tbuckley/cabot-search huggingface dataset:
Treatment with FLAG followed by second allogeneic stem cell transplant for relapsed acute myeloid leukemia and myelodysplastic syndrome.
Authors: Brian Pham, Rasmus Hoeg, Nisha Hariharan, Kathyryn Alvarez, Aaron Seth Rosenberg, Brian Andrew Jonas, Joseph M. Tuscano, Mehrdad Abedi
Journal: Journal of Clinical Oncology (2019)

e18503 Background: There is no standard treatment for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapsing after allogeneic stem cell transplant (SCT). Options include combination chemotherapy, withdrawal of immunosuppression, donor lymphocyte infusion (DLI), and second SCT. Previous studies have used fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG) or second SCT separately for salvage therapy. Our institution uses FLAG followed by SCT from the same donor (FLAG/SCT) in this setting. We report a retrospective study of FLAG/SCT in MDS and AML patients relapsed after SCT. Methods: Patients who received FLAG/SCT for treatment of relapsed AML or MDS between 2009 and 2018 were identified using the bone marrow transplant database at University of California Davis. Their baseline characteristics and outcomes were determined using the electronic medical record. Descriptive statistics and Kaplan-Meier survival analysis were used to describe patients, rates of graft-versus-host disease (GvHD) and estimate survival times. Results: Nineteen patients received FLAG/SCT for AML (n=18) and MDS (n=1). Median time to relapse from first SCT was 145 days (range 41 to 960 days). Prior to FLAG/SCT, 17 patients had medullary relapse (median bone marrow blasts 27%; range 7-85%). Two patients had extramedullary relapse. Eighteen (94.7%) patients achieved complete remission (CR) after FLAG/SCT. Median follow-up time was 354 days from the first day of FLAG/SCT (range 7 to 2144 days). Six patients (31.6%) relapsed with median time to relapse of 334 days (range 78 to 679 days) after treatment. Overall survival at 2 years was 52.5%. Causes of death were relapsed AML (n=4; 21.1%), infection (n=4; 21.1%) complications of GvHD (n=3,15.8 %), and brain herniation (n=1, 5.3%). Acute GvHD grade I-IV and new onset chronic GvHD occurred in thirteen (68.4%) and eight patients (42.1%), respectively. Conclusions: FLAG/SCT for AML and MDS relapsing after SCT resulted in a high remission rate. The overall survival of over two years suggests that the second SCT augmented the graft versus leukemia effect. The GvHD rate increased after second SCT, but the rate and severity were manageable. FLAG/ SCT is a reasonable option for relapsed AML and MDS after SCT.
Clinical significance of CXCR5-CXCL13 signaling in multiple myeloma.
Authors: Olayinka omoyitola Adebayo, Corey Young, Tiara Griffen, Kaylin Carey, Sha'Kayla Nunez, Sanjay R Jain, James Lillard
Journal: Journal of Clinical Oncology (2019)

