tbuckley/cabot-search huggingface dataset:
Treatment of pulmonary hypertension
Authors: A. J Peacock
Journal: BMJ (2003)

For understandable reasons, the pulmonary circulation remains an enigma to most doctors. This is because the cardinal symptom, dyspnoea, is shared with many more common diseases, and the signs of pulmonary hypertension are difficult to elicit for the non-specialist. Consequently, the delay between onset of symptoms and diagnosis is two years, and the mean survival from the time of diagnosis is only another two years in untreated patients with severe hypertension of the pulmonary artery. In the past, pulmonary hypertension was not treatable, but now several treatments are available.

Severe pulmonary hypertension, with a total prevalence of about 30-50/million, can be primary or associated with apparently disparate conditions including connective tissue disease, congenital heart disease, chronic pulmonary thromboembolism, HIV infection, use of an appetite suppressant, and liver disease. Surprisingly, nearly all these conditions have a similar histological picture of vascular remodelling. The pathobiology of pulmonary artery hypertension is now better understood. A gene for familial pulmonary arterial hypertension, which codes for BMPR2 a receptor in the transforming growth factor β (TGF-β) family, has been discovered. 1 2 This gene is also found in up to 26% of patients with so called sporadic pulmonary hypertension. The genetic abnormality perhaps must be accompanied by some additional environmental factor to cause pulmonary artery hypertension (“the double hit hypothesis”), and the remodelling occurs because that factor (or factors) acts in concert with disturbed BMPR signalling to cause an increase in production of cytokines and other factors.

In the …
Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I–III Triple-negative Breast Cancer (NeoSTOP)
Authors: Priyanka Sharma, Bruce F. Kimler, Anne O'Dea, Lauren Nye, Yen Y. Wang, Rachel Yoder, Joshua M. Staley, Lindsey Prochaska, Jamie Wagner, Amanda L. Amin, Kelsey Larson, Christa Balanoff, Manana Elia, Gregory Crane, Sheshadri Madhusudhana, Marc Hoffmann, Maureen Sheehan, Roberto Rodriguez, Karissa Finke, Rajvi Shah, Deepti Satelli, Anuj Shrestha, Larry Beck, Richard McKittrick, Robert Pluenneke, Vinay Raja, Venkatadri Beeki, Larry Corum, Jaimie Heldstab, Stephanie LaFaver, Micki Prager, Milind Phadnis, Dinesh Pal Mudaranthakam, Roy A. Jensen, Andrew K. Godwin, Roberto Salgado, Kathan Mehta, Qamar Khan
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. Patients and Methods: Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). Results: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P &amp;lt; 0.001) and febrile neutropenia (19% vs. 0%; P &amp;lt; 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). Conclusions: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.
Organs for transplantation.
Authors: S T Bartlett, D Oldach, S C Schimpff
Journal: BMJ (1989)

The British government has printed 10 million organ donor cards--as well as posters, car stickers, and leaflets--for distribution in a campaign to increase the number of organ transplants in the United Kingdom. Norman Fowler, Secretary of State for Social Services, suggested at a February 22, 1984, press conference that signing of donor cards might become a family occasion, so that all concerned would know of a person's wishes in the event of sudden death. He made it clear that the government has no plans to introduce a system of presumed consent for organ donation. Mr. Fowler also announced a commitment of additional government funds for renal services.
Abstract 16282: The Development of the New Treatment for Distressed Microvascular Dysfunction in Porcine Dilated Cardiomyopathy Model Using Induced Pluripotent Stem Cell Derived Cardiomyocyte Sheet
Authors: Kota Suzuki, Shigeru Miyagawa, Emiko Ito, Akima Harada, Takuji Kawamura, Ai Kawamura, Yoshiki Sawa
Journal: Circulation (2020)

