tbuckley/cabot-search huggingface dataset:
Depletion of Gprc5a Promotes Development of Diabetic Nephropathy
Authors: Xiaojie Ma, Angelina Schwarz, Sonia Zambrano Sevilla, Anna Levin, Kjell Hultenby, Annika Wernerson, Mark Lal, Jaakko Patrakka
Journal: Journal of the American Society of Nephrology (2018)

Background Renal glomeruli are the primary target of injury in diabetic nephropathy (DN), and the glomerular podocyte has a key role in disease progression. Methods To identify potential novel therapeutic targets for DN, we performed high-throughput molecular profiling of G protein–coupled receptors (GPCRs) using human glomeruli. Results We identified an orphan GPCR, Gprc5a, as a highly podocyte-specific gene, the expression of which was significantly downregulated in glomeruli of patients with DN compared with those without DN. Inactivation of Gprc5a in mice resulted in thickening of the glomerular basement membrane and activation of mesangial cells, which are two hallmark features of DN in humans. Compared with wild-type mice, Gprc5a-deficient animals demonstrated increased albuminuria and more severe histologic changes after induction of diabetes with streptozotocin. Mechanistically, Gprc5a modulated TGF- β signaling and activation of the EGF receptor in cultured podocytes. Conclusions Gprc5a has an important role in the pathogenesis of DN, and further study of the podocyte-specific signaling activity of this protein is warranted.
Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling
Authors: Harald Lund, Melanie Pieber, Roham Parsa, David Grommisch, Ewoud Ewing, Lara Kular, Jinming Han, Keying Zhu, Jik Nijssen, Eva Hedlund, Maria Needhamsen, Sabrina Ruhrmann, André Ortlieb Guerreiro-Cacais, Rasmus Berglund, Maria J. Forteza, Daniel F. J. Ketelhuth, Oleg Butovsky, Maja Jagodic, Xing-Mei Zhang, Robert A. Harris
Journal: Nature Immunology (2018)
Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts
Authors: Kwanghee Kim, Philip A. Watson, Souhil Lebdai, Sylvia Jebiwott, Alexander J. Somma, Stephen La Rosa, Dipti Mehta, Katie S. Murray, Hans Lilja, David Ulmert, Sebastien Monette, Avigdor Scherz, Jonathan A. Coleman
Journal: Clinical Cancer Research (2018)

Abstract Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer. Clin Cancer Res; 24(10); 2408–16. ©2018 AACR.
Acute Malnutrition and Anemia Among Rohingya Children in Kutupalong Camp, Bangladesh
Authors: Eva Leidman, Alexa Humphreys, Blanche Greene Cramer, Leonie Toroitich-Van Mil, Caroline Wilkinson, Anuradhha Narayan, Oleg Bilukha
Journal: JAMA (2018)

This survey study assesses the health and nutritional status of Rohingya children aged 6 to 59 months in the Kutupalong refugee camp in Bangladesh.
The landscape of the tumor-infiltrating B cell and its association with T-cell and tumor microenvironment in human cancers.
Authors: Young Kwang Chae, William Han Bae, Yeonjoo Choi, Young Suk Kim, Jonathan Forrest Anker, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

