responses to rheumatoid arthritis (RA) has been published but the mechanism is still not clear.<sup>1</sup> Infection based autoimmunity induced by citrullination of human proteins with P g. peptidyl arginine deiminase from RA patient (RA-PPAD) and crossreactivity binding induced by P g. was investigated using affinity purified RA patient antibodies and a monoclonal antibodies to cit-RA-PPAD. <h3>Objectives</h3> Antibodies to RA-PPAD isolated from an RA patients (RA-PPAD) was first time linked to target specific citrullinated ribosomal proteins. <h3>Methods</h3> Screening of RA sera was conducted on 37.830 unique human proteins on protein marcoarrays (http://www.engine-gmbh.de) with 30 RA sera. The autoantibody response to 840 different proteins was recorded and bioinformatically evaluated. Protein arrays were citrullinated with PAD2,4,rabbit PAD and RA-PPAD. Sera and affinity purified antibodies were used to detect reactivity to 840 autoantigens. <h3>Results</h3> A human protein macroarray consisting of 840 indentified autoantigens from RA patients was modified by human PAD2 and PAD4, rabbit PAD, and RA-PPAD form P g..Using cit specific monoclonal antibodies we identified the ribosomal proteins (RP), RPL18a, RPS27a, modified by PAD2, RPL18a and MRPS11 modifies by Pad4, and RPL7L1 modified by rabbit PAD specifically targeted. In addition 6 RA patient sera and 3 osteoarthritis (OA) control sera were used to identify the citrullinated RA-PPAD specific modified autoantigens not targeted when modified by human PAD2 or PAD4 or rabbit Pad. We identified the RA-PPAD citrullinated ribosomal Proteins RPL3, RPL21, RPS24, RPL9, RPL15, RPS24.RPS3a, MRPL28 specifically targeted by RA patients. This identifies ribosomal proteins as major specific RA-PPAD citrullination targets. Moreover, affinity purified antibodies bound to native and citrullinated RA-PPAD from 6 RA patient sera and 3 OA patient sera were tested for crossreactvity on citrullinated human proteinarray. Antibodies to citrullinated ribosomal proteins MRPS11, RPL21, RPS3a, RPL18a, RPS27a, MRPL28 were detected in the RA group but not in the OA control group. <h3>Conclusions</h3> Failure of <i>Porphyromonas gingivalis</i> clearance in RA patients leads to infection induced enzymatic mimicry based autoreactivity targeting evolutionary conserved human ribosomal proteins. Autoimmunity to ubiquitous self-antigens may trigger localized tissue damage in RA. <h3>Reference</h3> Ito Y, <i>et al</i>. Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease. <i>Science</i> 2014;346:363–368. <h3>Disclosure of Interest</h3> None declared.
Prophylactic Hypothermia for Severe Traumatic Brain Injury—Reply
Authors: D. James Cooper, Alistair D. Nichol, Colin McArthur
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Review of the EAST Practice Management Guideline: Evaluation and Management of Traumatic Diaphragmatic Injuries
Authors: Jose J. Diaz
Journal: JAMA Surgery (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
One size fits all?
Authors: Emma Rourke
Journal: BMJ (2012)

As I nervously took my seat in a lecture theatre packed with 300 fresh faced first year medics, I experienced the same mix of anxiety and enthusiasm as many others. Stepping into this windowless expanse represented an achievement. Like many state educated students, I had no one to hold my hand through the medical admissions process; no personal statement reviews, no practice interviews, and certainly no admissions test training.

On that first day of medical school, I believed everyone had run the same gauntlet to get there, but I soon found I was wrong. It has long been acknowledged that independently schooled students experience greater success in …
Obstructive sleep apnoea
Authors: Bharat Kumar, Walter Chua
Journal: BMJ (2010)

An overview of the disease and its treatment Obstructive sleep apnoea is a chronic sleep related breathing disorder characterised by frequent episodes of upper airway collapse (box 1). Once believed to be restricted to the affluent societies of the West, a growing body of evidence suggests that it transcends global socioeconomic divisions to affect a larger proportion of the world population than was originally thought.1 Despite the lack of awareness about the disease, it increases morbidity and mortality in patients by disrupting sleep patterns and inducing a generalised state of chronic inflammation secondary to hypoxia. Studies have also suggested that it correlates with several chronic diseases, including hypertension, cardiovascular disease, type 2 diabetes, and neurocognitive deficits, although causation has not been proved.2 #### Box 1 Glossary of terms3
Causes and patterns of readmissions in patients with common comorbidities: retrospective cohort study
Authors: Neil Chanchlani, Erin Russell
Journal: BMJ (2014)

#### The paper

Work in emergency medicine or medical/surgical assessment can often yield interesting days. Patients come to hospital for various reasons; some present because they are acutely unwell, some present with exacerbations of chronic illnesses, and others present because they require social and multidisciplinary input into their care and home environments.

