tbuckley/cabot-search huggingface dataset:
Latent Class Analysis Reveals COVID-19–related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids
Authors: Pratik Sinha, David Furfaro, Matthew J. Cummings, Darryl Abrams, Kevin Delucchi, Manoj V. Maddali, June He, Alison Thompson, Michael Murn, John Fountain, Amanda Rosen, Shelief Y. Robbins-Juarez, Matthew A. Adan, Tejus Satish, Mahesh Madhavan, Aakriti Gupta, Alexander K. Lyashchenko, Cara Agerstrand, Natalie H. Yip, Kristin M. Burkart, Jeremy R. Beitler, Matthew R. Baldwin, Carolyn S. Calfee, Daniel Brodie, Max R. O’Donnell
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.
P14.22 Quality indicators in neuro-oncology: modified Delphi process for the development of a quality indicator set for assessment of glioma care
Authors: D J Vanhauwaert, H Pinson, H De Schutter, E Van Eycken, S De Vleeschouwer, T Boterberg
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Quality Indicators (QIs) are important tools to assess the quality and variability of oncological care. However, their application in neuro-oncology is limited. The objective of this study was to develop a set of QIs for glioma, covering process and outcome indicators. METHODS First a systematic literature search was performed in peer-reviewed papers and grey literature to identify existing QIs in neuro-oncology and guidelines or recommendations that could be translated into new QIs. The PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) checklist and flow diagram were taken into account. The search strategy focused on diagnostics, treatment, follow-up and survival. For each (set of similar) recommendation(s) a QI was created that could easily be translated into a measurable proportion. Concordant QIs were rationalized to further reduce redundancy. Secondly a two round Delphi survey was organized amongst a multidisciplinary expert panel that was asked to score relevance for all proposed QIs. The panel consisted of neurosurgeons(4), radiation(3) and medical(3) oncologists, pathologists(3), radiologists(2), neurologists(1), nuclear medicine physicians(2) from university and non-university centers, and representatives of the Belgian Cancer Registry. RESULTS The conducted literature search in PubMed and Embase yielded 2392 abstracts. After screening and duplicate removal, 221 full text articles were assessed of which 79 were retained. In addition 28 references from the Grey literature were added. In total 240 recommendations and 30 QIs could be identified in this way. After translation of these recommendations into a measurable proportion, merging with the QIs found as such in the literature and rationalization, 148 QIs were presented to the expert panel. In the Delphi survey 15 of the 19 (79%) invited experts responded and eventually consensus was reached on 46 QIs that were considered relevant for the assessment of 6 different domains of neuro-oncological care: diagnosis and imaging (10), surgery (4), pathology (6), radio/chemotherapy (14), recurrence (5) and supportive treatment (7). CONCLUSION A set of 46 QIs grouped in 6 categories to assess the quality of care of glioma patients was developed. These QI’s are readily applicable dependent on the availability of population-based health care data
Neutrophils in cardiovascular disease: warmongers, peacemakers, or both?
Authors: Gopalkrishna Sreejit, Jillian Johnson, Robert M Jaggers, Albert Dahdah, Andrew J Murphy, Nordin M J Hanssen, Prabhakara R Nagareddy
Journal: Cardiovascular Research (2021)