76 Background: Compared to recent advances in our knowledge of T cell biology with success of immunotherapy, little progress has been made in understanding of the effects of B cells in tumor microenvironment and their interactions with T cells. Preclinical studies reported that B cells may have immune suppressive roles in tumor microenvironment via induction of T cell exhaustion. However, this association has not been shown in human tissues. We explored the landscape of tumor infiltrating B and T cells and their association with tumor microenvironment in various human cancers for which the FDA approved the use of immune checkpoint inhibitors. Methods: Expression patterns for 812 immune related genes from the TCGA database were utilized to define tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal clear cell carcinoma, skin cutaneous melanoma, lung squamous cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Odds ratios (ORs) of the numbers of tumors with versus without activated B cell infiltration by the presence of activated CD8T cell infiltration were calculated. Results: Immune landscape of the six human cancers showed a consistent inverse association between tumor infiltrating activated B and CD8 T cells (OR = 0.18, p &lt; 0.001). B cell infiltration was associated with increased expressions of immune checkpoints PD-L1, PD-1 and CTLA-4 and regulatory cytokines TGF-β, IL-10 and IL-35, which are known to be secreted by regulatory B cells. Angiogenic markers, such as angiopoietins, VEGF, MMP-9, CXCL10, CXCL11 and Tie2, showed differential expression patterns between B cell high and low groups. Conclusions: This is the first study that reports the inverse association between tumor infiltrating B and CD8 T cells in human tissues. The strong associations between B cell infiltration and increased expressions of suppressive cytokines and immune checkpoints suggest regulatory B cells may play a role in the T cell suppression in tumor microenvironment. Our results implicate that depleting B cells, leading to possible disinhibition of T cell activation, may be a future therapeutic option in potentiating T cell mediated immunity.
Overcoming safety challenges in CO therapy – Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels
Authors: Jakob Wollborn, Cornelius Hermann, Ulrich Goebel, Benjamin Merget, Christian Wunder, Sven Maier, Thomas Schäfer, Dominik Heuler, Klaus Müller-Buschbaum, Hartmut Buerkle, Lorenz Meinel, Martin A. Schick, Christoph Steiger
Journal: Journal of Controlled Release (2018)
Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)
Authors: Tobias Welte, R. Phillip Dellinger, Henning Ebelt, Miguel Ferrer, Steven M. Opal, Mervyn Singer, Jean-Louis Vincent, Karl Werdan, Ignacio Martin-Loeches, Jordi Almirall, Antonio Artigas, Jose Ignacio Ayestarán, Sebastian Nuding, Ricard Ferrer, Gonzalo Sirgo Rodríguez, Manu Shankar-Hari, Francisco Álvarez-Lerma, Reimer Riessen, Josep-Maria Sirvent, Stefan Kluge, Kai Zacharowski, Juan Bonastre Mora, Harald Lapp, Gabriele Wöbker, Ute Achtzehn, David Brealey, Axel Kempa, Miguel Sánchez García, Jörg Brederlau, Matthias Kochanek, Henrik Peer Reschreiter, Matthew P. Wise, Bernd H. Belohradsky, Iris Bobenhausen, Benjamin Dälken, Patrick Dubovy, Patrick Langohr, Monika Mayer, Jörg Schüttrumpf, Andrea Wartenberg-Demand, Ulrike Wippermann, Daniele Wolf, Antoni Torres
Journal: Intensive Care Medicine (2018)

The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. Trial registration: NCT01420744.
A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors.
Authors: Xuhui Bao, Stephen T. Keir, Smita K Nair, Ira Pastan, Darell D. Bigner, Vidyalakshmi Chandramohan
Journal: Journal of Clinical Oncology (2017)

102 Background: Immunotoxins can induce direct and rapid cytotoxicity by targeting specific tumor antigens. D2C7 is a unique recombinant immunotoxin targeting EGFRwt/EGFRvIII, two frequently overexpressed proteins on gliomas, and is currently being tested in a phase I/II clinical trial (NCT02303678) for recurrent malignant gliomas. Immunotoxins have also been shown to induce a secondary antitumor immune response via stimulation of cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors, which have successfully treated several advanced tumors by promoting the antitumor function of CTLs, may further enhance this immunotoxin-induced antitumor response. Thus, we hypothesize that combining D2C7 with immune checkpoint inhibitors will promote long-term tumor regression due to primary cytotoxicity and enhanced anti-tumor immunity. Methods: We developed a CT2A-mD2C7 mouse glioma cell line with robust in vitro cytotoxicity of D2C7 (IC 50 = 0.47 ng/mL). In vivo anti-tumor efficacy was evaluated by intratumoral injection of D2C7 combined with intraperitoneal injection of anti-CTLA4 or anti-PD1 antibodies in single-side and bilateral subcutaneous (SC) CT2A-mD2C7 glioma models in C57BL/6 immunocompetent mice. Results: In the single-side model, D2C7 monotherapy and combinatorial therapy showed a significant tumor growth delay (P &lt; 0.01). Complete regression ( ≥ 40%) was only observed in combinatorial therapy groups. All cured mice rejected the rechallenging of CT2A parental cells in the contralateral flank and the subsequent rechallenging of CT2A-mD2C7 cells in the brain. In the bilateral model, the larger right tumors were treated with D2C7/anti-CTLA4/anti-PD1 monotherapy or D2C7+anti-CTLA4/PD1 combinatorial therapy, while the left tumors were untreated by D2C7. In the groups where the right tumors were treated with monotherapy or combinatorial therapy, the left untreated tumors also grew much slower. Furthermore, the combinatorial therapy led to the most significantly delayed growth of the left untreated tumors (P &lt; 0.05). Conclusions: Immune checkpoint inhibitors can enhance D2C7-induced anti-tumor immunity to achieve a synergistic long-term tumor regression.
HIV incidence in western Kenya during scale-up of antiretroviral therapy and voluntary medical male circumcision: a population-based cohort analysis
Authors: Martien W Borgdorff, Daniel Kwaro, David Obor, George Otieno, Viviane Kamire, Frederick Odongo, Patrick Owuor, Jacques Muthusi, Lisa A Mills, Rachael Joseph, Mary E Schmitz, Peter W Young, Emily Zielinski-Gutierrez, Kevin M De Cock
Journal: The Lancet HIV (2018)
Abstract 20622: Endothelin Receptor Alteration Following Hemorrhagic Shock and Resuscitation by Centhaquin
Authors: Anil Gulati, Seema Briyal, Manish S Lavhale, Ravina Gandhakwala, Mahnoor Khan
Journal: Circulation (2017)

