tbuckley/cabot-search huggingface dataset:
Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis
Authors: Kaarina Kowalec, Galen E. B. Wright, Britt I. Drögemöller, Folefac Aminkeng, Amit P. Bhavsar, Elaine Kingwell, Eric M. Yoshida, Anthony Traboulsee, Ruth Ann Marrie, Marcelo Kremenchutzky, Trudy L. Campbell, Pierre Duquette, Naga Chalasani, Mia Wadelius, Pär Hallberg, Zongqi Xia, Philip L. De Jager, Joshua C. Denny, Mary F. Davis, Colin J. D. Ross, Helen Tremlett, Bruce C. Carleton
Journal: Nature Genetics (2018)
Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
Authors: Darren K. Patten, Giacomo Corleone, Balázs Győrffy, Ylenia Perone, Neil Slaven, Iros Barozzi, Edina Erdős, Alina Saiakhova, Kate Goddard, Andrea Vingiani, Sami Shousha, Lőrinc Sándor Pongor, Dimitri J. Hadjiminas, Gaia Schiavon, Peter Barry, Carlo Palmieri, Raul C. Coombes, Peter Scacheri, Giancarlo Pruneri, Luca Magnani
Journal: Nature Medicine (2018)
The Status of End-of-Life Care in the United States
Authors: Ezekiel J. Emanuel
Journal: JAMA (2018)

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NonA and CPX Link the Circadian Clockwork to Locomotor Activity in Drosophila
Authors: Weifei Luo, Fang Guo, Aoife McMahon, Shalise Couvertier, Hua Jin, Madelen Diaz, Allegra Fieldsend, Eranthie Weerapana, Michael Rosbash
Journal: Neuron (2018)
Primary Pulmonary Hypertension
Authors: StephenArcher, StuartRich
Journal: Circulation (2000)

Abstract—Primary pulmonary hypertension (PPH) is a syndrome of dyspnea, chest pain, and syncope defined by increased pulmonary vascular resistance and the absence of a known cause. It also occurs in a familial form, which is linked to unidentified genes on chromosome 2. This syndrome is characterized by abnormalities of pulmonary vascular biology in each compartment of the blood vessel. The lumen has a prothrombotic diathesis, the endothelium displays an excessive production of vasoconstrictors relative to vasodilators, and the smooth muscle cells are depolarized and calcium-overloaded, which is due in part to reduced expression of voltage-gated potassium channels (Kv). This causes vasoconstriction and may promote cell proliferation. The adventitia displays excessive remodeling, which is associated with exaggerated metalloproteinase and elastase activity. Conceptually, PPH seems to require a permissive genotype, a susceptible phenotype (eg, endothelial dysfunction) and, in many cases, an exogenous trigger...
Gastrostomy for epidermolysis bullosa
Authors: A.P.C. Zidorio, E.S. Dutra, L.C.G. Castro, K.M.B. Carvalho
Journal: British Journal of Dermatology (2018)

Epidermolysis bullosa (EB) is a life‐long, genetic blistering disorder which can affect internal surfaces as well as the skin. People with severe EB find eating difficult for many reasons including sore mouth, decayed teeth, difficulty swallowing and poor appetite. At the same time they need more protein and calories than normal, to repair skin which is constantly blistered, bleeding and breaking down. In other situations, eating problems can be bypassed by a “nasogastric” feeding tube passed through the nostril and into the stomach, but the sticky tape needed to hold it in place can damage EB skin. An alternative is a “gastrostomy” tube inserted directly through the belly skin into the stomach by a small operation and kept in place by an internal balloon so no tape is required. This paper from Brazil reviews the medical literature to find out whether a gastrostomy tube actually benefits EB patients. Due to the rarity of EB there have been no randomised controlled trials, and of 641 relevant papers, only 7 provided sufficient detail about patients and outcomes to address this question. They conclude that nutritional status usually, but not always improves, and even if it worsens some patients report better life quality, presumably because it relieves the stress of eating. Complications led to removal of the gastrostomy tube in 10% of patients. The accompanying commentary points out that more data is required to answer the many remaining questions about gastrostomy regarding technique, timing and diet as well as outcomes.
Abstract 88: A Crucial Role of BAG3 in Preventing Dilated Cardiomyopathy
Authors: Xi Fang, Julius Bogomolovas, Wei Zhang, Tongbin Wu, Canzhao Liu, Jennifer Lowe, Kunfu Ouyang, Zhiyuan Zhang, Xiaolong Ma, Yongxin Mu, Matthew Stroud, Dieu-Hung Lao, Nancy Dalton, Yusu Gu, Celine Wang, Michael Wang, Yan Liang, Stephan Lange, Kirk Peterson, Sylvia Evans, Ju Chen
Journal: Circulation Research (2017)