Abstract Neutrophils, the most abundant of all leucocytes and the first cells to arrive at the sites of sterile inflammation/injury act as a double-edged sword. On one hand, they inflict a significant collateral damage to the tissues and on the other hand, they help facilitate wound healing by a number of mechanisms. Recent studies have drastically changed the perception of neutrophils from being simple one-dimensional cells with an unrestrained mode of action to a cell type that display maturity and complex behaviour. It is now recognized that neutrophils are transcriptionally active and respond to plethora of signals by deploying a wide variety of cargo to influence the activity of other cells in the vicinity. Neutrophils can regulate macrophage behaviour, display innate immune memory, and play a major role in the resolution of inflammation in a context-dependent manner. In this review, we provide an update on the factors that regulate neutrophil production and the emerging dichotomous role of neutrophils in the context of cardiovascular diseases, particularly in atherosclerosis and the ensuing complications, myocardial infarction, and heart failure. Deciphering the complex behaviour of neutrophils during inflammation and resolution may provide novel insights and in turn facilitate the development of potential therapeutic strategies to manage cardiovascular disease.
Prior infection with SARS-CoV-2 WA1/2020 partially protects rhesus macaques against reinfection with B.1.1.7 and B.1.351 variants
Authors: Abishek Chandrashekar, Jinyan Liu, Jingyou Yu, Katherine McMahan, Lisa H. Tostanoski, Catherine Jacob-Dolan, Noe B. Mercado, Tochi Anioke, Aiquan Chang, Sarah Gardner, Victoria M. Giffin, David L. Hope, Felix Nampanya, Shivani Patel, Owen Sanborn, Daniel Sellers, Huahua Wan, Amanda J. Martinot, John J. Baczenas, Shelby L. O’Connor, Laurent Pessaint, Daniel Valentin, Benjamin Espina, Lauren Wattay, Maria G. Ferrari, Renita Brown, Anthony Cook, Deandre Bueno-Wilkerson, Elyse Teow, Hanne Andersen, Mark G. Lewis, Dan H. Barouch
Journal: Science Translational Medicine (2021)

SARS-CoV-2 WA1/2020 infection of rhesus macaques partially protects against reinfection with SARS-CoV-2 variants.
Crosstalk between N6-methyladenosine modification and circular RNAs: current understanding and future directions
Authors: Xin Wang, Rui Ma, Xilin Zhang, Lian Cui, Yangfeng Ding, Weimin Shi, Chunyuan Guo, Yuling Shi
Journal: Molecular Cancer (2021)

Abstract N 6 -methyladenosine (m 6 A) is a prevalent internal modification in eukaryotic RNAs regulated by the so-called “writers”, “erasers”, and “readers”. m 6 A has been demonstrated to exert critical molecular functions in modulating RNA maturation, localization, translation and metabolism, thus playing an essential role in cellular, developmental, and disease processes. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed single-stranded structures generated by back-splicing. CircRNAs also participate in physiological and pathological processes through unique mechanisms. Despite their discovery several years ago, m 6 A and circRNAs has drawn increased research interest due to advances in molecular biology techniques these years. Recently, several scholars have investigated the crosstalk between m 6 A and circRNAs. In this review, we provide an overview of the current knowledge of m 6 A and circRNAs, as well as summarize the crosstalk between these molecules based on existing research. In addition, we present some suggestions for future research perspectives.
Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE
Authors: Muhammad Zaki Hidayatullah Fadlullah, Wen Hao Neo, Michael Lie-a-ling, Roshana Thambyrajah, Rahima Patel, Renaud Mevel, Irène Aksoy, Nam Do Khoa, Pierre Savatier, Laura Fontenille, Syed Murtuza Baker, Magnus Rattray, Valerie Kouskoff, Georges Lacaud
Journal: Blood (2021)

