tbuckley/cabot-search huggingface dataset:
Association of the US President’s Emergency Plan for AIDS Relief’s Funding With Prevention of Mother-to-Child Transmission of HIV in Kenya
Authors: Dale A. Barnhart, Isaac Tsikhutsu, Duncan Kirui, Fredrick Sawe, Jane Muli, William Sugut, Nareen Abboud, Deborah Birx, Tiffany Hamm, Peter Coakley, Patrick W. Hickey, Vanessa Wolfman, Elizabeth Lee, Donna Spiegelman
Journal: JAMA Network Open (2019)

From 2004 to 2014, the US President's Emergency Plan for AIDS Relief (PEPFAR) invested more than $248 000 000 in the prevention of mother-to-child transmission (PMTCT) of HIV in Kenya. Concurrently, child mortality in Kenya decreased by half.To identify the extent to which the decrease in child mortality in Kenya is associated with PEPFAR funding for PMTCT of HIV.This population-based survey study conducted in Kenya estimated the association between annual per capita PEPFAR funding for PMTCT (annual PCF) and cumulative per capita PEPFAR funding for PMTCT (cumulative PCF), extracted using 2004-2014 country operational reports as well as individual-level health outcomes, extracted from the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys and the 2007 and 2012 Kenya AIDS Indicator Surveys. The study included children of female respondents to the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys who were born 1 to 60 months (for neonatal mortality) or 12 to 60 months (for infant mortality) before the survey, as well as female respondents who had recently given birth and reported on HIV testing during antenatal care (ANC) during the 2007-2014 surveys. Results were adjusted for year, province, and survey respondent characteristics. Statistical analysis was performed from July 8, 2016, to December 10, 2018.Neonatal mortality was defined as death within the first month of life and infant mortality was defined as death within the first year of life. HIV testing during ANC was defined as receiving counseling on PMTCT, undergoing an HIV test, and receiving test results during ANC.The analysis included 33 181 neonates (16 870 boys), 26 876 infants (13 679 boys), and 20 775 mothers (mean [SD] age, 28.0 [6.7] years). PEPFAR funding was not associated with neonatal mortality. A $0.33 increase in annual PCF, corresponding to the difference between the 75th and 25th (interquartile range) percentiles of funding, was significantly associated with a 16% (95% CI, 4%-27%) reduction in infant mortality after a 1-year lag. A 14% to 16% reduction persisted after 2- and 3-year lags, and comparable reductions were observed for unlagged and 1-year lagged cumulative PCF. An increase of 1 interquartile range in cumulative PCF was associated with a 7% (95% CI, 3%-11%) increase in HIV testing during ANC, which intensified with subsequent lags. Between 2004 and 2014, sustained funding levels of $0.33 annual PCF could have averted 118 039 to 273 924 infant deaths.Evidence from publicly available data suggests that PEPFAR's PMTCT funding was associated with a reduction in infant mortality and an increase in HIV testing during ANC in Kenya. The full outcome of funding may not be realized until several years after allocation.
Abstract 12354: Cardiac STAT3 Activation in Subacute Phase of Myocardial Infarction was Required for the Suppression of Adverse Cardiac Remodeling
Authors: Daichi Enomoto, Masanori Obana, Akimitsu Miyawaki, Tomomi Mohri, Makio Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yasushi Fujio
Journal: Circulation (2015)

