tbuckley/cabot-search huggingface dataset:
Deletion of Cbl-b inhibits CD8<sup>+</sup> T-cell exhaustion and promotes CAR T-cell function
Authors: Jitendra Kumar, Ritesh Kumar, Amir Kumar Singh, Elviche L Tsakem, Mahesh Kathania, Matthew J Riese, Arianne L Theiss, Marco L Davila, K Venuprasad
Journal: Journal for ImmunoTherapy of Cancer (2021)

Chimeric antigen receptor (CAR) T-cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors. This is partly because the CAR T cells become dysfunctional and exhausted in the tumor microenvironment. However, the key pathways responsible for impaired function of exhausted cells remain unclear, which is essential to overcome CAR T-cell exhaustion.Analysis of RNA-sequencing data from CD8+ tumor-infiltrating lymphocytes (TILs) led to identification of Cbl-b as a potential target. The sequencing data were validated using a syngeneic MC38 colon cancer model. To analyze the in vivo role of Cbl-b in T-cell exhaustion, tumor growth, % PD1+Tim3+ cells, and expression of effector cytokines were analyzed in cbl-b+/+ and cbl-b-/- mice. To evaluate the therapeutic potential of Cbl-b depletion, we generated a new CAR construct, hCEAscFv-CD28-CD3ζ.GFP, that recognizes human carcinoembryonic antigen (CEA). cbl-b+/+ and cbl-b-/- CEA-CAR T cells were generated by retroviral transduction. Rag-/- mice bearing MC38-CEA cells were injected with cbl-b+/+ and cbl-b-/- ; CEA-CAR T cells, tumor growth, % PD1+Tim3+ cells and expression of effector cytokines were analyzed.Our results show that the E3 ubiquitin ligase Cbl-b is upregulated in exhausted (PD1+Tim3+) CD8+ TILs. CRISPR-Cas9-mediated inhibition of Cbl-b restores the effector function of exhausted CD8+ TILs. Importantly, the reduced growth of syngeneic MC38 tumors in cbl-b-/- mice was associated with a marked reduction of PD1+Tim3+ CD8+ TILs. Depletion of Cbl-b inhibited CAR T-cell exhaustion, resulting in reduced MC38-CEA tumor growth, reduced PD1+Tim3+ cells and increased expression of interferon gamma, tumor necrosis factor alpha, and increased tumor cell killing.Our studies demonstrate that deficiency of Cbl-b overcomes endogenous CD8+ T-cell exhaustion, and deletion of Cbl-b in CAR T cells renders them resistant to exhaustion. Our results could facilitate the development of efficient CAR T-cell therapy for solid tumors by targeting Cbl-b.
Abstract 15202: Clinic BP During Follow Up is as Useful as Ambulatory Blood Pressure in Predicting Stroke
Authors: Kazuo Eguchi, Satoshi Hoshide, Shizukiyo Ishikawa, Kazuomi Kario
Journal: Circulation (2012)

Background: Ambulatory BP (ABP) has been reported to be a better marker than clinic BP in predicting future incidence of stroke. However, most of the studies which compared clinic BP vs. ABP adopte...
Abstract 15139: Improvement in LVEF in Outpatients With Heart Failure With Reduced Ejection Fraction: Data From CHAMP-HF
Authors: Adam D DeVore, Anne Hellkamp, Laine E Thomas, Puza P Sharma, Nancy M Albert, Javed Butler, J Herbert H Patterson, John Spertus, Fredonia Williams, Carol Duffy, Adrian F Hernandez, Gregg C Fonarow
Journal: Circulation (2019)

