tbuckley/cabot-search huggingface dataset:
A New Switch for TGFβ in Cancer
Authors: Hsi-Wen Yeh, Szu-Shuo Lee, Chieh-Yu Chang, Yaw-Dong Lang, Yuh-Shan Jou
Journal: Cancer Research (2019)

Abstract The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFβ responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPβ, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFβ responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.
Antisense Oligonucleotide Mediated Depletion of Factor XI Prevents Vascular Occlusion in An Experimental Thrombosis Model in Primates
Authors: Jeff R. Crosby, Ulla M Marzec, Chenguang Zhao, Dacao Gao, Alexey S Revenko, Anton Matafonov, David Gailani, Robert MacLeod, Andras Gruber, Stephen Hanson, Brett P. Monia
Journal: Blood (2011)
ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart
Authors: Yufeng Yao, Changqing Hu, Qixue Song, Yong Li, Xingwen Da, Yubin Yu, Hui Li, Ian M Clark, Qiuyun Chen, Qing K Wang
Journal: Cardiovascular Research (2019)

Abstract Aims Cardiac fibrosis is a major cause of heart failure (HF), and mediated by the differentiation of cardiac fibroblasts into myofibroblasts. However, limited tools are available to block cardiac fibrosis. ADAMTS16 is a member of the ADAMTS superfamily of extracellular protease enzymes involved in extracellular matrix (ECM) degradation and remodelling. In this study, we aimed to establish ADAMTS16 as a key regulator of cardiac fibrosis. Methods and results Western blot and qRT–PCR analyses demonstrated that ADAMTS16 was significantly up-regulated in mice with transverse aortic constriction (TAC) associated with left ventricular hypertrophy and HF, which was correlated with increased expression of Mmp2, Mmp9, Col1a1, and Col3a1. Overexpression of ADAMTS16 accelerated the AngII-induced activation of cardiac fibroblasts into myofibroblasts. Protein structural analysis and co-immunoprecipitation revealed that ADAMTS16 interacted with the latency-associated peptide (LAP)-transforming growth factor (TGF)-β via a RRFR motif. Overexpression of ADAMTS16 induced the activation of TGF-β in cardiac fibroblasts; however, the effects were blocked by a mutation of the RRFR motif to IIFI, knockdown of Adamts16 expression, or a TGF-β-neutralizing antibody (ΝAb). The RRFR tetrapeptide, but not control IIFI peptide, blocked the interaction between ADAMTS16 and LAP-TGF-β, and accelerated the activation of TGF-β in cardiac fibroblasts. In TAC mice, the RRFR tetrapeptide aggravated cardiac fibrosis and hypertrophy by up-regulation of ECM proteins, activation of TGF-β, and increased SMAD2/SMAD3 signalling, however, the effects were blocked by TGF-β-NAb. Conclusion ADAMTS16 promotes cardiac fibrosis, cardiac hypertrophy, and HF by facilitating cardiac fibroblasts activation via interacting with and activating LAP-TGF-β signalling. The RRFR motif of ADAMTS16 disrupts the interaction between ADAMTS16 and LAP-TGF-β, activates TGF-β, and aggravated cardiac fibrosis and hypertrophy. This study identifies a novel regulator of TGF-β signalling and cardiac fibrosis, and provides a new target for the development of therapeutic treatment of cardiac fibrosis and HF.
HMGB1 as a marker of tumor development in mice with spontaneous hepatoma and implanted MC38 adenocarcinoma
Authors: Xiang Da Dong, Petar Popovic, Michael T. Lotze, Kevin Stavely-O’carroll, Sri Chalikonda, David L. Bartlett, Herbert J. Zeh
Journal: Cancer Research (2005)

