tbuckley/cabot-search huggingface dataset:
Abstract 225: Assessing Sunitinib Cardiotoxicity Using Engineered Cardiac Microtissues
Authors: Rachel E Truitt, Bonnie Ky, Kenneth B Margulies
Journal: Circulation Research (2016)

Introduction: Sunitinib is an oral tyrosine kinase inhibitor that effectively treats a variety of solid tumors but carries a significant risk of hypertension and left ventricular (LV) dysfunction. Although AMP-K inhibition may be central to the development of cardiotoxicity, these mechanisms remain incompletely understood as does the pathogenic role of hypertension in the development of LV dysfunction. We hypothesized that sunitinib results in dose- and duration-dependent changes in cardiac energetics that are worsened by increased afterload. Methods: These studies employed the use of a cardiac microtissue (CMT) model where neonatal rat cardiomyocytes and fibroblasts self-assemble on microfabricated PDMS cantilevers. With these CMTs, afterload can be effectively modified (stiff vs. soft) through variations in the elastic modulus of the cantilevers. Caspase 3/7 activation and ATP levels were determined using luminescence assays. Spontaneous beating rate was assessed by counting the number of beats during a 1 min interval. Mitochondrial membrane potential (MMP) was measured by labeling cells with TMRM and analyzed via flow cytometry. Results: CMTs treated with as little as 1uM sunitinib for 4hrs demonstrated a nearly two-fold increase in activated caspase 3/7 compared to control (DMSO treated) CMTs. Moreover, there was a 2-fold increase in caspase activation when CMTs were cultured on stiff versus soft cantilevers (p=0.01). Dose - dependent decreases in spontaneous beating rate following treatment with 1uM sunitinib (p&gt;0.05) or 10uM sunitinib (p&lt;0.0001) were observed (p-values are compared to control). MMP decreased with 1uM sunitinib treatment after 4hr (28±2.7% vs. 22±2.1% for control, n= 2x10 4 , p&lt;0.05) and 8hr (22±2.2% vs. 27±1.4% for control, n= 2x10 4 , p&lt;0.05). ATP levels after 24hr of 1uM sunitinib treatment were also decreased relative to control (66.2± 2.4 pg vs. 53.4±3 pg; p=0.01). Conclusions: These findings demonstrate that the CMT model is a robust model to study sunitinib cardiotoxicity, and cardiotoxicity is a function of sunitinib dose, duration and afterload. Experiments with CMTs comprised of human iPS derived cardiomyocytes (iPS-CMs) are ongoing to understand the relevance of these findings in human cardiomyocytes.
病気にかかった人間の肝臓にCXCR4-陽性細胞を補充する、胆汁上皮細胞からの間質細胞派生因子1
Authors: Terada R, Yamamoto K, Hakoda T, Shimada N, Okano N, Baba S, Ninomiya Y, Shiratori Y, Gershwin Me
Journal: Hepatology (2002)
Bortezomib-Based Therapy Overcomes the Adverse Impact of Renal Impairment in Transplant Eligible Patients: An Analysis of the Prospective Randomized EMN02/HO95 Study
Authors: Meletios A. Dimopoulos, Efstathios Kastritis, Roman Hajek, Luca Dozza, Meral Beksac, Alessandra Larocca, Hans Erik Johnsen, Ulf-Henrik Mellqvist, Anders Waage, Sonja Zweegman, Heinz Ludwig, Lucia Pantani, Andrew Spencer, Anna Pascarella, Marina Martello, Susana Carvalho, Hlif Steingrimsdottir, Claudia Cellini, Petra Cornelisse, Rossella Troia, Patrizia Tosi, Bronno van der Holt, Mario Boccadoro, Pieter Sonneveld, Michele Cavo
Journal: Blood (2017)
Correcting flaws in GP funding: avoid missing pockets of deprivation and don’t penalise areas with reduced life expectancy
Authors: Susan Denton, Simon de Lusignan
Journal: BMJ (2021)

While we support the principles of “levelling up” funding for practices in deprived areas,1 the analysis failed to explore fundamental flaws in current allocation, namely its application to too wide a geographical area and that shorter life expectancy may reduce capitation.

Current approaches to allocation have been based at primary care organisation (PCO) level, using a complicated formula that includes an age …
The relationship between adrenocortical candidate gene expression and clinical response to hydrocortisone in patients with septic shock
Authors: Jeremy Cohen, Antje Blumenthal, Gabriel Cuellar-Partida, David M. Evans, Simon Finfer, Qiang Li, Johanna Ljungberg, John Myburgh, Elizabeth Peach, Joseph Powell, Dorrilyn Rajbhandari, Andrew Rhodes, Anne Senabouth, Balasubramanian Venkatesh
Journal: Intensive Care Medicine (2021)
Short cuts: What's new in the other general journals
Journal: BMJ (2005)