e19517 Background: Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells resulting in monoclonal immunoglobulins in the blood, bone marrow, and urine (1). According to a 2019 American Cancer Society (ACS) report, MM is now classified as subtypes of non-Hodgkin lymphoma (NHL). ACS expects there will be ~32,110 new MM cases (18,130 in men and 13,980 in women) and ~12,960 (6,990 in men and 5,970 in women) anticipated deaths in 2019. MM is a heterogenous disease; characterizing its molecular phenotypes is important for effective treatment of MM and predicting relapse. CXCL13-CXCR5 interactions are involved in malignancy cell homing, adhesion, signal transduction, and calcium flux, all of which promote MM progression. Methods: We analyzed RNA-sequence data from matched normal, primary and relapsed MM cases. Patient control mRNA samples matched primary tumor and relapse samples were acquired from dbGap (database of Genotypes and Phenotypes) to evaluate the mRNA expression patterns of CXCL13, CXCR5 and associated genes in MM. A bioinformatics strategy was used to integrate published genomic data from MM patients (n = 480) and identify genes associated with CXCL13-CXCR5 signaling. DESeq analysis was used to determine differentially expressed genes between normal tissues, primary tumor and relapse groups. Weighted gene co-expression network analysis (WGCNA) identified clusters of genes significantly associated with the molecular phenotypes of MM. Results: Notably, gene expression driven by NFAT and JUN, known to be activated by the CXCL13-CXCR5 axis, and plasma cell signaling pathways significantly correlated with select MM molecular phenotypes and patient survival. Ingenuity pathway analysis (IPA) was performed to analyze upstream regulators, gene interaction networks and canonical pathways. Taken together, our data show CXCR5-CXCL13 signaling networks are significantly expressed and associated with MM pathogenesis and plasma clonality. Conclusions: This study provides a better understanding of the heterogeneous nature of MM and the role of the CXCL13-CXCR5 axis in MM.
Association Between Electronic Cigarette Use and Smoking Reduction in France
Authors: Ramchandar Gomajee, Fabienne El-Khoury, Marcel Goldberg, Marie Zins, Cédric Lemogne, Emmanuel Wiernik, Emeline Lequy-Flahault, Lucile Romanello, Isabelle Kousignian, Maria Melchior
Journal: JAMA Internal Medicine (2019)

The electronic cigarette (EC) has become popular among smokers who wish to reduce their tobacco use levels or quit smoking, but its effectiveness as a cessation aid is uncertain.To examine the association of regular EC use with the number of cigarettes smoked per day, smoking cessation among current smokers, and smoking relapse among former smokers.The CONSTANCES (Consultants des Centres d'Examens de Santé) cohort study, based in France, began recruiting participants January 6, 2012, and is currently ongoing. Participants were enrolled in CONSTANCES through 2015, and included 5400 smokers (mean [SD] follow-up of 23.4 [9.3] months) and 2025 former smokers (mean [SD] follow-up of 22.1 [8.6] months) at baseline who quit smoking in 2010, the year in which ECs were introduced in France, or afterward. Analyses were performed from February 8, 2017, to October 15, 2018.The association between EC use and the number of cigarettes smoked during follow-up was studied using mixed regression models. The likelihood of smoking cessation was studied using Poisson regression models with robust sandwich variance estimators. The association between EC use and smoking relapse among former smokers was studied using Cox proportional hazards regression models. All statistical analyses were adjusted for sociodemographic characteristics, duration of follow-up, and smoking characteristics.Among the 5400 daily smokers (2906 women and 2494 men; mean [SD] age, 44.9 [12.4] years), regular EC use was associated with a significantly higher decrease in the number of cigarettes smoked per day compared with daily smokers who did not use ECs (-4.4 [95% CI, -4.8 to -3.9] vs -2.7 [95% CI, -3.1 to -2.4]), as well as a higher adjusted relative risk of smoking cessation (1.67; 95% CI, 1.51-1.84]). At the same time, among the 2025 former smokers (1004 women and 1021 men; mean [SD] age, 43.6 [12.1] years), EC use was associated with an increase in the rate of smoking relapse among former smokers (adjusted hazard ratio, 1.70; 95% CI, 1.25-2.30).This study's findings suggest that, among adult smokers, EC use appears to be associated with a decrease in smoking level and an increase in smoking cessation attempts but also with an increase in the level of smoking relapse in the general population after approximately 2 years of follow-up.
Effect of Universal Testing and Treatment on HIV Incidence — HPTN 071 (PopART)
Authors: Richard J Hayes, Deborah Donnell, Sian Floyd, Nomtha Mandla, Justin Bwalya, Kalpana Sabapathy, Blia Yang, Mwelwa Phiri, Ab Schaap, Susan H Eshleman, Estelle Piwowar-Manning, Barry Kosloff, Anelet James, Timothy Skalland, Ethan Wilson, Lynda Emel, David Macleod, Rory Dunbar, Musonda Simwinga, Nozizwe Makola, Virginia Bond, Graeme Hoddinott, Ayana Moore, Sam Griffith, Nirupama Deshmane Sista, Sten H Vermund, Wafaa El-Sadr, David N Burns, James R Hargreaves, Katharina Hauck, Christophe Fraser, Kwame Shanaube, Peter Bock, Nulda Beyers, Helen Ayles, Sarah Fidler
Journal: New England Journal of Medicine (2019)

