tbuckley/cabot-search huggingface dataset:
A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts
Authors: Jeannette Bigler, Michael Boedigheimer, James P. R. Schofield, Paul J. Skipp, Julie Corfield, Anthony Rowe, Ana R. Sousa, Martin Timour, Lori Twehues, Xuguang Hu, Graham Roberts, Andrew A. Welcher, Wen Yu, Diane Lefaudeux, Bertrand De Meulder, Charles Auffray, Kian F. Chung, Ian M. Adcock, Peter J. Sterk, Ratko Djukanović
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy.To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences.Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis.A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids.Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study. Clinical trial registered with www.clinicaltrials.gov (NCT01982162).
419. Allogenic CAR T-Cells Targeting CD123 for Adoptive Immunotherapy of Acute Myeloid Leukemia (AML)
Authors: Roman Galetto, Céline Lebuhotel, Patricia Françon, Agnès Gouble, Julianne Smith
Journal: Molecular Therapy (2015)

Chimeric antigen receptor (CAR)-redirected T-cells have given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. A limitation of the current autologous approach is that CAR T-cells must be manufactured on a "per patient basis". We have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" engineered CAR+ T-cell–based frozen products. This platform utilizes Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology to inactivate the TCRα constant (TRAC) gene, eliminating the potential for T-cells bearing alloreactive TCR's to mediate Graft versus Host Disease (GvHD). We have previously demonstrated that editing of the TRAC gene can be achieved at high frequencies, obtaining up to 80% of TCRα negative cells. This allows us to efficiently produce TCR-deficient T-cells that have been shown to no longer mediate alloreactivity in a xeno-GvHD mouse model. In addition to CAR expression, our T-cells are engineered to co-express the RQR8 gene as a safety feature, with the aim of rendering them sensitive to the monoclonal antibody rituximab. In this work we present the adaptation of this allogeneic platform to the production of T cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed in tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). To identify an effective CAR targeting CD123, we have screened multiple antigen recognition domains in the context of several different CAR architectures to identify candidates displaying activity against cell lines expressing variable levels of the CD123 antigen. Furthermore, experiments in an AML mouse model using anti-CD123 CAR T cells demonstrate important anti-tumor activity in vivo. The ability to carry out large scale manufacturing of allogeneic, non alloreactive CD123 specific T cells from a single healthy donor will thus offer the possibility of an off-the-shelf treatment that would be immediately available for administration to a large number of AML patients.
Comment on Pinsker et al. Randomized Crossover Comparison of Personalized MPC and PID Control Algorithms for the Artificial Pancreas. Diabetes Care 2016;39:1135–1142
Authors: Garry M. Steil
Journal: Diabetes Care (2016)

Pinsker et al. (1) compare the performance of an artificial pancreas system using a model predictive control (MPC) algorithm of their own design to the performance of the same system using a proportional integral derivative (PID) algorithm, also of their own design. They conclude that MPC performs better. The authors emphasize that MPC “comes in many flavors” but do not acknowledge the same for PID (1). Using a PID controller of their own design rather than a version that has undergone numerous design iterations, such as the Medtronic algorithm (2,3) or an interacting PID algorithm developed at Boston Children’s Hospital (4,5), makes their study less than compelling.

The authors argue that they designed their MPC and PID algorithms to have “the same level of aggressiveness” but, by their own …
The Genomic Landscape of Childhood T-Lineage Acute Lymphoblastic Leukemia
Authors: Yu Liu, John Easton, Ying Shao, Mark Wilkinson, Michael Edmonson, Xiaotu Ma, Malcolm A. Smith, Michael Rusch, Jaime Guidry Auvil, Daniela S. Gerhard, Mary V. Relling, Naomi J. Winick, Elizabeth Raetz, Meenakshi Devidas, Cheryl L. Willman, Richard C. Harvey, William L. Carroll, Kimberly P. Dunsmore, Stuart S. Winter, Brent L Wood, James R. Downing, Mignon L. Loh, Stephen P Hunger, Jinghui Zhang, Charles G. Mullighan
Journal: Blood (2015)
OC-036 A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury
Authors: C Paulding, J Singer, S Lewitzky, E Leroy, F Y Zhao, L Klickstein, T Wright, J Meyer
Journal: Gut (2010)