Defective protein quality control (PQC) systems are implicated in multiple diseases, with molecular chaperones/co-chaperones being critical to PQC. Cardiomyocytes are constantly challenged by mechanical and metabolic stress, placing great demand on the PQC system. Mutations and downregulation of the co-chaperone protein B cl-2- a ssociated athano g ene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to Dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and mechanisms by which the E455K mutation lead to DCM remained obscure. Here, we found that cardiac-specific BAG3 knockout (CKO) and cardiac-specific E455K BAG3 knockin mice developed DCM. Comparable phenotypes in the two mutants demonstrated that the E455K mutation resulted in loss-of-function, and experiments revealed that the E455K mutation disrupted interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a specific subset of proteins required for metabolic and contractile function of cardiomyocytes was enriched in the insoluble fraction. Together, these observations suggested that interaction between BAG3 and HSP70 was essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide new insight into the pathogenesis of heart failure caused by defects in BAG3 pathways, suggesting that increasing protein levels of BAG3 may be of therapeutic benefit in heart failure.
To Use or Not to Use 131I in Thyroid Cancer
Authors: Darlene Metter, William T. Phillips, Ronald C. Walker, Ralph Blumhardt
Journal: Clinical Nuclear Medicine (2018)

The purpose of the following commentary is to discuss recent controversies in the use of radioactive iodine for differentiated thyroid cancer (DTC).R. M. Tuttle (Thyroid 2010; 20:257-263), at Memorial Sloan Kettering Cancer Center, has enumerated the well-accepted goals of radioactive iodine therapy (RAIT) in DTC: (1) ablate residual thyroid to facilitate future surveillance, (2) "adjuvant therapy" for residual radioactive iodine-avid disease, and (3) a post-RAIT scan may reveal unknown local and/or distant metastases. Using these goals as a guide, the authors have critically reviewed a recent movement to decrease the use of RAIT in DTC that is being advocated by some investigators.As a result, a recent article has highlighted this new treatment philosophy. A 2017 publication in the Journal of Clinical Oncology (Molenaar et al, 2017 0:JCO.2017.75.0232) recommends that RAIT not be used in low- or intermediate-risk DTC. In this article, the authors claim that the RAIT risks in DTC, particularly leukemia, outweigh its potential benefits. This change, if adopted, in our opinion will have profound deleterious consequences on patient outcomes. We also have identified a major problem with the article of Molenaar et al. The authors use the American Thyroid Association's criteria for staging thyroid cancer. In our opinion, this method of staging is severely flawed. We also quantitatively compare the article's alleged risk of RAIT-induced leukemia with the benefits of RAIT for DTC.In summary, this matter must be debated before eliminating RAIT in low- or intermediate-risk DTC. If RAIT is eliminated for these patients, many such patients will no longer benefit from the RAIT goals listed by R. M. Tuttle, including the critical advantage of potentially improved overall and event-free survival.
Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18
Authors: C.-A. Voltin, H. Goergen, C. Baues, M. Fuchs, J. Mettler, S. Kreissl, J. Oertl, B. Klaeser, A. Moccia, A. Drzezga, A. Engert, P. Borchmann, M. Dietlein, C. Kobe
Journal: Annals of Oncology (2018)
Abstract 15379: Regulation of Long Non-Coding RNA Fingerprint by Cyclic Mechanical Stretch in Vascular Smooth Muscle Cells: Implications for Aortic Aneurysms
Authors: Laura-Eve Mantella, Krishna K Singh, Paul Sandhu, Crystal Kantores, Azza Ramadan, Nadiya Khyzha, Adrian Quan, Mohammed Al-Omran, Jason E Fish, Robert E Jankov, Subodh Verma
Journal: Circulation (2016)