A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent.
Patient Perspectives on Symptom Experience and Impact on Health-Related Quality of Life in Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myeloid Leukemia
Authors: Jill A Bell, Aaron Galaznik, Farrah A Pompilus, Sara Strzok, Robert J. Fram, Douglas V. Faller, Patrick Marquis
Journal: Blood (2017)
Incidence and time trends of joint surgery in patients with psoriatic arthritis: a register-based time series and cohort study from Denmark
Authors: Jørgen Guldberg-Møller, Rene Lindholm Cordtz, Lars Erik Kristensen, Lene Dreyer
Journal: Annals of the Rheumatic Diseases (2019)

To investigate time-trends and cumulative incidence of joint surgery among patients with psoriatic arthritis (PsA) compared with the general population.In this nationwide register-based cohort study, The Danish National Patient Registry was used to identify incident PsA patients. The 5-year incidence rates (IR) and incidence rate ratios (IRR) of joint surgery were calculated in four calendar-period defined cohorts. Each patient was matched with ten non-PsA individuals from the general population cohort (GPC). The cumulative incidences of any joint and joint-sacrificing surgery, respectively, were estimated using the Aalen-Johansen method.From 1996 to 2017, 11 960 PsA patients (mean age 50 years; 57% female) were registered. The IRR of any joint surgery was twice as high for PsA patients compared with GPCs across all calendar periods. Among patients with PsA, 2, 10 and 29% required joint surgery at 5, 10 and 15 years after diagnosis. The risk of surgery in PsA patients diagnosed at 18-40 years was higher (22%) than in GPC 60+ year old (20%) after 15 years of follow-up.The use of joint surgery among PsA patients remained around twofold higher from 1996 to 2012 compared with GPC. After 15 years of follow-up, nearly 30% of the PsA patients had received any surgery, and even a person diagnosed with PsA at the age of 18-40 years had a higher risk of surgery than GPCs of 60+ year old. Thus, the high surgical rates represent an unmet need in the current treatment of PsA.
Anti-CD45RB Antibody Therapy Attenuates Renal Ischemia-Reperfusion Injury by Inducing Regulatory B Cells
Authors: Taishi Fang, Tai Yeon Koo, Jae-Ghi Lee, Joon Young Jang, Yixuan Xu, Ju Hee Hwang, Sunjoo Park, Ji-Jing Yan, Jung-Hwa Ryu, Yeon-Mi Ryu, Sang-Yeob Kim, Kyung-Suk Suh, Jaeseok Yang
Journal: Journal of the American Society of Nephrology (2019)

