tbuckley/cabot-search huggingface dataset:
Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease
Authors: Davaasambuu Ganmaa, Buyanjargal Uyanga, Xin Zhou, Garmaa Gantsetseg, Baigali Delgerekh, Davaasambuu Enkhmaa, Dorjnamjil Khulan, Saranjav Ariunzaya, Erdenebaatar Sumiya, Batbileg Bolortuya, Jutmaan Yanjmaa, Tserenkhuu Enkhtsetseg, Ankhbat Munkhzaya, Murneren Tunsag, Polyna Khudyakov, James A. Seddon, Ben J. Marais, Ochirbat Batbayar, Ganbaatar Erdenetuya, Bazarsaikhan Amarsaikhan, Donna Spiegelman, Jadambaa Tsolmon, Adrian R. Martineau
Journal: New England Journal of Medicine (2020)

Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking.We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups.Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).
FRI0145 Body mass density in patients with systemic lupus erythematosus
Authors: DM Obradovic, RM Stojanovic, G Susic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Physiological processes, as ageing and menopause, natural influence (diet, physical activity) and many other factors are important in development of osteopenia (OPE) or osteoporosis (OPO). The possible influence of some previous diseases and medications on bone density was investigated, too. <h3>Objectives</h3> To estimate bone density in patient with Systemic Lupus Erythematosus (SLE) and to investigate the influence of BMI, age at onset of SLE, duration of disease, age in time of study, duration of CS treatment as a possible risk factors for OPE/OPO. <h3>Methods</h3> In follow-up study we investigated 57 female patients with SLE, mean age 44.73 ± 11.34 years (min22-max68), mean age at the onset of SLE 35.83 ± 11.18 yr.(15–64). The duration of SLE was 9.03 ± 7.22 yrs (1–32). Corticosteroide therapy was used for 8.40 ± 6.85 yr.(1–32). Body mass density was measured on L2-L4 segment of vertebral spine. DEXA LUNAR osteodensitometer was used. According to T score patients were classified as: normal (N group) 21 patients (T &gt;-1,0), osteopenic (OPE group) 23 pts (-2.5 &lt;T &lt;-1.0), and ospeoporotic (OPO group) 13 pts (T &lt;-2,5). <h3>Results</h3> No difference were noted in: BMI and in duration of SLE in groups investigated. The borderline difference was existed between N and OPO group in duration of CS treatment (p = 0.049). The relation between particular data where statistical significance was obtained in groups investigated is presented in the Table 1. <h3>Conclusion</h3> Low body mass density was found in elder group of patients with SLE, where the disease started later in perimenopause. Duration of disease, and duration of corticosteroid treatment did not influence BMD. Further studies will consider other factors possibly significant in development of osteoporosis in SLE (subsets of disease, immunological disturbances, cumulative dose of CS and known risk factors for osteoporosis.
Comparison of diagnostic accuracy of acoustic rhinometry and symptoms score for nasal allergen challenge monitoring
Authors: Ibon Eguiluz‐Gracia, Almudena Testera‐Montes, Maria Salas, Natalia Perez‐Sanchez, Adriana Ariza, Gador Bogas, Joan Bartra, Maria Jose Torres, Carmen Rondon
Journal: Allergy (2020)
Estimated County-Level Prevalence of Selected Underlying Medical Conditions Associated with Increased Risk for Severe COVID-19 Illness — United States, 2018
Authors: Hilda Razzaghi, Yan Wang, Hua Lu, Katherine E. Marshall, Nicole F. Dowling, Gabriela Paz-Bailey, Evelyn R. Twentyman, Georgina Peacock, Kurt J. Greenlund
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Risk for severe coronavirus disease 2019 (COVID-19)-associated illness (illness requiring hospitalization, intensive care unit [ICU] admission, mechanical ventilation, or resulting in death) increases with increasing age as well as presence of underlying medical conditions that have shown strong and consistent evidence, including chronic obstructive pulmonary disease, cardiovascular disease, diabetes, chronic kidney disease, and obesity (1-4).Identifying and describing the prevalence of these conditions at the local level can help guide decision-making and efforts to prevent or control severe COVID-19-associated illness.Below state-level estimates, there is a lack of standardized publicly available data on underlying medical conditions that increase the risk for severe COVID-19-associated illness.A small area estimation approach was used to estimate county-level prevalence of selected conditions associated with severe COVID-19 disease among U.S. adults aged ≥18 years (5,6) using self-reported data from the 2018 Behavioral Risk Factor Surveillance System (BRFSS) and U.S. Census population data.The median prevalence of any underlying medical condition in residents among 3,142 counties in all 50 states and the District of Columbia (DC) was 47.2% (range = 22.0%-66.2%);counties with the highest prevalence were concentrated in the Southeast and Appalachian region.Whereas the estimated number of persons with any underlying medical condition was higher in population-dense metropolitan areas, overall prevalence was higher in rural nonmetropolitan areas.These data can provide important local-level information about the estimated number and proportion of persons with certain underlying medical conditions to help guide decisions regarding additional resource investment, and mitigation and prevention measures to slow the spread of COVID-19.BRFSS is an annual, random-digit-dialed landline and mobile telephone survey of noninstitutionalized U.S. adults aged ≥18 years in all 50 states, DC, and U.S. territories.BRFSS collects self-reported information on selected health behaviors and conditions.Overall, 437,500 persons participated in the 2018 BRFSS survey, with a median weighted response rate of 49.9%.
The Effect of Blue-Light Filtering Intraocular Lenses on the Development and Progression of Neovascular Age-Related Macular Degeneration
Authors: Asaf Achiron, Uri Elbaz, Idan Hecht, Oriel Spierer, Adi Einan-Lifshitz, Petteri Karesvuo, Ilkka Laine, Raimo Tuuminen
Journal: Ophthalmology (2020)
Characterization of novel mutation E884K-EGFR at the highly conserved codon in differential targeted inhibition and signaling activation
Authors: Zhe Tang, Shan Jiang, Runlei Du, Sascha Dietrich, Titus Boggon, Balazs Halmos, Jeffrey Kern, Patrick Ma
Journal: Cancer Research (2007)

