tbuckley/cabot-search huggingface dataset:
A Novel Role for Calpain in the Endothelial Dysfunction Induced by Activation of Angiotensin II Type 1 Receptor Signaling
Authors: RosarioScalia, YulanGong, BrettBerzins, BrinFreund, DanielleFeather, GavinLandesberg, GouravMishra
Journal: Circulation Research (2011)

Rationale:The cytosolic protease calpain has been recently implicated in the vascular remodeling of angiotensin II (Ang II) type 1 receptor (AT1R) signaling. The role of Ang II/AT1R/calpain signaling on endothelial function, an important and early determinant of vascular pathology, remains though totally unknown. Accordingly, we investigated the role of calpain in the endothelial dysfunction of Ang II. Objective:To demonstrate a mechanistic role for calpain in the endothelial dysfunction induced by Ang II/AT1R signaling. To establish endothelial-expressed calpains as an important target of AT1R signaling. Methods and Results:Subchronic administration of nonpressor doses of Ang II to rats and mice significantly increased vascular calpain activity via AT1R signaling. Intravital microscopy studies revealed that activation of vascular expressed calpains causes endothelial dysfunction with increased leukocyte–endothelium interactions and albumin permeability in the microcirculation. Western blot and immunohist...
Health workers return medals for Ebola care in protest at UK “hostile environment” policy
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Around 20 aid workers who were honoured for their work in west Africa during the 2014-15 outbreak of Ebola disease have returned their medals to the UK government as a protest against the “hostile environment” policies introduced in the NHS.

The workers are calling for the government to repeal the October 2017 regulations that enforce immigration checks and upfront charging of 150% …
Contemporarily Treated Patients With Hodgkin Lymphoma Have Childbearing Potential in Line With Matched Comparators
Authors: Caroline E. Weibull, Anna L.V. Johansson, Sandra Eloranta, Karin E. Smedby, Magnus Björkholm, Paul C. Lambert, Paul W. Dickman, Ingrid Glimelius
Journal: Journal of Clinical Oncology (2018)

Purpose With excellent cure rates for young patients with Hodgkin lymphoma (HL), there is an increasing number of female survivors of HL interested in becoming pregnant. Here, we report childbearing among contemporarily treated HL survivors in comparison with the general population. Material and Methods Using Swedish registers, 449 women (ages 18 to 40 years) diagnosed with HL between 1992 and 2009 and in remission 9 months after diagnosis were identified. Patients were age- and calendar-year–matched to 2,210 population comparators. Rates of first postdiagnosis childbirth were calculated. Hazard ratios (HRs) with 95% CIs were estimated for different follow-up periods using Cox regression. Cumulative probabilities of first childbirth were calculated in the presence of the competing risk of death or relapse. Results Twenty-two percent of relapse-free patients with HL had a child during follow-up, and first childbirth rates increased over time, from 40.2 per 1,000 person-years (1992 to 1997) to 69.7 per 1,000 person-years (2004 to 2009). For comparators, childbirth rates remained stable (70.1 per 1,000 person-years). Patients diagnosed between 2004 and 2009 had a cumulative probability of childbirth similar to comparators. Three years or more after diagnosis, no differences in childbirth rates were observed between patients and comparators, regardless of stage or treatment. Patients who received six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone had a lower childbirth rate than comparators during the first 3 years (HR, 0.23; 95% CI, 0.06 to 0.94), as did patients who received six to eight courses of chemotherapy and radiotherapy (HR, 0.21; 95% CI, 0.07 to 0.65). Conclusion Childbearing potential among female survivors of HL has improved over time, and childbirth rates 3 years after diagnosis in contemporarily treated patients are, in the absence of relapse, similar to those in the general population, regardless of stage and treatment.
Angiotensin II Induces Myocyte Enhancer Factor 2- and Calcineurin/Nuclear Factor of Activated T Cell-Dependent Transcriptional Activation in Vascular Myocytes
Authors: EtsuSuzuki, HiroakiNishimatsu, HiroshiSatonaka, KennethWalsh, AtsuoGoto, MasaoOmata, ToshiroFujita, RyozoNagai, YasunobuHirata
Journal: Circulation Research (2002)