Regulatory B cells are a newly discovered B cell subset that suppresses immune responses. Recent studies found that both anti-CD45RB and anti-Tim-1 treatments regulate immune responses by inducing regulatory B cells; however, the role of these cells in renal ischemia-reperfusion injury (IRI) is unknown.Using mouse models, including T cell-deficient (RAG1 knockout and TCRα knockout) mice and B cell-deficient (μMT) mice, we investigated the effects of regulatory B cells and anti-CD45RB on IRI and the mechanisms underlying these effects.Adoptive transfer of regulatory B cells before or after IRI attenuated renal IRI. Anti-CD45RB treatment with or without anti-Tim-1 before IRI increased renal infiltration of CD19+Tim-1+ regulatory B and regulatory T cells. Anti-CD45RB decreased serum creatinine levels, pathologic injury score, tubular apoptosis, and proinflammatory cytokines levels, whereas IL-10 levels increased. Following IRI, anti-CD45RB with or without anti-Tim-1 also induced regulatory B cells, improving renal function and tubular regeneration. In RAG1 knockout mice with B cell transfer, TCRα knockout mice, and wild-type mice with T cell depletion, anti-CD45RB increased regulatory B cells and attenuated IRI. However, anti-CD45RB did not attenuate IRI in RAG1 knockout mice with T cell transfer or μMT mice and induced only mild improvement in wild-type mice with B cell depletion. Furthermore, B cell-deficient mice receiving B cells from IL-10 knockout mice (but not from wild-type mice) did not show renal protection against IRI when treated with anti-CD45RB.Anti-CD45RB treatment attenuated acute renal injury and facilitated renal recovery after IRI through induction of IL-10+ regulatory B cells, pointing to anti-CD45RB as a potential therapeutic strategy in renal IRI.
Tumor mutational burden (TMB) may be a promising predictive biomarker of response to PD-1/PD-L1 targeting in MSI-H colorectal cancer.
Authors: Marwan Fakih, Jaideep Singh Sandhu, Ching Ouyang, Ethan Sokol, Jeffrey S. Ross, Vincent A. Miller, Dean Lim, Joseph Chao, Daniel V.T. Catenacci, May Thet Cho, Fadi S. Braiteh, Steven Brad Maron, Leah Chase, Samuel Jacob Klempner, Siraj Mahamed Ali, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2019)

43 Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p &lt; 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p &lt; 0.001 and p &lt; 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMB high and TMB low groups. All 13 pts (100%) with TMB high had an OR, while only 2/9 (22%) pts with TMB low had an OR and 6/9 had PD. The median PFS for TMB high pts has not been reached (no progressors, median follow-up &gt; 18 mos), while the median PFS for TMB low pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25 th , 35 th , 50 th and 75 th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35 th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.
Pathophysiology and Mechanisms of Zika Virus Infection in the Nervous System
Authors: Kimberly M. Christian, Hongjun Song, Guo-li Ming
Journal: Annual Review of Neuroscience (2019)

In 2015, public awareness of Zika virus (ZIKV) rose in response to alarming statistics of infants with microcephaly being born to women who were infected with the virus during pregnancy, triggering global concern over these potentially devastating consequences. Although we have discovered a great deal about the genome and pathogenesis of this reemergent flavivirus since this recent outbreak, we still have much more to learn, including the nature of the virus-host interactions and mechanisms that determine its tropism and pathogenicity in the nervous system, which are in turn shaped by the continual evolution of the virus. Inevitably, we will find out more about the potential long-term effects of ZIKV exposure on the nervous system from ongoing longitudinal studies. Integrating clinical and epidemiological data with a wider range of animal and human cell culture models will be critical to understanding the pathogenetic mechanisms and developing more specific antiviral compounds and vaccines.
An international, randomized, open-label, phase III trial of adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine alone for surgically resected pancreatic adenocarcinoma (APACT): primary analysis and quality of life outcomes
Authors: M. Reni, H. Riess, E. O’Reilly, A. Santoro, J. Park, T. Bekaii-Saab, M. Tempero, Y. Shan, T. Macarulla, E. Van Cutsem, M. Noel, J. Berlin, A. Biankin, N. Dhani, G. Frassineti, D. Goldstein, A. Romano, Y. Le Bruchec, P. Philip
Journal: Annals of Oncology (2019)
The bread wheat epigenomic map reveals distinct chromatin architectural and evolutionary features of functional genetic elements
Authors: Zijuan Li, Meiyue Wang, Kande Lin, Yilin Xie, Jingyu Guo, Luhuan Ye, Yili Zhuang, Wan Teng, Xiaojuan Ran, Yiping Tong, Yongbiao Xue, Wenli Zhang, Yijing Zhang
Journal: Genome biology (2019)