In vitro generation and expansion of hematopoietic stem cells (HSCs) holds great promise for the treatment of any ailment that relies on bone marrow or blood transplantation. To achieve this, it is essential to resolve the molecular and cellular pathways that govern HSC formation in the embryo. HSCs first emerge in the aorta-gonad-mesonephros (AGM) region, where a rare subset of endothelial cells, hemogenic endothelium (HE), undergoes an endothelial-to-hematopoietic transition (EHT). Here, we present full-length single-cell RNA sequencing (scRNA-seq) of the EHT process with a focus on HE and dorsal aorta niche cells. By using Runx1b and Gfi1/1b transgenic reporter mouse models to isolate HE, we uncovered that the pre-HE to HE continuum is specifically marked by angiotensin-I converting enzyme (ACE) expression. We established that HE cells begin to enter the cell cycle near the time of EHT initiation when their morphology still resembles endothelial cells. We further demonstrated that RUNX1 AGM niche cells consist of vascular smooth muscle cells and PDGFRa+ mesenchymal cells and can functionally support hematopoiesis. Overall, our study provides new insights into HE differentiation toward HSC and the role of AGM RUNX1+ niche cells in this process. Our expansive scRNA-seq datasets represents a powerful resource to investigate these processes further.
Functional and Oncological Outcomes After Open Versus Robot-assisted Laparoscopic Radical Prostatectomy for Localised Prostate Cancer: 8-Year Follow-up
Authors: Anna Lantz, David Bock, Olof Akre, Eva Angenete, Anders Bjartell, Stefan Carlsson, Katarina Koss Modig, Martin Nyberg, Karin Stinesen Kollberg, Gunnar Steineck, Johan Stranne, Peter Wiklund, Eva Haglind
Journal: European Urology (2021)

Radical prostatectomy reduces mortality among patients with localised prostate cancer. Evidence on whether different surgical techniques can affect mortality rates is lacking. To evaluate functional and oncological outcomes 8 yr after robot-assisted laparoscopic prostatectomy (RALP) and open retropubic radical prostatectomy (RRP). We enrolled 4003 patients in a prospective, controlled, nonrandomised trial comparing RALP and RRP in 14 Swedish centres between 2008 and 2011. Data for functional outcomes were assessed via validated patient questionnaires administered preoperatively and at 12 and 24 mo and 8 yr after surgery. The primary endpoint was urinary incontinence. Functional outcomes at 8 yr were analysed using the modified Poisson regression approach. Urinary incontinence was not significantly different at 8 yr after surgery between RALP and RRP (27% vs 29%; adjusted risk ratio [aRR] 1.05, 95% confidence interval [CI] 0.90–1.23). Erectile dysfunction was significantly lower in the RALP group (66% vs 70%; aRR 0.93, 95% CI 0.87–0.99). Prostate cancer–specific mortality (PCSM) was significantly lower in the RALP group at 8 yr after surgery (40/2699 vs 25/885; aRR 0.56, 95% CI 0.34–0.93). Differences in oncological outcomes were mainly seen in the group with high D'Amico risk, with a lower risk of positive surgical margins (21% vs 34%), biochemical recurrence (51% vs 69%), and PCSM (14/220 vs 11/77) for RALP versus RRP. The main limitation is the nonrandomised design. In this prospective multicentre controlled trial, PCSM at 8 yr after surgery was lower for RALP in comparison to RRP. A causal relationship between surgical technique and mortality cannot be inferred, but the result confirms that RALP is oncologically safe. Taken together with better short-term results reported elsewhere, our findings confirm that implementation of RALP may continue. Our study comparing two surgical techniques for removal of the prostate for localised prostate cancer shows that a robot-assisted minimally invasive technique is safe in the long term. Together with previous results showing some better short-term effects with this approach, our findings support continued use of robot-assisted surgery.
Retraction Notice to: FoxP3 Acts as a Cotranscription Factor with STAT3 in Tumor-Induced Regulatory T Cells
Authors: Dewan Md Sakib Hossain, Abir K. Panda, Argha Manna, Suchismita Mohanty, Pushpak Bhattacharjee, Sankar Bhattacharyya, Taniya Saha, Sreeparna Chakraborty, Rajiv K. Kar, Tanya Das, Subhrangsu Chatterjee, Gaurisankar Sa
Journal: Immunity (2021)
A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair
Authors: Emilia M. Pulver, Chirantani Mukherjee, Gerarda van de Kamp, Stefan J. Roobol, Magdalena B. Rother, Hanneke van der Gulden, Roebi de Bruijn, Maria Valeria Lattanzio, Eline van der Burg, Anne Paulien Drenth, Nicole S. Verkaik, Kerstin Hahn, Sjoerd Klarenbeek, Renske de Korte-Grimmerink, Marieke van de Ven, Colin E.J. Pritchard, Ivo J. Huijbers, Bing Xia, Dik C. van Gent, Jeroen Essers, Haico van Attikum, Arnab Ray Chaudhuri, Peter Bouwman, Jos Jonkers
Journal: Cancer Research (2021)