Background: Among patients with heart failure with reduced ejection fraction (HFrEF), improvements in left ventricular EF (LVEF) are associated with better outcomes and remain an important treatmen...
The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo
Authors: Hyun Jeong Ju, Ju Hee Han, Min-Soo Kim, Si-Hyung Lee, Jung-Won Shin, Mira Choi, Ki-Heon Jeong, Tae Young Han, Chong Won Choi, Hee Jung Lee, Sang Ho Oh, Sang Hoon Lee, Dong Hyun Kim, Jeonghyun Shin, Jong Hee Lee, Sang Seok Kim, Hee Young Kang, Sung Eun Chang, Jeong-Soo Kim, Dong-Youn Lee, Gwang Seong Choi, Dae Hun Suh, You Chan Kim, Chul Jong Park, Ki-Ho Kim, Ai-Young Lee, Kyoung Chan Park, Mu-Hyoung Lee, Jung Min Bae
Journal: Journal of the American Academy of Dermatology (2021)
AB0176 Influence of nutrition on bone mineral density in patients with ankylosing spondylitis
Authors: H Franck, T Meurer
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> A sufficient alimentation of vitamin D and calcium is essential in the prevention and treatment of osteoporosis. Patients with ankylosing spondylitis have osteoporosis to a various degree. <h3>Objectives</h3> The aim of our study was to look at the influence of nutrition on bone mineral density in our patients with ankylosing spondylitis. <h3>Methods</h3> We examined 180 patients with ankylosing spondylitis fulfilled the modified New York criteria. The bone mineral density was measured with DEXA (QDR 4500) at the lumbar spine (LS) and right hip. Factors of nutrition were examined by a standardised questionnaire. <h3>Results</h3> Positive correlations with bone mineral density were only found with wine consumption. However, this correlation was week but was confirmed for both hip and LS bone mineral density measurements. <h3>Conclusion</h3> No significant correlations between milk and cheese intake with bone mineral density were found in patients with ankylosing spondylitis. Dietetic factors do not seem to influence much bone mineral density in patients with ankylosing spondylitis. Only wine consumption was found to have a influence on bone mineral density as is correlated with bone mineral density in our patients with ankylosing spondylitis.
Biophysical characterization of human whole salivary mucin: A dynamic light scattering study
Authors: Manish Mahajan, Mayank Saraswat, Vijay Kumar, N Shukla, Savita Yadav
Journal: Cancer Research (2008)

3195  Human salivary mucin ,a primary mucous membrane coating glycoprotein forms the first line of defense against adverse environments, attributed to the complex formation between mucin subunits and non mucin species. Aim of the study was to emphasize the effect of pH, denaturants (guanidinum hydrochloride, urea) and detergents (CHAPS, TRITON X -100, SDS on human whole salivary mucin. Hydrodynamic size distribution was measured using DLS. It was observed that aggregation was due to increase in hydrophobic interactions, believed to be accomplished by unfolding of the protein core. Whereas, the detergents which solubilize the proteins by decreasing hydrophobicity lead to disaggregation of mucin into smaller fragments. Mucin subjected to tobacco extract and upon subsequent addition of nicotine was found to have a disaggregating effect on it, suggesting nicotine may be one of the factors responsible for the disaggregating effect of tobacco on mucin ,an important carcinogenetic mechanism.
Efficacy and safety of apatinib in treatment of gastric cancer: A real-world study.
Authors: Yijie Ma, Hong Zong, Junsheng Wang, Yanzhen Guo, Huaimin LIU, Ning Li, Shundong Cang, Ke Shang, Xiaobing Chen, Jin Wang, Dezhi He, Wenying Deng, Peichun Sun, Zhen Zhang, Liguo Zhang, Feng Xu, Chuntao Tian, Chaofeng Qiao, Gongbin Chen, Suxia Luo
Journal: Journal of Clinical Oncology (2021)

