tbuckley/cabot-search huggingface dataset:
Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL
Authors: M. Martin, C. Zielinski, M. Ruiz-Borrego, E. Carrasco, N. Turner, E.M. Ciruelos, M. Muñoz, B. Bermejo, M. Margeli, A. Anton, Z. Kahan, T. Csöszi, M.I. Casas, L. Murillo, S. Morales, E. Alba, E. Gal-Yam, A. Guerrero-Zotano, L. Calvo, J. de la Haba-Rodriguez, M. Ramos, I. Alvarez, A. Garcia-Palomo, C. Huang Bartlett, M. Koehler, R. Caballero, M. Corsaro, X. Huang, J.A. Garcia-Sáenz, J.I. Chacón, C. Swift, C. Thallinger, M. Gil-Gil
Journal: Annals of Oncology (2020)

Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial.PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA.From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85).There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.
A golden age of asthma research
Authors: Paul M. O'Byrne, Ian D. Pavord
Journal: European Respiratory Journal (2020)

<b>There has been an extraordinary increase in the understanding of asthma pathogenesis and treatment over the past decade. The <i>ERJ</i> is launching a series of reviews to highlight these advances in asthma and identify areas that still require investigation.</b>https://bit.ly/2HrPfpO
Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management
Authors: Morie A. Gertz
Journal: American Journal of Hematology (2020)

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients.Age, hemoglobin level, platelet count, β2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes.Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine.Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
Abstract 17068: Do Post-Operative Nitrates Increase Mortality in Non-Cardiac Surgery Patients With Perioperative Myocardial Injury?
Authors: Harsh R Barot, Parag A Chevli, Abhishek Dutta, Padageshwar Sunkara, Geeth Sandeep Nadella, Harsh Barot, Tareq Islam, Daniel Beekman, Chaudry N Majeed, Dipendra Chaudhary, Chi-Cheng Huang
Journal: Circulation (2020)

Introduction: Myocardial injury after noncardiac surgery (MINS) is strongly associated with 30-day mortality, and data on its management is scarce. We hypothesized that postoperative nitrates (Isosorbide mononitrate, Isosorbide dinitrate, and scheduled Nitroglycerine) increase mortality in MINS patients. Methods: We used data from the Wake-Up T2MI registry, which is a single center, retrospective cohort of adults with elevated troponin (cTn) I (&gt;0.04 ng/dL) during hospitalization without acute coronary syndrome in a 2-year period (2009-2010). Cardiac procedures were excluded. Kaplan-Meier curves and a multivariate-adjusted Cox-proportional hazard models were performed to assess all-cause mortality at 90-days and 1-year among patients with and without nitrates upon discharge. Results: Total of 457 MINS patients were included in the final analysis. There was no significant difference in baseline characteristics and peak cTn among patients stratified by nitrates status. Prevalence of mortality in the nitrates group was significantly higher at 90-days (35.7% vs 10%, p = 0.002) and non-significantly higher at 1-year (42.9% vs. 22.4%, p = 0.073) compared to non-nitrates group. Survival benefit was significantly lower in the nitrates group at 90-days (log-rank p = 0.002) and at 1-year (log-rank p = 0.031) (Figure 1). In a multivariate-adjusted model, nitrates had a HR of 3.032 (1.018 - 9.026; p = 0.046) at 90-days and HR of 2.022 (0.809 - 5.054; p = 0.132) at 1-year (Figure 2). Conclusion: Nitrates on discharge were associated with increased mortality at 3-months and at 1-year in MINS patients. Further large-scale studies are required to validate our results.
Implications of Shortened Quarantine Among Household Contacts of Index Patients with Confirmed SARS-CoV-2 Infection — Tennessee and Wisconsin, April–September 2020
Authors: Melissa A. Rolfes, Carlos G. Grijalva, Yuwei Zhu, Huong Q. McLean, Kayla E. Hanson, Edward A. Belongia, Natasha B. Halasa, Ahra Kim, Jennifer Meece, Carrie Reed, H. Keipp Talbot, Alicia M. Fry
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

