tbuckley/cabot-search huggingface dataset:
BBCIC Research Network Analysis of First-Cycle Prophylactic G-CSF Use in Patients Treated With High–Neutropenia Risk Chemotherapy
Authors: Pamala A. Pawloski, Cara L. McDermott, James H. Marshall, Vanita Pindolia, Catherine M. Lockhart, Catherine A. Panozzo, Jeffrey S. Brown, Bernadette Eichelberger
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Chemotherapy-induced febrile neutropenia (FN) is prevented or minimized with granulocyte colony-stimulating factors (G-CSFs). Several G-CSF biosimilars are approved in the United States. The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) is a nonprofit initiative whose objective is to provide scientific evidence on real-world use and comparative safety and effectiveness of biologics and biosimilars using the BBCIC distributed research network (DRN). Patients and Methods: We describe real-world G-CSF use in patients with breast or lung cancer receiving first-cycle chemotherapy associated with high FN risk. We assessed hospitalizations for FN, availability of absolute neutrophil counts, and G-CSF–induced adverse events to inform future observational comparative effectiveness studies of G-CSF reference products and their biosimilars. A descriptive analysis of 5 participating national health insurance plans was conducted within the BBCIC DRN. Results: A total of 57,725 patients who received at least one G-CSF dose were included. Most (92.5%) patients received pegfilgrastim. FN hospitalization rates were evaluated by narrow (&lt;0.5%), intermediate (1.91%), and broad (2.99%) definitions. Anaphylaxis and hyperleukocytosis were identified in 1.15% and 2.28% of patients, respectively. This analysis provides real-world evidence extracted from a large, readily available database of diverse patients, characterizing G-CSF reference product use to inform the feasibility of future observational comparative safety and effectiveness analyses of G-CSF biosimilars. We showed that the rates of FN and adverse events in our research network are consistent with those reported by previous small studies. Conclusions: Readily available BBCIC DRN data can be used to assess G-CSF use with the incidence of FN hospitalizations. Insufficient laboratory result data were available to report absolute neutrophil counts; however, other safety data are available for assessment that provide valuable baseline data regarding the effectiveness and safety of G-CSFs in preparation for comparative effectiveness studies of reference G-CSFs and their biosimilars.
Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a <i>TP53</i>-Dependent Manner
Authors: James I. McDonald, Noor Diab, Elisa Arthofer, Melissa Hadley, Tomas Kanholm, Uzma Rentia, Stephanie Gomez, Angela Yu, Erin E. Grundy, Olivia Cox, Michael J. Topper, Xiaoyun Xing, Pamela L. Strissel, Reiner Strick, Ting Wang, Stephen B. Baylin, Katherine B. Chiappinelli
Journal: Cancer Research (2021)

Abstract Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response. To understand which REs are affected by epigenetic therapies in ovarian carcinoma, we assessed the effect of DNMTi and HDACi on ovarian carcinoma cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild-type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53-mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild-type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in ovarian carcinoma after epigenetic treatment and implicate p53 in RE transcriptional regulation. Significance: This study identifies the repetitive element targets of epigenetic therapies in ovarian carcinoma and indicates a role for p53 in this process. See interview with Katherine B. Chiappinelli, PhD, recipient of the 2022 Cancer Research Early Career Award: https://vimeo.com/720726570
High-density lipoprotein in Alzheimer's disease: From potential biomarkers to therapeutics
Authors: Yi Jin, Kudzai Chifodya, Guochen Han, Wenxin Jiang, Yun Chen, Yang Shi, Qiao Xu, Yilong Xi, Jun Wang, Jianping Zhou, Huaqing Zhang, Yang Ding
Journal: Journal of Controlled Release (2021)
27375 Dupilumab provides early and sustained improvement of sleep disturbance in children ≥ 6 years with severe atopic dermatitis (AD) and adolescents with moderate-to-severe AD
Authors: Amy S. Paller, Eric L. Simpson, Lisa A. Beck, H. Chih-ho Hong, Danielle Marcoux, Zhen Chen, Brad Shumel, Ashish Bansal, Ana B. Rossi, Jingdong Chao
Journal: Journal of the American Academy of Dermatology (2021)
Optimal Medical Therapy Prolongs Life Following Revascularization
Authors: Anita Slomski
Journal: JAMA (2021)

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Using single-cell sequencing technology to detect circulating tumor cells in solid tumors
Authors: Jiasheng Xu, Kaili Liao, Xi Yang, Chengfeng Wu, Wei Wu
Journal: Molecular Cancer (2021)

