tbuckley/cabot-search huggingface dataset:
Phase I results from a phase I/II study of orteronel, an oral, investigational, nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniel Peter Petrylak, Jitendra G. Gandhi, William R. Clark, Elisabeth I. Heath, Jianqing Lin, William K. Oh, David B. Agus, Omer Kucuk, Susan Moran, Jingyuan Wang, Michael Bargfrede, Glenn Liu
Journal: Journal of Clinical Oncology (2012)

4656 Background: The investigational agent orteronel (ortl, TAK-700) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is standard chemotherapy in mCRPC, this phase 1/2 study examined ortl + DP in men with mCRPC. Methods: The primary phase I objective was to determine the maximum dose of ortl 200–400 mg BID that can be administered safely with DP in castrate men (testosterone [T] &lt;50 ng/dL) with mCRPC, ≤1 prior chemotherapy and no ketoconazole/abiraterone ≤30 d prior. A 3+3 dose escalation was used with ortl 200 then 400 mg BID. Ortl dosed daily and D (75 mg/m 2 q3w) + P (5 mg BID) was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. Results: 14 men, median age 68 yrs (range 53–81), ECOG PS 0/1 (71%/29%), median PSA 59.4 ng/mL (5.2–1052), T 8.1 ng/dL (1.2–16.7), 9 with measurable disease, were treated. Median ortl exposure was 33.3 wks (6.3–59); 6 and 8 men received ortl 200 and 400 mg BID + DP, in cohorts 1 and 2, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 (2 x 3 pts); in cohort 2 (2 x 4 pts), 1 pt in group 1 had DLT (Gr3 related febrile neutropenia); no DLTs occurred in group 2. 3 pts discontinued due to AEs (2 D infusion reactions, 1 at each dose; 1 unrelated cardiorespiratory death at 200 mg). All men had at least 1 AE Gr ≥3 which were treatment-related in 11 men. The most common Gr ≥3 AEs were seen at both doses and included neutropenia 50% (n = 7), hyperglycemia 21% (n = 3), febrile neutropenia, infusion reaction, hyponatremia, decreased neutrophil count (2 each); at 400 mg only: fatigue, hypophosphatemia, and decreased WBC count (2 each). 7 men had serious AEs (SAEs), which were drug-related in 5. The most common SAE was febrile neutropenia in 2 men. At 3 mo, PSA50 and PSA90 rates were 86% and 36%, respectively; 12/14 men had a median PSA decline ≥70%; and median T declined to ≤0.2 ng/dL (0–10.7). The C max of D + ortl was similar to D alone. Conclusions: Ortl 200 mg and 400 mg BID + DP appears safe and tolerable with androgen-lowering activity at the maximum planned dose in mCRPC. There is no evidence of AE potentiation when ortl is administered with DP. The phase II portion of the study will use ortl 400 mg BID + DP.
The CXCL9 Polymorphism rs884304 Associates with Early CXCL9 Reconstitution and with Severe Chronic Graft-Versus-Host Disease (cGVHD) in Human Allograft Recipients
Authors: Hao Dai, Sivaramakrishna P. Rachakonda, Olaf Penack, Aleksandar Radujkovic, Carsten Müller-Tidow, Rajiv Kumar, Peter Dreger, Thomas Luft
Journal: Blood (2019)
Resequencing of 683 common bean genotypes identifies yield component trait associations across a north–south cline
Authors: Jing Wu, Lanfen Wang, Junjie Fu, Jibao Chen, Shuhong Wei, Shilong Zhang, Jie Zhang, Yongsheng Tang, Mingli Chen, Jifeng Zhu, Lei Lei, Qinghe Geng, Chunliang Liu, Lei Wu, Xiaoming Li, Xiaoli Wang, Qiang Wang, Zhaoli Wang, Shilai Xing, Haikuan Zhang, Matthew W. Blair, Shumin Wang
Journal: Nature Genetics (2019)
Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Transfusion-Dependent β-Thalassemia Treated at the Bambino Gesù Children's Hospital, Rome, Italy
Authors: Pietro Merli, Annalisa Ruggeri, Mattia Algeri, Giuseppina Li Pira, Giulia Ceglie, Katiana Gruppioni, Sanjeev Kommera, Jenfue Maa, Franco Locatelli
Journal: Blood (2019)
The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)
Authors: Brian I. Rini, Dena Battle, Robert A. Figlin, Daniel J. George, Hans Hammers, Tom Hutson, Eric Jonasch, Richard W. Joseph, David F. McDermott, Robert J. Motzer, Sumanta K. Pal, Allan J. Pantuck, David I. Quinn, Virginia Seery, Martin H. Voss, Christopher G. Wood, Laura S. Wood, Michael B. Atkins
Journal: Journal for ImmunoTherapy of Cancer (2019)