It is well known that angiotensin II (Ang II) is implicated in the phenotypic modulation and hypertrophy of vascular smooth muscle cells (VSMCs). To study the mechanisms by which Ang II contributes to the pathological changes of VSMCs, we examined whether Ang II stimulated myocyte enhancer factor 2 (MEF2)- and calcineurin/nuclear factor of activated T cell (NFAT)-dependent transcriptional activation of genes in VSMCs. Ang II increased the DNA binding activity of MEF2A and its expression at the protein level. Ang II induced c-jun promoter activity, and this increase was inhibited by dominant-negative mutants of MEF2A and mitogen-activated protein kinase kinase 6 but not by calcineurin inhibitors. Ang II stimulated NFAT DNA binding activity and NFAT-dependent gene transcription, and these effects of Ang II were inhibited by calcineurin inhibitors. Furthermore, Ang II induced the promoter activity of the nonmuscle-type myosin heavy chain B gene, which we used as a marker of the dedifferentiated state of VSMC...
Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications
Authors: Martijn J J Finken, Manouk van der Steen, Carolina C J Smeets, Marie J E Walenkamp, Christiaan de Bruin, Anita C S Hokken-Koelega, Jan M Wit
Journal: Endocrine Reviews (2018)

Children born small for gestational age (SGA), defined as a birth weight and/or length below -2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ∼10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below -2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk.
Colon cleansing efficacy and safety with 1 L NER1006 versus 2 L polyethylene glycol + ascorbate: a randomized phase 3 trial
Authors: Raf Bisschops, Jonathan Manning, Lucy Clayton, Richard Ng Kwet Shing, Marco Álvarez-González
Journal: Endoscopy (2018)

Abstract Background Polyethylene glycol (PEG)-based bowel preparations are effective cleansers but many require high-volume intake. This phase 3, randomized, blinded, multicenter, parallel-group, central reader-assessed study assessed the 1 L PEG NER1006 bowel preparation vs. standard 2 L PEG with ascorbate (2LPEG). Methods Patients undergoing colonoscopy were randomized (1:1:1) to receive NER1006, as an evening/morning (N2D) or morning-only (N1D) regimen, or evening/morning 2LPEG. Cleansing was assessed using the Harefield Cleansing Scale (HCS) and the Boston Bowel Preparation Scale (BBPS). Primary end points were overall bowel cleansing success and high-quality cleansing in the right colon. Modified full analysis set (mFAS) and per protocol (PP) analyses were performed. Mean cleansing scores were analyzed post hoc. Results Of 849 randomized patients, efficacy was analyzed in the following patient numbers (mFAS/PP): total n = 822/670; N2D n = 275/220; N1D n = 275/218; 2LPEG n = 272/232. mFAS established noninferiority. PP showed superiority for N2D on overall success (97.3 % vs. 92.2 %; P = 0.014), and for N2D and N1D on right colon high-quality cleansing (N2D 32.3 % vs. 15.9 %, P &lt; 0.001; N1D 34.4 % vs. 15.9 %, P &lt; 0.001) vs. 2LPEG. Using HCS, N2D and N1D attained superior segmental high-quality cleansing (P ≤ 0.003 per segment). N2D showed superior mean segmental HCS scores (P ≤ 0.007 per segment). Both N2D and N1D achieved superior mean overall (P &lt; 0.001 and P = 0.006) and right colon BBPS scores (P &lt; 0.001 and P = 0.013). N2D demonstrated superior right colon polyp detection (P = 0.024). Adherence, tolerability, and safety were comparable between treatments. Conclusions NER1006 is the first low-volume preparation to demonstrate superior colon cleansing efficacy vs. standard 2LPEG with ascorbate, with comparable safety and tolerability. European Clinical Trials Database (EudraCT)2014-002185-78TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 trial 2014-002185-78 at https://eudract.ema.europa.eu/
26 Opportunistic infections in inflammatory bowel disease: are we adhering to the ecco guidelines?
Authors: O Reed, N Bradley, R Hall, S Bhat
Journal: Gut (2017)

