tbuckley/cabot-search huggingface dataset:
Final Analysis of a Trial of M72/AS01<sub>E</sub> Vaccine to Prevent Tuberculosis
Authors: Dereck R. Tait, Mark Hatherill, Olivier Van Der Meeren, Ann M. Ginsberg, Elana Van Brakel, Bruno Salaun, Thomas J. Scriba, Elaine J. Akite, Helen M. Ayles, Anne Bollaerts, Marie-Ange Demoitié, Andreas Diacon, Thomas G. Evans, Paul Gillard, Elizabeth Hellström, James C. Innes, Maria Lempicki, Mookho Malahleha, Neil Martinson, Doris Mesia Vela, Monde Muyoyeta, Videlis Nduba, Thierry G. Pascal, Michele Tameris, Friedrich Thienemann, Robert J. Wilkinson, François Roman
Journal: New England Journal of Medicine (2019)

Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity.
Gilteritinib or Chemotherapy for Relapsed or Refractory <i>FLT3</i>-Mutated AML
Authors: Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Harry P. Erba, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Nahla Hasabou, Xuan Liu, Erkut Bahceci, Mark J. Levis
Journal: New England Journal of Medicine (2019)

Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML.In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
Evolutionary Analyses of Base-Pairing Interactions in DNA and RNA Secondary Structures
Authors: Michael Golden, Benjamin Murrell, Darren Martin, Oliver G Pybus, Jotun Hein
Journal: Molecular Biology and Evolution (2019)

Pairs of nucleotides within functional nucleic acid secondary structures often display evidence of coevolution that is consistent with the maintenance of base-pairing. Here, we introduce a sequence evolution model, MESSI (Modeling the Evolution of Secondary Structure Interactions), that infers coevolution associated with base-paired sites in DNA or RNA sequence alignments. MESSI can estimate coevolution while accounting for an unknown secondary structure. MESSI can also use graphics processing unit parallelism to increase computational speed. We used MESSI to infer coevolution associated with GC, AU (AT in DNA), GU (GT in DNA) pairs in noncoding RNA alignments, and in single-stranded RNA and DNA virus alignments. Estimates of GU pair coevolution were found to be higher at base-paired sites in single-stranded RNA viruses and noncoding RNAs than estimates of GT pair coevolution in single-stranded DNA viruses. A potential biophysical explanation is that GT pairs do not stabilize DNA secondary structures to the same extent that GU pairs do in RNA. Additionally, MESSI estimates the degrees of coevolution at individual base-paired sites in an alignment. These estimates were computed for a SHAPE-MaP-determined HIV-1 NL4-3 RNA secondary structure. We found that estimates of coevolution were more strongly correlated with experimentally determined SHAPE-MaP pairing scores than three nonevolutionary measures of base-pairing covariation. To assist researchers in prioritizing substructures with potential functionality, MESSI automatically ranks substructures by degrees of coevolution at base-paired sites within them. Such a ranking was created for an HIV-1 subtype B alignment, revealing an excess of top-ranking substructures that have been previously identified as having structure-related functional importance, among several uncharacterized top-ranking substructures.
OA02.08 Peritumoral and Intratumoral Radiomic Features Identify Aggressive Screen-Detected Early-Stage Lung Cancers
Authors: J. Perez Morales, I. Tunali, O. Stringfield, S. Eschrich, Y. Balagurunathan, R. Gillies, M. Schabath
Journal: Journal of Thoracic Oncology (2019)
Mental Pain as a Transdiagnostic Patient-Reported Outcome Measure
Authors: Giovanni A. Fava, Elena Tomba, Eva-Lotta Brakemeier, Danilo Carrozzino, Fiammetta Cosci, Ajándék Eöry, Tommaso Leonardi, Isabel Schamong, Jenny Guidi
Journal: Psychotherapy and Psychosomatics (2019)

