tbuckley/cabot-search huggingface dataset:
An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice
Authors: Liliane Khoryati, Minh Nguyet Pham, McKenna Sherve, Swarnima Kumari, Kevin Cook, Josh Pearson, Marika Bogdani, Daniel J. Campbell, Marc A. Gavin
Journal: Science Immunology (2020)

A CD25-dependent IL-2 mutein expanded regulatory T cells and controlled spontaneous diabetes in nonobese diabetic (NOD) mice.
RSSs set the odds for exclusion
Authors: Michael S. Krangel
Journal: The Journal of Experimental Medicine (2020)

In this issue of JEM, Wu et al. (https://doi.org/10.1084/jem.20200412) provide new insights into allelic exclusion. They demonstrate that Vβ-to-DβJβ rearrangement occurs stochastically on two competing Tcrb alleles, with suboptimal Vβ recombination signal sequences limiting synchronous rearrangements and essential for allelic exclusion.
HLA Genotyping in Synovial Sarcoma: Identifying HLA-A*02 and Its Association with Clinical Outcome
Authors: Evan Rosenbaum, Kenneth Seier, Chaitanya Bandlamudi, Mark Dickson, Mrinal Gounder, Mary L. Keohan, Ping Chi, Ciara Kelly, Sujana Movva, Benjamin Nacev, Noemi Simeone, Mark Donoghue, Emily K. Slotkin, Li-Xuan Qin, Cristina R. Antonescu, William D. Tap, Sandra P. D'Angelo
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS. Experimental Design: Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1–specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility. Results: A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995–3.813; P = 0.052]. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting. Conclusions: Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.
Clinical characteristics of allergic rhinitis patients in 13 metropolitan cities of China
Authors: Ming Zheng, Xiangdong Wang, Meng Wang, Wenyu She, Lei Cheng, Meiping Lu, Zhimin Xing, Furong Ma, Li Zhu, Lei Chen, Xiaoping Lin, Xuejun Jiang, Dongdong Zhu, Geng Xu, Weiping Wen, Weijia Kong, Jianjun Chen, Zezhang Tao, Yu Xu, Dehui Wang, Shixi Liu, Shenqing Wang, Weihong Jiang, Jingwu Sun, Changqing Zhao, Limin Suo, Hua Zhang, Luo Zhang
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Sequential Combination of Cognitive-Behavioral Treatment and Well-Being Therapy in Depressed Patients with Acute Coronary Syndromes: A Randomized Controlled Trial (TREATED-ACS Study)
Authors: Chiara Rafanelli, Sara Gostoli, Sara Buzzichelli, Jenny Guidi, Laura Sirri, Pamela Gallo, Enrica Marzola, Serena Bergerone, Gaetano Maria De Ferrari, Renzo Roncuzzi, Giuseppe Di Pasquale, Giovanni Abbate-Daga, Giovanni A. Fava
Journal: Psychotherapy and Psychosomatics (2020)

Introduction: Randomized controlled trials (RCT) of psychotherapeutic interventions have addressed depression and demoralization associated with acute coronary syndromes (ACS). The present trial introduces psychological well-being, an increasingly recognized factor in cardiovascular health, as a therapeutic target. Objective: This study was designed to determine whether the sequential combination of cognitive-behavioral therapy (CBT) and well-being therapy (WBT) may yield more favorable outcomes than an active control group (clinical management; CM) and to identify subgroups of patients at greater risk for cardiac negative outcomes. Methods: This multicenter RCT comparedCBT/WBT sequential combination versus CM, with up to 30 months of follow-up. One hundred consecutive depressed and/or demoralized patients (out of 740 initially screened by cardiologists after a first episode of ACS) were randomized to CBT/WBT associated with lifestyle suggestions (n = 50) and CM (n = 50). The main outcome measures included: severity of depressive symptoms according to the Clinical Interview for Depression, changes in subclinical psychological distress, well-being, and biomarkers, and medical complications and events. Results: CBT/WBT sequential combination was associated with a significant improvement in depressive symptoms compared to CM. In both groups, the benefits persisted at follow-up, even though the differences faded. Treatment was also related to a significant amelioration of biomarkers (platelet count, HDL, and D-dimer), whereas the 2 groups showed similar frequencies of adverse cardiac events. Conclusions: Addressing psychological well-being in the psychotherapeutic approach to ACS patients with depressive symptoms was found to entail important clinical benefits. It is argued that lifestyle changes geared toward cardiovascular health may be facilitated by a personalized approach that targets well-being.
A dynamic COVID-19 immune signature includes associations with poor prognosis
Authors: Adam G. Laing, Anna Lorenc, Irene del Molino del Barrio, Abhishek Das, Matthew Fish, Leticia Monin, Miguel Muñoz-Ruiz, Duncan R. McKenzie, Thomas S. Hayday, Isaac Francos-Quijorna, Shraddha Kamdar, Magdalene Joseph, Daniel Davies, Richard Davis, Aislinn Jennings, Iva Zlatareva, Pierre Vantourout, Yin Wu, Vasiliki Sofra, Florencia Cano, Maria Greco, Efstathios Theodoridis, Joshua D. Freedman, Sarah Gee, Julie Nuo En Chan, Sarah Ryan, Eva Bugallo-Blanco, Pärt Peterson, Kai Kisand, Liis Haljasmägi, Loubna Chadli, Philippe Moingeon, Lauren Martinez, Blair Merrick, Karen Bisnauthsing, Kate Brooks, Mohammad A. A. Ibrahim, Jeremy Mason, Federico Lopez Gomez, Kola Babalola, Sultan Abdul-Jawad, John Cason, Christine Mant, Jeffrey Seow, Carl Graham, Katie J. Doores, Francesca Di Rosa, Jonathan Edgeworth, Manu Shankar-Hari, Adrian C. Hayday
Journal: Nature Medicine (2020)