4020  Targeted therapy using epidermal growth factor receptor (EGFR) kinase inhibitors represents a major therapeutic advance in lung cancer treatment. Kinase domain mutations of the EGFR gene, most commonly L858R (exon 21) and short deletions in exon 19, have been shown to confer general sensitivity towards the EGFR kinase inhibitors gefitinib and erlotinib. We have recently described a unique somatic mutation, E884K (exon 22), that occurred in combination with the L858R mutation (L858R+E884K) in a patient with erlotinib-refractory stage IV non-small-cell lung cancer (NSCLC). This patient’s leptomeningeal metastases had a striking response to gefitinib monotherapy. Using stable transfects of Cos-7 cells expressing E884K-EGFR, we now show that this novel mutation conferred differential sensitivity to the two EGFR inhibitors. E884K increased receptor resistance to erlotinib, while synergistically sensitizing the receptor to gefitinib with corresponding downstream signaling inhibition. Moreover, E884K interacted with L858R in cis to enhance the mutant receptor sensitivity towards a dual EGFR/ERBB2 inhibitor. The E884K mutation was activating, yet the mutant receptor remained sensitive to EGF ligand stimulation with specific cellular phosphoproteome activation pattern distinct from that of L858R. The E884K mutation also had selective and differential effects on mutant EGFR downstream signaling, especially when in cis with the L858R mutation. E884K preferentially downregulated the AKT-mediated cell survival pathway while it upregulated c-CBL signaling and ERK1/2-STAT3-mediated cell proliferation pathway in a dominant fashion over L858R mutation. Bioinformatics sequence analysis revealed that the E884 residue within the kinase domain is highly conserved among tyrosine kinases including the ERBB family and the MET receptor. These findings suggest a critical role of the conserved E884 codon and its equivalents in tyrosine kinase signaling. Our results highlight the possibility of EGFR kinase domain mutations that can interact in cis to mediate differential sensitivity to specific kinase inhibitors and selective downstream phosphoproteomics signaling activation. Further structural studies of the mutations of EGFR and other kinase targets are warranted to improve targeted therapy and small molecule inhibitor design in lung cancer.
LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription
Authors: Zhongjie Lin, Shunjie Xia, Yuelong Liang, Lin Ji, Yu Pan, Shi Jiang, Zhe Wan, Liye Tao, Jiang Chen, Chengping Lin, Xiao Liang, Junjie Xu, Xiujun Cai
Journal: Theranostics (2020)