Backgroud: Cardiac STAT3 plays crucial roles in cardioprotection against acute injury after MI. However, mutated gp130-induced continuous STAT3 activation resulted in serious cardiac damage in the subacute phase of MI. Here, we examined the biological significance of intrinsic cardiac STAT3 during subacute/chronic phase of MI in a time specific manner using tamoxifen inducible cardiac specific STAT3 knockout mice (iCKO). Methods and Results: MI was generated by ligating the left coronary artery in mice. Immunoblotting revealed that STAT3 was rapidly activated in the myocardium, and that its activation was sustained to subacute phase after MI. To clarify the impact of cardiac STAT3 in subacute phase of MI, STAT3 gene was ablated by administering tamoxifen to α-MHC-MerCreMer/STAT3 flox/flox for 14 consecutive days from post-infarct day 11. As control mice, α-MHC-MerCreMer/STAT3 wild/wild mice were used. Importantly, MI-induced cardiac STAT3 activation was significantly decreased in iCKO mice at day 24. Intriguingly, the mortality was accelerated in iCKO mice compared with control mice, coincident with increased heart weight/body weight. Masson’s trichrome staining demonstrated that cardiac STAT3 ablation resulted in severe fibrosis (iCKO; 58.3±6.7%, control; 40.8±9.3%, p &lt;0.01, n=7 for control, n=8 for iCKO). Moreover, Echocardiography clarified that cardiac function was deteriorated in iCKO mice (FS: iCKO; 20.6±4.1%, control; 29.1±6.0%, p &lt;0.05, n=10 for control, n=11 for iCKO). In border area, marked myocardial injuries, including ROS production and hypertrophy, were observed in iCKO mice. Finally, immunohistochemistry revealed that capillary density was decreased in iCKO mice (iCKO; 1724.2±119.4 capillaries/mm 2 , control; 2110.5±77.7 capillaries/mm 2 , p &lt;0.01, n=30 fields from 5 mice for each). Conclusions: Cardiac STAT3 ablation in subacute phase of MI aggravated cardiac remodeling. The augmentation of STAT3 activity could be a therapeutic strategy for the prevention from the onset of chronic heart failure.
Relationship between dyspnea/oxygen saturation and leg discomfort/6-minute walking distance in patients with COPD participating in pulmonary rehabilitation
Authors: Lília Maia Santos, Paula Inês Pedro, Ana Dias, Cristina Braço Forte, Paula Raposo, Maria Fátima Rodrigues
Journal: Pulmonology (2019)

© 2019 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espana, ˜ S.L.U. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Targets and outcomes of psychotherapies for mental disorders: an overview
Authors: Pim Cuijpers
Journal: World Psychiatry (2019)

It is not yet clear what mental disorders are and what are the causal pathways that lead to them. That makes it difficult to decide what the targets and outcomes of psychotherapies should be. In this paper, the main types of targets and outcomes of psychotherapies are described, and a brief overview is provided of some of the main results of research on these types. These include symptom reduction, personal targets and outcomes from the patient's perspective, improvement of quality of life, intermediate outcomes depending on the theoretical framework of the therapist, negative outcomes to be avoided, and economic outcomes. In line with the dominance of the DSM and ICD systems for diagnoses, most research has been focused on symptom reduction. This considerable body of research, with hundreds of randomized trials, has shown that for most mental disorders effective psychotherapies are available. There is also research showing that psychotherapies can result in improvement of quality of life in most mental disorders. However, relatively little research is available on patient-defined outcomes, intermediate outcomes, negative outcomes and economic outcomes. Patients, relatives, therapists, employers, health care providers and society at large each have their own perspectives on targets and outcomes of psychotherapies. The perspective of patients should have more priority in research, and a standardization of outcome measures across trials is much needed.
Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain
Authors: Ted M. Kremer, Mark E. Lindsay, T. Bernard Kinane, Megan H. Hawley, Brent P. Little, Mari Mino-Kenudson
Journal: New England Journal of Medicine (2019)

A 22-year-old woman with congenital heart disease and joint laxity presented to the hospital because of chest pain, cough, and dyspnea. When she was 2 months of age, bronchiolitis had developed, and at 24 months she had undergone a right upper lobectomy for congenital lobar emphysema. A diagnostic test was performed.
Primary Care Selection
Authors: Scott Heiser, Patrick H. Conway, Rahul Rajkumar
Journal: JAMA (2019)

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Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques
Authors: Bin Jiang, Xufeng Fu, Li Yan, Shanshan Li, Dongliang Zhao, Xiaoyan Wang, Yanchao Duan, Yaping Yan, Enqin Li, Kunhua Wu, Briauna Marie Inglis, Weizhi Ji, Ren-He Xu, Wei Si
Journal: Theranostics (2019)