Introduction: The progression of dilated cardiomyopathy (DCM) mainly involves genetic mutations or ischemia at the cellular level, leading to microvascular dysfunction associated with cell death, interstitial fibrosis, and high wall stress. Radical treatment of DCM requires how to ameliorate its microcirculation and integrate cardiomyocytes created ex vivo into recipient myocardium. Hypothesis: The induced pluripotent stem cell derived cardiomyocyte sheets (iPS-sheet) has therapeutic potential by the improvement of microcirculation in a porcine DCM model. Methods: The iPS-sheets were generated from clinical grade human iPS cells. A DCM model was created by tachycardia pacing, and iPS-sheet was transplanted with immunosuppressive agents 1 month after the initiation of the pacing. We compared the therapeutic efficacy functionally and pathologically between the iPS-sheet transplant group (iPS-group) and the sham group after 1 month of transplantation. Results: On echocardiography, the iPS group showed a significant improvement in contractility compared to the sham group (LVEF 4 weeks after transplantation iPS vs. sham 49.0±6.5% vs. 36.4±3.3%, p&lt;0.05, Figure A). Pressure-volume loop analysis revealed that a significant decrease in left ventricular end diastolic pressure and an improvement in end-systolic pressure-volume relationship in the iPS group (Figure B). Ammonia PET showed improvement in myocardial blood flow at both rest and stress in iPS group (Figure C). Histological analysis revealed that the density of CD31-positive capillaries in transplanted area was significantly greater in the iPS group than the sham group. Immunostaining revealed iPS-sheet were detected on the epicardium of the distressed myocardium (Figure D). Conclusions: The iPS sheet showed engraftment in distressed myocardium, leading to amelioration in cardiac function through improving microcirculation with angiogenesis in porcine DCM model.
Molecular and biochemical characterization of MUC17
Authors: Wade M. Junker, Nicolas Moniaux, Aajay Singh, Surinder K. Batra
Journal: Cancer Research (2006)

2624  The study of mucins as membrane localized glycoproteins that present a restricted pattern of expression in the human body is better defining normal tissues from their malignant counterparts. Mucin 17 (MUC17) is a large, membrane-anchored glycoprotein displayed primarily in the gastrointestinal tract where it likely serves a role in protection from this extra-cellular environment. We have found that MUC17 is aberrantly expressed in pancreatic tumor cells and tumor cell lines. No expression of MUC17 is detected in normal pancreas or in benign pancreatitis. It is therefore hypothesized that MUC17 is associated with pancreatic cancer, and its expression pattern may be a valuable marker for the diagnosis of this lethal disease. Understanding the biochemical and molecular events that lead to an altered MUC17 expression is highly warranted. The membrane-tethered mucin family members are synthesized as distinct forms including; membrane-bound, secreted, and deleted of the large mucin central domain. MUC17 is herein shown to give rise to two alternatively spliced mRNAs that code specifically for membrane-bound and secreted forms of the protein. The identification of both transcripts was shown in AsPC-1 (pancreatic adenocarcinoma) and Ls174T (colonic adenocarcinoma) cells lines which highly express MUC17. Evolutionary pressures are reported to have maintained clusters of related mucin genes at specific chromosomal loci including: 11p15.5 (secreted, gel forming - MUC2, -5AC, -5B, -6), 3q29 (soluble, non-gel forming MUC4, MUC20) and those under study at 7q22 (membrane-bound MUC3A/B, -12, -17) Radiation hybridization mapping has revealed that three GI track specific mucins (MUC3, MUC12, and MUC17) are clustered on the short arm of chromosome 7 within close proximity of each other. It stands to reason that some nature of co-regulatory control exists for these mucins and an altered expression of the clustered genes has implications in the diseased state. Therefore, expression of MUC17 was knocked-down in AsPC-1 and Ls174T cell lines. Clones were tested for MUC3, MUC12, and MUC17 expression alongside their parental cell lines to investigate phenotypic changes induced by the absence of MUC17 in the 7q22 cluster. Western blot and immunohistochemical analyses using rabbit polyclonal antibody generated against MUC17 confirmed MUC17 in pancreatic cancer cell lines, pancreatic adenocarcinoma, and colonic adenocarcinoma tissue sections. In conclusion, our new results provide the evidences for the existence of an alternative MUC17 transcript (which codes for a secreted form of the protein) and further show that MUC17 is aberrantly expressed in pancreatic adenocarcinoma where its exact implication will be determined in the near future.
Abstract 10272: Aging is Associated With Impaired Cardiac Autonomic Nervous System and Brain-derived Neurothrophic Factor (bdnf) Production
Authors: Andrea Elia, Alessandro Cannavo, Maria Nolano, Nicola Ferrara, Nazareno Paolocci, Giuseppe Rengo
Journal: Circulation (2019)

Introduction: Several studies have shown that aging is associated with alteration in the autonomic nervous system (ANS). In particular, aging is characterized by increased circulating catecholamine...
Abstract 13700: Role of Parp1-pkm2 Axis in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension
Authors: Tsukasa Shimauchi, Junichi Omura, Sandra Breuils Bonnet, Valerie Nadeau, Eve Tremblay, Yann Grobs, Francois Potus, Roxane Paulin, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet
Journal: Circulation (2020)