4699  Introduction: Expression of iNOS in human tumor was first described in colorectal adenocardinoma cell lines (Radomski et al., 1991). Because metastatic activity, host defense mechanisms, and level of differentiation seem to be correlated to iNOS expression, a role for iNOS has been proposed in the onset and progression of malignant diseases. Under physiological condition, NO acts as an intracellular secondary messenger and provides an efficient system for cellular regulation, interaction, and defense. The expression of 3 isoforms of NOS in human gliomas and in peritumoral areas have been analyzed by several groups. Although the induction of iNOS has been noted in human meningioma (Bakshi et al., 1998; Broholm et al., 2003; Ellie et al., 1995; Hara et al., 1996), a clear correlation between meningiomas and iNOS expression has not been established. Methods: Human meningiomas of benign, atypical, and anaplastic/malignant grade (n=10) were excised and primary explant cultures obtained. Histopathological confirmation of grade was obtained. Using western blot , expression of inducible nitric oxide synthase (iNOS) was demonstrated for cultured cells and intact tissue fragments. Integrity of downstream NO signaling pathways was tested by exposing cultured cells at early passage to NO donor compounds. The downstream actions of NO take two forms: (1) cGMP-dependent; and (2) cGMP-independent, which are mediated by reactive nitrogen species produced by the interaction of NO with oxygen (O2) or with superoxide radicals (O2.-). The first was tested by measuring levels of guanyl cyclase and of cGMP, and the second by assay of nitrotyrosine formation, in NO-donor stimulated cells of each grade. Results: A clear correlation was shown between iNOS expression and the degree of tumor malignancy, with lowest expression seen in benign tumors and highest seen in those of anaplastic grade. In malignant meningioma cells both membrane-bound and soluble guanylyl cyclase (sGC) were un-regulatable and the cGMP levels were very low despite significantly high levels of iNOS expression. In contrast, in benign meningioma cells sGC responded to NO normally and a marked increase of cGMP was observed upon NO donor stimulation. Thus, the downstream pathways of NO signaling in malignant meningioma appear to be shut down. In additional experiments a significant increase in nitrotyrosine formation (a biomarker for cGMP-independent NO action) was detected in malignant cells. Conclusion: iNOS expression correlates with degree of malignancy in meningiomas. Although , in anaplastic meningiomas cGMP-dependent signaling pathways are inactive but cGMP-independent pathways are not. These data suggest that in malignant meningioma cells, iNOS overexpression may contribute to a survival advantage mediated by protein tyrosine nitration.
Pre-eclampsia: pathophysiology and clinical implications
Authors: Graham J Burton, Christopher W Redman, James M Roberts, Ashley Moffett
Journal: BMJ (2019)

Abstract Pre-eclampsia is a common disorder that particularly affects first pregnancies. The clinical presentation is highly variable but hypertension and proteinuria are usually seen. These systemic signs arise from soluble factors released from the placenta as a result of a response to stress of syncytiotrophoblast. There are two sub-types: early and late onset pre-eclampsia, with others almost certainly yet to be identified. Early onset pre-eclampsia arises owing to defective placentation, whilst late onset pre-eclampsia may center around interactions between normal senescence of the placenta and a maternal genetic predisposition to cardiovascular and metabolic disease. The causes, placental and maternal, vary among individuals. Recent research has focused on placental-uterine interactions in early pregnancy. The aim now is to translate these findings into new ways to predict, prevent, and treat pre-eclampsia.
Abstract P301: Adipocytokines and Vitamin D in a Biracial Sample of Young Metabolically Healthy Obese and Metabolically Abnormal Obese Women
Authors: Sarah M Camhi, Tongjian You, Laura L Hayman, Aviva Must, Alice H Lichtenstein
Journal: Circulation (2016)