It has been demonstrated that mesenchymal stem cells (MSCs) differentiated from human embryonic stem cells (hESCs), name EMSCs, can treat a variety of autoimmune and inflammatory diseases, with similar efficacies to those achieved with MSCs derived from somatic tissues such as bone marrow (BMSCs).The chance increases even higher for EMSCs, than somatic tissue derived MSCs, to become a cell drug as the former can be produced in large scale from an unlimited hESC line with easier quality control and less biosafety concern.We have further demonstrated that both human ESCs and EMSCs, after aggregation to form spheroids, can tolerate hypoxic and ambient conditions (AC) for over 4 and 10 days, respectively, without loss of their viability and alteration of their functions.Based on these advantages, we decided to test whether EMSC spheroids, made in large quantity and delivered through a long-term distance at AC, can treat osteoarthritis spontaneously developed in rhesus macaques (M.mulatta) monkeys as well as the allogenic MSCs.Methods: Xenogeneic AC-transported EMSC spheroids or allogenic BMSCs were injected into the articular cavity of both knees of the monkeys at 3 animals per group.Another two macaques were injected the same way with saline as controls.Results: Both EMSCs and BMSCs groups showed significant amelioration indicated by the reduction of swelling joint size and amplification of keen flare angle post-treatment, compared to the control group.Examinations via X-ray and MRI also indicated the decrease of inflammation and osteophyma, and recovery of the synovium and cartilage in both treated groups.No sign of allergy or graft versus host disease was observed in the animals. Conclusion:Our results demonstrate that human EMSC spheroids can prevent the osteoarthtitis progression and ameliorate osteoarthritis in the rhesus macaques as well as allogenic BMSCs, and this study shall help advance the clinical application of EMSCs.
Neurofibromatosis 1 (NF1) and gastrointestinal stromal tumors (GISTs): Five-year experience from a regional center in United Kingdom.
Authors: Venkata Ramesh Bulusu, Ruth Casey, Olivier Giger, Nicholas Carroll, Eamonn Maher
Journal: Journal of Clinical Oncology (2019)

11035 Background: NF1 is an inherited autosomal dominant condition characterised by multifocal neurofibromas, café au lait spots, Lisch nodules, freckling. GISTs are the most common mesenchymal tumour of the gastrointestinal tract occurring in NF1 patients. We present our 5 year experience of NF1 associated GISTs from a regional centre in United Kingdom. Methods: 15 patients with GISTs associated with NF1 syndrome were identified from the database. Clinical, pathological, molecular and treatment outcomes were analysed. Results: N = 15. Male-3 and female-12. Median age 46 years. 33% were multifocal and 67% unifocal. Primary site Stomach-6.6%, duodenum-33%, small bowel-67%, colon 6.6%. Presenting symptoms: Abdominal pain-47%, anemia/bleed-40% and incidental finding-13%. Tumour size 0.5-23 cm, median 9 cm. Mitotic index 0-15, median 4 mitoses/5mm 2 . Risk stratification-Low/intermediate risk 60% and high risk 40%. Histology was spindle cell in 87% and mixed in 13%. All GISTs were CD117 and DOG-1 +ve. SDHB expression was preserved in all GISTs. No activation mutations were detected in KIT (exons 9, 11, 13, 17), PDGFRA (exons 12, 14, 18) and BRAF. Treatment: 67% had the primary GIST resected. None had adjuvant imatinib. 6 patients had been treated with tyrosine kinase inhibitors. 1 partial response lasting &lt; 3 months was observed with Imatinib. No durable responses were seen with Imatinib or Sunitinib or Regorafenib. All 5 patients with metastatic disease died within one year of diagnosis. Conclusions: GISTs associated with NF1 syndrome are rare. Median age of diagnosis is a decade earlier than KIT/PDGFRA mutated GISTs. We observed that NF1 associated GISTs occur predominantly in small bowel, are mostly spindle cell histology and have female preponderance. No durable responses were noted with Imatinib or Sunitinib or Regorafenib. There is an urgent need for systematic international collaboration to identify druggable pathways/targets in NF1 GISTs. Any trials should be multicentre/ multinational to expedite recruitment.
Silencing the early lung cancer marker hnRNP A2/B1 affects sensitivity to Gefitinib in a NSCLC cell line
Authors: Jordi Tauler, James Mulshine
Journal: Cancer Research (2008)

