tbuckley/cabot-search huggingface dataset:
Treatment patterns among patients with advanced urothelial carcinoma following discontinuation of PD1/L1 inhibitor therapy.
Authors: Alicia K. Morgans, Simrun Kaur Grewal, Zsolt Hepp, Rupali Fuldeore, Shardul Odak, Cynthia Macahilig, Alicia C. Shillington, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

414 Background: There are a lack of published real-world data on treatment patterns for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) previously treated with programmed death 1/ligand 1 inhibitor (PD-1/L1i) therapy. The objective of this study was to characterize the clinical characteristics and treatments among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1i therapy. Methods: We performed a retrospective chart review at 26 geographically diverse clinical sites in the US. Patients aged ≥18 years with histologically or cytologically confirmed urothelial carcinoma and radiographic evidence of metastatic or locally advanced disease were identified. Included patients had initiated and subsequently discontinued PD-1/L1i therapy in the 1L or 2L setting for la/mUC between May 15, 2016-July 31, 2018. All patients had follow-up through October 31, 2019. Data were summarized using descriptive statistics. Results: Among the 300 patients included in the chart review, 198 (66%) received PD-1/L1i therapy as 1L and 102 (34%) as 2L therapy. Mean (SD) age at la/mUC diagnosis was 69.4 (8.7) years, and a majority of patients were male (66.0%) and White (74.7%). Consistent with age, most patients (82.7%) had comorbidities at la/mUC diagnosis; 39.7% hypertension, 23.7% coronary artery disease, 17.7% pulmonary disease, and 9.3% renal disease. At initiation of therapy, a higher proportion of patients who received 1L PD-1/L1i therapy had an Eastern Cooperative Oncology Group performance status of 2 or more than patients who received 2L PD-1/L1i therapy (36.8% vs 22.5%, respectively). Following discontinuation of PD-1/L1i therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The most common subsequent therapies in 2L were gemcitabine monotherapy (24%), gemcitabine plus cisplatin or carboplatin (22%), PD-1/L1i therapy (22%), and taxane monotherapy (19%). The most common subsequent therapies received in 3L were taxane monotherapy (50%), pemetrexed (17%), and PD-1/L1i therapy (16%). Overall, switching from one PD-1/L1i therapy to another distinct PD-1/L1i therapy occurred in approximately 20% of patients, with “better efficacy/survival” noted by treatment teams as the most common reason for switching therapy among this subgroup. Conclusions: In this real-world case series, only a minority of patients with la/mUC who discontinued PD-1/L1i therapy received subsequent therapy. Among those that did, no clear standard of care was observed and approximately one-fifth of patients were treated with a second PD-1/L1i therapy after the first failed to control disease. Collectively, the data highlight significant unmet need for patients with la/mUC who discontinue PD-1/L1i therapy.
Impact of bridging chemotherapy on clinical outcome of CD19 CAR T therapy in adult acute lymphoblastic leukemia
Authors: Karlo Perica, Jessica Flynn, Kevin J. Curran, Isabelle Rivere, Xiuyan Wang, Brigitte Senechal, Elizabeth Halton, Claudia Diamonte, John Pineda, Yvette Bernal, Mithat Gonen, Michel Sadelain, Renier J. Brentjens, Jae H. Park
Journal: Leukemia (2021)
Covid 19: Why we can’t risk another wave
Authors: Fiona Godlee
Journal: BMJ (2021)

The opening of schools across the UK and elsewhere in the world will bring relief to many families.It will also give children back the educational, social, and safeguarding benefits of interacting with teachers and friends.This is a vital, but still risky, step toward emerging safely from lockdown.Children's futures are not the only things at stake if we get this wrong.
Landscape of circulating tumor DNA (ctDNA) abnormalities in advanced prostate cancer (aPCa): Distinctions in African American (AA) versus Caucasian (Ca) patients.
Authors: Pedro C. Barata, Umang Swami, Adam Kessel, Ellen Jaeger, Sergiusz Wesolowski, Jonathan Chipman, Mehmet Asim Bilen, Elisabeth I. Heath, Lakshminarayanan Nandagopal, Daniel A. Vaena, Benjamin Louis Maughan, Roberto Nussenzveig, Mark Yandell, Manish Kohli, Neeraj Agarwal, Oliver A. Sartor
Journal: Journal of Clinical Oncology (2021)