common in patients with osteoporosis compared with people with normal bone mineral density or osteopenia, stratifying for bone mineral density within the group with osteoporosis did not provide additional information.The three patients with multiple myeloma, however, all had evidence of established osteoporosis, suggesting that measurement of M component may be informative in this group.Referral patterns vary between osteoporosis clinics, depending on guidelines and the availability of bone densitometry.In our clinic, 46% of referred patients fulfilled the World Health Organization definition of osteoporosis.This agrees closely with the 41% to 53% 9 10 reported by clinics in the United Kingdom and United States. 11The most important limitation of our study was that we could not calculate the false negative rate.To do this we would have had to rule out non-secretory myeloma and light chain disease by carrying out skeletal x rays and marrow biopsies in all patients with osteoporosis referred to our clinic.It is possible, however, to estimate the number of false negative tests by extrapolating from Mayo clinic data on the distribution of multiple myeloma subtypes at diagnosis.The number of patients with multiple myeloma in our study is a conservative estimate, because we did not assess urine Bence-Jones protein.Light chain disease, however, is less common and the expense would be greater.Thus, about 600 urine analyses would be needed to diagnose a single case of light chain multiple myeloma in patients with osteoporosis if 20% 12 of cases of secretory multiple myeloma are of the light chain variant.We know from other studies that normal bone mineral density does not rule out multiple myeloma, 13 14 but owing to the low prevalence of the disease in referred patients without osteoporosis, we cannot make a strong case for vigilance for M component in the absence of osteoporosis.
Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors
Authors: Jian Li, Yanhong Deng, Weijie Zhang, Ai-Ping Zhou, Weijian Guo, Jianwei Yang, Ying Yuan, Liangjun Zhu, Shukui Qin, Silong Xiang, Haolan Lu, John Gong, Ting Xu, David Liu, Lin Shen
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Monoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously. Methods This open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival. Results One hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0–52.8), and the disease control rate was 66.0% (95% CI 56.0–75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5–97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7–82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1–2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events. Conclusions This is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer. Trial registration ClinicalTrials.gov, NCT03667170. Registered 10 September 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03667170 .
Metabolic features of cancer cells impact immunosurveillance
Authors: Adrien Joseph, Pan Juncheng, Michele Mondini, Nizar Labaied, Mauro Loi, Julien Adam, Antoine Lafarge, Valentina Astesana, Florine Obrist, Christophe Klein, Norma Bloy, Gautier Stoll, Nicolas Signolle, Catherine Genestie, Diane Damotte, Marco Alifano, Alexandra Leary, Patricia Pautier, Philippe Morice, Sebastien Gouy, Eric Deutsch, Cyrus Chargari, Marie-Caroline Dieu-Nosjean, Isabelle Cremer, Judith Michels, Guido Kroemer, Maria Castedo
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types. Methods Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR low ) and cisplatin-resistant (PAR high ) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry. Results The infiltration of tumors by CD8 T and DC-LAMP + cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p&lt;0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=−0.39, p=0.034 in LACC, R=−0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR high ). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086). Conclusions Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer
Authors: Jamie M. Sperger, Hamid Emamekhoo, Rana R. McKay, Charlotte N. Stahlfeld, Anupama Singh, Xinyi E. Chen, Lucia Kwak, Cole S. Gilsdorf, Serena K. Wolfe, Xiao X. Wei, Rebecca Silver, Zhenwei Zhang, Michael J. Morris, Glenn Bubley, Felix Y. Feng, Howard I. Scher, Dana Rathkopf, Scott M. Dehm, Toni K. Choueiri, Susan Halabi, Andrew J. Armstrong, Alexander W. Wyatt, Mary-Ellen Taplin, Shuang G. Zhao, Joshua M. Lang
Journal: Journal of Clinical Oncology (2021)

