tbuckley/cabot-search huggingface dataset:
Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two <i>F508del</i> Alleles
Authors: Simon Y. Graeber, Constanze Vitzthum, Sophia T. Pallenberg, Lutz Naehrlich, Mirjam Stahl, Alexander Rohrbach, Marika Drescher, Rebecca Minso, Felix C. Ringshausen, Claudia Rueckes-Nilges, Jan Klajda, Julian Berges, Yin Yu, Heike Scheuermann, Stephanie Hirtz, Olaf Sommerburg, Anna-Maria Dittrich, Burkhard Tümmler, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. Methods: This prospective, observational, multicenter study assessed clinical outcomes including FEV1% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8–16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5–72.4; P < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1–57.6; P < 0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl− secretion to a level of 47.4% of normal (IQR, 19.3–69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7–66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers
Authors: Lingling Zhu, Jiewei Liu, Jiang Chen, Qinghua Zhou
Journal: Journal of Hematology & Oncology (2021)

The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.
19P Therapeutic targets in non-small cell lung cancer: Preclinical and human studies of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression and its associated molecular landscape
Authors: J. Adam, A-M. Lefebvre, C. Nicolazzi, C. Larois, F. Attenot, F. Falda-Buscaiot, C. Dib, N. Ternès, N. Masson, A-L. Bauchet, B. Demers, M. Chadjaa, S. Sidhu, C. Combeau, J-C. Soria, J-Y. Scoazec, S. Naimi, E. Angevin, M. Chiron, C. Henry
Journal: Annals of Oncology (2021)
7P Distinct immune gene programs associated with host tumor immunity, neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC
Authors: P. Rocha, J. Zhang, R. Laza-Briviesca, A. Cruz-Bermúdez, K. Yoshimura, C. Behrens, A. Pataer, E.R. Parra, C. Haymaker, J. Fujimoto, S.G. Swisher, J.V. Heymach, D.L. Gibbons, J.J. Lee, B. Sepesi, T. Cascone, L.M. Solis, M. Provencio, H. Kadara, I.I. Wistuba
Journal: Annals of Oncology (2021)
Making Sense of Milestones Data—Guiding Residents or Assessing Training Programs?
Authors: Karen E. Hauer, Patricia S. O’Sullivan
Journal: JAMA Network Open (2021)

Competencies and milestones are intended to fulfill the aim of outcomes-based education, in which desired outcomes of training, rather than content or hours in particular rotations, drive curriculum planning.Introduced in 2013, the Milestones program explicates performance within the 6 Accreditation Council for Graduate Medical Education (ACGME) competencies.Whereas competencies identify outcomes deemed essential for practice across specialties, Milestones elaborate specialty-specific skills, knowledge, and behaviors indicating progression within each competency.Park et al 1 examined national Milestone ratings of family medicine (FM) residents to investigate the reliability of Milestones data, evaluate learner-and program-level effects, and identify potential learning trajectories for each subcompetency.This analysis benefits from a large data set and harnesses opportunities for learning analytics based on ratings for 22 subcompetency
157P Surufatinib plus toripalimab in patients with advanced small cell lung cancer (SCLC) after failure of first-line systemic chemotherapy
Authors: Y. Cheng, L. Shen, X. Yu, Z. Chen, L. Song, Y. Zhang, C. Wu, M. Lu, H. Gao, W. Chen, M. Yang, Y. Ma, J. Zhou, H. Shi, P. Tan, S. Fan, W. Su
Journal: Annals of Oncology (2021)
Genetic Ablation of Nuclear Receptor Interacting Protein 1 (NRIP1) Sensitizes Acute Myeloid Leukemia Cells to Retinoic Acids
Authors: Raveen Stephen Stallon Illangeswaran, Sreeja Karathedath, Abhirup Bagchi, Bharathi M Rajamani, Balaji Balakrishnan, Vikram Mathews, Shaji Ramachandran Velayudhan, Poonkuzhali Balasubramanian
Journal: Blood (2021)
Abstract 11036: Enhanced Oxygen Utilization Efficiency with Concomitant Activation of the AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knock-Out Mice
Authors: Jeejabai Radhakrishnan, Alvin Baetiong, Raul J Gazmuri
Journal: Circulation (2021)