2668  Heterogeneous nuclear ribonucleoprotein (hnRNP A2/B1) is overexpressed in lung tumors. Several clinical trials have shown that elevated expression of hnRNP A2/B1 in exfoliated bronchial epithelial cells correlates with eventual development of lung cancer. Cells with high levels of hnRNP A2/B1 expression have also been reported to manifest multiple molecular features of genetic injury. To study the mechanism linking hnRNP A2/B1 overexpression and progression of lung cancer, we have knocked down hnRNPA2/B1 mRNA in lung cancer cell line (A549, NSCLC) with a specific siRNA vector-based system from Oligoengine. A549 cells were transfected with an empty vector (EV) as a control and with the silencing construct for hnRNP A2/B1 (siA). Silencing of hnRNP A2/B1 was confirmed at mRNA and protein level. As a first step to elucidate the functional consequences of silencing hnRNP A2/B1 we used the microarray technique using Affymetrix U133A Plus 2.0 microarrays including 38500 well-characterized human genes. Results from microarray analysis were filtered through a high stringency statistical test (p value =1.5). We obtained a list of 232 genes differentially expressed between EV A549 cells and siA A549 cells. To investigate more precisely the functional effects of hnRNP A2/B1 silencing, the list of 232 genes was analyzed using Ingenuity Pathway Systems, a web-based software able to cluster genes showing coordinated expression. This method allowed us to identify pathways and functions affected by hnRNP A2/B1 silencing. As a result of this analysis, 117 genes were distributed in eight clusters, showing that 43% of them were involved in cancer and 41% in cell signaling. Among them, several genes playing a role on survival pathways were identified such as AKT, ErbB3, Fibronectin-1, TGFβ-2, HIPK2 and GDF15. Most of them were downregulated after silencing hnRNP A2/B1. However, ErbB3 showed an increase at mRNA level, which is consistent with its previously described role in Gefitinib resistance. Interestingly, silencing hnRNP A2/B1 in A549 siA cells increased sensitivity to Gefitinib treatment compared to A549 EV cells where hnRNP A2/B1 is overexpressed. According to these results, we hypothesize that hnRNP A2/B1 overexpression has a protective cellular effect in lung cancer cell lines manifested as a protective effect against therapeutic agents. Further experiments are being conducted to investigate how silencing of hnRNP A2/B1 affects survival pathways and sensitivity to therapeutic agents, which could allow us to understand the role of hnRNP A2/B1 in cancer progression.
TCR-like antibodies in cancer immunotherapy
Authors: Qinghua He, Zhaoyu Liu, Zhihua Liu, Yuxiong Lai, Xinke Zhou, Jinsheng Weng
Journal: Journal of Hematology & Oncology (2019)

Cancer immunotherapy has been regarded as the most significant scientific breakthrough of 2013, and antibody therapy is at the core of this breakthrough. Despite significant success achieved in recent years, it is still difficult to target intracellular antigens of tumor cells with traditional antibodies, and novel therapeutic strategies are needed. T cell receptor (TCR)-like antibodies comprise a novel family of antibodies that can recognize peptide/MHC complexes on tumor cell surfaces. TCR-like antibodies can execute specific and significant anti-tumor immunity through several distinct molecular mechanisms, and the success of this type of antibody therapy in melanoma, leukemia, and breast, colon, and prostate tumor models has excited researchers in the immunotherapy field. Here, we summarize the generation strategy, function, and molecular mechanisms of TCR-like antibodies described in publications, focusing on the most significant discoveries.
Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity
Authors: Heng Yang, Lin Xia, Jian Chen, Shuqing Zhang, Vincent Martin, Qingqing Li, Shangqing Lin, Jinfeng Chen, Joseph Calmette, Min Lu, Lingyi Fu, Jie Yang, Zhizhong Pan, Kuai Yu, Jingjing He, Eric Morand, Géraldine Schlecht-Louf, Roman Krzysiek, Laurence Zitvogel, Boxi Kang, Zeming Zhang, Andrew Leader, Penghui Zhou, Laurence Lanfumey, Minxin Shi, Guido Kroemer, Yuting Ma
Journal: Nature Medicine (2019)
Corrigendum to “A carrier-free multiplexed gene editing system applicable for suspension cells” [Biomaterials 217 (2019) 119298]
Authors: Anna Ju, SungWon Lee, Young Eun Lee, Ki-Cheol Han, Jin-Chul Kim, Sang Chul Shin, Hyun Jung Park, Eunice EunKyeong Kim, Seokmann Hong, Mihue Jang
Journal: Biomaterials (2019)
New 2019 SLE EULAR/ACR classification criteria are valuable for distinguishing patients with SLE from patients with pSS
Authors: Florence Assan, Raphaele Seror, Xavier Mariette, Gaetane Nocturne
Journal: Annals of the Rheumatic Diseases (2019)