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods: A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. Results: miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo. Conclusions: Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.
Expression of cadherin-17 is associated with advanced stage of gastric carcinoma
Authors: Reiko Ito, Naohide Oue, Junici Motoshita, Hirofumi Nakayama, Kazuya Kuraoka, Kazuhiro Yoshida, Wataru Yasui
Journal: Cancer Research (2004)

4923  Cadherin-17 (CDH17), also called liver-intestine cadherin, is a structurally unique member of the cadherin superfamily. CDH17 is expressed in intestine, intestinal metaplasia of the stomach and intestinal-type gastric carcinoma. It has been reported that transcription factor CDX2 regulates CDH17 gene expression in the gastrointestinal tract. Recent study reported that the expression of CDH17 could be useful as a marker for predicting the outcome of patients with pancreas cancers. We have examined the gene expression profiles of gastric cancer by SAGE and found that the expression of CDH17 was one of the up-regurated genes in the advanced cases. In the present study, we examined the expression of CDH17 protein in primary gastric carcinoma tissues and corresponding non-neoplastic mucosa by immunohistochemistry, and analyzed the correlation of CDH17 expression with clinicopathological characteristics. CDH17 protein expression was detected not only in the intestinal metaplasia of the stomach but also detected in 63/94 (67%) of gastric adenocarcinomas. Carcinomas with CDH17 expression was significantly more frequent in advanced stage cases (80%) than in early stage (53%). Medullary type carcinoma expressed CDH17 more frequently than scirrhous type. There was a tendency that the expression of CDH17 was associated with well differentiated type. Moreover, the prognosis of the patients with positive CDH17 expression was significantly poorer than that of the negative cases (p=0.0314). These results suggested that the expression of CDH17 was characteristic of the advanced cases and that it has a potential for the useful prognostic marker of gastric carcinomas.
Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection
Authors: Yongguang Liu, Jianmin Hu, Ding Liu, Song Zhou, Jun Liao, Guorong Liao, Siqiang Yang, Zefeng Guo, Yuzhu Li, Shichao Li, Hua Chen, Ying Guo, Ming Li, Lipei Fan, Liuyang Li, Anqi Lin, Ming Zhao
Journal: Theranostics (2020)

Rationale: Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. Methods: High-quality transcriptomes were generated from three healthy human kidneys and two CKTR biopsies. Unsupervised clustering analysis of biopsy specimens was performed to identify fifteen distinct cell types, including major immune cells, renal cells and a few types of stromal cells. Single-sample gene set enrichment (ssGSEA) algorithm was utilized to explore functional differences between cell subpopulations and between CKTR and normal cells. Results: Natural killer T (NKT) cells formed five subclasses, representing CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs) and natural killer cells (NKs). Memory B cells were classified into two subtypes, representing reverse immune activation. Monocytes formed a classic CD14+ group and a nonclassical CD16+ group. We identified a novel subpopulation [myofibroblasts (MyoF)] in fibroblasts, which express collagen and extracellular matrix components. The CKTR group was characterized by increased numbers of immune cells and MyoF, leading to increased renal rejection and fibrosis. Conclusions: By assessing functional differences of subtype at single-cell resolution, we discovered different subtypes that correlated with distinct functions in CKTR. This resource provides deeper insights into CKTR biology that will be helpful in the diagnosis and treatment of CKTR.
Magnetic Resonance Guided Navigation of Untethered Microgrippers
Authors: Arijit Ghosh, Yizhang Liu, Dmitri Artemov, David H. Gracias
Journal: Advanced Healthcare Materials (2020)