Patient-reported outcomes (PROs) refer to any report coming directly from patients about how they function or feel in relation to a health condition or its therapy. PROs have been applied in medicine for the assessment of the impact of clinical phenomena. Self-report scales and procedures for assessing physical pain in adults have been developed and used in clinical trials. However, insufficient attention has been dedicated to the assessment of mental pain. The aim of this paper is to outline the implications that assessment of mental pain may entail in psychiatry and medicine, with particular reference to a clinimetric index. A simple 10-item self-rating questionnaire, the Mental Pain Questionnaire (MPQ), encompasses the specific clinical features of mental pain and shows good clinimetric properties (i.e., sensitivity, discriminant and incremental validity). The preliminary data suggest that the MPQ may qualify as a PRO measure to be included in clinical trials. Assessment of mental pain may have important clinical implications in intervention research, both in psychopharmacology and psychotherapy. The transdiagnostic features of mental pain are supported by its association with a number of psychiatric disorders, such as depression, anxiety, eating disorders, as well as borderline personality disorder. Further, addressing mental pain may be an important pathway to prevent and diminish the opioid epidemic. The data summarized here indicate that mental pain can be incorporated into current psychiatric assessment and included as a PRO measure in treatment outcome studies.
Exposure to Bisphenol A and Bisphenol S and Incident Type 2 Diabetes: A Case–Cohort Study in the French Cohort D.E.S.I.R.
Authors: Fanny Rancière, Jérémie Botton, Rémy Slama, Marlène Z. Lacroix, Laurent Debrauwer, Marie Aline Charles, Ronan Roussel, Beverley Balkau, Dianna J. Magliano
Journal: Environmental Health Perspectives (2019)

The question of whether exposure to bisphenol A (BPA) contributes to the development of type 2 diabetes is still unresolved. Most epidemiological evidence on the association between BPA and diabetes is from cross-sectional studies or longitudinal studies with single urinary measurements. No prospective study has examined exposure to BPA analogs such as bisphenol S (BPS) in relation to incident type 2 diabetes.We aimed to investigate whether exposure to BPA and BPS, assessed at up to two time points, was associated with the incidence of type 2 diabetes.We performed a case-cohort study on 755 participants without diabetes at baseline and followed-up over 9 y as part of the French prospective cohort Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.). BPA-glucuronide (BPA-G) and BPS-glucuronide (BPS-G) were assessed in fasting spot urine samples collected during the health examinations at baseline and 3 y later. Associations with incident diabetes were examined using Prentice-weighted Cox regression models adjusted for potential confounders.A total of 201 incident cases of type 2 diabetes were diagnosed over the follow-up, including 30 in the subcohort. Compared with participants with the lowest average BPA exposure (below the first quartile), participants in the second, third, and fourth quartile groups of exposure had a near doubling of the risk of type 2 diabetes, with a hazard ratio (HR) = 2.56 (95% CI: 1.16, 5.65), 2.35 (95% CI: 1.07, 5.15), and 1.56 (95% CI: 0.68, 3.55), respectively. The detection of BPS-G in urine at one or both time points was associated with incident diabetes, with an HR = 2.81 (95% CI: 1.74, 4.53).This study shows positive associations between exposure to BPA and BPS and the incidence of type 2 diabetes, independent of traditional diabetes risk factors. Our results should be confirmed by recent, population-based observational studies in different populations and settings. Overall, these findings raise concerns about using BPS as a BPA substitute. Further research on BPA analogs is warranted. https://doi.org/10.1289/EHP5159.
A phase III randomized, placebo-controlled trial of docetaxel (D) with or without gefitinib (G) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): A trial of the Eastern Cooperative Oncology Group (ECOG)
Authors: A. Argiris, M. Ghebremichael, J. Gilbert, B. Burtness, A. Forastiere
Journal: Journal of Clinical Oncology (2009)