Abstract The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. Significance: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. See related commentary by Mishra et al., p. 6080
Abstract 1926: The Incidence, Predictors, and Outcome of Delayed Stent Fracture After Successful Implantation of Sirolimus-Eluting Stents
Authors: Hisashi Umeda, Tomoko Gochi, Mitsunori Iwase, Ryoji Ishiki, Hideo Izawa, Junji Toyama, Toyoaki Murohara
Journal: Circulation (2007)

Background: Recently, stent fracture (SF) of sirolimus-eluting stents (SES) has been shown to be associated with an increased risk of restenosis after SES implantation. We sought to assess the incidence, predictors, and clinical outcome of SF after implantation of SES. Methods: A consecutive series of 430 lesions of 382 patients treated with SES followed by coronary angiography at 6 to 9 months were analyzed. SF was defined as complete transverse liner separation or single or multiple stent strut fracture. Results: At follow up, SF occurred in 33 of 430 lesions (7.7%), and 32 of 382 patients (8.4%). In 23 of 33 lesions (69.7%), SF was found in a single point, whereas SF occurred in 2 or more points per lesion in 10 lesions (30.3%). Minimal lumen diameter was significantly smaller in patients with SF (2.11±0.64 mm vs. 2.52±0.60 mm, P &lt;0.001), presumably due to greater late lumen loss (0.36±0.57 mm vs. 0.08±0.50 mm, P =0.005). Consequently, in-stent restenosis in lesions with SF was observed more frequently than non-SF lesions (15.2% vs. 4.0%, P =0.004). At 450 days, however, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target lesion revascularization) was similar in patients with and without SF (9.1% vs. 7.1%, P =0.722). Multivariable predictors of SF were shown in Figure . Conclusions: The occurrence of SF 6 to 9 months after implantation of SES in consecutive “real-world” patients was relatively common, which did not lead to an increased risk of adverse cardiac events at 450 days. Total stent length, the reduction in the lesion angle by stenting, and lesions located on the right coronary artery were identified as predictors of SF after implantation of SES.
A multiplexed circulating tumor DNA detection platform engineered from 3D-coded interlocked DNA rings
Authors: Sha Yang, Xinyu Zhan, Xiaoqi Tang, Shuang Zhao, Lianyu Yu, Mingxuan Gao, Dan Luo, Yunxia Wang, Kai Chang, Ming Chen
Journal: Bioactive Materials (2021)

Circulating tumor DNA (ctDNA) is a critical biomarker not only important for the early detection of tumors but also invaluable for personalized treatments. Currently ctDNA detection relies on sequencing. Here, a platform termed three-dimensional-coded interlocked DNA rings (3D-coded ID rings) was created for multiplexed ctDNA identification. The ID rings provide a ctDNA recognition ring that is physically interlocked with a reporter ring. The specific binding of ctDNA to the recognition ring initiates target-responsive cutting via a restriction endonuclease; the cutting then triggers rolling circle amplification on the reporter ring. The signals are further integrated with internal 3D codes for multiplexed readouts. ctDNAs from non-invasive clinical specimens including plasma, feces, and urine were detected and validated at a sensitivity much higher than those obtained through sequencing. This 3D-coded ID ring platform can detect any multiple DNA fragments simultaneously without sequencing. We envision that our platform will facilitate the implementation of future personalized/precision medicine.
Disrupted Family Plans and Exacerbated Inequalities Associated With COVID-19 Pandemic
Authors: Philip N. Cohen
Journal: JAMA Network Open (2021)