Introduction Lumiracoxib is a selective COX-2 inhibitor that was developed for the symptomatic treatment of osteoarthritis and acute pain. Concerns over liver injury, primarily at chronic doses >100 mg once daily, led to the withdrawal of lumiracoxib in most major drug markets worldwide. A genome-wide association study was performed to identify genetic markers associated with lumiracoxib-related liver injury. Methods Using DNA (n=10 057) collected during the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), a multistaged case-control pharmacogenetic study was conducted to identify genetic markers associated with the risk of developing elevations of liver aminotransferases (ALT/AST) during treatment with lumiracoxib. TARGET was a 52-week, gastrointestinal clinical safety outcomes study which demonstrated that lumiracoxib (400 mg once daily) reduced the risk of a definite or probable upper GI ulcer complication by 79% compared to NSAIDs (naproxen 500 mg twice daily and ibuprofen 800 mg three times daily) in non-aspirin treated osteoarthritis patients. Results Several single nucleotide polymorphisms (SNPs) from the MHC class II region on chromosome 6 were found to be associated with liver aminotransferase elevations five times the upper limit of normal (>5×ULN) in patients treated with lumiracoxib (top SNP p=2.8E-10). These findings were replicated in an independent set of patients with elevated aminotransferases (>3×ULN) (top SNP p=4.4E-12). To further refine the association results, HLA genotyping and analysis were conducted and a very strong association was identified (top HLA allele p=6.8E-25). Conclusion The study described here identified a highly significant association between HLA alleles and lumiracoxib-related liver injury. These results offer the potential to improve the safety profile of lumiracoxib by excluding patients at elevated risk for developing liver injury.
The change in prostate cancer presentation and diagnosis coinciding with screening recommendations.
Authors: Franklin Gaylis, Jae Choi, Paul Dato, Edward Cohen, Renee Calabrese, Hillary Prime, A. Karim Kader
Journal: Journal of Clinical Oncology (2016)

95 Background: The controversy surrounding prostate cancer (PCa) screening resulted in the United States Preventative Services Task Force (USPSTF) and several primary care societies to recommend against this practice. We examined the characteristics of men evaluated in a large urology practice for an elevated prostate specific antigen (PSA) and the subsequent PCa diagnoses since the USPTF recommendation. Methods: Characteristics of all men presenting for an elevated PSA from August 2011 to August 2014 were prospectively collected in a database. Age at the time of biopsy, self-declared race, insurance status, family history, digital rectal examination findings, PSA within 6 months of biopsy, biopsy history, prostate volume, number of cores sampled, pathologic read (number and percent cores positive, Gleason grading) were all recorded. Kruskall-Wallis rank sum tests were used to compare across all years with post-hoc Dunn’s tests for pairwise multiple comparisons using Bonferroni adjustment. Results: The number of men referred for elevated PSA dropped from 933 in year 1 to 754 by year 3 (19%) with a concomitant drop in the number of biopsies performed in newly referred men from 461 to 370 (20%). The group’s prostate biopsy volume decreased by 15% (1,133 biopsies in year 1 compared to 958 in year 3). Median pre-biopsy PSA increased across all years from 7.0 ng/ml to 8.1 ng/ml (p = 0.0006) with a rise in the proportion of men having PSAs &gt; 10 from 28% to 38%. In the post-hoc analysis, median pre-biopsy PSA was significantly different between years 1 and 3 (p = 0.0002) and years 2 and 3 (p = 0.017) but not years 1 and 2 (p = 0.33). The biopsy positivity rate increased slightly from 46% to 50% across all years with a rise in the proportion of men having Gleason scores (GS) ≥ 8 from 21% to 30% (p = 0.0001). In the post-hoc analysis, median GS was significantly different between year 1 and year 3 (p &lt; 0.0001) and year 2 to year 3 (p = 0.0004) but not year 1 to year 2 (p = 0.12). Conclusions: Our findings suggest a significant grade migration coincident with recommendations against PSA screening. While possibly desirable in the short term, should this trend continue we may miss the window of curability for many men.
699. Effective AAV9 Vector Delivery to Nasal Mucosa for Protection Against Airborne Challenge with Influenza A and B
Authors: Marco Crosariol, Ghazal Stity, Omua Ahonkhai, Erik Wielechowski, Angelica C. Medina-Jaszek, Arbans Sandhu, Julie Johnston, Martin Lock, Anna Tretiakova, James M. Wilson, Maria P. Limberis
Journal: Molecular Therapy (2016)