Bread wheat is an allohexaploid species with a 16-Gb genome that has large intergenic regions, which presents a big challenge for pinpointing regulatory elements and further revealing the transcriptional regulatory mechanisms. Chromatin profiling to characterize the combinatorial patterns of chromatin signatures is a powerful means to detect functional elements and clarify regulatory activities in human studies.In the present study, through comprehensive analyses of the open chromatin, DNA methylome, seven major chromatin marks, and transcriptomic data generated for seedlings of allohexaploid wheat, we detected distinct chromatin architectural features surrounding various functional elements, including genes, promoters, enhancer-like elements, and transposons. Thousands of new genic regions and cis-regulatory elements are identified based on the combinatorial pattern of chromatin features. Roughly 1.5% of the genome encodes a subset of active regulatory elements, including promoters and enhancer-like elements, which are characterized by a high degree of chromatin openness and histone acetylation, an abundance of CpG islands, and low DNA methylation levels. A comparison across sub-genomes reveals that evolutionary selection on gene regulation is targeted at the sequence and chromatin feature levels. The divergent enrichment of cis-elements between enhancer-like sequences and promoters implies these functional elements are targeted by different transcription factors.We herein present a systematic epigenomic map for the annotation of cis-regulatory elements in the bread wheat genome, which provides new insights into the connections between chromatin modifications and cis-regulatory activities in allohexaploid wheat.
Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R<sup>2</sup>-CHOP in subjects with previously untreated, high-risk DLBCL.
Authors: Grzegorz S. Nowakowski, Wolfgang Willenbacher, Richard Greil, Thomas Stauffer Larsen, Krish Patel, Ulrich Jäger, Robert F. Manges, Lorenz H. Trumper, Corinne Haioun, Hele Everaus, Nagesh Kalakonda, Jeanna Knoble, Peter Brown, Judit Meszaros Joergensen, David Cunningham, Neus Domper, Marie-Laure Casadebaig, Oliver Manzke, Javier Munoz
Journal: Journal of Clinical Oncology (2019)

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R 2 -CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R 2 -CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.
SMURF-seq: efficient copy number profiling on long-read sequencers
Authors: Rishvanth K. Prabakar, Liya Xu, James Hicks, Andrew D. Smith
Journal: Genome biology (2019)

We present SMURF-seq, a protocol to efficiently sequence short DNA molecules on a long-read sequencer by randomly ligating them to form long molecules. Applying SMURF-seq using the Oxford Nanopore MinION yields up to 30 fragments per read, providing an average of 6.2 and up to 7.5 million mappable fragments per run, increasing information throughput for read-counting applications. We apply SMURF-seq on the MinION to generate copy number profiles. A comparison with profiles from Illumina sequencing reveals that SMURF-seq attains similar accuracy. More broadly, SMURF-seq expands the utility of long-read sequencers for read-counting applications.
Abstract 16203: Primary Prevention of Ischemic Heart Disease With Aspirin Reduces the Severity of Clinical Presentation
Authors: Sasa Pavasovic, Peter L Amaduzzi, Zorana Vasiljevic, Davor Milicic, Sasko Kedev, Olivia Manfrini, Marija Valvukis, Marija Zdravkovic, Marialuisa Scarpone, Akos Koller, Gordana Krljanac, Edina Cenko, Lina Badimon, Raffaele Bugiardini
Journal: Circulation (2018)

Introduction: The USPSTF has recommended the use of preventive aspirin in all subjects aged 55-79 years without known heart disease when the potential benefit of a reduction in myocardial infarctio...
Mutated NPM1 As Target for Immunotherapy of Acute Myeloid Leukemia
Authors: Dyantha I. Van Der Lee, Helena M. Bijen, Renate S. Hagedoorn, Willy M. Honders, Michel G.D. Kester, Dirk M. van der Steen, Arnoud H. de Ru, Inge Jedema, Hendrik Veelken, Mirjam H.M. Heemskerk, Peter A. van Veelen, J.H. Frederik Falkenburg, Marieke Griffioen
Journal: Blood (2017)