Introduction: Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on ETA and ETB receptors and has been implicated in hemorrhagic shock (HS). Centhaquin, a cardiovascular active agent, is ...
Abstract 16460: Differential Impact Of Cigarette Smoking On Prognosis In Women Compared With Men With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention
Authors: Lixia Yang, Zhijian Wang
Journal: Circulation (2016)

Background:  Cigarette smoking is an important risk factor for worse outcomes in patients with coronary artery disease. Whether smoking confers the same excess risk for women versus men is not known. Therefore, we sought to investigate the effect of cigarette smoking on clinical outcomes in women versus men with coronary artery disease undergoing elective percutaneous coronary intervention (PCI) after adjusting for other risk factors.   Methods:  We prospectively followed up a total of 10,462 patients undergoing elective PCI between January, 2013 and June, 2014 in our cardiovascular center. All the patients were stratified according to smoking status and sex. The impact of cigarette smoking on long-term all-cause death and the interaction between the effect of smoking on death and sex were evaluated by Cox regression model taking smoking status as a time-varying variable.   Results:  Among 6,482 men and 3,980 women undergoing PCI, the prevalence of cigarette smoking was 42.5% (n = 2754) and 10.4% (n = 412) respectively at baseline (p    Conclusion:  Despite a low prevalence of smoking in women versus men among patients undergoing PCI, quitting smoking is more challenging in women. Smoking confers a higher excess risk of all-cause death among women compared with men.
Virus in Semen and the Risk of Sexual Transmission
Authors: Heinz Feldmann
Journal: New England Journal of Medicine (2018)

Sexual contact is the primary route of human transmission for sexually transmitted infections (STIs). Traditional STIs are caused by a variety of pathogens, and classic examples of STIs include chlamydia, gonorrhea, syphilis, the acquired immunodeficiency syndrome, and genital herpes. Recently, reports showing virus detection in the semen of men infected with viruses that had previously been unknown to be sexually transmitted have caught the attention of infectious disease specialists, public health officials, and the media. Two of the more prominent examples are Zika virus (ZIKV) and Ebola virus (EBOV), which have been found in symptomatically infected patients and disease survivors.1,2 . . .
25P A non-pathway-specific approach in EGFR and KRAS mutant or squamous cell histology non-small cell lung cancer (NSCLC)
Authors: M. Ito, C. Codony-Servat, J. Codony-Servat, I. Attili, J. Berenguer, J. Bracht, N. Gil, M. Okada, N. Karachaliou, R. Rosell
Journal: Journal of Thoracic Oncology (2018)
Clonorchis sinensis omega-class glutathione transferases are reliable biomarkers for serodiagnosis of clonorchiasis and opisthorchiasis
Authors: J.-G. Kim, C.-S. Ahn, B. Sripa, K.S. Eom, I. Kang, W.-M. Sohn, Y. Nawa, Y. Kong
Journal: Clinical Microbiology and Infection (2018)

To determine the potential for immunodiagnostic application of two recombinant forms of Clonorchis sinensis omega-class glutathione transferases (rCsGSTo1 and rCsGSTo2) against human small liver-fluke C. sinensis and Opisthorchis viverrini infections.Specific antibody levels against rCsGSTo1 and rCsGSTo2 in patients' sera of egg-positive opisthorchiasis (n = 87) and clonorchiasis (n = 120), as well as those in sera from patients with other helminthic infections (n = 252) and healthy controls (n = 40) were retrospectively analysed by ELISA.We observed highly positive correlation coefficients between specific antibody levels against rCsGSTo1 and rCsGSTo2 and egg counts per gramme of faeces (EPG) of patients with opisthorchiasis (n = 87; r = 0.88 for rCsGSTo1 and r = 0.90 for rCsGSTo2). Sera from opisthorchiasis patients whose EPG counts >100 (n = 43) revealed high antibody titres against both antigens. Patients' sera with low EPG counts (<100, n = 44) also exhibited reliable sensitivities of 93.2% and 97.7% for rCsGSTo1 and rCsGSTo2, respectively. Sera from clonorchiasis patients showed sensitivities of 90% (108/120 samples) and 89.2% (107/120 sera) for rCsGSTo1 and rCsGSTo2. Overall diagnostic sensitivities for liver-fluke infections were 92.3% for rCsGSTo1 (191/207 samples) and 93.2% for rCsGSTo2 (193/207 samples). Specificities were 89.7% (rCsGSTo1) and 97.6% (rCsGSTo2).Detection of specific antibody levels against rCsGSTo1 or rCsGSTo2 might be promising for the serodiagnosis of patients infected with these two phylogenetically close carcinogenic liver-flukes.
Neutrophil lymphocyte ratio (NLR) as a predictor of outcomes with immune checkpoint inhibitor (ICI) therapy in genitourinary cancer and melanoma.
Authors: Ghayathri Jeyakumar, Naresh Bumma, SeongHo Kim, Craig Landry, Amy Weise, Lawrence E. Flaherty, Elisabeth I. Heath, Cynthia Silski, Erich Zechar, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2017)