To transition the AAV-mediated passive immunization strategy for protection against influenza A and B from mice to humans, an efficient vector delivery strategy is needed. Here, we demonstrate the ability of AAV9 expressing anti-influenza A and B antibodies (FI6 and CR8033, respectively) coupled with an intranasal mucosal atomization device (IMAD) to effectively protect mice against challenge with pandemic and seasonal influenza. First, we determined that an equimolar combination of AAV9.FI6 and AAV9.CR8033 vectors delivered intranasally at a dose of 5×1010 GC/KG per mouse effectively protected mice against lethal intranasal challenge with influenza A (PR8) or influenza B (B/Lee/40), respectively. In an effort to progress AAV9 into the clinic, we next determined vector compatibility with the IMAD for loss in volume, vector titer and vector potency. Groups of mice were intranasally administered a mixture of AAV9.FI6 and AAV9.CR8033 as well as a mixture of AAV9.FI6 and AAV9.CR8033 that was processed through the IMAD. Seven days later, the mice were challenged with 5LD50 of PR8 or B/Lee/40. No difference in effectiveness of protection against influenza A or B was observed when the vector mixture was processed through the IMAD. We next translated this approach to the nose of macaques, a model more closely related to the human nose that is the target tissue. In this model, we assessed the kinetics of the onset of transgene expression and stability of expression when vector was delivered via the IMAD compared with traditional, direct liquid delivery. At the conclusion of the study, vector biodistribution was also examined. Overall, no significant differences in the kinetics and profile of gene expression or vector biodistribution were observed between the two delivery methods. In conclusion, we demonstrate the safety and effectiveness of AAV-mediated prophylaxis against influenza A and B when vectors are delivered via the IMAD, an easy-to-use device that localizes transduction to the site of influenza infection, the nasal mucosa.
Retrospective research for efficacy and safety of modified FOLFIRINOX as 1st line therapy for advanced pancreatic cancer
Authors: Masayoshi Dazai, Kazuharu Suzuki, Masahito Nakajima, Masataka Yagisawa, Yoshimitu Kobayashi, Taiki Kudo, Kazuhiro Takahashi, Susumu Sogabe, Hisashi Oda, Takuto Miyagishima
Journal: Annals of Oncology (2015)
Abstract LB-142: Functional role of DNA methyltransferase1 (DNMT1) in regulation of mammary stem/progenitor and cancer stem cells
Authors: Rajneesh Pathania, Sabarish Ramachandran, Puttur Prasad, Vadivel Ganapathy, Muthusamy Thangaraju
Journal: Cancer Research (2015)