Purpose: Adipocytokines and vitamin D (vitD) concentrations may contribute to cardiometabolic risk profiles in obese populations. To address this potential relationship we assessed levels of adipocytokines and vitD concentrations between young metabolically healthy obese (MHO) and metabolically abnormal obese (MAO) black and white women. Methods: Project Health included 46 overweight/obese young women (BMI ≥25 kg/m2, age=19-35 years, 61% Black). Women were classified as MHO (&lt;2 abnormal cardiometabolic risk factors) or MAO (≥2 abnormal cardiometabolic risk factors) based on: blood pressure ≥130/85 mmHg; triglycerides ≥150 mg/dL; HDL-C &lt;50 mg/dL; glucose ≥100 mg/dL; CRP ≥90th %tile; HOMA-IR ≥90th %tile). Serum levels of high sensitivity C-reactive protein (CRP) were measured by an immunoturbidimetric assay; levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by an electrochemiluminescence immunoassay; adiponectin by an enzyme-linked immunosorbent assay; and 25-hydroxyvitamin D (vitD) by a radioimmunoassay. Total body fat was measured by dual x-ray absorptiometry. Pearson correlations were used to test the associations between body fat and serum measures. T-tests and linear regression (adjusting for race and body fat) were used to examine differences between MHO and MAO. Results: Compared to MAO (n=9, 20%), MHO (n=37; 80%) had significantly lower BMI values (MHO: 30.5±3.5; MAO: 34.3±3.9 kg/m2, p=0.004), but there was no significant difference in body fat (mean in total sample: 45.3±6.2%). CRP concentration was significantly associated with higher body fat (%) in MAO (r=0.78, p=0.007), but this relationship was not significant in MHO. IL-6, TNF-α and vitD were not significantly correlated with percent body fat in either MHO or MAO. Compared to MHO, MAO had significantly higher CRP levels (log mg/L MHO: 0.82±1.2 vs. MAO 1.8±0.9, p=0.01); and significantly lower adiponectin levels (log ng/mL MHO: 9.7±0.5 vs. MAO 9.0±0.3; p=0.0004). These differences remained significant after adjusting for race and body fat. There were no significant differences between MHO and MAO for IL-6, TNF-α or VitD levels. Conclusion: Compared to MHO, young women who are MAO have higher levels of CRP and lower levels of adiponectin even after controlling for potential confounders. Our findings suggest that chronic inflammation may play an important role in the mechanism of abnormal cardiometabolic risk as it differentiates young MHO and MAO women.
CMR for Identifying the Substrate of Ventricular Arrhythmia in Patients With Normal Echocardiography
Authors: Daniele Andreini, Antonio Dello Russo, Gianluca Pontone, Saima Mushtaq, Edoardo Conte, Marco Perchinunno, Marco Guglielmo, Ana Coutinho Santos, Marco Magatelli, Andrea Baggiano, Simone Zanchi, Eleonora Melotti, Laura Fusini, Paola Gripari, Michela Casella, Corrado Carbucicchio, Stefania Riva, Gaetano Fassini, Letizia Li Piani, Cesare Fiorentini, Antonio L. Bartorelli, Claudio Tondo, Mauro Pepi
Journal: JACC. Cardiovascular imaging (2019)
Impact of Depression and Anxiety on Change to Physical Activity Following a Pragmatic Diabetes Prevention Program Within Primary Care: Pooled Analysis From Two Randomized Controlled Trials
Authors: Thomas Yates, Laura J. Gray, Joseph Henson, Charlotte L. Edwardson, Kamlesh Khunti, Melanie J. Davies
Journal: Diabetes Care (2019)

OBJECTIVE The impact of major affective disorders on the effectiveness of diabetes prevention programs at promoting health behaviors has not been established. We investigated whether depression modifies the effectiveness of two pragmatic diabetes prevention programs at promoting increased physical activity. RESEARCH DESIGN AND METHODS This study pooled data from two cluster randomized controlled trials (Walking Away from Type 2 Diabetes and Let’s Prevent Type 2 Diabetes) that included individuals at high risk of type 2 diabetes who were recruited from primary care. The trials used very similar intervention methods to promote physical activity and had annual follow-up over a 36-month period. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale, and physical activity was measured by a piezoelectric pedometer (Let’s Prevent Type 2 Diabetes) or an accelerometer (Walking Away from Type 2 Diabetes) and expressed as steps per day. RESULTS This analysis included 1,163 individuals (571 control, 592 intervention) who had concurrent baseline and follow-up data for ambulatory activity, depression, and anxiety. The median depression score was 3 at baseline; 11% of individuals were classified as having mild to severe depression. Those with no depressive symptoms at baseline or during follow-up increased their ambulatory activity by 592 steps per day (P &amp;lt; 0.001); this effect decayed by 88 steps per day (95% CI 21, 155) for every additional depressive symptom score at baseline, and each increase in the depressive symptom score between baseline and follow-up further attenuated the intervention effect by 99 steps per day (95% CI 2, 196). CONCLUSIONS Both depressive symptom burden at baseline and change in this burden are associated with a graded reduction in the effectiveness of diabetes prevention programs at increasing physical activity in primary care.
Venetoclax induces sustained complete responses in refractory/relapsed patients with cardiac AL amyloidosis.
Authors: Fabien Le Bras, Jehan Dupuis, François Lemonnier, Silvia Oghina, Diane Bodez, Amandine Ladaique, Alizee Maarek, Louise Roulin, Asma Beldi Ferichou, Valerie Frenkel, Corinne Haioun, Thibaud Damy, Karim Belhadj
Journal: Journal of Clinical Oncology (2019)