37 Background: Immunotherapy, such as PD-1 and PD L1, has been recently approved in melanoma and genitourinary cancers (GU) such as renal cell carcinoma and urothelial carcinoma. There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR (ratio of absolute values of neutrophils to lymphocytes) as predictors of response, progression free survival (PFS) and overall survival (OS) in patients treated with PD1 or PD L1 inhibitors. We extrapolated from renal cell data with NLR and used a value of 4 as cutoff. Other known prognostic clinical factors assessed were age, race, and smoking status. Methods: Regulatory approval was obtained. A retrospective chart review of melanoma and genitourinary cancer patients at Karmanos Cancer Institute, treated with ICI was conducted. Data were collected on demographics, smoking status, pretherapy NLR, and post 4 doses of ICI. Association with clinical outcomes (response rate, PFS and OS) was conducted by univariable and multivariable analyses. A log-rank test was used to compare PFS and OS. Results: 143 pts, (59 GU and 84 Melanoma) were evaluated with median age of 61yrs (range, 24-87). 11 pts (19%) and 5 (6%) were African American (AA) in GU and melanoma respectively. 61 pts (43%) were smokers in total. Pretherapy NLR&lt;4 and ≥4 was seen in 97(68%) and 46 (32%) pts. The table summarizes the results of the analysis. Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in GU and melanoma cancers. NLR is an easily applicable predictive factor, however validation of this observation is required in a larger sample size. [Table: see text]
S-1/docetaxel compared with the other standard S-1 based regimens as a first-line chemotherapy for patients with advanced gastric cancer.
Authors: Tetsuya Kusumoto, Koji Ando, Satoshi Ida, Yasue Kimura, Hiroshi Saeki, Eiji Oki, Masaru Morita, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2013)

e15173 Background: S-1 monotherapy or S-1/CDDP have remained important as a standard chemotherapy regimen for patients with advanced gastric cancer (AGC), based on the randomized phase III trials. Although S-1/docetaxel has been reported highly active and well tolerated for AGC by many researchers, it could not show the superiority compared with S-1 monotherapy in the recent international randomized trial. We have also demonstrated that it might be effective for patients with Stage III AGC in both preoperative and postoperative adjuvant setting. The aim of this study was to evaluate efficacy, toxicity and validity of S-1/docetaxel retrospectively, compared with the standard regimens. Methods: We conducted a retrospective review of the data of 89 patients with AGC who received chemotherapy who were given S-1-containing regimens as the first line chemotherapy; 15 patients treated with S-1 monotherapy, 21 with S-1/CDDP, and 53 with S-1/docetaxel. The objective response, adverse event (AE), progression-free survival (PFS), and overall survival (OS) were compared between the three groups. Results: The overall response rates (ORRs) were obtained 6.7%, 38.1% and 30.2% for S-1 monotherapy, S-1/CDDP, and S-1/docetaxel, respectively. The incidence of AEs was more frequent in S-1 based combined treatments than in the S-1 monotherapy, however there was no significant difference in the severe AEs between each group. Survival data showed that the PFSs were 121 days, 199 days and 178 days, respectively, and there was the significant difference between S-1 monotherapy and S-1/docetaxel (p&lt;0.05). The overall survival showed that the MSTs were not significantly different. The conversion rate to the subsequent treatments following S-1 monotherapy was higher than the other treatments. Conclusions: S-1/docetaxel was active and well tolerated for the patients with ARGC as the first line. Although the Japanese guideline for treatment of gastric cancer recommends S-1 monotherapy or S-1/CDDP as the standard regimens, docetaxel could be applied for patients with AGC in case of CDDP-resistant or –naïve patients.