Background: Right ventricular failure (RVF) is a poor prognostic factor for pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative stress-induced DNA damage, and glycolysis are key RVF-driven pathways triggering cardiomyocytes (CM) dysfunction. Persistent DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and pro-inflammatory responses through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite the tremendous attention to PARP1/PKM2 axis in many pathologies, their implication in RVF remains unexplored. We hypothesized sustained PARP1 activation accounts for nuclear PKM2 localization, contributing to CM dysfunction and transition from compensated (cRVH) to decompensated RVH(dRVH). Methods and Results: We found by WB and IF that PARP1/PKM2 expression/activity is increased in dRVH (patients died from RVF, n=9) compared to cRVH (Cardiac index &gt;2.2, n=14) and control donors (n=14) and correlates with RV hypertrophy and fibrosis. Similar findings were found in two rat models of RVF (monocrotaline; MCT, pulmonary artery banding; PAB). In addition, cardiac inflammation (NF-kB, HMGB1, IL-8, CCL-2, SOCS3, CD68), oxidative DNA damage (MTH1, 8-oxodG), and apoptosis (TUNEL) were significantly increased in dRVH compared to cRVH (human and rat models). In vitro , we confirmed by WB and IF that oxidative DNA damage (H 2 O 2 ) induce nuclear expression of PARP1/PKM2 in CM leading to the release of inflammatory mediators (NFkB, HMGB1) and cell death. These effects were prevented by pharmacological inhibition of PARP1 (ABT888) and enforced cytosolic retention of PKM2 (TEPP46 and DASA58). In vivo , PARP1 inhibition (Olaparib; 10mg/kg) as well as TEPP46 (25mg/kg) delayed progression of RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) in PAB rats (n=8 per groups). Preliminary data indicate CM-specific inactivation of PARP1 induces resistance to RVF in PAB mice (All p&lt;0.05). Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical integrator of oxidative stress, inflammation, and metabolic dysfunction during pathological RVF. Modulating PARP1/PKM2 axis may represent a promising avenue for ameliorating RVF in PAH.
Antenatal screening for Down's syndrome.
Authors: N. Bhatti, A. Mackie
Journal: BMJ (1992)

syndrome is effective in practice and can be readily integrated into routine antenatal care.'They do not, however, deal with the thorny issue of in- formed consent.This is a crucial point because under common law patients have the right to receive sufficient information, in a way that they can understand, about the screening programme, including any substantial risks, so that they can make a balanced judgment..
Two-Stage Turnbull-Cutait Pull-Through Coloanal Anastomosis for Low Rectal Cancers
Authors: Diwakar Pandey, Vivek Sukumar, Avanish Saklani
Journal: JAMA Surgery (2020)

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Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections
Authors: Elisa Pose, Mar Coll, Celia Martínez‐Sánchez, Zhutian Zeng, Bas G. J. Surewaard, Cristina Català, María Velasco‐de Andrés, Juan José Lozano, Sílvia Ariño, David Fuster, Aida Niñerola‐Bazán, Isabel Graupera, Érica Muñoz, Francisco Lozano, Pau Sancho‐Bru, Paul Kubes, Pere Ginès
Journal: Hepatology (2020)

Background and Aims Bacterial infections are common and severe in cirrhosis, but their pathogenesis is poorly understood. Dysfunction of liver macrophages may play a role, but information about their function in cirrhosis is limited. Our aims were to investigate the specific profile and function of liver macrophages in cirrhosis and their contribution to infections. Macrophages from human cirrhotic livers were characterized phenotypically by transcriptome analysis and flow cytometry; function was assessed in vivo by single photon emission computerized tomography in patients with cirrhosis. Serum levels of specific proteins and expression in peripheral monocytes were determined by ELISA and flow cytometry. In vivo phagocytic activity of liver macrophages was measured by spinning disk intravital microscopy in a mouse model of chronic liver injury. Approach and Results Liver macrophages from patients with cirrhosis overexpressed proteins related to immune exhaustion, such as programmed death ligand 1 (PD‐L1), macrophage receptor with collagenous structure (MARCO), and CD163. In vivo phagocytic activity of liver macrophages in patients with cirrhosis was markedly impaired. Monocytes from patients with cirrhosis showed overexpression of PD‐L1 that paralleled disease severity, correlated with its serum levels, and was associated with increased risk of infections. Blockade of PD‐L1 with anti‐PD‐L1 antibody caused a shift in macrophage phenotype toward a less immunosuppressive profile, restored liver macrophage in vivo phagocytic activity, and reduced bacterial dissemination. Conclusion Liver cirrhosis is characterized by a remarkable impairment of phagocytic function of macrophages associated with an immunosuppressive transcriptome profile. The programmed cell death receptor 1/PD‐L1 axis plays a major role in the impaired activity of liver macrophages. PD‐L1 blockade reverses the immune suppressive profile and increases antimicrobial activity of liver macrophages in cirrhosis.
Abstract 13688: Shocking: Cardioversion in Cardiogenic Shock Has Limited Success
Authors: William A Janes, Wendy Y Craig, Jonathan M Nichols, Henry W Sesselberg
Journal: Circulation (2020)