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.
Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit
Authors: Francesco Cucco, Sharon Barrans, Chulin Sha, Alexandra Clipson, Simon Crouch, Rachel Dobson, Zi Chen, Joe Sneath Thompson, Matthew A. Care, Thomas Cummin, Josh Caddy, Hongxiang Liu, Anne Robinson, Anna Schuh, Jude Fitzgibbon, Daniel Painter, Alexandra Smith, Eve Roman, Reuben Tooze, Catherine Burton, Andrew J. Davies, David R. Westhead, Peter W. M. Johnson, Ming-Qing Du
Journal: Leukemia (2019)

Abstract Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC / BCL2 double-hit ( MYC / BCL2 -DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC / BCL2 -DH ( n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC / BCL2 -DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC / BCL2 -DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.
Checkpoint inhibitors and conventional therapy for central nervous system lymphoma
Authors: D.I. Shmidt, A.N. Gavrilenko, A.Y. Polushin, E. Kondakova, K. Lepik, N. Medvedeva, A. Klimovich, Y. Zalyalov, N. Mikhaylova, B. Afanasyev
Journal: Annals of Oncology (2019)
Chili Pepper Consumption and Mortality in Italian Adults
Authors: Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Emilia Ruggiero, Amalia De Curtis, Mariarosaria Persichillo, Claudio Tabolacci, Francesco Facchiano, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello, Licia Iacoviello, Giovanni de Gaetano, Maria Benedetta Donati, Licia Iacoviello, Marialaura Bonaccio, Americo Bonanni, Chiara Cerletti, Simona Costanzo, Amalia De Curtis, Giovanni de Gaetano, Augusto Di Castelnuovo, Maria Benedetta Donati, Francesco Gianfagna, Mariarosaria Persichillo, Teresa Di Prospero, Jos Vermylen, Ignacio De Paula Carrasco, Simona Giampaoli, Antonio Spagnuolo, Deodato Assanelli, Vincenzo Centritto, Simona Costanzo, Marco Olivieri, Marco Olivieri, Augusto Di Castelnuovo, Marialaura Bonaccio, Simona Costanzo, Alessandro Gialluisi, Francesco Gianfagna°, Emilia Ruggiero, Amalia De Curtis, Sara Magnacca, Benedetta Izzi, Francesco Gianfagna, Annalisa Marotta, Fabrizia Noro, Americo Bonanni, Francesca De Lucia, Mariarosaria Persichillo, Francesca Bracone, Francesca De Lucia, Salvatore Dudiez, Livia Rago, Livia Rago, Simona Costanzo, Amalia De Curtis, Licia Iacoviello, Teresa Panzera, Mariarosaria Persichillo
Journal: Journal of the American College of Cardiology (2019)
Insulin Dosing for Fat and Protein: Is it Time?
Authors: Carmel E.M. Smart, Bruce R. King, Prudence E. Lopez
Journal: Diabetes Care (2019)

The impact of dietary fat and protein on postprandial glycemia in type 1 diabetes (T1D) and the need to adjust for them in the mealtime insulin dose have been controversial (1,2). Recently, carefully designed randomized trials in individuals living with T1D have shown protein and fat consumed in meals with carbohydrate reduce the early postprandial rise (1–2 h) and contribute to postprandial hyperglycemia in the late (3–6 h) postprandial period (3–5). In clinical practice, continuous glucose monitoring highlights the glycemic effects of different meal types demonstrating that mealtime insulin dosing strategies based on carbohydrate counting alone have limitations. There is a need for an evidence-based, safe, and practical method to guide insulin adjustments for high-fat, high-protein meals. In this issue of Diabetes Care , Bell et al. (6) address the pressing clinical question of optimal insulin adjustments for meals containing differing amounts of dietary fat. This is important because postprandial hyperglycemia has been identified as a risk factor for the development of long-term complications of diabetes (7), and higher fat diets have increased in popularity in recent years.