156 Background: AA have substantially higher prostate cancer incidence rates, are diagnosed at a younger age and with a more advanced stage as compared to Ca. However, after adjusting for known prognostic factors, AA have an increased overall survival. We hypothesized that these differences might be due to the underlying changes in the genomic landscape which can be revealed by liquid biopsy. Methods: Real world comprehensive genomic profiling of ctDNA from aPCa patients from two institutions. The first ctDNA results as reported by Guardant 360 panel (Redwood City, CA) were included. Association between genetic mutation and gene were tested using Barnard’s test. To account for multiple testing, we used Benjamini-Hochberg’s False Discovery Rate adjustment across all tests to determine thresholds for false discovery rates. Same analysis was performed using a Bayesian Network Machine learning approach. Results: Overall, 361 patients with aPCa (81 AA and 280 Ca) were included in the analysis. Pathogenic genomic alterations were found in 87.0% of the cases, more frequently TP53 (42.4%), AR (34.1%), PIK3CA (13.9%), BRAF (12.7%), NF1 (10.8%) and MYC (10.0%). Targetable alterations of interest included DNA repair genes [BRCA 2 (7.8%), BRCA 1 (4.4%), ATM (6.4%), CDK12 (2.2%)], PIK3CA/mTOR/AKT (19.1%), PTEN (3.3%) and NTRK (1.9%). MSI-high was found in 4 patients. AA as compared to Ca had a significantly higher prevalence of CDK12 (20.7% vs. 3.8%, p=0.016) and GNA11 mutations (3.7% vs. 0.4%, p=0.0225). BayesNet analysis also supported these results (table). Conclusions: In this dataset, liquid biopsy of ctDNA was useful for genetic characterization of aPCa and reveal differences in the molecular phenotype of AA and Ca in aPCa with potential clinical implications. These findings support ongoing research on the clinical utility of non-invasive genotyping and therapeutic response monitoring with a focus on AA population. [Table: see text]
Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis based on duration and cycles of 1L chemotherapy.
Authors: Yohann Loriot, Thomas Powles, Miguel Ángel Climent Durán, Srikala S. Sridhar, Joaquim Bellmunt, Daniel Peter Petrylak, Jing Wang, Nuno Matos Costa, Robert J Laliberte, Alessandra Di Pietro, Petros Grivas, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2021)

438 Background: Avelumab 1L maintenance is approved in the United States for patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy based on significantly prolonged overall survival (OS) vs BSC seen in the phase III JAVELIN Bladder 100 trial (NCT02603432). However, optimal duration of 1L chemotherapy is unknown and some patients are unable to receive 6 cycles. We report a post hoc analysis of efficacy by duration or number of cycles of 1L chemotherapy. Methods: Eligible patients with unresectable locally advanced or metastatic UC that had not progressed with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin were randomized to receive maintenance avelumab + BSC or BSC alone within 4-10 weeks. Subgroups were defined by quartiles (Qs) for duration (&lt;Q1 [&lt;15.0 weeks], Q1-Q2 [15.0 to &lt;18.0 weeks], Q2-Q3 [18.0 to &lt;20.1 weeks], and &gt;Q3 [&gt;20.1 weeks]) or estimated number of cycles (4, 5, or 6) of 1L chemotherapy. Duration of chemotherapy included dosing delays/interruptions, and the decision to stop 1L chemotherapy was at the investigator’s discretion. Treatment arms were compared using an unstratified Cox proportional hazards model for OS. The potential impact of baseline characteristics on treatment patterns or dose intensity was not explored. Results: Numbers of patients in 1L chemotherapy subgroups were generally well balanced between arms (Table). An OS benefit was observed for avelumab + BSC vs BSC alone across subgroups with differing durations or cycles of 1L chemotherapy (Table). A progression-free survival benefit was also observed for avelumab + BSC vs BSC alone across subgroups. No significant treatment-by-cycle interaction (at 0.05 level) was observed. Conclusions: Improved OS was observed with avelumab 1L maintenance vs BSC alone irrespective of duration or cycles of 1L chemotherapy received prior to entering the trial. Among patients who stopped 1L chemotherapy prior to 6 cycles, avelumab 1L maintenance still provided an OS benefit. Clinical trial information: NCT02603432 . Research Sponsor: Pfizer Inc, Pharmaceutical/Biotech Company[Table: see text]
Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy
Authors: Biaggio Uricoli, Lacey A. Birnbaum, Priscilla Do, James M. Kelvin, Juhi Jain, Emma Costanza, Andrew Chyong, Christopher C. Porter, Sarwish Rafiq, Erik C. Dreaden
Journal: Advanced Healthcare Materials (2021)