For a junior on the “frontline,” perhaps the most gut-wrenching moment is when you’re asked to see a patient who you’ve recently discharged from your care. You wonder whether you made a mistake in prescribing or if you discharged them too early. Then begins the attempt to diagnose the patient and, rather defensively, to find out whose fault it is that they’ve re-presented to hospital.

We know that about a fifth of patients who are discharged from hospital bounce back into hospital via GP referral or re-present through the emergency department within 30 days after discharge.1 Reasons for readmission include adverse drug events, avoidable infection, complications of procedures and treatments, and preventable acute exacerbations of chronic illnesses.

The authors of this study wanted to ascertain why patients get readmitted and offer solutions as to how we can reduce the numbers. They hypothesised that patients’ comorbidities could play an important role. Comorbidities can be defined as the simultaneous coexistence of more than one health condition in a single individual—for example, someone who has chronic obstructive pulmonary disease (COPD) and insulin dependent diabetes is said to have both comorbidities.1

There is already evidence to suggest that a patient’s primary diagnosis on readmission (within 30 days) differs from the primary diagnosis responsible for the index—or original—admission, suggesting that there must be other factors at play. Additionally, studies have suggested …
Response by Mahler et al to Letter Regarding Article, “Safely Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge: HEART Pathway Accelerated Diagnostic Protocol”
Authors: Simon A. Mahler, Kristin M. Lenoir, Brian J. Wells, Gregory L. Burke, Pamela W. Duncan, L. Douglas Case, David M. Herrington, Jose-Franck Diaz-Garelli, Wendell M. Futrell, Brian C. Hiestand, Chadwick D. Miller
Journal: Circulation (2019)
Abstract A26: Analysis of alternative splicing events in high- and low-grade bladder tumors
Authors: André Luiz Ventura Sávio, Ricardo Piuco, Katia Ramos Moreira Leite, Daisy Maria Favero Salvadori, Pedro Alexandre Favoretto Galante, Luiz Otavio Ferraz Penalva
Journal: Clinical Cancer Research (2018)

Abstract Functioning primarily in the rearrangement of identical pre-mRNA into different molecules, the alternative splicing (AS) contributes to the organism proteomic diversity. There are still unknown AS events, especially the aberrant splicing events that are associated to nonfunctional final products or tumorigenesis. For instance, hallmarks, such as apoptosis, metastasis, and angiogenesis, of certain types of cancer are known to be affected by some kind of aberrant splicing event. As examples, for BCLX gene, antiapoptotic and proapoptotic isoforms have been discovered, and, for the VEGFA gene, changes between proangiogenic and antiangiogenic isoforms expression have been detected in tumors and normal-matched samples, as well as among several distinct tissues. We hypothesize that AS events can also be associated and contribute to the origin and maintenance of specific tumor types and sub-types. We characterized the AS events in 35 samples of primary bladder tumors, classified as 20 high-grade (cells poorly differentiated, invasive and metastatic tumor), 11 low-grade (cell differentiated, noninvasive tumor), and 5 normal tissues. To access the AS events, we generated in total 2.5 billion of reads using RNAseq. The next step was mapping these reads against the human reference genome, using a set of in-house and publicly available pipelines to detect AS events in high-/low-grade bladder samples and normal tissues. As result, we observed 992 significant splicing events on high-grade tumors as compared to normal samples, 796 significant events on low-grade versus normal samples, and 871 significant events on low-grade versus high-grade tumors. After looking for some of these events in combinations of tumor grades and control, we found a tumor-specific isoform for RPS24 gene and five splicing events of genes RPL13A, RPL3, RPL37A, RPS27A, and RPL34 that are unique to high-grade tumors. We believe that these low-/high-grade AS specific events should be further studied in order to contribute to the understanding and to the development of new drugs for bladder tumors presenting low- or high-grade. Citation Format: André Luiz Ventura Sávio, Ricardo Piuco, Katia Ramos Moreira Leite, Daisy Maria Favero Salvadori, Pedro Alexandre Favoretto Galante, Luiz Otavio Ferraz Penalva. Analysis of alternative splicing events in high- and low-grade bladder tumors [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A26.