PURPOSE Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy. MATERIALS AND METHODS A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board–approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings. RESULTS Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 v 22.4 months; P &lt; .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months v not reached; P &lt; .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 v 12 months; P &lt; .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 v 40.6 months; P &lt; .01; HR = 4.64 [1.82 to 17.41]). CONCLUSION We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.
Nanotechnology against COVID-19: Immunization, diagnostic and therapeutic studies
Authors: Akbar Hasanzadeh, Masoomeh Alamdaran, Sepideh Ahmadi, Helena Nourizadeh, Mohammad Aref Bagherzadeh, Mirza Ali Mofazzal Jahromi, Perikles Simon, Mahdi Karimi, Michael R. Hamblin
Journal: Journal of Controlled Release (2021)
Prognostic models for mortality after cardiac surgery in patients with infective endocarditis: a systematic review and aggregation of prediction models
Authors: Borja M. Fernandez-Felix, Laura Varela Barca, Esther Garcia-Esquinas, Andrea Correa-Pérez, Nuria Fernández-Hidalgo, Alfonso Muriel, Jesus Lopez-Alcalde, Noelia Álvarez-Diaz, Jose I. Pijoan, Aida Ribera, Enrique Navas Elorza, Patricia Muñoz, María del Carmen Fariñas, Miguel Ángel Goenaga, Javier Zamora
Journal: Clinical Microbiology and Infection (2021)
Albuminuria and Prognosis Among Individuals With Atherosclerotic Cardiovascular Disease
Authors: Yejin Mok, Shoshana H. Ballew, Richard Brandon Stacey, Joseph Rossi, Silvia Koton, Anna Kucharska-Newton, Patricia P. Chang, Josef Coresh, Wayne Rosamond, Kunihiro Matsushita
Journal: Journal of the American College of Cardiology (2021)
Correspondence on ‘Impact of COVID-19 pandemic on patients with large-vessel vasculitis in Italy: a monocentric survey’
Authors: Fernando Montero, Isabel Castrejón, Julia Martínez-Barrio, Juan Carlos Nieto-González, Javier Rivera, José María Álvaro-Gracia, Juan Molina Collada
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Abstract</h3> One step along the pathogenesis of Systemic lupus erythematosus (SLE) is associated with polymorphonuclear leukocyte (PMN) death and their ineffective removal by M2-macrophages. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein with unexpected immunosuppressive function in M2-macrophages and myeloid cells. To investigate the role of SPARC in autoimmunity, we adopted a pristane–induced model of lupus in mice, which recapitulates clinical manifestations of human SLE. <i>Sparc</i><sup><i>-/-</i></sup> mice developed earlier and more severe renal disease, lung and liver parenchymal damage than the WT counterpart. Most prominently, <i>Sparc</i><sup><i>-/-</i></sup> mice had anticipated and severe occurrence of arthritis. An intermediate phenotype was obtained in <i>Sparc</i><sup><i>+/-</i></sup> hemizygous mice, a result that suggests <i>Sparc</i> gene-dosage as relevant in autoimmune-related events. Mechanistically, a defective <i>Sparc</i> expression in PMN blocks their clearance by macrophages, through a defective delivery of eat-me and don’t eat-me signals. <i>Sparc-/-</i> PMN that escape macrophage scavenging becomes a source of autoantigens for dendritic cell (DC) presentation and a direct stimulus for IL-17 expression in γδ-T-cells. Gene profile analysis of synovial biopsies of knees affected by SLE-associated arthritis showed an inverse correlation between SPARC and key autoimmune genes. These results point to SPARC down-regulation as a key event characterizing SLE and associated rheumatoid arthritis pathogenesis.
The IL-17 Receptor IL-17RA Is Expressed By Early Erythroid Progenitors and Stimulates Erythropoiesis
Authors: Yung Hwang, Daniel Hidalgo, Betsabeh Khoramian Tusi, Samuel Wolock, Caleb Weinreb, Allon Moshe Klein, Merav Socolovsky
Journal: Blood (2017)
Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
Authors: Kit I. Tong, Sharon Yoon, Keren Isaev, Mehran Bakhtiari, Tracy Lackraj, Michael Y. He, Jesse Joynt, Anjali Silva, Maria C. Xu, Gilbert G. Privé, Housheng Hansen He, Rodger E. Tiedemann, Elizabeth A. Chavez, Lauren C. Chong, Merrill Boyle, David W. Scott, Christian Steidl, Robert Kridel
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL. Experimental Design: We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy. Results: We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment. Conclusions: Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Alemtuzumab for Treatment-Naïve and Relapsed-Refractory Severe Acquired Aplastic Anemia
Authors: Nayara Ribeiro Guedes, Juliana Goncalves, Marcelo Lacerda, Maria Cristina Nunez, Ana Rita F B Medeiros, Ana Carolina Kirchmeyer, Andre domingues Pereira, Patricia Eiko Yamakawa, Melca Oliveira Barros, Matheus Vescovi, Mihoko Yamamoto, Celso Arrais
Journal: Blood (2017)
Associations of genetic risk and smoking with incident COPD
Authors: Pei-Dong Zhang, Xi-Ru Zhang, Ao Zhang, Zhi-Hao Li, Dan Liu, Yu-Jie Zhang, Chen Mao
Journal: European Respiratory Journal (2021)

Background Genetic factors and smoking contribute to chronic obstructive pulmonary disease (COPD), but whether a combined polygenic risk score (PRS) is associated with incident COPD and whether it has a synergistic effect on smoking remains unclear. We aimed to investigate the association of the PRS with COPD and explore whether smoking behaviours could modify such association. Methods Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals for the association of the PRS and smoking with COPD. Results The study included 439 255 participants (mean age 56.5 years; 53.9% female), with a median follow-up of 9.0 years. PRS lasso containing 2.5 million variants showed better discrimination and a stronger association for incident COPD than PRS 279 containing 279 genome-wide significance variants. Compared with low genetic risk, the HRs of medium and high genetic risk were 1.39 (95% CI 1.31–1.48) and 2.40 (95% CI 2.24–2.56), respectively. The HR of high genetic risk and current smoking was 11.62 (95% CI 10.31–13.10) times that of low genetic risk and never smoking. There were significant interactions between PRS lasso and smoking status for incident COPD (p interaction &lt;0.001). From low genetic risk to high genetic risk, the HRs of current smoking increased from 4.32 (95% CI 3.69–5.06) to 6.89 (95% CI 6.21–7.64) and the population-attributable risks of smoking increased from 42.7% to 61.1%. Conclusions The PRS constructed from millions of variants below genome-wide significance showed significant associations with incident COPD. Participants with a high genetic risk may be more susceptible to developing COPD when exposed to smoking.