Linda G. Kahn, PhD, MPH; Leonardo Trasande, MD, MPP; Mengling Liu, PhD; Shilpi S. Mehta-Lee, MD; Sara G. Brubaker, MD, MS; Melanie H. Jacobson, PhD, MPH
Reporting Findings From Mediation Analyses
Authors: Phil B. Fontanarosa
Journal: JAMA (2021)

Hopin Lee, PhD; Aidan G. Cashin, PhD; Sarah E. Lamb, DPhil; Sally Hopewell, DPhil; Stijn Vansteelandt, PhD; Tyler J. VanderWeele, PhD; David P. MacKinnon, PhD; Gemma Mansell, PhD; Gary S. Collins, PhD; Robert M. Golub, MD; James H. McAuley, PhD; AGReMA group; A. Russell Localio, PhD; Ludo van Amelsvoort, PhD; Eliseo Guallar, PhD; Judith Rijnhart, PhD; Kimberley Goldsmith, PhD; Amanda J. Fairchild, PhD; Cara C. Lewis, PhD; Steven J. Kamper, PhD; Christopher M. Williams, PhD; Nicholas Henschke, PhD
Response-guided treatment optimization in the I-SPY2 trial.
Authors: Ebunoluwa Olunuga, Jessica E. Gibbs, Wen Li, Sara Venters, Amy Delson, Angela DeMichele, Claudine Isaacs, Nola M. Hylton, Gabrielle Betty Rocque, Laura Esserman
Journal: Journal of Clinical Oncology (2021)

222 Background: As new tools for prognostic prediction and assessment of treatment response in breast cancer are developed, there is growing interest in treatment optimization strategies to reduce toxic therapy or add additional therapy as needed. The I-SPY 2 trial utilizes a new predictive tool “PreRCB,” which includes mid-treatment MRI and core biopsy responses, to identify patients likely to have a pCR (pathologic complete response) who can de-implement, or forgo, standard-of-care anthracycline-based chemotherapy (AC) after treatment with a taxane + investigational agent. This study assesses initial de-implementation eligibility and selection within the I-SPY2 trial. Methods: All patients enrolled in I-SPY2 since September of 2020 (when the preRCB protocol was first introduced to the trial) who completed the first treatment regimen were evaluated. Patients were only considered for de-implementation of AC if the mid-treatment biopsy was routed to site clinical pathology for review for residual invasive disease. In these patients, preRCB was determined to be predictive of pCR if there was 1) no invasive cancer on the core biopsy and 2) MRI findings met subtype-specific functional tumor volume criteria. Patients meeting criteria for predicted pCR could be offered the option to go directly to surgery by their provider, foregoing pre-operative AC, with the option to receive AC post-operatively should the surgical specimen reveal residual disease. The following outcomes (n,%) were descriptively evaluated: patients participating in I-SPY2, sites with at least one patient evaluated for de-implementation using pre-RCB, patients eligible for de-implementation, patients with surgical RCB assessment, and patients who de-implemented chemotherapy. Results: From September 2020 – May 2021, 145 patients were eligible for analysis. 9/20 (45%) sites with eligible I-SPY patients had at least one patient considered for preRCB assessment. Only 46 patients (32%) had clinical reads on their biopsies, as required for preRCB evaluation. Of these, 48% (14/29) of patients met both MRI and pathology criteria to de-implement AC. However, only seven (50%) of these patients chose to proceed to surgery without preoperative AC. Of those who did not have a predicted pCR using preRBC criteria, 87.5% (28/32) received AC as recommended by the protocol and 12.5% (4/32) did not receive preoperative AC. Conclusions: These pilot results demonstrate slow uptake of this strategy by patients and clinicians. We are currently interviewing patients and physicians to identify and assess facilitators and barriers for patients and physicians to pursue response-guided treatment regimes. Understanding these motivations will create the opportunity to engage site, providers, and patients to engage in research optimizing chemotherapy treatment. Clinical trial information: NCT01042379.