Introduction:  Emerging evidence suggests that long noncoding RNAs (lncRNAs) may be a cellular hub for the coordination of cellular processes involved in health and disease. Alterations in the characteristics of vascular smooth muscle cells (VSMCs), triggered largely by changes in mechanical stress, play a critical role in the pathophysiology of vascular diseases like aneurysms and hypertension.   Hypothesis:  LncRNAs are involved in mechanical stretch-induced changes in HASMCs.   Methods:  Total RNA was extracted with TRIzol. LncRNAs and mRNAs were profiled with the Arraystar Human LncRNA Microarray V3.0. Aneurysmal and non-aneurysmal samples were collected from patients undergoing aortic arch repair and the aortas of ApoE -/-  mice infused for 4 weeks with angiotensin II or saline. Gene expression was quantified via qRT-PCR. For knockdown studies, HASMCs were transfected with 10 nM siLincRNA-p21 or 5 nM scrambled control (nM). Apoptosis was assessed using Annexin V/PI double staining.   Results:  Of the 30,586 human lncRNAs screened in HASMCs, 580 were differentially expressed (P  -/-  mice (N = 3, P  Bax ,  Puma ,  Noxa , and  Mdm2  under conditions of stretch (N = 3, P    Conclusions:  We describe the first transcriptome profile of stretch-induced changes in HASMCs. The data implicate lincRNA-p21 as a mechanoresponsive regulator of aneurysm formation in mice and humans, and provide novel insights into the regulatory switches governing aberrant VSMC remodeling, which may have importance in the pathogenesis of aneurysms and hypertension.
Prospective follow-up of a cohort of 112 patients with leptomeningeal metastases of breast cancer recruited from 2007 to 2011: Prognostic factors.
Authors: Fahed Zairi, Nuria Kotecki, Isabelle Rodrigues, Marie-Christine Baranzelli, Charles Andre, François Dubois, Patrick Devos, Matthieu Faivre-Pierret, Richard Assaker, Jacques Bonneterre, Emilie Le Rhun
Journal: Journal of Clinical Oncology (2012)

2070 Background: Around 5% of patients with breast cancers (BC) will develop leptomeningeal metastasis (LM). The incidence may increase. Methods: We reported the description and outcome of 112 consecutive BC patients diagnosed with LM in our institution from 2007 to 2011. Correlations between characteristics and overall survival (OS) were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox model). Results: BC were invasive ductal carcinoma in 69.7%. Estrogen and progesterone receptors were detected in respectively 61.6 and 44.6%. HER2 expression was observed in 26%. 23% were triple negative. Median time between BC diagnosis and LM diagnosis was 44 months. At LM diagnosis, median age was 54 and median Performance Status (PS) was 2. CSF cytology and cerebrospinal MRI were positive in respectively 72,5% and 87%. 103 (92%) LM patients received IT liposomal cytarabine as 1st line of treatment (ventricular device in 47%). IT therapy could be associated with systemic treatment in 58% of the cases and cerebral radiotherapy for LM in 14% of the cases. Clinical response after 1st line treatment was observed in 57%, CSF response in 30,5%, MRI response in 62,5%. 24 patients received a 2nd line of IT thiotepa, 6 a 3rd line of IT methotrexate. The more significant prognostic factors (p&lt;0,0001) were initial PS, associated systemic treatment and triple negative BC status. Other significant predictors of OS were thiotepa as 2nd line treatment (p=0,0004), intracranial hypertension at LM diagnosis (p=0,019), associated cerebral radiotherapy (p=0,02), progesterone receptor status (p=0,04). Median OS of the 103 treated patients was 3,8 months (4,75 months for 0-2 PS and 1,6 months for 3-4 PS patients). Conclusions: Median OS was consistent those of other recent cohorts of BC LM. Our results confirm the role of a very early diagnosis, before the degradation of the general status. The association with systemic treatment or cerebral radiotherapy is indicated when possible.
Smad1 Protects Cardiomyocytes From Ischemia-Reperfusion Injury
Authors: MitsuruMasaki, MasahiroIzumi, YuichiOshima, YoshikazuNakaoka, TadashiKuroda, RyusukeKimura, ShokoSugiyama, KazuoTerai, MasafumiKitakaze, KeikoYamauchi-Takihara, IchiroKawase, HisaoHirota
Journal: Circulation (2005)