Cytokine signaling is critical to a range of biological processes including cell development, tissue repair, aging, and immunity. In addition to acting as key signal mediators of the immune system, cytokines can also serve as potent immunotherapies with more than 20 recombinant products currently Food and Drug Administration (FDA)-approved to treat conditions including hepatitis, multiple sclerosis, arthritis, and various cancers. Yet despite their biological importance and clinical utility, cytokine immunotherapies suffer from intrinsic challenges that limit their therapeutic potential including poor circulation, systemic toxicity, and low tissue- or cell-specificity. In the past decade in particular, methods have been devised to engineer cytokines in order to overcome such challenges and here, the myriad strategies are reviewed that may be employed in order to improve the therapeutic potential of cytokine and chemokine immunotherapies with applications in cancer and autoimmune disease therapy, as well as tissue engineering and regenerative medicine. For clarity, these strategies are collected and presented as they vary across size scales, ranging from single amino acid substitutions, to larger protein-polymer conjugates, nano/micrometer-scale particles, and macroscale implants. Together, this work aims to provide readers with a timely view of the field of cytokine engineering with an emphasis on early-stage therapeutic approaches.
Para-aminobenzoic acid (PABA) enhances the in-vitro tumor response of ovarian cancer to Topotecan (TTN) through mitochondrial-mediated apoptosis
Authors: Michael T. Buckley, David Newman, Leonard F. Liebes, Elissa L. Kramer, Bruce Ng, James S. Babb, Peter C. Brooks, John P. Curtin
Journal: Cancer Research (2005)

5319  Objectives: We tested the effect of PABA when combined with TTN on ovarian cancer cell proliferation, and generation of reactive oxygen species (ROS) as a marker for mitochondrial-mediated apoptosis. We also examined the effect of duration of exposure to PABA. Methods: SKOV-3 cells were maintained in DMEM media with 10% FBS. 5x103 cells were plated in 96 well plates overnight. Cells were treated with PABA at 100 ug/ml for either 7 or 18 days and were then treated with varying concentrations of TTN (0 to 5uM). At the end of treatment (24 hours), cell proliferation and viability was measured using a Cell Proliferation Assay Kit (Chemicon International, Inc, Temecula, CA). For measurement of ROS, PABA- treated and PABA-free cells were exposed to either 1 or 2.5 uM TTN. Treated cells were incubated in 5 uM dihydroethidine (Molecular Probes, Eugene, OR) at 37°C for 15 min, harvested by trypsinization and washed. ROS generation was determined by measuring the number of ethidium-positive cells via FACS analysis. Mixed model analysis of variance was used to assess the impact of the treatment components on the fraction of cells surviving compared to untreated cells. Results: For both 7 day and 18 day exposure to PABA, and at all concentrations of TTN, PABA caused significantly greater growth inhibition (GI) in the SKOV-3 cells compared to TTN treatment alone (p=0.043). However, the length of exposure to PABA had no significant effect (p=0.807) on GI. There was no statistically significant interaction (p>0.39) between TTN and either PABA (presence versus absence) or length of exposure to PABA (7 versus 18 days) suggesting an absence of synergism between PABA and TTN in SKOV-3 cells. At 1 uM TTN, the GI achieved with 7 days PABA exposure was improved by 18% over TTN alone and for 18 days’exposure by 21% over TTN alone. Five-week treatment of the cells with PABA even without TTN increased the percent of ethidium-positive cells 36-fold from 6.71 ± 0.95 (S.D.) without PABA to 240.24 ± 13.31 with PABA. Treatment with TTN showed no effect on ROS generation. Conclusions: PABA, which has been shown to upregulate cdc25a (Peter Brooks, unpublished data), increases the growth inhibition caused by TTN in ovarian cancer cells. This is associated with an increase in mitochondrial stress in these cells as indicated by an increased ROS generation. This implies that addition of PABA to TTN chemotherapy in ovarian cancer might improve tumor response through mitochondrial-mediated apoptosis. Supported by DOD OC010016 and the Chemotherapy Foundation.
Automated identification of clinical features from sparsely annotated 3-dimensional medical imaging
Authors: Nadav Rakocz, Jeffrey N. Chiang, Muneeswar G. Nittala, Giulia Corradetti, Liran Tiosano, Swetha Velaga, Michael Thompson, Brian L. Hill, Sriram Sankararaman, Jonathan L. Haines, Margaret A. Pericak-Vance, Dwight Stambolian, Srinivas R. Sadda, Eran Halperin
Journal: npj Digital Medicine (2021)