182 Background: Apatinib is a small molecule TKI inhibitor, which had been approved in China for treatment of advanced gastric cancer refractory to two or more lines of prior chemotherapy. Its efficacy and safety have been demonstrated in previous randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. This study aimed to evaluate the anti-tumor activity and toxicity of apatinib in real world. Methods: Patients older than 18 years with histologically diagnosed with gastric cancer were enrolled and treated with either apatinib alone or in combination with other drugs. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR). The adverse events were also recorded. Results: From March 2018 to March 2019, a total of 1000 patients were enrolled. Among them, 48(0.48%), 13(0.13%), 225 (22.5%), 389 (38.9%), and 325 (32.5%) patients received apatinib as postoperative auxiliary-, neoadjuvant-, first-, second-, and third- or higher line therapy, respectively. Efficacy evaluation was performed in 901 patients. Thirty-five patients achieved complete response (CR), 116 patients achieved partial response (PR), 596 patients achieved stable disease (SD), and 154 patients had progressive disease (PD), illustrating an ORR of 16.76% and a DCR of 82.91%. The mPFS was 5.32 months (95% CI, 4.93-5.75), and mOS was 9.76 months (95% CI, 8.97-10.81). In addition, the mOS of apatinib in first-line, second-line, and third-line treatments were 12.68 months, 9.49 months, and 7.62 months, respectively. Patients received apatinib in combination with other drugs had longer survival than apatinib alone, with mPFS 5.62 months vs 4.47 months and mOS 10.81 months vs 7.95 months. Such phenomenon was also observed in ORR (18.21% vs 13.04%, P&lt; 0.001) and DCR (84.88% vs 77.87%, P&lt; 0.001). The main adverse events (AE) were anemia (67.2%), thrombocytopenia (36.2%), leukopenia (34.5%)and anorexia (37.6%). The most common grade 3-4 adverse events included neutropenia, anemia and thrombocytopenia. Conclusions: In the real world, apatinib showed promising efficacy and manageable toxicities in patients with gastric cancer. Patients benefit more when received apatinib combination therapy. Clinical trial information: NCT03478943.
AB0974 ANALYSIS OF DYSLIPIDEMIA IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: A. S. H. Chen, J. H. Lee, H. Ya-Chiao, H. H. Yu, L. C. Wang, Y. T. Lin, Y. H. Yang, B. L. Chiang
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease and is characterized by multiple autoantibodies associated with a multisystem illness. However, studies of dyslipidemia in pediatric SLE patients are limited. Objectives: The aim of our study is to describe the lipid profiles associated with disease activity and organ damage and their correlation with laboratory parameters in pediatric SLE patients. Methods: We retrospectively reviewed medical records from a single tertiary hospital in Taipei, Taiwan from 2002 to 2018. One hundred and twenty-four patients diagnosed with SLE were included. Dyslipidemia is defined as elevations in total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG) levels, and a reduction in high-density lipoprotein (HDL) levels. We gathered all of the lipid profiles, clinical characteristics, and laboratory parameters from each patient. Pediatric SLE patients participated in this study, based on their lipid profile, were classified as dyslipidemic or not. The mean values of each evaluated parameters were calculated and analyzed with generalized estimating equation (GEE) method. Results: Total thirty-one SLE patients were enrolled; twenty-four (77%) patients had dyslipidemia. The levels of total cholesterol, TG, and LDL in the dyslipidemic group are significantly higher than those of non-dyslipidemia (214.0 mg/dL vs 145.0 mg/dL, 130.1 mg/dL vs 76.4 mg/dL, 138.7 mg/dL vs 82.0 mg/dL; respectively). The mean values of white blood cell count (6726/µL) in dyslipidemia group are significantly higher than non-dyslipidemia group (4521/µL; p =0.0157). In contrast, the level of high-sensitivity CRP in the non-dyslipidemia group (0.2 mg/dL) are significantly lower than those of patients with dyslipidemia (0.49 mg/dL; p =0.0486). Conclusion: It has been well known that CRP could suppress HDL and increase TG and that elevation of CRP might indicate increased cardiovascular risk. Our results demonstrated that elevated high sensitivity CRP levels were noted in SLE patients with dyslipidemia. It is suggested that routine monitoring of cardiovascular risk factors, such as dyslipidemia, should be recommended for pediatric SLE patients. References: [1]Szabó, M.Z., Szodoray, P. &amp; Kiss, E. Immunol Res (2017) 65: 543. [2]Atta, A.M., Silva, J.P.C.G., Santiago, M.B. et al. Clin Rheumatol (2018) 37: 1539. [3]Yu, H.H., Chen, P.C., Yang, Y.H. Atherosclerosis. 2015; 243(1): 11–18. Acknowledgments: The authors acknowledge statistical assistance provided by the Center of Statistical Consultation and Research in the Department of Medical Research, National Taiwan University Hospital Disclosure of Interests: None declared
The SEE Study: Safety, Efficacy, and Equity of Implementing Autonomous Artificial Intelligence for Diagnosing Diabetic Retinopathy in Youth
Authors: Risa M. Wolf, T.Y. Alvin Liu, Chrystal Thomas, Laura Prichett, Ingrid Zimmer-Galler, Kerry Smith, Michael D. Abramoff, Roomasa Channa
Journal: Diabetes Care (2021)

OBJECTIVE Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Screening for DR is recommended in children and adolescents, but adherence is poor. Recently, autonomous artificial intelligence (AI) systems have been developed for early detection of DR and have been included in the American Diabetes Association’s guidelines for screening in adults. We sought to determine the diagnostic efficacy of autonomous AI for the diabetic eye exam in youth with diabetes. RESEARCH DESIGN AND METHODS In this prospective study, point-of-care diabetic eye exam was implemented using a nonmydriatic fundus camera with an autonomous AI system for detection of DR in a multidisciplinary pediatric diabetes center. Sensitivity, specificity, and diagnosability of AI was compared with consensus grading by retinal specialists, who were masked to AI output. Adherence to screening guidelines was measured before and after AI implementation. RESULTS Three hundred ten youth with diabetes aged 5–21 years were included, of whom 4.2% had DR. Diagnosability of AI was 97.5% (302 of 310). The sensitivity and specificity of AI to detect more-than-mild DR was 85.7% (95% CI 42.1–99.6%) and 79.3% (74.3–83.8%), respectively, compared with the reference standard as defined by retina specialists. Adherence improved from 49% to 95% after AI implementation. CONCLUSIONS Use of a nonmydriatic fundus camera with autonomous AI was safe and effective for the diabetic eye exam in youth in our study. Adherence to screening guidelines improved with AI implementation. As the prevalence of diabetes increases in youth and adherence to screening guidelines remains suboptimal, effective strategies for diabetic eye exams in this population are needed.
Development and Multiple Validation of the Protein Multi-marker Panel for Diagnosis of Pancreatic Cancer
Authors: Yoseop Kim, Injoon Yeo, Iksoo Huh, Jaenyeon Kim, Dohyun Han, Jin-Young Jang, Youngsoo Kim
Journal: Clinical Cancer Research (2021)