Background— We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury. Methods and Results— The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the α-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene–positive mouse hearts. To examine ...
Abstract 17070: The Renin-angiotensin System Regulates Expression of Cyr61 and β3 Integrins in Atheroma in ApoE–/– Mice With Unilateral Renal Artery Ligation
Authors: Alokkumar Pathak, Jianhua Huang, Mauricio Rojas, George A Stouffer
Journal: Circulation (2016)

Introduction:  Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions, stimulates growth responses of cultured smooth muscle cells (SMC) and is upregulated by angiotensin II (Ang II).   Hypothesis:  Determine whether Cyr61 is expressed in atheroma from ApoE –/–  mice with unilateral renal artery ligation.   Methods and Results:  18 week old ApoE –/–  mice were randomized to unilateral renal artery ligation (RAL), RAL + treatment with irbesartan, RAL + treatment with aliskiren or sham-surgery for 90 days. RAL reduced blood flow (60 ± 6% of baseline values), increased renin mRNA levels in the ligated kidney, and elicited a mild, sustained increase in systolic blood pressure compared to sham-surgery. Lipid deposition, measured by Oil-red O staining, was increased approximately 3 fold in the aortic arch and 2 fold in the descending aorta in the RAL group compared to sham-surgery. Treatment with irbesartan or aliskiren prevented the hypertensive response and reduced descending aorta lipid deposition to a level that was statistically similar to sham-surgery. Aliskiren, but not irbesartan, prevented the increase in aortic arch lipid deposition. Atheromas in the abdominal aorta showed intense staining for Cyr61 in RAL mice but patchy, diffuse and less intense staining in RAL + irbesartan (43% less staining) and RAL + aliskiren (60% less staining) mice. Atheromas showed generalized and intense staining for β 3  integrins that co-localized with Cyr61 in mice with RAL. In contrast, β 3  integrin staining was localized, discrete and even non-existent in atheromas from RAL + irbesartan and RAL + aliskiren mice. Sham-surgery mice had no atheromas and minimal staining for Cyr61 and β 3  integrins. Studies in cultured rat aortic SMC showed that Cyr61 was secreted in response to treatment with Ang II and that echistatin, a function-blocking disintegrin that binds α v β 3  integrins on SMC, reduced Cyr61-induced proliferation, migration and signaling.   Conclusions:  Cyr61 and β 3  integrins are expressed in aortic atheroma from ApoE –/–  mice with unilateral RAL and this expression is regulated by the renin-angiotensin system.
Abstract 18198: Obesity Paradox in Heart Failure: Impact on death
Authors: Sharath K Kumar, Rajiv Mahajan, Dennis Lau, Prashanthan Sanders
Journal: Circulation (2016)