Abstract Circulating tumor cells are tumor cells with high vitality and high metastatic potential that invade and shed into the peripheral blood from primary solid tumors or metastatic foci. Due to the heterogeneity of tumors, it is difficult for high-throughput sequencing analysis of tumor tissues to find the genomic characteristics of low-abundance tumor stem cells. Single-cell sequencing of circulating tumor cells avoids interference from tumor heterogeneity by comparing the differences between single-cell genomes, transcriptomes, and epigenetic groups among circulating tumor cells, primary and metastatic tumors, and metastatic lymph nodes in patients' peripheral blood, providing a new perspective for understanding the biological process of tumors. This article describes the identification, biological characteristics, and single-cell genome-wide variation in circulating tumor cells and summarizes the application of single-cell sequencing technology to tumor typing, metastasis analysis, progression detection, and adjuvant therapy.
Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance
Authors: Y. Loriot, A. Marabelle, J.P. Guégan, F.X. Danlos, B. Besse, N. Chaput, C. Massard, D. Planchard, C. Robert, C. Even, M. Khettab, L. Tselikas, L. Friboulet, F. André, I. Nafia, F. Le Loarer, J.C. Soria, A. Bessede, A. Italiano
Journal: Annals of Oncology (2021)
301. Viral Genome DNA/Lipoplexes Elicit In Situ Oncolytic Viral Replication and Potent Antitumor Efficacy Via Systemic Delivery
Journal: Molecular Therapy (2012)

Abstract   Modifying the viral genome to express potent and cancer-selective therapeutic genes has enhanced the role of adenoviruses (Ads) in cancer molecular therapeutics. However, the efficacy of Ad systemic delivery  in vivo  is limited by neutralizing antibodies, short blood circulation time, and high levels of nonspecific liver uptake resulting in hepatotoxicity. We therefore investigated the systemic delivery of tumor necrosis factor-related apoptosis-inducing ligand-expressing oncolytic Ad genome DNA (pmT-d19/stTR) via lipid envelopment as an alternative approach for cancer virotherapy in an orthotopic lung cancer model. Cationic liposomes (DOTAP/DOPE) were complexed with pmT-d19/stTR to generate pmT-d19/stTR + DOTAP/DOPE with the average diameter of which was 143.3 ± 5.7 nm at the optimal DNA:lipid ratio (1:6). Systemic administration of pmT-d19/stTR + DOTAP/DOPE elicited highly effective antitumor responses  in vivo , with tumor volumes decreasing 94.5%, 90.5%, and 92.4% compared to phosphate buffered saline-, naked Ad (mT-d19/stTR)-, or pmT-d19/stTR-treated groups, respectively. Additionally, innate immune responses and Ad-specific neutralizing antibodies were significantly decreased in pmT-d19/stTR + DOTAP/DOPE-treated mice compared to those in the mT-d19/stTR-treated group. The biodistribution profile analyzed by quantitative-PCR and immunohistochemical analysis demonstrated that viral replication occurred preferentially in tumor tissues. Moreover, the viral genome tumor-to-liver ratio was significantly elevated in pmT-d19/stTR + DOTAP/DOPE-treated mice, which was 934- and 27-fold greater than the mT-d19/stTR- and pmT-d19/stTR-treated mice, respectively. These results demonstrate that systemic delivery of oncolytic viral genome DNA with liposomes is a powerful alternative to naked Ad, overcoming the limited clinical applicability of conventional Ads and enabling effective treatment of disseminated metastatic tumors.
Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity
Authors: Susan N. Christo, Maximilien Evrard, Simone L. Park, Luke C. Gandolfo, Thomas N. Burn, Raissa Fonseca, Dane M. Newman, Yannick O. Alexandre, Nicholas Collins, Natasha M. Zamudio, Fernando Souza-Fonseca-Guimaraes, Daniel G. Pellicci, David Chisanga, Wei Shi, Laurent Bartholin, Gabrielle T. Belz, Nicholas D. Huntington, Andrew Lucas, Michaela Lucas, Scott N. Mueller, William R. Heath, Florent Ginhoux, Terence P. Speed, Francis R. Carbone, Axel Kallies, Laura K. Mackay
Journal: Nature Immunology (2021)
mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates
Authors: Kizzmekia S. Corbett, Anne P. Werner, Sarah O’ Connell, Matthew Gagne, Lilin Lai, Juan I. Moliva, Barbara Flynn, Angela Choi, Matthew Koch, Kathryn E. Foulds, Shayne F. Andrew, Dillon R. Flebbe, Evan Lamb, Saule T. Nurmukhambetova, Samantha J. Provost, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Alex Van Ry, Zackery Flinchbaugh, Timothy S. Johnston, Elham Bayat Mokhtari, Prakriti Mudvari, Amy R. Henry, Farida Laboune, Becky Chang, Maciel Porto, Jaclyn Wear, Gabriela S. Alvarado, Seyhan Boyoglu-Barnum, John-Paul M. Todd, Bridget Bart, Anthony Cook, Alan Dodson, Laurent Pessaint, Katelyn Steingrebe, Sayda Elbashir, Manjari Sriparna, Andrew Pekosz, Hanne Andersen, Kai Wu, Darin K. Edwards, Swagata Kar, Mark G. Lewis, Eli Boritz, Ian N. Moore, Andrea Carfi, Mehul S. Suthar, Adrian McDermott, Mario Roederer, Martha C. Nason, Nancy J. Sullivan, Daniel C. Douek, Barney S. Graham, Robert A. Seder
Journal: Nature Immunology (2021)
治療抵抗性高血圧症(RH)と心血管疾患(CVD)に対する腎デナベーション(RDN)のトランスレーショナルリサーチ
Authors: Yamamoto Eiichiro, Hirata Yoshihiro, Tokitsu Takanori, Kusaka Hiroaki, Sueta Daisuke, Tsujita Kenichi, Kaikita Koichi, Hokimoto Seiji, Mitsuyama Shokei, Ogawa Hisao
Journal: Circulation (2016)
Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure
Authors: Nicola R. Pugliese, Francesco Paneni, Matteo Mazzola, Nicolò De Biase, Lavinia Del Punta, Luna Gargani, Alessandro Mengozzi, Agostino Virdis, Lorenzo Nesti, Stefano Taddei, Andreas Flammer, Barry A. Borlaug, Frank Ruschitzka, Stefano Masi
Journal: European Journal of Heart Failure (2021)
Helmet noninvasive ventilation compared to facemask noninvasive ventilation and high-flow nasal cannula in acute respiratory failure: a systematic review and meta-analysis
Authors: Dipayan Chaudhuri, Rehman Jinah, Karen E.A. Burns, Federico Angriman, Bruno L. Ferreyro, Laveena Munshi, Ewan Goligher, Damon Scales, Deborah J. Cook, Tommaso Mauri, Bram Rochwerg
Journal: European Respiratory Journal (2021)