Introduction: Atrial fibrillation (AF) and atrial flutter (Aflutter) are common in cardiogenic shock patients in the Cardiac ICU (CICU). Electrical cardioversion (CV) can restore sinus rhythm, but carries the risk of transient hemodynamic deterioration. There has been little research in the efficacy and safety of electrical CV for AF/Aflutter in the CICU. Objective: Describe success of CV in AF/Aflutter in cardiogenic shock patients in the CICU. Methods: We identified Maine Medical Center CICU patients from 1/1/2015 to 12/31/19 who were in cardiogenic shock and underwent electrical CV for AF/Aflutter. Cardiogenic shock was defined by depressed cardiac index (&lt;2.2L/m^2 or inotrope use), hypotension (systolic BP &lt;90 mmHg, MAP &lt;65 mmHg, or vasopressor use), and Lactate &gt; 2mmol/L. If a patient had multiple CVs, only the first was analyzed. Results: Twenty patients met the inclusion criteria. Initially, 16 of 20 CVs were successful, however only 10 patients were in SR 24 hours after CV and only 7 were in SR at CICU discharge (Figure 1). The median LVEF was 20%, similar between groups (p-value = 0.52 initially, 0.37 at 24 hours, and 0.18 at CICU discharge). Only 1 patient was on mechanical support. The type of AF was varied (35% newly diagnosed, 55% paroxysmal, and 10% persistent). In patients with new AF, 85% were in SR initially, 57% at 24 hours, and 28% at CICU discharge. All patients received amiodarone. Inotrope use was similar, however no patients on vasopressors were in SR at CICU discharge (5/13 vs 0/7, p=0.11). Only 1 patient suffered an adverse effect (sinus bradycardia). Diabetes (p = 0.064) was the only characteristic to nearly predict lack of CV success at CICU discharge. Conclusions: 1. Electrical CV in patients admitted to the CICU in cardiogenic shock had a high initial success rate, however success was short-lived. 2. CV did not cause serious adverse effects. 3. Larger registries/trials are needed to predict which subgroups of CICU patients benefit from CV for Afib/Aflutter.
Abstract 15646: Pathological Assessment of Primary Graft Dysfunction Does Not Suggest a Prominent Role for an Adaptive Immune Response
Authors: Lillian Benck, Daniel Manzoor, Evan P Kransdorf, Jignesh K Patel, Daniel Luthringer, Jon A Kobashigawa
Journal: Circulation (2020)

Introduction: Primary graft dysfunction (PGD) is a major cause of mortality following heart transplant (HT). Pathological characteristics of PGD have not been well characterized. We sought to describe the clinical and pathological characteristics of patients who died or were re-transplanted due to PGD. Methods: We identified a cohort of 161 HT recipients between 3/7/2012 to 12/31/17 who developed PGD. Of these, 40 patients had severe PGD, and 16 died in the first month post-transplant. Autopsy or explant pathology was available in 6 patients, which was compared to pathology from the first endomyocardial biopsy in 24 patients with severe PGD that survived. Results: Of the 6 patients for whom pathology was available, mean age was 54, four were male and five were white. Half had non-ischemic dilated cardiomyopathy. Two were sensitized. Five patients had severe PGD and one patient had moderate PGD. There were five deaths and one re-transplant. On pathologic examination, most patients (4/6) had broad areas of myocardial necrosis with diffuse vascular thrombosis. Two patients had focal areas of myocardial necrosis. In no cases was there evidence of cellular rejection (ACR) or antibody-mediated rejection (AMR). In the 24 survivors of severe PGD, median age was 54 , twenty were male and half were white. Five were sensitized. On pathologic examination, ischemic changes were found in 10 patients (42%). While there was no significant ACR, 7/24 (30%) of cases showed evidence of either AMR 1 or AMR 2. Conclusions: In patients succumbing to moderate or severe PGD, PGD was associated with diffuse myocardial necrosis and vascular thrombi. In survivors of severe PGD, the most prominent finding was diffuse ischemic changes on routine heart biopsy. In both, there was no evidence of cellular rejection, however there was significant incidence of AMR, possibly induced by ischemic changes. These findings suggest that severe PGD may have an ischemic component characterized by vascular thrombosis.