We have previously reported in HEK 293T cells and in constitutive cyclophilin-D (Cyp-D) knock-out (KO) mice that Cyp-D ablation downregulates oxygen consumption (VO 2 ) and triggers an adaptive response that manifests in higher exercise endurance with less VO 2 . This adaptive response involves a metabolic switch toward preferential utilization of glucose via the AMPK-TBC1D1 signaling nexus. We now investigated whether a similar response could be triggered in mice after acute ablation of Cyp-D using conditional KO (CKO) mice by subjecting them to treadmill exercise involving five running sessions. At their first treadmill running session, CKO mice and controls had comparable VO 2 (208.4±17.9 vs 209.1±16.8 ml/kg·min -1 ), VCO 2 (183.6±17.2 vs 184.8±16.9 ml/kg·min -1 ), and RER (0.88±0.043 vs 0.88±0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO 2 (genotype &amp; session interaction p&lt;0.001) with less prominent reduction in VCO 2 resulting in significantly increased RER (genotype &amp; session interaction p=0.013). The increase in RER was consistent with preferential utilization of glucose as respiratory substrate (4.6±0.8 vs 4.0± 0.9 mg/min, p=0.003). CKO mice also performed a significantly higher treadmill work for given VO 2 expressed as a power/VO 2 ratio (7.4±0.2 x 10 -3 vs 6.7±0.2 10 -3 ratio, p=0.025). Analysis of CKO skeletal muscle tissue after completion of five treadmill running sessions showed enhanced AMPK activation (0.669±0.06 vs 0.409±0.11 pAMPK/β-tubulin ratio, p=0.005) and TBC1D1 inactivation (0.877±0.16 vs 0.565±0.09 pTBC1D1/β-tubulin ratio, p&lt;0.05) accompanied by increased glucose transporter-4 levels consistent with activation of the AMPK-TBC1D1 signaling nexus enabling increased glucose utilization. Taken together, our study demonstrates that like constitutive Cyp-D ablation, acute Cyp-D ablation also induces a state of increased O 2 utilization efficiency, paving the way for exploring the use of a pharmacological approach to elicit the same response, which could be beneficial under O 2 limiting conditions.
NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies
Authors: Marina Konopleva, Nitin Jain, Courtney L Andersen, Natalia Couto Francisco, Nairouz Elgeioushi, Rosalind Hobson, Martin Scott, John Stone, Shringi Sharma, Pablo Morentin Gutierrez, Raoul Tibes, Barry Davies, Thomas Winkler, Giulia Fabbri, Fathima Zumla Cader, Nicole McNeer
Journal: Blood (2021)
Population study of the gut microbiome: associations with diet, lifestyle, and cardiometabolic disease
Authors: Rebecca L. Walker, Hera Vlamakis, Jonathan Wei Jie Lee, Luke A. Besse, Vanessa Xanthakis, Ramachandran S. Vasan, Stanley Y. Shaw, Ramnik J. Xavier
Journal: Genome Medicine (2021)

The human gut harbors trillions of microbes that play dynamic roles in health. While the microbiome contributes to many cardiometabolic traits by modulating host inflammation and metabolism, there is an incomplete understanding regarding the extent that and mechanisms by which individual microbes impact risk and development of cardiovascular disease (CVD). The Framingham Heart Study (FHS) is a multi-generational observational study following participants over decades to identify risk factors for CVD by correlating genetic and phenotypic factors with clinical outcomes. As a large-scale population-based cohort with extensive clinical phenotyping, FHS provides a rich landscape to explore the relationships between the gut microbiome and cardiometabolic traits.We performed 16S rRNA gene sequencing on stool from 1423 participants of the FHS Generation 3, OMNI2, and New Offspring Spouse cohorts. Data processing and taxonomic assignment were performed with the 16S bioBakery workflow using the UPARSE pipeline. We conducted statistical analyses to investigate trends in overall microbiome composition and diversity in relation to disease states and systematically examined taxonomic associations with a variety of clinical traits, disease phenotypes, clinical blood markers, and medications.We demonstrate that overall microbial diversity decreases with increasing 10-year CVD risk and body mass index measures. We link lifestyle factors, especially diet and exercise, to microbial diversity. Our association analyses reveal both known and unreported microbial associations with CVD and diabetes, related prescription medications, as well as many anthropometric and blood test measurements. In particular, we observe a set of microbial species that demonstrate significant associations with CVD risk, metabolic syndrome, and type 2 diabetes as well as a number of shared associations between microbial species and cardiometabolic subphenotypes.The identification of significant microbial taxa associated with prevalent CVD and diabetes, as well as risk for developing CVD, adds to increasing evidence that the microbiome may contribute to CVD pathogenesis. Our findings support new hypothesis generation around shared microbe-mediated mechanisms that influence metabolic syndrome, diabetes, and CVD risk. Further investigation of the gut microbiomes of CVD patients in a targeted manner may elucidate microbial mechanisms with diagnostic and therapeutic implications.
Patent Foramen Ovale Closure—Harnessing Clinical Trial Evidence to Inform Individualized Treatment Decisions
Authors: Robert W. Yeh, Doreen DeFaria Yeh
Journal: JAMA (2021)