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19. A common immune signature in the blood of patients with COVID-19, who are otherwise clinically heterogeneous, sheds light into the pathogenesis and clinical progression of the disease.
Synergistic effects of immunoregulation and osteoinduction of ds-block elements on titanium surface
Authors: Lan Chen, Donghui Wang, Jiajun Qiu, Xianming Zhang, Xingdan Liu, Yuqin Qiao, Xuanyong Liu
Journal: Bioactive Materials (2020)

Ds-block elements have been gaining increasing attention in the field of biomaterials modification, owing to their excellent biological properties, such as antibiosis, osteogenesis, etc. However, their function mechanisms are not well understood and conflicting conclusions were drawn by previous studies on this issue, which are mainly resulted from the inconsistent experimental conditions. In this work, three most widely used ds-block elements, copper, zinc, and silver were introduced on titanium substrate by plasma immersion ion implantation method to investigate the rule of ds-block elements in the immune responses. Results showed that the implanted samples could decrease the inflammatory responses compared with Ti sample. The trend of anti-inflammatory effects of macrophages on samples was in correlation with cellular ROS levels, which was induced by the implanted biomaterials and positively correlated with the number of valence electrons of ds-block elements. The co-culture experiments of macrophages and bone marrow mesenchymal stem cells showed that these two kinds of cells could enhance the anti-inflammation and osteogenesis of samples by the paracrine manner of PGE2. In general, in their steady states on titanium substrate (Cu2+, Zn2+, Ag), the ds-block elements with more valence electrons exhibit better anti-inflammatory and osteogenic effects. Moreover, molecular biology experiments indicate that the PGE2-related signaling pathway may contribute to the desired immunoregulation and osteoinduction capability of ds-block elements. These findings suggest a correlation between the number of valence electrons of ds-block elements and the relevant biological responses, which provides new insight into the selection of implanted ions and surface design of biomaterials.
Abstract 12172: Age-varying Effects of Risk Factors on Cardiovascular Disease and Mortality: A Nationwide Cohort Study
Authors: Hokyou Lee, Norrina B Allen, Donald M Lloyd-Jones, So Mi J Cho, Hyeon Chang Kim
Journal: Circulation (2019)

Introduction: Prior studies suggest differential impacts of cardiovascular risk factors throughout lifetime. We evaluated age-varying associations of risk factors with cardiovascular disease (CVD) ...
Genetic disruption of the p27kip1 confers antiestrogen insensitivity and metastasis potential on human breast cancer cells
Authors: Jianming Xu, Yuhui Yuan, Li Qin, Dan Liu, Ray-Chang Wu, Paola Mussi, Suoling Zhou, Zhou Songyang
Journal: Cancer Research (2006)