Abstract Tumor propagation is the hallmark feature of the cancer stem/tumor propagating cells. Several genetic and epigenetic components are involved in regulation of this process; however, DNA methylation provides a potential epigenetic mechanism for the cellular memory, which needed to preserve the tumorigenic potential through repeated cell divisions. Further, DNA methylation plays a critical role in stem/progenitor cell maintenance wherein the DNMT proteins get enriched in undifferentiated cells and thereby it retains the regenerative capacity while suppressing differentiation. However, the precise role of DNMTs in maintaining stem/progenitor and tumorigenic phenotype in constantly replenished organ, like mammary glands and mammary tumor is not yet known. Here we show that Dnmt1 is required for mammary gland outgrowth and terminal end bud development and that mammary-gland specific Dnmt1 deletion in mice leads to significant reduction in mammary stem/progenitor cell formation. Interestingly, Dnmt1 deletion almost completely abolishes Neu-Tg- and C3(1)-SV40-Tg- driven mammary tumor formation and metastasis. This phenomenon is associated with significant reduction in cancer stem cell (CSC) formation. Similar observations were also recapitulated using pharmacological inhibitors of Dnmts in Neu-Tg mice. To unravel the cause of tumorigenicity of tumor propagating cells, we used genome-wide methylation and RNA sequence approach and find that DNA methylation plays a vital role in regulation of abnormal self-renewal by hypermethylating genes that are involved in development and cell commitment pathways; thereby leading to immortality and autonomous growth to the tumor propagating cells. Overall, our studies provide the first in vivo evidence that DNMT1 is indispensable for mammary stem, progenitor and cancer stem cell formation and that functional inactivation of this gene drastically reduces mammary tumor formation even in the aggressive triple-negative breast cancer subtype. Furthermore, we identified ISL1 as a functional target of DNMT1 in tumor progenitor cells, and stable expression of ISL1 induces apoptosis in cancer stem cells. Thus, DNMT1 specific inhibitors could have a great impact on eradication of cancer stem cells and associated disease recurrence, and ISL1 hypermethylation status could be used as a prognostic marker for early breast cancer diagnosis. Citation Format: Rajneesh Pathania, Sabarish Ramachandran, Puttur Prasad, Vadivel Ganapathy, Muthusamy Thangaraju. Functional role of DNA methyltransferase1 (DNMT1) in regulation of mammary stem/progenitor and cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-142. doi:10.1158/1538-7445.AM2015-LB-142
Notice of Retraction: Das RR, Singh M. Oral Zinc for the Common Cold. <i>JAMA</i>. 2014;311(14):1440-1441.
Authors: Rashmi Ranjan Das, Meenu Singh
Journal: JAMA (2016)

only resulted in a modest increase in the rate of abdominal hysterectomy and no statistically significant increase in major complication rates.Despite surgeon proficiency, a percentage of women undergoing hysterectomy will always require laparotomy, and some patients are better served by undergoing abdominal hysterectomy.Efforts should continue to promote minimally invasive surgery when feasible and to improve the safety of all modalities of hysterectomy.
Caring for heavily pretreated patients with metastatic breast cancer (MBC): Carboplatin (CBDCA) - gemcitabine (GCB) combination is effective and well tolerate
Authors: C. Catania, F. Nolè, A. Balduzzi, L. Franceschelli, C. Marenghi, L. Corsetto, G. Sanna, C. Noberasco, M. G. Zampino, A. Goldhirsch
Journal: Journal of Clinical Oncology (2004)

724 Background: Patients (pts) with MBC often receive intensive chemotherapy to halt disease progression. Subsequent treatment choices are thus complex due to cumulative toxicity of previous therapies, to paucity of effective cytotoxic regimens with a low toxicity burden, and to compromised performance status. Methods: A combination of CBDCA (AUC4, Calvert) plus GCB (1250 mg/m2 Days 1 & 8, than reduced to 1000 mg/m2 ) was given to 28 pts with MBC (median age: 50 yrs, range: 31–72; PS 0–1/2: 25/3). All patients previously received chemotherapy for metastatic disease, 21 had ≥ 3 chemotherapy regimens; 11 pts had disease resistant to both anthracycline and taxanes. Results: After the first 4 pts were treated, GCB-dose was reduced from 1250 to 1000 mg/m2 because of limiting haematological toxicity on day 1 or 8, requiring treatment delay/omission: neutropenia G3 (2 pt) / G4 (1 pt), thrombocytopenia G4 (1 pt), anemia G3 (1 pt). After GCB dose-reduction, we observed G3–4 thrombocytopenia (21%,) and neutropenia (50%), with 1 episode of febrile neutropenia not requiring hospitalisation. Subjective toxicity was mild, without non-haematolgical G3–4 toxicity but G3 skin-reaction (3 pts). Partial responses were observed in 5/23 pts valuable (22%); stable disease and disease progression in 7 and 12 pts, respectively. Two patients with partial responses and 2 with disease stabilisation were observed in the 11 pts resistant to both taxanes and anthracycline. Conclusions: This regimen is effective and well-tolerated and might be considered a reasonable treatment option for heavily pretreated patients. No significant financial relationships to disclose.
Use of Risk Models to Predict Death in the Next Year Among Individual Ambulatory Patients With Heart Failure
Authors: Larry A. Allen, Daniel D. Matlock, Susan M. Shetterly, Stanley Xu, Wayne C. Levy, Laura B. Portalupi, Colleen K. McIlvennan, Jerry H. Gurwitz, Eric S. Johnson, David H. Smith, David J. Magid
Journal: JAMA Cardiology (2016)