Abstract Microsurgical tools offer a path to less invasive clinical procedures with improved access, reduced trauma, and better recovery outcomes. There are a variety of rigid and flexible endoscopic devices that have significantly advanced diagnostics and microsurgery. However, they rely on wires or tethers for guidance and operation of small end‐effector tools. While untethered physiologically responsive microgrippers have been previously shown to excise tissue from deep gastrointestinal locations in animal models, there are challenges associated with guiding them along paths and moving them to specific locations. In this communication, the magnetic dipole moment of untethered thermally responsive grippers is optimized for efficient coupling to external magnetic resonance (MR) fields. Gripper encapsulation in a millimeter sized wax pellet reduces the friction with the surrounding tissue and MR Navigation (MRN) of a 700 µm sized microgripper is realized within narrow channels in tissue phantoms and in an ex vivo porcine esophagus. The results show convincing proof‐of‐concept evidence that it is possible to sequentially image, move, and guide a submillimeter functional microsurgical tool in tissue conduits using a commercial preclinical MR system, and when combined with prior demonstrations of physiologically responsive in vivo biopsy are an important step towards the clinical translation of untethered microtools.
Erythropoietin receptor in B cells plays a role in bone remodeling in mice
Authors: Naamit Deshet-Unger, Albert Kolomansky, Nathalie Ben-Califa, Sahar Hiram-Bab, Dafna Gilboa, Tamar Liron, Maria Ibrahim, Zamzam Awida, Anton Gorodov, Howard S. Oster, Moshe Mittelman, Martina Rauner, Ben Wielockx, Yankel Gabet, Drorit Neumann
Journal: Theranostics (2020)

Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. Methods: We have combined specifically-designed experimental mouse models and in vitro based osteoclastogenesis assays, as well as PCR analysis of gene expression. Results: (i) EPO treatment in vivo increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured in vivo and in vitro, as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis in vitro was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3+CD115+), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo.
Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease
Authors: Jessica L. Centa, Francine M. Jodelka, Anthony J. Hinrich, Tyler B. Johnson, Joseph Ochaba, Michaela Jackson, Dominik M. Duelli, Jill M. Weimer, Frank Rigo, Michelle L. Hastings
Journal: Nature Medicine (2020)
Intestinal CD8αα IELs derived from two distinct thymic precursors have staggered ontogeny
Authors: Roland Ruscher, S. Thera Lee, Oscar C. Salgado, Elise R. Breed, Sara H. Osum, Kristin A. Hogquist
Journal: The Journal of Experimental Medicine (2020)

CD8αα intraepithelial lymphocytes (IELs) are abundant T cells that protect the gut epithelium. Their thymic precursors (IELps) include PD-1+ type A and Tbet+ type B populations, which differ in their antigen-receptor specificities. To better understand CD8αα IEL ontogeny, we performed “time-stamp” fate mapping experiments and observed that it seeds the intestine predominantly during a narrow time window in early life. Adoptively transferred IELps parked better in the intestines of young mice than in adults. In young mice, both type A and type B IELps had an S1PR1+ and α4β7+ emigration- and mucosal-homing competent phenotype, while this was restricted to type A IELps in adults. Only CD8αα IELs established in early life were enriched in cells bearing type B IELp TCR usage. Together, our results suggest that the young intestine facilitates CD8αα IEL establishment and that early IELs are distinct from IELs established after this initial wave. These data provide novel insight into the ontogeny of CD8αα IELs.