Abstract Purpose: To develop and validate a protein-based, multi-marker panel that provides superior pancreatic ductal adenocarcinoma (PDAC) detection abilities with sufficient diagnostic performance. Experimental Design: A total of 959 plasma samples from patients at multiple medical centers were used. To construct an optimal, diagnostic, multi-marker panel, we applied data preprocessing procedure to biomarker candidates. The multi-marker panel was developed using a training set comprised of 261 PDAC cases and 290 controls. Subsequent evaluations were performed in a validation set comprised of 65 PDAC cases and 72 controls. Further validation was performed in an independent set comprised of 75 PDAC cases and 47 controls. Results: A multi-marker panel containing 14 proteins was developed. The multi-marker panel achieved AUCs of 0.977 and 0.953 for the training set and validation set, respectively. In an independent validation set, the multi-marker panel yielded an AUC of 0.928. The diagnostic performance of the multi-marker panel showed significant improvements compared with carbohydrate antigen (CA) 19-9 alone (training set AUC = 0.977 vs. 0.872, P &amp;lt; 0.001; validation set AUC = 0.953 vs. 0.832, P &amp;lt; 0.01; independent validation set AUC = 0.928 vs. 0.771, P &amp;lt; 0.001). When the multi-marker panel and CA 19-9 were combined, the diagnostic performance of the combined panel was improved for all sets. Conclusions: This multi-marker panel and the combined panel showed statistically significant improvements in diagnostic performance compared with CA 19-9 alone and has the potential to complement CA 19-9 as a diagnostic marker in clinical practice.
Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors
Authors: Ling-juan Zhang, Christian F. Guerrero-Juarez, Stella X. Chen, Xiaowei Zhang, Meimei Yin, Fengwu Li, Shuai Wu, Joyce Chen, Min Li, Yingzi Liu, Shang I. B. Jiang, Tissa Hata, Maksim V. Plikus, Richard L. Gallo
Journal: Science Translational Medicine (2021)

Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor-β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator-activated receptor-γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.
Face masks in the post-COVID-19 era: a silver lining for the damaged tuberculosis public health response?
Authors: Koen Vanden Driessche, Precious Z Mahlobo, Rouxjeane Venter, Judy Caldwell, Karen Jennings, Andreas H Diacon, Mark F Cotton, Ronald de Groot, Niel Hens, Florian M Marx, Robin M Warren, Hridesh Mishra, Grant Theron
Journal: The Lancet Respiratory Medicine (2021)
Targetable mutations in gastrointestinal malignancies: A comparison of RAS mutant and RAS wild type tumors.
Authors: Jamie Randall, Hongkun Wang, Sheryl Krevsky Elkin, Gail Payne, Sarah Mullaly, Erica Marchlik, Dan Barnett, Danny Rayes, Raymond Wadlow, Lindsey Tishman, Timothy Lewis Cannon
Journal: Journal of Clinical Oncology (2021)