Background Although small randomised controlled trials (RCTs) and observational studies have examined helmet noninvasive ventilation (NIV), uncertainty remains regarding its role. We conducted a systematic review and meta-analysis to examine the effect of helmet NIV compared to facemask NIV or high-flow nasal cannula (HFNC) in acute respiratory failure. Methods We searched multiple databases to identify RCTs and observational studies reporting on at least one of mortality, intubation, intensive care unit (ICU) length of stay, NIV duration, complications or comfort with NIV therapy. We assessed study risk of bias using the Cochrane Risk of Bias 2 tool for RCTs and the Ottawa–Newcastle Scale for observational studies, and rated certainty of pooled evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) framework. Results We separately pooled data from 16 RCTs (n=949) and eight observational studies (n=396). Compared to facemask NIV, based on low certainty of evidence, helmet NIV may reduce mortality (relative risk 0.56, 95% CI 0.33–0.95) and intubation (relative risk 0.35, 95% CI 0.22–0.56) in both hypoxic and hypercapnic respiratory failure, but may have no effect on duration of NIV. There was an uncertain effect of helmet NIV on ICU length of stay and development of pressure sores. Data from observational studies were consistent with the foregoing findings but of lower certainty. Based on low and very low certainty data, helmet NIV may reduce intubation compared to HFNC, but its effect on mortality is uncertain. Conclusions Compared to facemask NIV, helmet NIV may reduce mortality and intubation; however, the effect of helmet NIV compared to HFNC remains uncertain.
Increased Angiotensin-Converting Enzyme 2 and Loss of Alveolar Type II Cells in COVID-19–related Acute Respiratory Distress Syndrome
Authors: Ludovic Gerard, Marylene Lecocq, Caroline Bouzin, Delphine Hoton, Gregory Schmit, Joao Pinto Pereira, Virginie Montiel, Thomas Plante-Bordeneuve, Pierre-François Laterre, Charles Pilette
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.
Impaired Tubular Secretion of Organic Solutes in Advanced Chronic Kidney Disease
Authors: Robert D. Mair, Seolhyun Lee, Natalie S. Plummer, Tammy L. Sirich, Timothy W. Meyer
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement In patients with CKD, the clearance of waste solutes removed by tubular secretion may be altered to an extent that is disproportionate to the reduction in the GFR. However, an average change in the clearance of secreted waste solutes relative to the GFR in CKD has not been reported, possibly because studies performed so far have included few subjects with advanced CKD. The authors found that the secretory clearance of many waste solutes is reduced relative to the GFR in patients with an eGFR&lt;12 ml/min per 1.73 m 2 . As patients approach dialysis, to the extent that secreted solutes contribute to uremic symptoms, reductions in fractional clearances of secreted solutes might cause such symptoms to increase out of proportion to the reduction in GFR. Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the GFR in CKD. Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. Methods To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 patients with CKD and an eGFR of 7±2 ml/min per 1.73 m 2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in patients with CKD and to those of creatinine in controls. Results Metabolomic analysis identified 39 secreted solutes with fractional clearance &gt;3.0 in control participants. Fractional clearance values in patients with CKD were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p -cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for patients with CKD; P &lt;0.001), p -cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for patients with CKD; P &lt;0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8; P &lt;0.001) but not for hippurate (10.2±3.8 versus 8.4±2.6; P =0.13). Conclusions Secretory clearances for many solutes are reduced more than the GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.
In vitro expansion of FVB/N Tg MMTVneu primary tumor cells
Authors: Jill Gershan, Katie Palen, Rimas Orentas
Journal: Cancer Research (2008)