The new 2019 SLE European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for systemic lupus erythematosus (SLE) have been recently published.1 These criteria have been developed to find a better equilibrium between specificity and sensitivity compared with the previous criteria (SLE ACR-19972 and SLE Systemic Lupus International Collaborating Clinics (SLICC)3). Even if these criteria have been built for classification, they could be useful in clinical practice in patients with a suspicion of systemic autoimmune disease (AID) to differentiate patients with SLE from patients with another systemic AID, such as primary Sjogren’s syndrome (pSS), scleroderma or myositis. SLE and pSS share biological and clinical similarities. In clinical practice, it is frequently difficult to differentiate these two diseases. Moreover, SLE and Sjogren’s syndrome (SS) may overlap. The aim of this study was to explore the utility of the 2019 SLE EULAR/ACR criteria compared with the …
Transcriptomic Analysis Reveals Prognostic Molecular Signatures of Stage I Melanoma
Authors: Rohit Thakur, Jonathan P. Laye, Martin Lauss, Joey Mark S. Diaz, Sally Jane O'Shea, Joanna Poźniak, Anastasia Filia, Mark Harland, Joanne Gascoyne, Juliette A. Randerson-Moor, May Chan, Tracey Mell, Göran Jönsson, D. Timothy Bishop, Julia Newton-Bishop, Jennifer H. Barrett, Jérémie Nsengimana
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Previously identified transcriptomic signatures have been based on primary and metastatic melanomas with relatively few American Joint Committee on Cancer (AJCC) stage I tumors, given difficulties in sampling small tumors. The advent of adjuvant therapies has highlighted the need for better prognostic and predictive biomarkers, especially for AJCC stage I and stage II disease. Experimental Design: A total of 687 primary melanoma transcriptomes were generated from the Leeds Melanoma Cohort (LMC). The prognostic value of existing signatures across all the AJCC stages was tested. Unsupervised clustering was performed, and the prognostic value of the resultant signature was compared with that of sentinel node biopsy (SNB) and tested as a biomarker in three published immunotherapy datasets. Results: Previous Lund and The Cancer Genome Atlas signatures predicted outcome in the LMC dataset (P = 10−8 to 10−4) but showed a significant interaction with AJCC stage (P = 0.04) and did not predict outcome in stage I tumors (P = 0.3–0.7). Consensus-based classification of the LMC dataset identified six classes that predicted outcome, notably in stage I disease. LMC class was a similar indicator of prognosis when compared with SNB, and it added prognostic value to the genes reported by Gerami and colleagues. One particular LMC class consistently predicted poor outcome in patients receiving immunotherapy in two of three tested datasets. Biological characterization of this class revealed high JUN and AXL expression and evidence of epithelial-to-mesenchymal transition. Conclusions: A transcriptomic signature of primary melanoma was identified with prognostic value, including in stage I melanoma and in patients undergoing immunotherapy.
TGF-β signaling controls <i>Foxp3</i> methylation and T reg cell differentiation by modulating Uhrf1 activity
Authors: Xiang Sun, Yu Cui, Haiyun Feng, Haifeng Liu, Xiaolong Liu
Journal: The Journal of Experimental Medicine (2019)

Regulatory T (T reg) cells are required for the maintenance of immune homeostasis. Both TGF-β signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-β signaling participates in the epigenetic regulation of Foxp3 remains largely unknown. Here we showed that T cell–specific ablation of Uhrf1 resulted in T reg–biased differentiation in TCR-stimulated naive T cells in the absence of TGF-β signaling, and these Foxp3+ T cells had a suppressive function. Adoptive transfer of Uhrf1−/− naive T cells could significantly suppress colitis due to increased iT reg cell generation. Mechanistically, Uhrf1 was induced upon TCR stimulation and participated in the maintenance of DNA methylation patterns of T reg cell–specific genes during cell division, while it was phosphorylated upon TGF-β stimulation and sequestered outside the nucleus, and ultimately underwent proteasome-dependent degradation. Collectively, our study reveals a novel epigenetic mechanism of TGF-β–mediated iT reg cell differentiation by modulating Uhrf1 activity and suggests that Uhrf1 may be a potential therapeutic target in inflammatory diseases for generating stable iT reg cells.