129 Background: KRAS and NRAS (RAS) mutations are considered driver mutations in gastrointestinal malignancies such as colorectal and pancreatic cancer. Our institution obtains broad molecular testing (commercial panels with full exon coverage of at least 300 genes) for all stage IV gastrointestinal malignancies that are reviewed at an internal molecular tumor board (MTB). The MTB subjectively felt there was less benefit from comprehensive molecular testing in RAS mutant tumors and wished to quantify this using standardized analysis according to validated guidelines. Methods: We performed a retrospective cohort study of 209 consecutive genomic sequencing results of advanced gastrointestinal malignancies at our institution dating from March 2016 until December 2019. We compared the number of “targetable” mutations in the RAS mutant and wild type (WT) malignancies, as analyzed by an interpretation service according to the Association of Molecular Pathology (AMP) guidelines. A lower AMP score corresponds to a higher level of evidence as a predictive biomarker. We also compared molecular tumor board specific recommendations for each group (excluding recommendations regarding RAS such as EGFR mAbs). Results: There were 134 RAS mutant and 75 RAS WT cases. Alterations with AMP scores of 1A,1B, and 1C were more commonly seen in the RAS WT population 18/75 and 9/134 respectively (24.0% versus 6.7% p-value=0.0004). 39 of 75 cases in RAS WT and 27/134 in RAS mutant (52.0 versus 20.1%, p-value &lt;0.0001) cohort had at least one alteration that was deemed actionable by our institution’s current MTB criteria. Conclusions: Actionable mutations were significantly less common in the RAS mutant versus RAS WT population, and further studies assessing the value of comprehensive genomic testing in RAS mutant gastrointestinal malignancies may be warranted. [Table: see text]
Changes in NAD and Lipid Metabolism Drive Acidosis-Induced Acute Kidney Injury
Authors: Milica Bugarski, Susan Ghazi, Marcello Polesel, Joana R. Martins, Andrew M. Hall
Journal: Journal of the American Society of Nephrology (2021)

The kidney plays an important role in maintaining normal blood pH. Metabolic acidosis (MA) upregulates the pathway that mitochondria in the proximal tubule (PT) use to produce ammonia and bicarbonate from glutamine, and is associated with AKI. However, the extent to which MA causes AKI, and thus whether treating MA would be beneficial, is unclear.Gavage with ammonium chloride induced acute MA. Multiphoton imaging of mitochondria (NADH/membrane potential) and transport function (dextran/albumin uptake), oxygen consumption rate (OCR) measurements in isolated tubules, histologic analysis, and electron microscopy in fixed tissue, and urinary biomarkers (KIM-1/clara cell 16) assessed tubular cell structure and function in mouse kidney cortex.MA induces an acute change in NAD redox state (toward oxidation) in PT mitochondria, without changing the mitochondrial energization state. This change is associated with a switch toward complex I activity and decreased maximal OCR, and a major alteration in normal lipid metabolism, resulting in marked lipid accumulation in PTs and the formation of large multilamellar bodies. These changes, in turn, lead to acute tubular damage and a severe defect in solute uptake. Increasing blood pH with intravenous bicarbonate substantially improves tubular function, whereas preinjection with the NAD precursor nicotinamide (NAM) is highly protective.MA induces AKI via changes in PT NAD and lipid metabolism, which can be reversed or prevented by treatment strategies that are viable in humans. These findings might also help to explain why MA accelerates decline in function in CKD.
Abstract 429: First-Line Vasopressor Agent for Cardiogenic Shock Due to Acute Myocardial Infarction: Results From Tokyo CCU Network Registry
Authors: Tadashi Ashida, Tsukasa Yagi, Ken Nagao, Norihiro Kuroki, Tadateru Takayama, Yusuke Hosokawa, Jun Nakata, Masanari Kuwabara, Takeshi Yamamoto, Morimasa Takayama
Journal: Circulation (2019)

Background: In the guidelines for cardiogenic shock, norepinephrine, as compared with dopamine, was associated with fewer cases of arrhythmia and may be a better first-line vasopressor agent. However, few clinical studies have investigated the effects of optimal first-line vasopressor agents for patients with poor renal function. Methods: From a multicenter, prospective, cohort registry of emergency cardiovascular patients in Tokyo between 2013 and 2016, we identified adult patients with cardiogenic shock due to acute myocardial infarction (AMI) who received either norepinephrine, dopamine or both as a vasopressor agent without mechanical circulatory supports. Study patients were divided into 4 groups according to estimated glomerular filtration rate (eGFR). The primary endpoint was all-cause mortality at 30 days after admission. Results: Of the 4,034 patients with cardiogenic shock due to AMI, 665 were eligible for this study; 419 received norepinephrine (N group), 154 dopamine (D group), and 92 both agents (B group). There was a significant difference in the all-cause mortality rate between the three groups in the whole cohort (16.0% in the N group, 9.7% in the D group and 40.2% in the B group, P&lt;0.001). In addition, there was a significant difference in the all-cause mortality rate between the three groups in the subgroups of patients with eGFR stage 3a and 3b. (Figure). After adjustment of independent factors for mortality, the odds ratio of the D group (reference, the N group) was 0.51 (95%CI 0.26-0.99, p=0.049). Conclusion: Compared with norepinephrine, dopamine was associated with a lower all-cause mortality rate for patients with cardiogenic shock due to AMI, especially patients with poor renal function.