The mechanisms by which all three macronutrients impact blood glucose levels in people with T1D is shown in Fig. 1. Dietary carbohydrate is absorbed and rapidly increases the blood glucose concentration (8). Dietary protein results in a delayed and more prolonged increase in blood glucose levels by conversion of amino acids to glucose through gluconeogenesis, as well as an influence on multiple hormones including glucagon, cortisol, growth hormone, insulin-like growth factor 1, and ghrelin, thus increasing insulin resistance (9). Dietary fat also results in a delayed glycemic response by a number of mechanisms. Free fatty acids act via peroxisome proliferator–activated receptors and free fatty acid receptors to impact …
Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Flurabine Improves Transplant Outcomes in Older MDS Patients
Authors: Betul Oran, Kwang Woo Ahn, Caitrin Fretham, Mithun Vinod Shah, Ryotaro Nakamura, Bart L. Scott, Ronald Sobecks, Uday Popat, Wael Saber
Journal: Blood (2019)
Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer
Authors: Isabelle Ray-Coquard, Patricia Pautier, Sandro Pignata, David Pérol, Antonio González-Martín, Regina Berger, Keiichi Fujiwara, Ignace Vergote, Nicoletta Colombo, Johanna Mäenpää, Frédéric Selle, Jalid Sehouli, Domenica Lorusso, Eva M Guerra Alía, Alexander Reinthaller, Shoji Nagao, Claudia Lefeuvre-Plesse, Ulrich Canzler, Giovanni Scambia, Alain Lortholary, Frederik Marmé, Pierre Combe, Nikolaus de Gregorio, Manuel Rodrigues, Paul Buderath, Coraline Dubot, Alexander Burges, Benoît You, Eric Pujade-Lauraine, Philipp Harter
Journal: New England Journal of Medicine (2019)

Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown.
Updating and reasoning: Different processes, different models, different functions
Authors: Laura Kelly, Janani Prabhakar, Sangeet Khemlani
Journal: Behavioral and Brain Sciences (2019)

Abstract Two issues should be addressed to refine and extend the distinction between temporal updating and reasoning advocated by Hoerl &amp; McCormack. First, do the mental representations constructed during updating differ from those used for reasoning? Second, are updating and reasoning the only two processes relevant to temporal thinking? If not, is a dual-systems framework sensible? We address both issues below.
Letter by Pal et al Regarding Article, “Impact of Bridge to Transplantation With Continuous-Flow Left Ventricular Assist Devices on Posttransplantation Mortality: A Propensity-Matched Analysis of the United Network of Organ Sharing Database”
Authors: Nirvik Pal, Aaron Lim, Mark Nelson
Journal: Circulation (2019)