Background  The use of immunomodulators for inflammatory bowel disease (IBD) has significantly improved disease management. However, these treatments increase the risk of infection. Screening for immunity to serious infection is recommended but compliance with these recommendations is unknown.  Aim  To assess adherence to the European Crohns and Colitis Organisation (ECCO) screening guidelines and the rates of developing opportunistic infections in a cohort of IBD patients.  Method  All patients currently on biological therapy were identified from a database of IBD patients within the Southern Health Trust. Case records were retrospectively reviewed to identify compliance with screening guidelines, and subsequent development of opportunistic infection.  Results  78 patients were receiving biologics +/− immunomodulators. 62 (79.5%) of patients had Crohn’s disease. The majority were pre-screened appropriately for infection (77.9%) with 99% of patients being pre-screened for TB. 72.8% of patients had the recommended viral serology checked.  Six patients (7.69%) developed infections. The majority did not require hospital admission (66. 7%). Two patients (33.3%) developed sepsis requiring hospital admission. There was no mortality related to infection.  Infection was more frequent in patients that were on both an immunomodulator and biological therapy (11.9% vs 2.8%, p=0.13) than biological therapy alone.  No patient developed, was treated for or reactivated latent tuberculosis.  Conclusions  In this IBD cohort screening for infection was appropriate but could be further optimised. Risk of infection in this cohort was lower than in previous studies. Better adherence to screening recommendations and vigilance for infection may reduce the morbidity associated with immunosuppression in IBD.
Abstract 11925: Differences in End-of-Life Preferences and Planning by Prognosis in Patients Hospitalized With Acute Decompensated Heart Failure
Authors: Kathleen A Young, Jacob J Strand, Margaret M Redfield, Shannon M Dunlay
Journal: Circulation (2016)

Introduction: In patients with heart failure, preferences for end-of-life (EOL) care and involvement in advance care planning can vary over their illness trajectory. The aim of this study was to compare EOL preferences by prognosis, assessed using the validated Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, in patients hospitalized with acute decompensated heart failure (ADHF). Hypothesis: EOL preferences and planning vary by prognosis. Methods: Between January 2014 and January 2016, Southeastern Minnesota residents hospitalized with ADHF at Mayo Clinic hospitals in Rochester, MN were prospectively recruited into an observational cohort study. Information on EOL preferences and advance care planning were assessed by patient questionnaire. MAGGIC risk scores and associated 1-year mortality estimates were calculated using patient characteristics at the time of hospital admission and stratified by quartile. The associations of EOL preferences/ planning and prognosis were examined using two sample t-tests and linear regression. Results: Among 400 patients (mean age 77.7 years, 46% female), predicted 1-year mortality ranged from 3.9-72.5% (median 22.5%). Patients with higher estimated mortality (worse prognosis) more often elected Do Not Resuscitate (DNR) status (p=0.001) and more often had an advanced directive (p&lt;0.001, Table). No other differences in EOL preferences or planning by prognosis were observed. Conclusions: In community patients hospitalized with ADHF, resuscitation preferences and rates of completion of advance care planning documents varied with prognosis, though patient-clinician EOL discussions and awareness and attitudes about EOL options did not.
A Lump in the Neck
Authors: Michael C. Honigberg, Amanda A. Westlake, Gabriel K. Griffin, Anand Vaidya, Jennifer A. Johnson
Journal: New England Journal of Medicine (2018)