One of the core challenges in applying machine learning and artificial intelligence to medicine is the limited availability of annotated medical data. Unlike in other applications of machine learning, where an abundance of labeled data is available, the labeling and annotation of medical data and images require a major effort of manual work by expert clinicians who do not have the time to annotate manually. In this work, we propose a new deep learning technique (SLIVER-net), to predict clinical features from 3-dimensional volumes using a limited number of manually annotated examples. SLIVER-net is based on transfer learning, where we borrow information about the structure and parameters of the network from publicly available large datasets. Since public volume data are scarce, we use 2D images and account for the 3-dimensional structure using a novel deep learning method which tiles the volume scans, and then adds layers that leverage the 3D structure. In order to illustrate its utility, we apply SLIVER-net to predict risk factors for progression of age-related macular degeneration (AMD), a leading cause of blindness, from optical coherence tomography (OCT) volumes acquired from multiple sites. SLIVER-net successfully predicts these factors despite being trained with a relatively small number of annotated volumes (hundreds) and only dozens of positive training examples. Our empirical evaluation demonstrates that SLIVER-net significantly outperforms standard state-of-the-art deep learning techniques used for medical volumes, and its performance is generalizable as it was validated on an external testing set. In a direct comparison with a clinician panel, we find that SLIVER-net also outperforms junior specialists, and identifies AMD progression risk factors similarly to expert retina specialists.
Correction to: Salinomycin effectively eliminates cancer stem-like cells and obviates hepatic metastasis in uveal melanoma
Authors: Jingfeng Zhou, Shenglan Liu, Yun Wang, Wei Dai, Hailin Zou, Shubo Wang, Jing Zhang, Jingxuan Pan
Journal: Molecular Cancer (2021)

An amendment to this paper has been published and can be accessed via the original article.
Airborne occupational exposures and the risk of developing respiratory symptoms and airway obstruction in the Lifelines Cohort Study
Authors: Md Omar Faruque, H Marike Boezen, Hans Kromhout, Roel Vermeulen, Ute Bültmann, Judith M Vonk
Journal: Thorax (2021)

Objectives To date, only a few studies have investigated the associations between occupational exposures and respiratory outcomes longitudinally in the general population. We investigated the associations between occupational exposures and the development of respiratory symptoms and airway obstruction in the Lifelines Cohort Study. Methods We included 35 739 occupationally active subjects with data on chronic cough, chronic phlegm, chronic bronchitis or airway obstruction at baseline and approximately 4.5 years follow-up. Exposures to biological dust, mineral dust, gases/fumes, pesticides, solvents and metals in the current job at baseline were estimated with the ALOHA+job-exposure matrix (JEM). Airway obstruction was defined as FEV 1 /FVC below the lower limit of normal. Logistic regression analysis adjusted for baseline covariates was used to investigate the associations. Results At follow-up, 1888 (6.0%), 1495 (4.7%), 710 (2.5%) and 508 (4.5%) subjects had developed chronic cough, chronic phlegm, chronic bronchitis and airway obstruction, respectively. High exposure to biological dust was associated with a higher odds to develop chronic cough and chronic bronchitis. High exposure to pesticides was associated with a higher odds for the development of all respiratory symptoms and airway obstruction. In the multiple exposures analyses, only the association between pesticides exposure and respiratory symptoms remained. Conclusions Subjects exposed to high pesticides had a higher odds to develop respiratory symptoms on average 4.5 years later. Control measures should be taken to reduce pesticides exposure among the working population to prevent respiratory symptoms and airway obstruction.
Abstract 11941: Treatment Gap of Primary Prevention Patients Presenting With Acute Coronary Syndrome: Impact of Not Following 2013 American College of Cardiology/American Heart Association Guidelines
Authors: Aakash Bavishi, Travis Howard, JooHo Kim, Brent Hiramoto, Jacob Pierce, Parrykumar Mendapara, Jonathan Alhalel, Han-wei Wu, Neil Stone
Journal: Circulation (2018)

Introduction: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines identified four groups most likely to benefit from statin therapy. Among these were a lower ris...
Prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission
Authors: Mitja Jevnikar, Olivier Sanchez, Richard Chocron, Marc Andronikof, Maurice Raphael, Olivier Meyrignac, Laure Fournier, David Montani, Benjamin Planquette, Mary Soudani, Athénaïs Boucly, Jeremie Pichon, Mariana Preda, Antoine Beurnier, Sophie Bulifon, Andrei Seferian, Xavier Jaïs, Olivier Sitbon, Laurent Savale, Marc Humbert, Florence Parent
Journal: European Respiratory Journal (2021)