6011 Background: G is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with modest single-agent activity in SCCHN. We hypothesized that the addition of G to D will enhance therapeutic efficacy. Methods: Eligibility criteria included R/M SCCHN; any number of prior regimens (excluding D and EGFR inhibitors); ECOG performance status (PS) 2, if previously untreated, or ECOG PS 0–2, if prior chemotherapy for R/M SCCHN or as part of potentially curative therapy &lt; 6 months (mo) earlier. Patients (pts) were randomly assigned to receive D 35 mg/m 2 IV on days 1,8,15, every 28 days plus placebo (arm A) or the same D regimen plus G 250 mg orally, once daily (arm B) until disease progression. Stratification factors were PS, prior chemotherapy and weight loss. At the time of progression, treatment could be unblinded and, for pts in the placebo arm, single-agent G 250 mg/d initiated. We sought to demonstrate an improvement in median overall survival (OS) from 6 to 8.4 mo (28.6% reduction in HR). A total accrual of 314 eligible pts and 286 failures were needed to attain 80% power with 2.5% type I error. Results: 270 pts were enrolled (arm A, n = 136; arm B, n = 134). The study was terminated at interim analysis in November 2008 because it was highly unlikely that the primary endpoint could be met. 60% of pts had ECOG PS of 2; 72% had prior chemotherapy. 24 pts in arm A received G at progression. Data on subsequent treatment with EGFR inhibitors were not collected. Median OS was 6 mo in arm A versus 6.8 mo in arm B (p = 0.74); HR 1.04 (95% CI, 0.79–1.35). Objective response rate in 168 evaluable pts was 6% in arm A vs. 14% in arm B (p = 0.16). Median time to progression was 2 mo and 3.5 mo (p = 0.03) and median progression-free survival 2.2 mo and 3.3 mo (p = 0.18) in arms A and B, respectively. Common grade 3/4 adverse events (AE) in arm A (n = 121) vs. B (n = 115) were neutropenia 1/2 vs. 2/0; fatigue 16/4 vs. 14/0; diarrhea 3/0 vs. 11/1; nausea 4/1 vs. 5/0; vomiting 4/0 vs. 1/1; pneumonia 8/1 vs. 6/1. There were 2 grade 5 AE in arm A and 5 in arm B. Conclusions: The addition of G to D is well tolerated and improves time to progression but not survival in previously treated and poor PS pts with R/M SCCHN. [Table: see text]
Laparoscopic versus open pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score matching analysis
Authors: Wentao Zhou, Weiwei Jin, Dansong Wang, Chao Lu, Xuefeng Xu, Renchao Zhang, Tiantao Kuang, Yucheng Zhou, Wenchuan Wu, Dayong Jin, Yiping Mou, Wenhui Lou
Journal: Cancer Communications (2019)

A growing body of evidence supports the use of laparoscopic pancreaticoduodenectomy (LPD) as an efficient and feasible surgical technique. However, few studies have investigated its applicability in pancreatic ductal adenocarcinoma (PDAC), and the long-term efficacy of LPD on PDAC remains unclear. This study aimed to compare the short- and long-term outcomes between LPD and open pancreaticoduodenectomy (OPD) for PDAC.The data of patients who had OPD or LPD for PDAC between January 2013 and September 2017 were retrieved. Their postoperative outcomes and survival were compared after propensity score matching.A total of 309 patients were included. After a 2:1 matching, 93 cases in the OPD group and 55 in the LPD group were identified. Delayed gastric emptying (DGE), particularly grade B/C DGE, occurred less frequently in the LPD group than in the OPD group (1.8% vs. 36.6%, P < 0.001; 1.8% vs. 22.6%, P = 0.001). The overall complication rates were significantly lower in the LPD group than in the OPD group (49.1% vs. 71.0%, P = 0.008), whereas the rates of major complications were similar (10.9% vs. 14.0%, P = 0.590). In addition, the median overall survival was comparable between the two groups (20.0 vs. 18.7 months, P = 0.293).LPD was found to be technically feasible with efficacy similar to OPD for patients with PDAC.
A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis
Authors: Carol Robertson-Plouch, John R. Stille, Peng Liu, Claire Smith, Dorothy Brown, Margaret Warner, Leijun Hu, Matthew J. Fisher
Journal: Science Translational Medicine (2019)

An inhibitor of microsomal prostaglandin E synthase-1 demonstrates proof-of-concept clinical efficacy in dogs with osteoarthritis.
A Perspective: Division of Lung Diseases at Fifty
Authors: Gail G. Weinmann, Thomas L. Croxton, Neil R. Aggarwal, Michael J. Twery, James P. Kiley, Neil Aggarwal, Julie Bamdad, Koyeli Banerjee, Karen Bienstock, Marishka Brown, Elisabet Caler, Sandra Colombini-Hatch, Matthew Craig, Thomas Croxton, Jacqueline Ellis, Amy Faiola, Josh Fessel, Michelle Freemer, Weiniu Gan, Peyvand Ghofrani, Anthony Jackson, Roya Kalantari, James Kiley, Marrah Lachowicz-Scroggins, Aaron Laposky, Caron Lee, Sara Lin, Aruna Natarajan, Patricia Noel, Lisa Postow, Antonello Punturieri, Lora A. Reineck, Ann Rothgeb, Barry Schmetter, John Sheridan, Rhonise Simpson, Xenia Tigno, Michael Twery, Lisa Viviano, Louis Vuga, Gail Weinmann, Lei Xiao
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