We read the article by Truby et al 1 with great interest.The expert authors once again demonstrate that given the risk factors (propensity-matched), bridge to transplantation with a left ventricular assist device (LVAD) confers significantly higher risk of early posttransplantation mortality.Although the findings are not new and have been shown before (body mass index, 2 glomerular filtration rate 3 ), they are in contrast to the conclusions from another recent review by another expert in the field, Dardas. 4Although LVAD improves wait-list survival (primary reason for implantation), complications of LVAD and certain patient profiles are associated with poor outcomes after heart transplantation.First, in our opinion, patients receiving LVAD as a bridge to transplantation after failing medical optimization are physiologically an entirely different entity compared with those who never needed an LVAD before heart transplantation.This is alluded to in the Discussion by the authors that any cross-sectional assessment of organ function at 1 point in time may not capture the natural history of the device therapy.In other words, registrybased variables are treated as discrete, whereas in the clinical course, they may be more continuous in nature.Second, we would like to caution the reader that the United Network for Organ Sharing database over time incorporates and reflects ever-modifying changes in evolving technology (in this case, axial flow to centrifugal flow to hydrodynamic to magnetic levitation), selection strategy, donor criteria, and organ allocation, depending on the sample time period.This may be a reason that the same United Network for Organ Sharing database has resulted in several studies with contradictory results in the present context.Third, with increasingly clinically efficient LVAD pumps, it is probably time to refocus our perspective and to start emphasizing prospective trials for medical optimization with LVAD therapy before heart transplantation (pulmonary hypertension, renal function, etc) for improved posttransplantation outcomes (bridge to candidacy), rather than investing more in comparative studies between 2 incongruous groups.Last, more future trials for optimal timing 5 for both LVAD implantation and heart transplantation need to be determined so that the maximal benefits of device optimization can be achieved before complications of the device take precedence.
Polypeptide-corticosteroid conjugates as a topical treatment approach to psoriasis
Authors: Irene Dolz-Pérez, Marwa A. Sallam, Esther Masiá, Daniel Morelló-Bolumar, M. Dolores Pérez del Caz, Patrick Graff, Doaa Abdelmonsif, Sarah Hedtrich, Vicent J. Nebot, María J. Vicent
Journal: Journal of Controlled Release (2019)
Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial
Authors: Christopher C Butler, Alike W van der Velden, Emily Bongard, Benjamin R Saville, Jane Holmes, Samuel Coenen, Johanna Cook, Nick A Francis, Roger J Lewis, Maciek Godycki-Cwirko, Carl Llor, Sławomir Chlabicz, Christos Lionis, Bohumil Seifert, Pär-Daniel Sundvall, Annelies Colliers, Rune Aabenhus, Lars Bjerrum, Nicolay Jonassen Harbin, Morten Lindbæk, Dominik Glinz, Heiner C Bucher, Bernadett Kovács, Ruta Radzeviciene Jurgute, Pia Touboul Lundgren, Paul Little, Andrew W Murphy, An De Sutter, Peter Openshaw, Menno D de Jong, Jason T Connor, Veerle Matheeussen, Margareta Ieven, Herman Goossens, Theo J Verheij
Journal: The Lancet (2019)
Staphylococcus epidermidis Contributes to Healthy Maturation of the Nasal Microbiome by Stimulating Antimicrobial Peptide Production
Authors: Qian Liu, Qingyun Liu, Hongwei Meng, Huiying Lv, Yao Liu, Junlan Liu, Hua Wang, Lei He, Juanxiu Qin, Yanan Wang, Yingxin Dai, Michael Otto, Min Li
Journal: Cell Host & Microbe (2019)
Phosphatidylserine Suppresses T Cells Through GPR174, and Co-Inhibition of Adenosine Receptors and GPR174 Synergistically Enhances Th1 Cytokine Production
Authors: M.A. Gavin, A. Gragerov, E. Espling, A. Rohde, T. Sexton, C. Doulami, G. Gaitanaris
Journal: Annals of Oncology (2019)
Association Between Cigarette Smoking and Multiple Sclerosis
Authors: Mattia Rosso, Tanuja Chitnis
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Cigarette smoking is a common environmental exposure and addiction, which has severe health consequences. Smoking is a risk factor for multiple sclerosis (MS); also, smoking has been associated with disease activity and overall prognosis for patients with MS. <h3>Observations</h3> Cigarette smoking is an irritative agent on the lungs, in which a proinflammatory cascade starts that culminates in autoimmunity. Inflammation may increase the risk of MS in some individuals, in a process driven by antigen cross-reactivity between lung antigens and myelin antigens. Genetics plays a central role in the individual predisposition to mounting an autoimmune reaction. Also, free radicals, cyanates, and carbon monoxide in cigarette smoke may be directly toxic to neurons. Patients with MS who smoke have higher rates of disease activity, faster rates of brain atrophy, and a greater disability burden. Some of the outcomes of smoking were found to be reversible, which makes counseling key. <h3>Conclusions and Relevance</h3> The pathways involved in cigarette smoking should be further analyzed to understand the mechanisms whereby smoking worsens MS prognosis. The proinflammatory and neurotoxic outcomes of cigarette smoking may be shared by other environmental exposures, such as pollution and organic solvents. From a global perspective, efforts should be made to diminish the prevalence of cigarette smoking in patients with MS.
An Open Label Study of Alpn-101, a First-in-Class Dual CD28/ICOS Antagonist, in Subjects with Steroid-Resistant or Steroid-Refractory Acute Graft Versus Host Disease (aGVHD)
Authors: Jing Yang, Jan L. Hillson, Kristi L. Manjarrez, Jennifer R. Wiley, Gary D. Means, Stacey R. Dillon, Stanford L. Peng
Journal: Blood (2019)
RETRACTED ARTICLE: N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1
Authors: Hongsheng Wang, Qianqian Deng, Ziyan Lv, Yuyi Ling, Xue Hou, Zhuojia Chen, Xiaoxiao Dinglin, Shuxiang Ma, Delan Li, Yingmin Wu, Yanxi Peng, Hongbing Huang, Likun Chen
Journal: Molecular Cancer (2019)