1831  Our goal is to expand and immortalize patient derived primary tumor cells in vitro with subsequent transduction with immune co-stimulatory molecules to produce autologous cell-based tumor vaccines. The bypass of telomerase independent senescence (M0) and/or telomerase dependent senescence and crisis (M1 and M2) of biopsy-derived tumor cells poses the greatest challenge for this project. Using the Weinberg model, we hypothesized that altering anti-proliferative and apoptotic signals would allow primary tumor cells to acquire unlimited replicative potential in vitro.  Spontaneously arising tumors in FVB/N Tg MMTVneu mice contain a HER-2/neu deregulated growth signaling pathway, and active telomerase. Despite these features, freshly harvested early passage cells are senescent, and after about 3 weeks in culture they undergo crisis. In an effort to bypass senescence and crisis in early passage tumor cells we transduced them (MOI 20) with lentiviral vectors (Lentigen, Inc.) encoding oncogenes that block anti-proliferative signals (HPV E6E7, SV40 large T antigen, or Bcl2) or alter intracellular signaling circuits (SV40 small T antigen, Ha-RasV12 or c-Myc). Instead of blocking senescence and enhancing proliferation, the transduced cells expanded slower than non-transduced cells and eventually died.  Non-transduced cells that survived crisis expanded, were no longer senescent, and maintained greater than 90% neu expression. These “adapted” cells proliferated faster than early passage cells, but did not grow as fast as the NT2.5 FVB/N Tg MMTVneu cell line (gift of E. Jaffe, Johns Hopkins Univ). The “adapted” cells proliferate in low serum MEGM media whereas the NT2.5 cells require 20% serum for optimal proliferation. There was no proliferative advantage when the “adapted” tumor cells were transduced with the same set of oncogenes. NT2.5 cells were not affected by oncogene transduction and continued to proliferate rapidly.  Spontaneous tumors arising in the FVB/N tg MMTVneu mice have characteristics that potentially render them independent of exogenous growth signals with limitless in vivo replicative potential. Introducing oncogenes that confer insensitivity to growth inhibitory and apoptotic signals, however, did not augment the survival of these cells in vitro. The senescence experienced by freshly harvested tumor cells may be dependent on altered growth signals unique to in vitro culture. “Adapted” cells appear to be an intermediate cell type that is no longer senescent, survives in low serum MEGM media and does not proliferate as robustly as the NT2.5 cell line, yet remains prone to senescence upon transduction with oncogenes. Thus, while the ability to transform primary cells with a discrete set of immortalization genes has been accomplished, the delicate balance between growth and senescence required for the in vitro expansion of primary cancer cells has yet to be defined.
Art in Endoscopy: “The Garden of Earthly Delights”
Authors: Gertjan Rasschaert
Journal: Endoscopy (2021)

This image, captured during a routine screening colonoscopy, shows a sigmoid diverticulum filled with fecaloid material. The distension creates an elevated border which makes this image both beautiful and unusual. Despite the non-inflamed mucosal appearance, it could be considered as the origin of an imminent diverticulitis as Hieronymus Bosch might have painted it in the left panel of his triptych “The Garden of Earthly Delights,” where the pink fountain of paradise contains a peeping owl in its gloomy niche as a symbol of emergent filth and evil.