To prevent further transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), CDC currently recommends that persons who have been in close contact with someone with SARS-CoV-2 infection should quarantine (stay away from other persons) for 14 days after the last known contact.* However, quarantine might be difficult to maintain for a prolonged period. A shorter quarantine might improve compliance, and CDC recommends two options to reduce the duration of quarantine for close contacts without symptoms, based on local circumstances and availability of testing: 1) quarantine can end on day 10 without a test or 2) quarantine can end on day 7 after receiving a negative test result.† However, shorter quarantine might permit ongoing disease transmission from persons who develop symptoms or become infectious near the end of the recommended 14-day period. Interim data from an ongoing study of household transmission of SARS-CoV-2 were analyzed to understand the proportion of household contacts that had detectable virus after a shortened quarantine period. Persons who were household contacts of index patients completed a daily symptom diary and self-collected respiratory specimens for 14 days. Specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR). Among 185 household contacts enrolled, 109 (59%) had detectable SARS-CoV-2 at any time; 76% (83/109) of test results were positive within 7 days, and 86% (94 of 109) were positive within 10 days after the index patient's illness onset date. Among household contacts who received negative SARS-CoV-2 test results and were asymptomatic through day 7, there was an 81% chance (95% confidence interval [CI] = 67%-90%) of remaining asymptomatic and receiving negative RT-PCR test results through day 14; this increased to 93% (95% CI = 78%-98%) for household members who were asymptomatic with negative RT-PCR test results through day 10. Although SARS-CoV-2 quarantine periods shorter than 14 days might be easier to adhere to, there is a potential for onward transmission from household contacts released before day 14.
First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn’s disease: an open-label multicentre randomised controlled trial
Authors: Maria M E Jongsma, Martine A Aardoom, Martinus A Cozijnsen, Merel van Pieterson, Tim de Meij, Michael Groeneweg, Obbe F Norbruis, Victorien M Wolters, Herbert M van Wering, Iva Hojsak, Kaija-Leena Kolho, Thalia Hummel, Janneke Stapelbroek, Cathelijne van der Feen, Patrick F van Rheenen, Michiel P van Wijk, Sarah T A Teklenburg-Roord, Marco W J Schreurs, Dimitris Rizopoulos, Michail Doukas, Johanna C Escher, Janneke N Samsom, Lissy de Ridder
Journal: Gut (2020)

Objective In newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. Design In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3–17 years old, weighted Paediatric CD Activity Index score (wPCDAI) &gt;40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI &lt;12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. Results 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). Conclusions FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. Trial registration number ClinicalTrials.gov Registry ( NCT02517684 ).
Recombinant adeno-associated virus-mediated gene transfer into hematopoietic progenitor cells [published erratum appears in Blood 1995 Feb 1;85(3):862]
Authors: S Goodman, X Xiao, RE Donahue, A Moulton, J Miller, C Walsh, NS Young, RJ Samulski, AW Nienhuis
Journal: Blood (1994)
Prioritizing Family-Centered Mental Health Care for Pediatric Patients With Eating Disorders—Reply
Authors: Matthew G. Biel, Michael H. Tang, Barry Zuckerman
Journal: JAMA Pediatrics (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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Pediatrics journal
Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes
Authors: Shuai Hu, Runhong Han, Long Chen, Weisong Qin, Xiaodong Xu, Jingsong Shi, Xiaodong Zhu, Mingchao Zhang, Caihong Zeng, Zheng Tang, Hao Bao, Zhihong Liu
Journal: The Journal of Experimental Medicine (2020)

Podocyte injury is a common hallmark in various glomerular diseases. The level of LRRC55 was increased in podocytes of patients with focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), and membranous nephropathy (MN). Upregulated LRRC55 and increased intracellular Ca2+ led to BK channel activation and the loss of intracellular potassium, resulting in apoptosome formation and caspase-3 activation in angiotensin II (Ang II)-treated podocytes. Knockout of Lrrc55 or the BK channel prevented the BK current and ameliorated podocyte injury in Ang II-treated mice. Upstream, NFATc3 regulated the expression of LRRC55. Increased LRRC55 expression in podocytes was also evident in animal models of FSGS, DN, and MN. Treatment with losartan or LRRC55 siRNA suppressed LRRC55 expression, prevented BK channel activation, and attenuated podocyte injury in animal models of FSGS, DN, and MN. In conclusion, upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes in FSGS, DN, and MN. LRRC55 inhibition may represent a new therapeutic approach for podocyte injury.
MEK Inhibition Reverses Aberrant Signaling in Melanoma Cells through Reorganization of NRas and BRAF in Self Nanoclusters
Authors: Oren Yakovian, Julia Sajman, Rand Arafeh, Yair Neve-Oz, Michal Alon, Yardena Samuels, Eilon Sherman
Journal: Cancer Research (2020)