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Abstract 12349: Rehabilitation Reduces Depression After Cardiac Arrest
Authors: Katharyn L Flickinger, Melissa Repine, Kara Deliman, Elizabeth R Skidmore, Jon Rittenberger, Jonathan D Ledyard, Adam N Frisch, Clifton W CALLAWAY, Jonathan Elmer
Journal: Circulation (2021)

Introduction: Over 70,000 Americans are discharged from the hospital after surviving cardiac arrest (CA) each year. CA survivors experience depressive symptoms that adversely affect quality of life. Exercise, facilitated through cardiac rehabilitation (CR), improves mood after traumatic brain injury. CR is inconsistently offered to CA survivors but may improve recovery. Aims: Determine if: 1) CA survivors receiving CR have less severe depressive symptoms than CA survivors who do not receive CR, and 2) CA survivors receiving CR have less severe depressive symptoms after CR than before. Methods: Chart review including CA survivors between 2016-2019 who received CR or were enrolled in the control arm of a randomized trial in which depression was assessed prospectively. Demographic and cardiac arrest characteristics were recorded for all patients. The Patient Health Questionnaire (PHQ-9) used to quantify depressive symptoms in CR participants at the beginning and end of 12-36 sessions of CR. PHQ-9 was also assessed 6 months after hospital discharge in control subjects. We compared PHQ-9 within and between groups using t-tests. Results: We included 25 patients (15 male), with mean age 54 (SD 17) years, 16 of whom CR and 9 of whom were enrolled in the trial’s control arm. In patients who received CR, PHQ-9 score decreased from a mean of 5 (SD 5) before CR to mean of 1 (SD 1) after CR [difference -4 (95% CI -4 to -1; p=0.01)]. Among patients who received CR, mean PHQ-9 after CR was lower than that of controls 6 months after discharge [control group mean 6 (SD 5); difference -5 (95% CI -9 to -2; p=0.001)]. Conclusions: CR may improve depressive symptoms in CA survivors. Future studies should investigate other benefits, dose-response and optimal timing of CR.
Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline
Authors: Nimish A. Mohile, Hans Messersmith, Na Tosha Gatson, Andreas F. Hottinger, Andrew Lassman, Jordan Morton, Douglas Ney, Phioanh Leia Nghiemphu, Adriana Olar, Jeffery Olson, James Perry, Jana Portnow, David Schiff, Anne Shannon, Helen A. Shih, Roy Strowd, Martin van den Bent, Mateo Ziu, Jaishri Blakeley
Journal: Journal of Clinical Oncology (2021)

To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults.ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature.Fifty-nine randomized trials focusing on therapeutic management were identified.Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.
Correction: <i>Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer</i>
Journal: Journal for ImmunoTherapy of Cancer (2021)

On August 27, 2021, the indication for atezolizumab in combination with nab-paclitaxel as treatment for patients with triple-negative breast cancer (TNBC) whose tumors express PD-L1 was voluntarily withdrawn by the manufacturer.According to the press release announcing the withdrawal, the decision was not related to any changes in either the efficacy or safety associated with atezolizumab but rather to recent changes in the treatment landscape for TNBC.In light of the withdrawal, 'Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer' has been updated.The following changes have been made to the manuscript.Amendments to the original text are shown in italics.The amendments below are grouped by the sections in which they appear in the order of the original publication.The updated text now reads: 'At the time of publication, two ICIs were FDAapproved specifically for the treatment of advanced/metastatic TNBC: atezolizumab and pembrolizumab.The indication for atezolizumab was withdrawn in 2021.Both breast cancer-specific approvals were for ICIs given in combination with cytotoxic Correction
Communication and Remote Care Delivery for an Aging Population With Kidney Disease
Authors: Devika Nair
Journal: JAMA Network Open (2021)