1530  The genetic changes and molecular mechanisms underlying the progression of estrogen-dependent breast cancers to estrogen-independent and antiestrogen-resistant breast cancers, a major problem of endocrine therapy, are unclear. Here, we used an enhanced retroviral mutagen (ERM) system to screen the entire genome for identifying the loss- or gain-of-function mutations that could confer this critical progression. We show that the T47D estrogen-dependent human breast cancer cell line contains only one p27kip1 allele coding for the p27 cyclin-dependent kinase inhibitor. An ERM insertion into the p27kip1 locus of T47D cells disrupted the p27kip1 gene and caused estrogen-independent and antiestrogen-resistant breast cancer cell growth even these cells were still ERα positive. Disruption of p27 in T47D cells resulted in several changes. First, CDK2 activity was increased in the absence of estrogen or presence of tamoxifen or ICI. Second, AIB1, a cancer-overexpressed transcriptional coactivator, was hyper-phosphorylated, which made AIB1 a super-coactivator for E2F1. Third, overactivation of E2F indirectly stimulated Akt activation, which in turn promoted cell survival, motility and invasion. Both T47D and p27-deficient T47D cells formed solid tumors after injected into the mammary fat pads of ovariectomized nude mice treated with estradiol, but failed to develop tumors in placebo-treated mice, suggesting that inactivation of p27 alone is not sufficient to develop estrogen-independent tumors in the mammary gland although it is sufficient to maintain estrogen-independent cell growth in culture. Nevertheless, when the p27-deficient T47D cells were intravenously injected into the nude mice, they formed metastatic lung tumors in 3 weeks in an ovarian hormone-independent manner. In contrast, no lung tumors were observed in nude mice injected with T47D cells. In summary, out results demonstrate that p27 is required not only for estrogen dependency and antiestrogen sensitivity of ER-positive breast cancer cells but also for inhibition of cell motility, invasion and metastasis of breast cancer cells.
FRI0179 Nailfold capillaroscopy in systemic lupus erythematosus patients with and without antiphospholipid syndrome
Authors: V Riccieri, A Spadaro, T Rinaldi, R Scrivo, F Ceccarelli, G Valesini
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Nailfold capillaroscopy is able to evaluate microcirculatory damage in many different diseases and a high prevalence of capillary abnormalities has been reported in systemic lupus erythematosus (SLE). <h3>Objectives</h3> Considering that the vascular involvement is of primary importance in antiphospholipid syndrome (APS), it can be of interest to examine the capillaroscopic features of those SLE patients having secondary APS. <h3>Methods</h3> 29 SLE patients entered the study, 13 had secondary APS (M/F = 1/12; mean age = 45.5 yrs; mean disease duration = 5.85 yrs) while the other 16 patients (M/F = 1/15; mean age = 36.6 yrs; mean disease duration = 7.2 yrs) had no clinical or laboratory signs of APS. There were no significant differences regarding the number of ARA criteria or ECLAM and SLEDAI scores between the two groups. Each patient underwent nailfold capillaroscopy to detect the following abnormalities: morphological alterations of capillaries, variability of capillary loop lenght, presence of microhaemorrages, irregular distribution of capillaries and sludging of blood. Moreover to score these changes a semiquantitative rating scale was adopted, according to previous studies. <h3>Results</h3> Although not statistically significant, more frequent variability of capillary loop lenght (77% vs 44%), presence of microhaemorrages (23% vs 12.5%), sludging of blood (23% vs 12.5%) as well as capillaroscpopic score &gt;1 (77% vs 44%) were found in patients with SLE/APS respect to those with SLE alone. However in our SLE/APS patients the presence of capillaroscopic microhaemorrages was significantly associated to thrombocytopenia (p &lt; 0.034) and the finding of shorter capillary loop length was related to the occurrence of livedo reticularis (p &lt; 0.05). <h3>Conclusion</h3> Thus we suggest that nailfold capillaroscopy can be useful to better define SLE patients with APS, helping to identify some microvascular changes that seem related to clinical and laboratory features of APS.
Allostatic Load and Its Impact on Health: A Systematic Review
Authors: Jenny Guidi, Marcella Lucente, Nicoletta Sonino, Giovanni A. Fava
Journal: Psychotherapy and Psychosomatics (2020)

Allostatic load refers to the cumulative burden of chronic stress and life events. It involves the interaction of different physiological systems at varying degrees of activity. When environmental challenges exceed the individual ability to cope, then allostatic overload ensues. Allostatic load is identified by the use of biomarkers and clinical criteria.To summarize the current knowledge on allostatic load and overload and its clinical implications based on a systematic review of the literature.PubMed, PsycINFO, Web of Science, and the Cochrane Library were searched from inception to December 2019. A manual search of the literature was also performed, and reference lists of the retrieved articles were examined.We considered only studies in which allostatic load or overload were adequately described and assessed in either clinical or non-clinical adult populations.A total of 267 original investigations were included. They encompassed general population studies, as well as clinical studies on consequences of allostatic load/overload on both physical and mental health across a variety of settings.The findings indicate that allostatic load and overload are associated with poorer health outcomes. Assessment of allostatic load provides support to the understanding of psychosocial determinants of health and lifestyle medicine. An integrated approach that includes both biological markers and clinimetric criteria is recommended.
Diagnostic Yield of Electroanatomic Voltage Mapping in Guiding Endomyocardial Biopsies
Authors: Michela Casella, Antonio Dello Russo, Marco Bergonti, Valentina Catto, Edoardo Conte, Elena Sommariva, Alessio Gasperetti, Giulia Vettor, Fabrizio Tundo, Rita Sicuso, Stefania Rizzo, Saima Mushtaq, Domenico Della Rocca, Giulio Pompilio, Luigi Di Biase, Daniele Andreini, Andrea Natale, Cristina Basso, Claudio Tondo
Journal: Circulation (2020)