e19538 Background: Venetoclax (VEN) is an orally bioavailable small molecule inhibitor of the anti-apoptotic protein BCL-2 and has been shown to have efficacy against myeloma (MM), particularly in patients that harbor t(11;14). Approximately, 50% of AL amyloidosis patients will exhibit t(11;14) making VEN an attractive therapeutic option. Methods: We here report the results of a retrospective analysis of a monocentric series of refractory/relapsed (R/R) patients (pts) heavily pretreated with cardiac AL amyloidosis treated in a french academic center. VEN was given daily alone or in association with dexamethasone (DEX), with or without bortezomib (BTZ). Treatment was planned to be administered until progression. Results: Between February 2017 and January 2019, 7 consecutive R/R pts have been treated. All had received previous BTZ and daratumumab (DARA) containing regimen. Baseline characteristics were: median age: 72.7 years (range 40-84), Mayo Clinic stage: stage I in 2 pts, stage II in 3 and stage IIIA in 2. All patients but one had in addition to cardiac deposit, systemic involvement including kidney, joint, neurologic, gastro-intestinal tract, lymph node and muscle. All but one pts were refractory to their last treatment consisting of DARA-DEX with or without IMID. The t(11;14) translocation was present in 5 pts, absent in 1 and undetermined in 1 pts. Two pts had concomitant MM at diagnosis. Median number of previous line treatments was 4 (3-5). Five patients received VEN- BTZ- DEX as described in MM (PMID: 28847998), 1 with DEX and 1 as monotherapy. Five pts received 400 mg/d, one 200 mg/d and one 100 mg/d. Median duration of treatment was 76 days (30-713). All patients but one are still on treatment. One patient treated with 400 mg/d had a dose reduction to 100 mg/d due to grade 2 diarrhea. Four patients received at least 2 cycles and were evaluable for response. One 84 y old patient in stable disease after 1 cycle died due to influenza infection. 2 patients received only one cycle of treatment. Hematological complete response occurred in 2/4 (50%) patients, after 63 and 27 days. Interestingly, responses were sustained as the 2 responders were still on therapy after 76 and 713 days. This later patient, refractory to 2 previous lines had a cardiac and neurologic response. The 2 responding patients had proven t(11:14). Conclusions: On this limited series of heavily pretreated patients with R/R AL cardiac amyloidosis VEN used as a single agent or in combination can induce prolonged response and seems a promising drug with an acceptable safety profile in patients with t(11;14).
Multicenter phase I/II study of nivolumab combined with paclitaxel plus ramucirumab as the second-line treatment in patients with advanced gastric cancer
Authors: S. Kadowaki, N. Izawa, K. Minashi, T. Nishina, T. Yamanaka, K. Muro, Y. Sunakawa, S. Hironaka, T. Kajiwara, Y. Kawakami, T. Nakajima
Journal: Annals of Oncology (2019)
A Cultural Sea Change: Mindfulness for Surgical Residents
Authors: Feyza Sancar
Journal: JAMA (2019)

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Abstract 20338: Impact of Intravascular Ultrasound and Final Kissing Balloon Dilatation on Long-Term Clinical Outcome in Percutaneous Revascularization With 1-Stent Strategy for Left Main Coronary Artery Stenosis
Authors: Jang Hoon Lee, Hong Nyun Kim, Joon Hyuk Song, Namkyun Kim, Jae Hyung Roh, Myung Hwan Bae, Dong Heon Yang, Hun Sik Park, Yongkeun Cho, Shung Chull Chae, Jihyun Sohn, Se Yong Jang
Journal: Circulation (2017)