A 44-year-old man presented to his primary care physician in July with a large mass on the right side of his neck. He had had known infection with the human immunodeficiency virus (HIV) for the past 20 years and was receiving antiretroviral therapy. His CD4+ T-cell count was 700 cells per cubic millimeter and his HIV viral load, which had been measured 2 weeks before presentation, was less than 20 copies per milliliter. He had noticed the mass 1 week before presentation. . . .
Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies
Authors: Vanessa M. Tubb, Deborah S. Schrikkema, Nathan P. Croft, Anthony W. Purcell, Carsten Linnemann, Manon R. Freriks, Frederick Chen, Heather M. Long, Steven P. Lee, Gavin M. Bendle
Journal: Journal for ImmunoTherapy of Cancer (2018)

Mutation-derived neoantigens represent an important class of tumour-specific, tumour rejection antigens, and are attractive targets for TCR gene therapy of cancer. The majority of such mutations are patient-specific and targeting these requires a fully personalized approach. However, some mutations are found recurrently among cancer patients, and represent potential targets for neoantigen-specific TCR gene therapy that is more widely applicable. Therefore, we have investigated if some cancer mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles and can form targets for TCR gene therapy. We initially focused on identifying HLA class I neoepitopes derived from calreticulin (CALR) exon 9 mutations, found in ~ 80% of JAK2wt myeloproliferative neoplasms (MPN). Based on MHC class I peptide predictions, a number of peptides derived from mutant CALR (mCALR) were predicted to bind to HLA-A*03:01 and HLA-B*07:02. However, using mass spectrometry and ex vivo pMHC multimer staining of PBMC from MPN patients with CALR exon 9 mutations, we found no evidence that these peptides were naturally processed and presented on the surface of mCALR-expressing target cells. We next developed a protocol utilizing pMHC multimers to isolate CD8+ T cells from healthy human donor PBMC that are specific for mCALR and additional putative neoepitopes found recurrently in hematological malignancies. Using this approach, CD8+ T cells specific for HLA-A*03:01- and HLA-B*07:02-presented mCALR peptides and an HLA-A*11:01-presented mutant FBXW7 (mFBXW7) peptide were successfully isolated. TCRs isolated from mCALR-specific CD8+ T cell populations were not able to recognize target cells engineered to express mCALR. In contrast, mFBXW7-specific CD8+ T cells were able to recognize target cells engineered to express mFBXW7. In conclusion, while we found no evidence for mCALR derived neoepitope presentation in the context of the HLA class I alleles studied, our data suggests that the recurrent pR465H mutation in FBXW7 may encode an HLA-A*11:01 presented neoepitope, and warrants further investigation as a target for T cell based immunotherapy of cancer.
<i>SOX17</i> Mutations in Japanese Patients with Pulmonary Arterial Hypertension
Authors: Takahiro Hiraide, Masaharu Kataoka, Hisato Suzuki, Yuki Aimi, Tomohiro Chiba, Kohsuke Kanekura, Toru Satoh, Keiichi Fukuda, Shinobu Gamou, Kenjiro Kosaki
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Predicting breast tumor proliferation from whole-slide images: The TUPAC16 challenge
Authors: Mitko Veta, Yujing J. Heng, Nikolas Stathonikos, Babak Ehteshami Bejnordi, Francisco Beca, Thomas Wollmann, Karl Rohr, Manan A. Shah, Dayong Wang, Mikael Rousson, Martin Hedlund, David Tellez, Francesco Ciompi, Erwan Zerhouni, David Lanyi, Matheus Viana, Vassili Kovalev, Vitali Liauchuk, Hady Ahmady Phoulady, Talha Qaiser, Simon Graham, Nasir Rajpoot, Erik Sjöblom, Jesper Molin, Kyunghyun Paeng, Sangheum Hwang, Sunggyun Park, Zhipeng Jia, Eric I-Chao Chang, Yan Xu, Andrew H. Beck, Paul J. van Diest, Josien P.W. Pluim
Journal: Medical Image Analysis (2019)
UTx With Deceased Donors Also Places Risks and Burdens on Third Parties
Authors: Heidi Mertes, Kristof Van Assche
Journal: The American Journal of Bioethics (2018)