21-year-old National Heart Institute to become the National Heart and Lung Institute (NHLI) to consolidate pulmonary research from across NIH under one office.Over the last 50 years, this office, which became the Division of Lung Diseases (DLD) in July 1972, has grown from a budget of $5 million to one of $734 million in 2018, has released over 350 initiatives, and has expanded to now fund about 1,800 grants and contracts each year.Simultaneously, attendance at the annual American Thoracic Society meetings has soared from approximately 2,000 in 1969 to over 16,000 in 2017.Many partners and stakeholders have contributed to this growth and progress.This perspective highlights DLD's role among them in implementing a collective and coordinated vision for NIH extramural pulmonary research.From the very beginning, DLD engaged stakeholders for advice on research programs through a series of task forces.The first, convened in 1969, brought together government agencies and professional societies; the second brought together U.S. pulmonary program directors; and a third, chaired by Dr. Claude Lenfant, who had arrived in 1970 as Associate Director for the Lung Programs, focused on respiratory medicine (1).By the time President Richard Nixon signed the National, Heart, Blood Vessels, Lung, and Blood Act in September 1972, DLD had received input from hundreds of stakeholders that established foundational guiding principles for the DLD (2).These early recommendations emphasized the importance of 1) elucidation of basic processes as a key to developing treatments, 2) research that can inform patient care and well-being, 3) partnerships and multidisciplinary teams, 4) training in the latest techniques and their application at the community level, and 5) development of new methods to inform the research of tomorrow.The five research areas outlined in this perspective illustrate the DLD's continued adherence to these principles and its use of focused programs and initiatives to advance pulmonary science and medicine.
MAP9 Loss Triggers Chromosomal Instability, Initiates Colorectal Tumorigenesis, and Is Associated with Poor Survival of Patients with Colorectal Cancer
Authors: Shiyan Wang, Junzhe Huang, Chuangen Li, Liuyang Zhao, Chi Chun Wong, Jianning Zhai, Yunfei Zhou, Wen Deng, Yong Zeng, Shanshan Gao, Yanquan Zhang, Guoping Wang, Xin Yuan Guan, Hong Wei, Sunny H. Wong, Housheng H. He, Jerry W. Shay, Jun Yu
Journal: Clinical Cancer Research (2019)

Chromosomal instability (CIN) is a common phenomenon in colorectal cancer, but its role and underlying cause remain unknown. We have identified that mitotic regulator microtubule-associated protein 9 (MAP9) is a critical regulator of CIN in colorectal cancer. We thus studied the effect of MAP9 loss on colorectal cancer in Map9-knockout mice and in cell lines.We generated colon epithelial-specific Map9-knockout mice and evaluated colorectal cancer development. Effect of Map9 knockout on colorectal cancer progression was determined in chemical or ApcMin/+ -induced colorectal cancer. Molecular mechanism of MAP9 was determined using spectral karyotyping, microtubule assays, and whole-genome sequencing (WGS). Clinical significance of MAP9 was examined in 141 patients with CRC.Spontaneous colonic tumors (9.1%) were developed in colon epithelium-specific Map9-knockout mice at 17 months, but none was observed in wild-type littermates. Map9 deletion accelerated colorectal cancer formation both in ApcMin/+ mice and azoxymethane-treated mice, and reduced survival in ApcMin/+ mice. Mechanistically, MAP9 stabilized microtubules and mediated mitotic spindle assembly. MAP9 also maintained the spindle pole integrity and protected K-fiber from depolymerization at spindle poles. MAP9 loss induced severe mitosis failure, chromosome segregation errors, and aneuploidy, leading to transformation of normal colon epithelial cells. WGS confirmed enhanced CIN in intestinal tumors from Map9 knockout ApcMin/+ mice. In patients with colorectal cancer, MAP9 was frequently silenced and its downregulation was associated with poor survival.MAP9 is a microtubule stabilizer that contributes to spindle stability and inhibits colorectal tumorigenesis, supporting the role of MAP9 as a tumor suppressor for preventing CIN in colorectal cancer.
Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium
Authors: Michael Goggins, Kasper Alexander Overbeek, Randall Brand, Sapna Syngal, Marco Del Chiaro, Detlef K Bartsch, Claudio Bassi, Alfredo Carrato, James Farrell, Elliot K Fishman, Paul Fockens, Thomas M Gress, Jeanin E van Hooft, R H Hruban, Fay Kastrinos, Allison Klein, Anne Marie Lennon, Aimee Lucas, Walter Park, Anil Rustgi, Diane Simeone, Elena Stoffel, Hans F A Vasen, Djuna L Cahen, Marcia Irene Canto, Marco Bruno
Journal: Gut (2019)

The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.