Background: Electroanatomic voltage mapping (EVM) is a promising modality for guiding endomyocardial biopsies (EMBs). However, few data support its feasibility and safety. We now report the largest cohort of patients undergoing EVM-guided EMBs to show its diagnostic yield and to compare it with a cardiac magnetic resonance (CMR)–guided approach. Methods: We included 162 consecutive patients undergoing EMB at our institution from 2010 to 2019. EMB was performed in pathological areas identified at EVM and CMR. CMR and EVM sensitivity and specificity regarding the identification of pathological substrates of myocardium were evaluated according to EMB results. Results: Preoperative CMR showed late gadolinium enhancement in 70% of the patients, whereas EVM identified areas of low voltage in 61%. Right (73%), left (19%), or both ventricles (8%) underwent sampling. EVM proved to have sensitivity similar to CMR (74% versus 77%), with specificity being 70% and 47%, respectively. In 12 patients with EMB-proven cardiomyopathy, EVM identified pathological areas that had been undetected at CMR evaluation. Sensitivity of pooled EVM and CMR was as high as 95%. EMB analysis allowed us to reach a new diagnosis, different from the suspected clinical diagnosis, in 39% of patients. The complications rate was low, mostly related to vascular access, with no patients requiring urgent management. Conclusions: EVM proved to be a promising tool for targeted EMB because of its sensitivity and specificity for identification of myocardial pathological substrates. EVM was demonstrated to have accuracy similar to CMR. EVM and CMR together conferred a positive predictive value of 89% on EMB.
Analysis of DNA repair activity for ynk1, the yeast homologue of the metastasis suppressor NM23
Authors: Andrea Ladanyi, Jozsef Tovari, Tamas Lorincz, Erzsebet Raso, Judit Dobos, Jozsef Timar
Journal: Cancer Research (2006)

4320  NM23-H1 was first identified by virtue of its reduced expression in highly metastatic melanoma and breast carcinoma cells, and the ability of forced NM23-H1 expression to inhibit metastatic potential without significant impact on the transformed phenotype. NM23-H1 exhibits nucleoside diphosphate kinase (NDPK) activity, catalyzing the transfer of γ-phosphate between nucleoside triphosphate and nucleoside diphosphate via a “ping-pong” mechanism. In addition to NDPK activity, NM23-H1 also exhibits both protein histidine kinase and 3’-5’exonuclease activities. Generally, enzymes that contain 3’-5’ exonuclease activity are involved directly in DNA repair processes and the maintenance of genomic stability. We hypothesized that loss of the 3’-5’ exonuclease activity of NM23-H1 during tumor progression impairs genomic integrity, thereby enhancing metastatic potential. In an effort to quantify the contribution of NM23-H1 to DNA repair, we have initiated experiments in the yeast Saccharomyces cerevisiae. Yeast provide excellent eukaryotic models for DNA repair research, since knockout strains are available for essentially all genes and DNA repair mechanisms are relatively well-characterized. In this project, we measured the extent to which expression of ynk1(the yeast homologue of the human metastasis suppressor NM23-H1) is required for genomic integrity. Mutation rates were measured in a haploid ynk1 knockout (ynk1Δ) strain using the standard CAN1 forward mutation assay. The ynk1 deletion had no effect on spontaneous mutation rate, but did result in increased mutations (2.2-fold) upon treatment with the DNA methylating agent, methyl methanesulfonate. Moreover, UV radiation induced a more marked (7-fold) deficit of DNA repair in the ynk1Δ strain as compared with the wild-type counterpart. Current efforts are being devoted to analyzing DNA repair activity in ynk1Δ strains that harbor second knockouts in a variety of known DNA repair genes (e.g. Ddc1, Rad17, Mec3, Msh2 and Fen1). Such double-knockout strains may magnify the ynk1-dependent mutator phenotype, as well as facilitate identification of the relevant biochemical activity(s) of the NM23-H1 molecule by complementation with wild-type and enzymatically-defective mutant forms of the protein.
Cost-Effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group Screening Guidelines to Prevent Heart Failure in Survivors of Childhood Cancer
Authors: Matthew J. Ehrhardt, Zachary J. Ward, Qi Liu, Aeysha Chaudhry, Anju Nohria, William Border, Joy M. Fulbright, Daniel A. Mulrooney, Kevin C. Oeffinger, Paul C. Nathan, Wendy M. Leisenring, Louis S. Constine, Todd M. Gibson, Eric J. Chow, Rebecca M. Howell, Leslie L. Robison, Gregory T. Armstrong, Melissa M. Hudson, Lisa Diller, Yutaka Yasui, Saro H. Armenian, Jennifer M. Yeh
Journal: Journal of Clinical Oncology (2020)

Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited.