tbuckley/cabot-search huggingface dataset:
Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma
Authors: Jean Hoffman-Censits, Sumanta Pal, Constanze Kaiser, Beiying Ding, Joaquim Bellmunt
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Atezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not well characterized. Objective To report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP). Design, setting, and participants A total of 218 patients were enrolled at 36 US study sites (November 2015–August 2016), and the trial ended following the approval of atezolizumab by the US Food and Drug Administration. This post hoc analysis investigated outcomes in specific study subgroups. Intervention Atezolizumab 1200 mg was administered intravenously every 3 weeks until loss of clinical benefit, unacceptable toxicity, death, consent withdrawal, decision to discontinue, commercial availability, or study closure. Outcome measurements and statistical analysis Response Evaluation Criteria in Solid Tumors V.1.1 responses and safety were evaluated by baseline renal function and histology. Results and limitations Objective responses occurred in 0/6 (0%), 4/19 (21%), 1/27 (3.7%), and 12/62 (19%) of evaluable patients with creatinine clearance (CrCl) &lt;30, 30–45, 45–60, and ≥60 mL/min, respectively, and stable disease was seen in three patients with CrCl &lt;30 mL/min. Objective responses were seen in 13/102 patients (13%) with urothelial carcinoma (UC) histology only and in 4/12 patients (33%) with UC with MVH. Treatment-related adverse event frequencies ranged from 35% to 54% across the earlier indicated CrCl subgroups and they were also similar in patients with pure UC or UC with MVH (46%). Conclusions In this EAP mUC subgroup analysis, clinical benefit of atezolizumab occurred in patients with compromised renal function or MVH UC tumors. Safety was comparable across subgroups. Patient summary We examined the efficacy and safety of atezolizumab for UC in certain patients participating in an EAP. We found that responses to atezolizumab occurred, and safety was similar, in most patient subgroups with varying levels of kidney functioning or less common types of tumor tissue histology.
Response by Gheblawi et al to Letter Regarding Article, “Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2”
Authors: Mahmoud Gheblawi, Kaiming Wang, Anissa Viveiros, Quynh Nguyen, Jiu-Chang Zhong, Anthony J. Turner, Mohan K. Raizada, Maria B. Grant, Gavin Y. Oudit
Journal: Circulation Research (2020)
CRISPR-Cas12a with an oAd Induces Precise and Cancer-Specific Genomic Reprogramming of EGFR and Efficient Tumor Regression
Authors: A-Rum Yoon, Bo-Kyeong Jung, Eunyoung Choi, Eugene Chung, JinWoo Hong, Jin-Soo Kim, Taeyoung Koo, Chae-Ok Yun
Journal: Molecular Therapy (2020)

CRISPR-Cas12a represents a class 2/type V CRISPR RNA-guided endonuclease, holding promise as a precise genome-editing tool in vitro and in vivo. For efficient delivery of the CRISPR-Cas system into cancer, oncolytic adenovirus (oAd) has been recognized as a promising alternative vehicle to conventional cancer therapy, owing to its cancer specificity; however, to our knowledge, it has not been used for genome editing. In this study, we show that CRISPR-Cas12a mediated by oAd disrupts the oncogenic signaling pathway with excellent cancer specificity. The intratumoral delivery of a single oAd co-expressing a Cas12a and a CRISPR RNA (crRNA) targeting the epidermal growth factor receptor (EGFR) gene (oAd/Cas12a/crEGFR) induces efficient and precise editing of the targeted EGFR gene in a cancer-specific manner, without detectable off-target nuclease activity. Importantly, oAd/Cas12a/crEGFR elicits a potent antitumor effect via robust induction of apoptosis and inhibition of tumor cell proliferation, ultimately leading to complete tumor regression in a subset of treated mice. Collectively, in this study we show precise genomic reprogramming via a single oAd vector-mediated CRISPR-Cas system and the feasibility of such system as an alternative cancer therapy. CRISPR-Cas12a represents a class 2/type V CRISPR RNA-guided endonuclease, holding promise as a precise genome-editing tool in vitro and in vivo. For efficient delivery of the CRISPR-Cas system into cancer, oncolytic adenovirus (oAd) has been recognized as a promising alternative vehicle to conventional cancer therapy, owing to its cancer specificity; however, to our knowledge, it has not been used for genome editing. In this study, we show that CRISPR-Cas12a mediated by oAd disrupts the oncogenic signaling pathway with excellent cancer specificity. The intratumoral delivery of a single oAd co-expressing a Cas12a and a CRISPR RNA (crRNA) targeting the epidermal growth factor receptor (EGFR) gene (oAd/Cas12a/crEGFR) induces efficient and precise editing of the targeted EGFR gene in a cancer-specific manner, without detectable off-target nuclease activity. Importantly, oAd/Cas12a/crEGFR elicits a potent antitumor effect via robust induction of apoptosis and inhibition of tumor cell proliferation, ultimately leading to complete tumor regression in a subset of treated mice. Collectively, in this study we show precise genomic reprogramming via a single oAd vector-mediated CRISPR-Cas system and the feasibility of such system as an alternative cancer therapy.
AGA White Paper: Roadmap for the Future of Colorectal Cancer Screening in the United States
Authors: Joshua E. Melson, Thomas F. Imperiale, Steven H. Itzkowitz, Xavier Llor, Michael L. Kochman, William M. Grady, Robert E. Schoen, Carol A. Burke, Aasma Shaukat, Linda Rabeneck, Uri Ladabaum, Robert Bresalier, Brennan Spiegel, Judy Yee, Thomas Wang, David Lieberman, Srinadh Komanduri, V. Raman Muthusamy, Neelendu Dey
Journal: Clinical Gastroenterology and Hepatology (2020)
Stress Ulcer Prophylaxis for ICU Patients
Authors: Crisanto M. Torres, Sergio B. Navarrete
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Multiparametric Magnetic Resonance Imaging Alone is Insufficient to Detect Grade Reclassification in Active Surveillance for Prostate Cancer
Authors: Carissa E. Chu, Peter E Lonergan, Samuel L. Washington, Janet E Cowan, Katsuto Shinohara, Antonio C. Westphalen, Peter R. Carroll, Matthew R Cooperberg
Journal: European Urology (2020)
Abstract A56: Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells
Authors: Mark W. Nachtigal, Frank Schweizer, Gilbert Arthur
Journal: Clinical Cancer Research (2020)

Abstract Glycosylated antitumor ether lipids (GAELs) are a promising class of investigational anticancer agents with potent antitumor activity against a range of cancers, including platinum-resistant high-grade serous ovarian cancer (HGSOC). We previously demonstrated that epithelial ovarian cancer (EOC) cell lines (HGSOC and endometrioid) and primary cells derived from patient ascites (HGSOC and clear cell) were sensitive to the cell-killing effects of D-glucosamine-derived GAELs via an apoptosis-independent mechanism. However, D-linked carbohydrates are metabolized by endogenous glucosidases in vivo, rendering the GAEL inactive. Thus, the aim of the current study was to synthesize a novel class of GAELs with L-linked carbohydrates and to evaluate their efficacy in EOC cell lines and patient samples. Out of seven novel compounds tested, L-rhamnose-GAEL was identified as the compound with the greatest efficacy for killing EOC cell lines and patient cells that were grown under adherent or nonadherent (3D) conditions. The drug-sensitive and drug-resistant syngeneic endometrioid EOC cell lines, A2780s and A2780cp, respectively, as well as the NIH:OVCAR-3 and COV362 HGSOC lines, were incubated with L-rhamnose-GAEL for 48 hours and the CC50 determined as 15 μM for A2780s, 22.5 μM for A2780cp, and 5 μM for NIH:OVCAR-3 and COV362 cells. Similar experiments were conducted with primary EOC cells, chemo-naïve EOC126 (clear-cell adenocarcinoma), and platinum-resistant EOC 183I (HGSOC). Cell viability decreased in a dose-dependent manner with CC50 of 12 μM for EOC126 and 22.5 μM for EOC183l. For comparison, when EOC126 and EOC183I were grown as 3D cultures the CC50for cisplatin was 20 μM and 40 μM, respectively. To evaluate the effect of using low-dose treatment of L-rhamnose-GAEL on primary EOC cells (chemo-naive and chemoresistant), cells were exposed to L-rhamnose-GAEL for 96 hours. These studies revealed that prolonged incubation led to low CC50 of 1-5 μM. These results showed that primary EOC cells derived from chemo-naïve and platinum-resistant patients were sensitive to the L-rhamnose-GAEL and offer a novel drug class capable of killing chemotherapy-resistant EOC cells. Citation Format: Mark W. Nachtigal, Frank Schweizer, Gilbert Arthur. Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A56.
DNA Hybridization Measured with Graphene Transistor Arrays
Authors: Kokoura Mensah, Ismaïl Cissé, Aurélie Pierret, Michael Rosticher, José Palomo, Pascal Morfin, Bernard Plaçais, Ulrich Bockelmann
Journal: Advanced Healthcare Materials (2020)

Arrays of field-effect transistors are fabricated from chemical vapor deposition grown graphene (GFETs) and label-free detection of DNA hybridization performed down to femtomolar concentrations. A process is developed for large-area graphene sheets, which includes a thin Al2 O3 layer, protecting the graphene from contamination during photolithographic patterning and a SiOx capping for biocompatibility. It enables fabrication of high-quality transistor arrays, exhibiting stable close-to-zero Dirac point voltages under ambient conditions. Passivation of the as-fabricated chip with a layer composed of two different oxides avoids direct electrochemical contact between the DNA solutions and the graphene layer during hybridization detection. DNA probe molecules are electrostatically immobilized via poly-l-lysine coating of the chip surface. Adsorption of this positively charged polymer induces a positive shift of the Dirac point and subsequent immobilization of negatively charged DNA probes induces a negative shift. Spatially resolved hybridization of DNA sequences is performed on the GFET arrays. End-point as well as real-time in situ measurements of hybridization are achieved. A detection limit of 10 fm is observed for hybridization of 20-nucleotide DNA targets. Typical voltage signals are around 100 mV and spurious drifts below 1 mV per hour.
Concerns and needs of patients with systemic lupus erythematosus regarding hydroxychloroquine supplies during the COVID-19 pandemic: results from a patient-centred survey
Authors: Marlene Plüß, Gamal Chehab, Peter Korsten
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Abstract</h3> The omicron variant of SARS-CoV-2 infected very large numbers of SARS-CoV-2 vaccinated and convalescent individuals<sup>1–3</sup>. The penetrance of this variant in the antigen experienced human population can be explained in part by the relatively low levels of plasma neutralizing activity against Omicron in people who were infected or vaccinated with the original Wuhan-Hu-1 strain<sup>4–7</sup>. The 3<sup>rd</sup> mRNA vaccine dose produces an initial increase in circulating anti-Omicron neutralizing antibodies, but titers remain 10-20-fold lower than against Wuhan-Hu-1 and are, in many cases, insufficient to prevent infection<sup>7</sup>. Despite the reduced protection from infection, individuals that received 3 doses of an mRNA vaccine were highly protected from the more serious consequences of infection<sup>8</sup>. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving 3 mRNA vaccine doses<sup>9,10</sup>. We find that the 3<sup>rd</sup> dose is accompanied by an increase in, and evolution of, anti-receptor binding domain specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the 2<sup>nd</sup> vaccine dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared to antibodies obtained after the 2<sup>nd</sup> vaccine dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells that differed from the persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analyzed neutralizing antibodies in the memory compartment obtained from individuals receiving a 3<sup>rd</sup> mRNA vaccine dose neutralized Omicron. Thus, individuals receiving 3 doses of an mRNA vaccine encoding Wuhan-Hu-1, have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help explain why a 3<sup>rd</sup> dose of an mRNA vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.
‘Vesicular eruption in COVID‐19 – to exclude varicella’: reply from the authors
Authors: A. Català, C. Galván Casas, G. Carretero Hernández, I. García‐Doval
Journal: British Journal of Dermatology (2020)

We and agree with Drs Lim and Tey on the need to exclude varicella in vesicular eruptions in patients with COVID‐19, as this diagnosis has important implications. Once that it is established that some patients with COVID‐19 can have a vesicular eruption, there is a need to further characterize this group of patients. The link of some of these lesions with herpesvirus infections is very likely. One patient was excluded from our study with a diagnosis of varicella or disseminated herpes zoster.
Covid-19: research methods must be flexible in a crisis
Authors: Subhradip Karmakar, Ruby Dhar, Babban Jee
Journal: BMJ (2020)

Glasziou and colleagues raise some essential points but still seem quite judgmental of the covid-19 research community.1