Impact of Intravascular Ultrasound and Final Kissing Balloon Dilatation on Long-Term Clinical Outcome in Percutaneous Revascularization with 1-Stent Strategy for Left Main Coronary Artery Stenosis:...
Effect of sleep deprivation and exercise on reaction threshold in adults with peanut allergy: A randomized controlled study
Authors: Shelley Dua, Monica Ruiz-Garcia, Simon Bond, Stephen R. Durham, Ian Kimber, Clare Mills, Graham Roberts, Isabel Skypala, James Wason, Pamela Ewan, Robert Boyle, Andrew Clark
Journal: Journal of Allergy and Clinical Immunology (2019)
Sandoz rituximab (GP2013; SDZ-RTX) for the treatment of diffuse large B-cell lymphoma (DLBCL): Interim safety results of the non-interventional, observational, multicenter, open-label REFLECT study.
Authors: Manfred Welslau, Norbert Marschner, Thomas Wolff, Burkhard Joerg Otremba, Julian Topaly, Larissa Bittencourt da Silva
Journal: Journal of Clinical Oncology (2019)

e19020 Background: SDZ-RTX is approved in Europe for the same indications as reference rituximab, based on the totality of evidence for biosimilarity. REFLECT, a real-world study of SDZ-RTX as curative therapy for treatment-naïve CD20 + DLBCL, represents the first biosimilar rituximab post-approval study in DLBCL. Methods: The study includes patients (pts) aged ≥18 years, eligible for rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). R-CHOP is administered according to product label. The primary endpoint is complete response rate at the end of treatment. Secondary endpoints include overall response rate, progression-free survival at 12 months, and adverse events (AE). Data are collected at baseline and every study visit for 12 months (efficacy) and ≥30 days after last SDZ-RTX dose (safety). No imputation for missing data is planned; endpoints are summarized descriptively. Results: In an interim analysis (cut off: Sep 6, 2018; recruitment approx. 50% complete), the full analysis set comprised 80 pts: 38 males (47.5%) and 42 females (52.5%), with median (min, max) age 68.5 years (23, 91); 70% of pts were aged ≥60 years. In total, 6 pts have discontinued. Most pts had little or no restriction in daily activities; &gt;80% had ECOG score of 0 (34%) or 1 (50%). B-symptoms were reported in 15 pts (19%). Extranodal infiltration was observed in 40 pts (50%) and bulky disease was observed in 9 pts (11.3%). Most pts had early stage (I–IIB: 63.8%), low to intermediate risk disease (IPI Score 0–2: 61.3%). A summary of safety is reported in the Table. AEs were reported in 53 (66%) pts and 19 (24%) pts had serious AEs. Treatment-related AEs were reported in 13 pts (16%). The most frequent AEs were polyneuropathy (n=10, 12.5%), anemia (n=8, 10%), and fatigue (n=8, 10%). Conclusions: Interim baseline data are as expected for treatment-naïve pts with CD20 + DLBCL; safety results are as expected for rituximab-based treatment. The study is ongoing. [Table: see text]
Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention
Authors: Diogo Mosqueira, James G.W. Smith, Jamie R. Bhagwan, Chris Denning
Journal: Trends in Molecular Medicine (2019)

HighlightsHCM is a prevalent and complex disease governed by multiple molecular mechanisms, and there is currently no efficient cure. New treatment strategies are under development, and several drugs are reaching the final stages of clinical trials, with partial efficacy.HCM disease models vary in complexity. Furthermore, they are limited by sample availability, demanding logistics, preparation artefacts, oversimplicity, and species-differences relative to the human cardiovascular physiology, often producing conflicting results.Application of genome-editing technology to hPSCs enables unlimited isogenic sets of heart cells in which the primary mutation is the only change, allowing elucidation of disease phenotypes and genetic causation.Uncovering new disease mechanisms and targets will pave the way to more efficient HCM therapeutics.AbstractHypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings. In this article we compare recent progress in unveiling multiple HCM mechanisms in different models, highlighting similarities and discrepancies. We explore how insight is facilitating the design of new HCM therapeutics, including those that regulate metabolism, contraction and heart rhythm, providing a future perspective for treatment of HCM.