While making the case for uterus retrieval from multi-organ donors, Bruno and Arora (2018) presume that it is self-evident that “uterus removal should occur only after procurement of vital organs.”...
An argument for how (and why) to incentivise replication
Authors: Piers D. L. Howe, Amy Perfors
Journal: Behavioral and Brain Sciences (2018)

Although Zwaan et al. (2018) have made a compelling case as to why direct replications should occur more frequently than they do, they do not address how such replications attempts can best be encouraged. We propose a novel method for incentivising replication attempts and discuss some issues surrounding its implementation.
Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma
Authors: Stuart MacGregor, Jue-Sheng Ong, Jiyuan An, Xikun Han, Tiger Zhou, Owen M. Siggs, Matthew H. Law, Emmanuelle Souzeau, Shiwani Sharma, David J. Lynn, Jonathan Beesley, Bronwyn Sheldrick, Richard A. Mills, John Landers, Jonathan B. Ruddle, Stuart L. Graham, Paul R. Healey, Andrew J. R. White, Robert J. Casson, Stephen Best, John R Grigg, Ivan Goldberg, Joseph E. Powell, David C. Whiteman, Graham L. Radford-Smith, Nicholas G. Martin, Grant W. Montgomery, Kathryn P. Burdon, David A. Mackey, Puya Gharahkhani, Jamie E. Craig, Alex W. Hewitt
Journal: Nature Genetics (2018)
Biochemical Recurrence of Prostate Cancer Presenting as Solitary Testicular Metastasis on 68Ga-Labeled Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography
Authors: Gul Ege Aktas, Vuslat Yürüt Çaloğlu, Hakan Akdere, Busem Binboğa Tutuğ, Gülay Durmuş Altun
Journal: Clinical Nuclear Medicine (2018)

Prostate adenocarcinoma (PCa) is the most frequently diagnosed malignancy in the male population, with the most common sites for secondary lesions being the lymph nodes, bones, and lungs. Testicular metastases from PCa are very rare and mostly identified incidentally after therapeutic orchiectomy for advanced PCa or during autopsy. Here we present a case involving a 64-year-old man with biochemical recurrence of castrated oligometastatic PCa that presented as solitary testicular metastasis on Ga-PSMA ligand positron emission tomography/computed tomography.
Prospective Study of Psychosocial Outcomes of Having Contralateral Prophylactic Mastectomy Among Women With Nonhereditary Breast Cancer
Authors: Patricia A. Parker, Susan K. Peterson, Yu Shen, Isabelle Bedrosian, Dalliah M. Black, Alastair M. Thompson, Jonathan C. Nelson, Sarah M. DeSnyder, Robert L. Cook, Kelly K. Hunt, Robert J. Volk, Scott B. Cantor, Wenli Dong, Abenaa M. Brewster
Journal: Journal of Clinical Oncology (2018)

Purpose The incidence of contralateral prophylactic mastectomy (CPM) has continued to increase. We prospectively examined psychosocial outcomes before and up to 18 months after surgery in women who did or did not have CPM. Methods Women with unilateral, nonhereditary breast cancer completed questionnaires before and 1, 6, 12, and 18 months after surgery. Primary psychosocial measures were cancer worry and cancer-specific distress. Secondary measures were body image, quality of life (QOL), decisional satisfaction, and decisional regret. Results A total of 288 women (mean age, 56 years; 58% non-Hispanic white) provided questionnaire data, of whom 50 underwent CPM. Before surgery, women who subsequently received CPM had higher cancer distress ( P = .04), cancer worry ( P < .001), and body image concerns ( P < .001) than women who did not have CPM. In a multivariable repeated measures model adjusted for time, age, race/ethnicity, and stage, CPM was associated with more body image distress ( P < .001) and poorer QOL ( P = .02). There was a significant interaction between time point and CPM group for cancer worry ( P
The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis
Authors: Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E. Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V. Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, Hiroshi Seno
Journal: Journal of Clinical Investigation (2018)

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia–derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.