Introduction:  Increasing body mass index (BMI) has been associated with incident heart failure (HF) and studies have shown a protective effect of elevated BMI in chronic HF.   Hypothesis:  To evaluate the risk of HF and HF related mortality in obesity and study the impact of purposeful weight loss.   Methods:  Pubmed/ Embase was searched with keywords of “heart failure” AND “obesity”. 4637 references were initially identified. After exclusions, 7 studies (n=366228, follow up: 12.3±6.4 years) reporting on the risk of HF in patients with obesity, 14 studies (n=45424; follow up: 4.4±3 years) reporting on HF related mortality in patients with obesity, and 9 studies (n=1111) reporting the impact of purposeful weight loss on cardiac structure and function in obesity were analysed by random-effects meta-analysis.   Results:  There was a ‘J curve’ effect of body mass index (BMI) on risk of HF (BMI 30 to 34.5: OR=2.1 [95% CI 1.36 - 3.24]; BMI>35: OR=1.97[CI 1.12 to 3.47]). Paradoxically an inverse relationship between BMI and HF related mortality (BMI 30 to 34.5: OR=0.69 [CI 0.57 to 0.85]; BMI>35: OR=0.46 [CI 0.38 to 0.55]) was noted. Purposeful weight loss resulted in reduced left atrial size (SMD -0.48, 95% CI -0.95- to -0.01; p=0.05), left ventricular mass index (-10.9g/m 2 , 95% CI -15.3 to -6.6; p   Conclusions:  BMI has a J curve relationship with HF risk and paradoxically an inverse relationship with HF related mortality. Importantly, purposeful weight reduction results in improvement in cardiac indices suggesting other factors such as cachexia and ‘additional causes’ of HF may be responsible for excessive mortality with normal BMI.
Homeobox Protein Hex Induces SMemb/Nonmuscle Myosin Heavy Chain-B Gene Expression Through the cAMP-Responsive Element
Authors: KenichiSekiguchi, MasahikoKurabayashi, YukoOyama, YasushiAihara, ToruTanaka, HironosukeSakamoto, YoichiHoshino, TsugiyasuKanda, TomoyukiYokoyama, YukioShimomura, HirokazuIijima, YoshioOhyama, RyozoNagai
Journal: Circulation Research (2001)

Abstract—Recent studies have shown that the homeobox gene Hex plays an important role in inducing differentiation of vascular endothelial cells. In this study, we examined the expression of Hex in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Immunohistochemistry showed a marked induction of Hex protein in neointimal VSMCs after balloon injury in rat aorta. Western and reverse transcriptase–polymerase chain reaction analyses demonstrated that Hex was abundantly expressed in cultured VSMCs, whereas it was undetectable in other cell types or in normal aorta. The expression pattern of Hex was similar to that of SMemb/NMHC-B, a nonmuscle isoform of myosin heavy chain that we have previously reported to be a molecular marker of dedifferentiated VSMCs. We next examined the role of Hex in SMemb gene transcription. Promoter analysis demonstrated that the sequence identical to consensus cAMP-responsive element (CRE) located at −481 of the SMemb promoter was critical for Hex responsiveness. Mutant Hex ...
The soluble isoform of human Fcɛ<scp>RI</scp> is an endogenous inhibitor of IgE‐mediated mast cell responses
Authors: S. Moñino‐Romero, L. Erkert, K. Schmidthaler, S. C. Diesner, B. F. Sallis, L. Pennington, T. Jardetzky, H. C. Oettgen, B. Bohle, E. Fiebiger, Z. Szépfalusi
Journal: Allergy (2018)

The soluble isoform of FcɛRI, the high-affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions.To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions.FcεRI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by FcεRI cross-linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal-associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE-dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild-type) and IgE-/- (IgE-deficient) mice.Antigen-specific cross-linking of IgE-loaded FcɛRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcɛRI activation induces sFcɛRI release. We demonstrated that generation of sFcɛRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcɛRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFcɛRI is an inhibitor of the human innate IgE effector axis, implying that sFcɛRI and omalizumab potentially inhibit each other in vivo.sFcɛRI is produced after antigen-specific IgE/FcɛRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcɛRI and IgE-mediated activation. Our results imply, therefore, that sFcɛRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.