<h3>Importance</h3> The clinical practice guidelines for heart failure recommend the use of validated risk models to estimate prognosis. Understanding how well models identify individuals who will die in the next year informs decision making for advanced treatments and hospice. <h3>Objective</h3> To quantify how risk models calculated in routine practice estimate more than 50% 1-year mortality among ambulatory patients with heart failure who die in the subsequent year. <h3>Design, Setting, and Participants</h3> Ambulatory adults with heart failure from 3 integrated health systems were enrolled between 2005 and 2008. The probability of death was estimated using the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk calculator. Baseline covariates were collected from electronic health records. Missing covariates were imputed. Estimated mortality was compared with actual mortality at both population and individual levels. <h3>Main Outcomes and Measures</h3> One-year mortality. <h3>Results</h3> Among 10 930 patients with heart failure, the median age was 77 years, and 48.0% of these patients were female. In the year after study enrollment, 1661 patients died (15.9% by life-table analysis). At the population level, 1-year predicted mortality among the cohort was 9.7% for the SHFM (C statistic of 0.66) and 17.5% for the MAGGIC risk calculator (C statistic of 0.69). At the individual level, the SHFM predicted a more than 50% probability of dying in the next year for 8 of the 1661 patients who died (sensitivity for 1-year death was 0.5%) and for 5 patients who lived at least a year (positive predictive value, 61.5%). The MAGGIC risk calculator predicted a more than 50% probability of dying in the next year for 52 of the 1661 patients who died (sensitivity, 3.1%) and for 63 patients who lived at least a year (positive predictive value, 45.2%). Conversely, the SHFM estimated that 8496 patients (77.8%) had a less than 15% probability of dying at 1 year, yet this lower-risk end of the score range captured nearly two-thirds of deaths (n = 997); similarly, the MAGGIC risk calculator estimated a probability of dying of less than 25% for the majority of patients who died at 1 year (n = 914). <h3>Conclusions and Relevance</h3> Although heart failure risk models perform reasonably well at the population level, they do not reliably predict which individual patients will die in the next year.
272. Rapid Identification of Tumor- and Neoantigen-Reactive T-Cell Receptors for Personalized Immunotherapy
Authors: Anna Pasetto, Alena Gros, Paul F. Robbins, Drew C. Deniger, Todd D. Prickett, Maria R. Parkhurst, Rodrigo Matus-Nicodemos, Daniel C. Douek, Jared Gartner, Katarzyna Trebska-McGowan, Jessica Crystal, Steven A. Rosenberg
Journal: Molecular Therapy (2016)

Adoptive transfer of T-cell receptor (TCR) gene engineered T-cells targeting tumor-associated antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T-cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. We thus developed a multi-step strategy that involved CDR3-TCRB deep sequencing of tumor infiltrating lymphocytes and matching of TCRA-TCRB pairs by pairSEQ and single cell RT-PCR. CDR3 TCRA-TCRB pairs identified with this approach, were then reconstructed to full length based on IMGT database [http://www.imgt.org], synthetized and cloned into non-viral and retroviral expression vectors. T-cells were gene-engineered with these TCRs and tested against tumor cell lines and antigen presenting cells expressing tandem minigenes encoding mutated tumor neoantigens and/or pulsed with corresponding mutated peptides. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes including reactivity against neoantigens. These data demonstrate the feasibility of developing a rapid approach for the identification of tumor-reactive TCRs that can be used for personalized TCR-gene therapy.