Abstract Background Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy. Methods The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated. Results miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3’UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m 6 A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer. Conclusions Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.
Abstract P095: Assessing Improvement Of eGFR Risk Classification In Meta-analysis: An Example of CKD-EPI and MDRD Study Equations On Cardiovascluar Mortality (for The CKD-PC Collaborators)
Authors: Kunihiro Matsushita, Yingying Sang, Mark Woodward, Bakthtawar K Mahmoodi, Brad C Astor, Andrew S Levey, Josef Coresh
Journal: Circulation (2012)

Purpose: Risk prediction models are assessed by calibration, discrimination, and reclassification. Net reclassification improvement (NRI) is a popular reclassification statistic in clinical epidemiology. However, methods to assess NRIs in a meta-analysis are not well described. Using an example of the CKD-EPI and the MDRD Study equations, we demonstrate a method to meta-analyze NRIs for eGFR category based on different equations. Methods: In a sample of 29 of 46 cohorts joining the CKD Prognosis Consortium (CKD-PC), NRI was calculated for reclassification across the following six eGFR categories (≥90, 60–89, 45–59, 30–44, 15–29, &lt;15 ml/min/1.73m 2 ) for CKD-EPI vs. MDRD Study equations. Standard errors of NRIs were calculated in analogy to McNemar’s test for paired proportions as √{(proportion of reclassification to high risk [low eGFR] category in those who developed events + proportion of reclassification to low risk [high eGFR] category in those who developed)/(# of events) + (reclassification to low risk category in those who did not develop events + reclassification to high risk category in those who did not develop)/(# of no events)}. NRIs were meta-analyzed in a random effects model applying the metan command in STATA. Results: There were a total of 830,132 participants and 22,647 deaths due to cardiovascular disease (coronary heart disease, stroke, or heart failure). NRIs for cardiovascular mortality based on eGFR category varied from −0.07 to 0.27 (p-values from &lt;0.001 to 0.921; 22 of 29 studies with p&lt;0.05) among cohorts. Standard errors also varied from 0.005 to 0.049. Meta-analyzed NRI was 0.09 (95% CI: 0.07–0.12, p&lt;0.001), suggesting that the CKD-EPI equation classifies individuals more correctly than the MDRD Study equation. The I-squared was 96.0% (p&lt;0.001), suggesting high heterogeneity across studies. Conclusion: We demonstrated how to meta-analyze NRIs, which estimate the clinical risk implication of new eGFR equations on cardiovascular disease, a leading cause of death among individuals with CKD.
Room for both intellectual titans and vocationalists in medicine
Authors: Steven Ford
Journal: BMJ (2019)

Should medical schools relax academic admission criteria?1 With my A levels, I’d barely qualify for a plumbing apprenticeship now. The only conceivable explanations for my admission to medical school are that someone misread my results, my old headmaster had some dirt on the dean, or well stuffed brown envelopes changed hands.

I attended everything—no exceptions—and read mountains of books and journals. Notwithstanding, I …