Hotspot mutations of the oncogenes BRAF and NRas are the most common genetic alterations in cutaneous melanoma. Still, the nanoscale organization and signal coupling of these proteins remain incompletely understood, particularly upon expression of oncogenic NRas mutants. Here we employed single-molecule localization microscopy to study the nanoscale organization of NRas and BRAF at the plasma membrane (PM) of melanoma cells. NRas and BRAF resided in self-clusters that did not associate well in resting cells. In EGF-activated cells, NRas clusters became more diffused while overall protein levels at the PM increased; thus allowing enhanced association of NRas and BRAF and downstream signaling. In multiple melanoma cell lines, mutant NRas resided in more pronounced self-clusters relative to wild-type (WT) NRas yet associated more with the clustered and more abundant BRAF. In cells resistant to trametinib, a clinical MEK inhibitor (MEKi), a similar coclustering of NRas and BRAF was observed upon EGF activation. Strikingly, treatment of cells expressing mutant NRas with trametinib reversed the effect of mutant NRas expression by restoring the nonoverlapping self-clusters of NRas and BRAF and by reducing their PM levels and elevated pERK levels caused by mutant NRas. Our results indicate a new mechanism for signal regulation of NRas in melanoma through its nanoscale dynamic organization and a new mechanism for MEKi function in melanoma cells carrying NRas mutations but lacking MEK mutations. SIGNIFICANCE: Nanoscale dynamic organization of WT and mutant NRas relative to BRAF serves as a regulatory mechanism for NRas signaling and may be a viable therapeutic target for its sensitivity to MEKi.
Comparing the Approach to Radical Prostatectomy Using the Multiport da Vinci Xi and da Vinci SP Robots: A Propensity Score Analysis of Perioperative Outcomes
Authors: Marcio Covas Moschovas, Seetharam Bhat, Marco Sandri, Travis Rogers, Fikret Onol, Elio Mazzone, Shannon Roof, Alexandre Mottrie, Vipul Patel
Journal: European Urology (2020)
Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy
Authors: Roberta Turiello, Mariaelena Capone, Diana Giannarelli, Elva Morretta, Maria Chiara Monti, Gabriele Madonna, Domenico Mallardo, Lucia Festino, Rosa Azzaro, Mitchell P Levesque, Laurence Imhof, Benjamin Weide, Teresa Amaral, Marc Chevrier, Antje Sucker, Piotr Rutkowski, Dirk Schadendorf, Celeste Lebbe, Jason John Luke, Kilian Wistuba-Hamprecht, Reinhard Dummer, Aldo Pinto, Silvana Morello, Paolo A Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy. Methods Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients. Results Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p&lt;0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001). Conclusion Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.
Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study
Authors: I. Tomos, A. Karakatsani, E.D. Manali, C. Kottaridi, A. Spathis, S. Argentos, S.A. Papiris
Journal: Pulmonology (2020)

Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE).TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls.Seventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035).Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.
Improving clinical trial outcomes in amyotrophic lateral sclerosis
Authors: Matthew C. Kiernan, Steve Vucic, Kevin Talbot, Christopher J. McDermott, Orla Hardiman, Jeremy M. Shefner, Ammar Al-Chalabi, William Huynh, Merit Cudkowicz, Paul Talman, Leonard H. Van den Berg, Thanuja Dharmadasa, Paul Wicks, Claire Reilly, Martin R. Turner
Journal: Nature Reviews Neurology (2020)
Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia
Authors: Charles Craddock, Aimee Jackson, Justin Loke, Shamyla Siddique, Andrea Hodgkinson, John Mason, Georgia Andrew, Sandeep Nagra, Ram Malladi, Andrew Peniket, Maria Gilleece, Rahuman Salim, Eleni Tholouli, Victoria Potter, Charles Crawley, Keith Wheatley, Rachel Protheroe, Paresh Vyas, Ann Hunter, Anne Parker, Keith Wilson, Jiri Pavlu, Jenny Byrne, Richard Dillon, Naeem Khan, Nicholas McCarthy, Sylvie D. Freeman
Journal: Journal of Clinical Oncology (2020)

Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials.
Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial
Authors: Masakazu Toi, Shigeru Imoto, Takanori Ishida, Yoshinori Ito, Hiroji Iwata, Norikazu Masuda, Hirofumi Mukai, Shigehira Saji, Akira Shimizu, Takafumi Ikeda, Hironori Haga, Toshiaki Saeki, Kenjiro Aogi, Tomoharu Sugie, Takayuki Ueno, Takayuki Kinoshita, Yuichiro Kai, Masahiro Kitada, Yasuyuki Sato, Kenjiro Jimbo, Nobuaki Sato, Hiroshi Ishiguro, Masahiro Takada, Yasuo Ohashi, Shinji Ohno
Journal: The Lancet Oncology (2020)