Keren Ladin, PhD, MSc; Thalia Porteny, PhD, MSc; Julia M. Perugini; Kristina M. Gonzales, BS; Kate E. Aufort, BS; Sarah K. Levine, BA; John B. Wong, MD; Tamara Isakova, MD; Dena Rifkin, MD; Elisa J. Gordon, PhD, MPH; Ana Rossi, MD; Susan Koch-Weser, ScD; Daniel E. Weiner, MD, MS
Routine universal testing versus selective or incidental testing for oropharyngeal Chlamydia trachomatis in women in the Netherlands: a retrospective cohort study
Authors: Ymke J Evers, Geneviève A F S van Liere, Nicole H T M Dukers-Muijrers, Jan van Bergen, Sophie Kuizenga-Wessel, Christian J P A Hoebe
Journal: The Lancet Infectious Diseases (2021)
Genomic and Immune Signatures Predict Sustained MRD Negativity in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone (D-KRd)
Authors: Francesco Maura, Eileen M Boyle, Benjamin Diamond, Patrick Blaney, Hussein Ghamlouch, Bachisio Ziccheddu, Yubao Wang, Kylee H Maclachlan, James E. Hoffman, Hani Hassoun, Sham Mailankody, Urvi A Shah, Carlyn Tan, Malin Hultcrantz, Michael Scordo, Dickran Kazandjian, Gunjan L Shah, Heather J Landau, David J. Chung, Sergio Giralt, Benedetto Bruno, Yanming Zhang, Arnaldo A Arbini, Ahmet Dogan, Alexander Lesokhin, Faith E Davies, Neha Korde, Gareth J Morgan, Ola Landgren
Journal: Blood (2021)
Abstract 9934: High Mean Arterial Pressure Aggravates Cerebral Hemodynamics After Extracorporeal Resuscitation in Swine
Authors: Yael Levy, Alice Hutin, Nicolas Polge, fanny lidouren, Matthias Kohlhauer, Rocio Fernandez Para, Pierre-Louis Leger, Guillaume Debaty, Keith G Lurie, Lionel Lamhaut, Bijan Ghaleh, Renaud Tissier
Journal: Circulation (2021)

Introduction: Extracorporeal cardiopulmonary resuscitation (E-CPR) is used for the treatment of refractory cardiac arrest but the optimal target to reach for mean arterial pressure (MAP) remains to be determined. Hypothesis: We hypothesized that MAP levels modify cerebral hemodynamics during E-CPR. Accordingly, we tested two MAP targets (65-75 vs 80-90 mmHg) in a porcine model of E-CPR. Methods: Pigs were anesthetized and instrumented for the evaluation of cerebral and systemic hemodynamics. They were submitted to 15 min of untreated ventricular fibrillation followed by 30 min of E-CPR. Electric attempts of defibrillation were then delivered until resumption of spontaneous circulation (ROSC). Extracorporeal circulation was initially set to an average flow of 40 ml/kg/min with a standardized volume expansion in both groups. The dose of epinephrine was set to reach either a standard or a high MAP target level (65-75 vs 80-90 mmHg, respectively). Animals were followed during 120 min after ROSC. Results: Six animals were included in both groups. After cardiac arrest, MAP was maintained at the expected level (Figure). During E-CPR, high MAP transiently improved carotid blood flow as compared to standard MAP. This blood flow progressively decreased after ROSC in high vs standard MAP, while intra-cranial pressure increased. Interestingly, this was associated with a significant decrease in cerebral oxygen consumption (26±8 vs 54±6 L O 2 /min/kg at 120 min after ROSC, respectively; p&lt;0.01) (Figure). The pressure reactivity index (PRx), which is the correlation coefficient between arterial blood pressure and intracranial pressure, became positive in high MAP (0.47±0.02) vs standard MAP group (-0.16±0.10), demonstrating altered cerebral autoregulation with high MAP. Conclusion: Increasing MAP above 80 mmHg with epinephrine aggravates cerebral hemodynamics after E-CPR. Figure: Mean arterial pressure (MAP), cerebral blood flow and oxygen consumption (*, p&lt;0.05)