A high prevalence of venous thromboembolism (VTE) has been reported during intensive care unit (ICU) hospitalisation in patients with severe coronavirus disease 2019 (COVID-19) [1, 2]. In most cases, the diagnosis of pulmonary embolism (PE) was incidental as patients underwent computed tomography pulmonary angiography (CTPA) for aggravation of their respiratory condition. Higher mortality is also described in patients with high D-dimer levels suggesting that VTE complication may contribute to unfavourable prognosis [3, 4]. Even though, prevalence of thromboembolic complications during ICU hospitalisation seems to be high, the prevalence of pulmonary embolism at hospital admission for COVID-19 is unknown and may be underestimated. There is a high prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission <https://bit.ly/3reaLjv>
Reply: Fixed breathing protocols in multiple-breath-washout testing: truly an option in children?
Authors: Sylvia Verbanck, Daniel Schuermans, Manuel Paiva, Paul D. Robinson, Eef Vanderhelst
Journal: European Respiratory Journal (2021)

We agree with the challenges discussed by A-C. Kentgens and co-workers for the adoption of fixed breathing protocols outside the adult range assessed in our study, but we want to clarify that we were not recommending imposing 1 L breathing outside the age range studied [1]. The main intention of our research letter was to illustrate the impact of different breathing protocols on variability of multiple breath washout (MBW) outcomes by choosing a cohort where both protocols were readily feasible. By expressing the tidal volume ( V T) dependence that we observed in adults in terms of mL·kg−1, we then aimed to make observations about whether the pronounced variability shown with tidal breathing may affect existing paediatric data. Consistent with a concurrent publication by Handley et al . Adult studies point to two sources of lung clearance index variability that could be explored to improve LCI sensitivity <https://bit.ly/36o>RJ1I
An emergent neural coactivity code for dynamic memory
Authors: Mohamady El-Gaby, Hayley M. Reeve, Vítor Lopes-dos-Santos, Natalia Campo-Urriza, Pavel V. Perestenko, Alexander Morley, Lauren A. M. Strickland, István P. Lukács, Ole Paulsen, David Dupret
Journal: Nature Neuroscience (2021)
Generation of Pulmonary Endothelial Progenitor Cells for Cell-based Therapy Using Interspecies Mouse–Rat Chimeras
Authors: Guolun Wang, Bingqiang Wen, Xiaomeng Ren, Enhong Li, Yufang Zhang, Minzhe Guo, Yan Xu, Jeffrey A. Whitsett, Tanya V. Kalin, Vladimir V. Kalinichenko
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Although pulmonary endothelial progenitor cells (EPCs) hold promise for cell-based therapies for neonatal pulmonary disorders, whether EPCs can be derived from pluripotent embryonic stem cells (ESCs) or induced pluripotent stem cells remains unknown.Objectives: To investigate the heterogeneity of pulmonary EPCs and derive functional EPCs from pluripotent ESCs.Methods: Single-cell RNA sequencing of neonatal human and mouse lung was used to identify the heterogeneity of pulmonary EPCs. CRISPR/Cas9 gene editing was used to genetically label and purify mouse pulmonary EPCs. Functional properties of the EPCs were assessed after cell transplantation into neonatal mice with S52F Foxf1 mutation, a mouse model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interspecies mouse–rat chimeras were produced through blastocyst complementation to generate EPCs from pluripotent ESCs for cell therapy in ACDMPV mice.Measurements and Main Results: We identified a unique population of EPCs, FOXF1+cKIT+ EPCs, as a subset of recently described general capillary cells (gCAPs) expressing SMAD7, ZBTB20, NFIA, and DLL4 but lacking mature arterial, venous, and lymphatic markers. FOXF1+cKIT+ gCAPs are reduced in ACDMPV, and their transcriptomic signature is conserved in mouse and human lungs. After cell transplantation into the neonatal circulation of ACDMPV mice, FOXF1+cKIT+ gCAPs engraft into the pulmonary vasculature, stimulate angiogenesis, improve oxygenation, and prevent alveolar simplification. FOXF1+cKIT+ gCAPs, produced from ESCs in interspecies chimeras, are fully competent to stimulate neonatal lung angiogenesis and alveolarization in ACDMPV mice.Conclusions: Cell-based therapy using donor or ESC/induced pluripotent stem cell–derived FOXF1+cKIT+ endothelial progenitors may be considered for treatment of human ACDMPV.