We need to accept that our society is going through an extraordinary crisis, and research institutions worldwide are facing unprecedented challenges just to remain operational. Under these difficult circumstances, it’s not unusual to use slightly abridged yet highly innovative approaches2 to tackle scientific …
Relative Hypotension and Adverse Kidney-related Outcomes among Critically Ill Patients with Shock. A Multicenter, Prospective Cohort Study
Authors: Rakshit Panwar, Sanjay Tarvade, Nicholas Lanyon, Manoj Saxena, Dustin Bush, Miranda Hardie, John Attia, Rinaldo Bellomo, Frank Van Haren, Dustin Bush, Miranda Hardie, Claire Cattigan, Laurin Glasby, Matthew Martin, Steve O’Donoghue, Therese Starr, Mary Nourse, Shakira Spiller, Helen Rodgers, Allison Bone, Gail Brinkerhoff, Glenn Eastwood, Heidi Buhr, Debra Hutch, James Wun, Jennene Miller, Debra Inskip
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidney-related outcomes among critically ill patients with shock.Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation.Methods: At seven multidisciplinary ICUs, 302 patients, aged ≥40 years and requiring ≥4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled. We assessed the time-weighted average of the mean perfusion pressure (MPP) deficit (i.e., the percentage difference between patients' preillness basal MPP and achieved MPP) during vasopressor support and the percentage of time points with an MPP deficit > 20% as key exposure variables. New significant AKI was defined as an AKI-stage increase of two or more (Kidney Disease: Improving Global Outcome creatinine-based criteria).Measurements and Main Results: The median MPP deficit was 19% (interquartile range, 13-25), and 54% (interquartile range, 19-82) of time points were spent with an MPP deficit > 20%. Seventy-three (24%) patients developed new significant AKI; 86 (29%) patients developed MAKE. For every percentage increase in the time-weighted average MPP deficit, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 5.6% (95% confidence interval, 2.2-9.1; P = 0.001) and 5.9% (95% confidence interval, 2.2-9.8; P = 0.002), respectively. Likewise, for every one-unit increase in the percentage of time points with an MPP deficit > 20%, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 1.2% (0.3-2.2; P = 0.008) and 1.4% (0.4-2.4; P = 0.004), respectively.Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes.Study registered with Australian New Zealand Clinical Trial Registry (ACTRN 12613001368729).
A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis
Authors: Tae Gyu Oh, Susy M. Kim, Cyrielle Caussy, Ting Fu, Jian Guo, Shirin Bassirian, Seema Singh, Egbert V. Madamba, Ricki Bettencourt, Lisa Richards, Ruth T. Yu, Annette R. Atkins, Tao Huan, David A. Brenner, Claude B. Sirlin, Michael Downes, Ronald M. Evans, Rohit Loomba
Journal: Cell Metabolism (2020)
FTO-Dependent <i>N</i><sup>6</sup>-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling
Authors: Hao Huang, Yinu Wang, Manoj Kandpal, Guangyuan Zhao, Horacio Cardenas, Yanrong Ji, Anusha Chaparala, Edward J. Tanner, Jianjun Chen, Ramana V. Davuluri, Daniela Matei
Journal: Cancer Research (2020)

-Methyladenosine (m
Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis
Authors: Naim Ouldali, Marie Pouletty, Patricia Mariani, Constance Beyler, Audrey Blachier, Stephane Bonacorsi, Kostas Danis, Maryline Chomton, Laure Maurice, Fleur Le Bourgeois, Marion Caseris, Jean Gaschignard, Julie Poline, Robert Cohen, Luigi Titomanlio, Albert Faye, Isabelle Melki, Ulrich Meinzer
Journal: The Lancet Child & Adolescent Health (2020)
Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis
Authors: Elena Pachera, Shervin Assassi, Gloria A. Salazar, Mara Stellato, Florian Renoux, Adam Wunderlin, Przemyslaw Blyszczuk, Robert Lafyatis, Fina Kurreeman, Jeska de Vries-Bouwstra, Tobias Messemaker, Carol A. Feghali-Bostwick, Gerhard Rogler, Wouter T. van Haaften, Gerard Dijkstra, Fiona Oakley, Maurizio Calcagni, Janine Schniering, Britta Maurer, Jörg H.W. Distler, Gabriela Kania, Mojca Frank-Bertoncelj, Oliver Distler
Journal: Journal of Clinical Investigation (2020)

TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis.
JAK inhibitors in COVID-19: the need for vigilance regarding increased inherent thrombotic risk
Authors: Puja Mehta, Coziana Ciurtin, Marie Scully, Marcel Levi, Rachel C. Chambers
Journal: European Respiratory Journal (2020)

<b>JAK inhibitors have promising therapeutic potential in COVID-19 with dual anti-inflammatory and anti-viral effects. Vigilance to the potentially increased thrombotic risk associated with JAKi is recommended, given the hypercoagulability of COVID-19.</b>https://bit.ly/2NQ15K5
Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1
Authors: Anusha Seneviratne, Yumeng Han, Eunice Wong, Edward R.H. Walter, Lijun Jiang, Luke Cave, Nicholas J. Long, David Carling, Justin C. Mason, Dorian O. Haskard, Joseph J. Boyle
Journal: Circulation Research (2020)

The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an AMPK (AMP-activated protein kinase)/ATF1 (activating transcription factor-1) pathway that directs Mhem macrophages through coregulation of HO-1 (heme oxygenase-1; HMOX1) and lipid homeostasis genes.We asked whether this pathway had an in vivo role in mice.Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow-derived macrophages, heme induced HO-1, lipid regulatory genes including LXR (lipid X receptor), the growth factor IGF1 (insulin-like growth factor-1), and the splenic red pulp macrophage gene Spic. This response was lost in bone marrow-derived macrophages from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between days 8 and 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-; n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent.Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution. Graphic Abstract: An online graphic abstract is available for this article.