tbuckley/cabot-search huggingface dataset:
Cost-effectiveness Analysis of Bariatric Surgery for Patients With Nonalcoholic Steatohepatitis Cirrhosis
Authors: Matthew J. Klebanoff, Kathleen E. Corey, Sumeyye Samur, Jin G. Choi, Lee M. Kaplan, Jagpreet Chhatwal, Chin Hur
Journal: JAMA Network Open (2019)

Obesity is the most common risk factor for nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease that can lead to cirrhosis and hepatocellular carcinoma. Weight loss can be an effective treatment for obesity and may slow the progression of advanced liver disease.To assess the cost-effectiveness of bariatric surgery in patients with NASH and compensated cirrhosis.This economic evaluation study used a Markov-based state-transition model to simulate the benefits and risks of laparoscopic sleeve gastrectomy (SG), laparoscopic Roux-en-Y gastric bypass (GB), and intensive lifestyle intervention (ILI) compared with usual care in patients with NASH and compensated cirrhosis and varying baseline weight (overweight, mild obesity, moderate obesity, and severe obesity). Patients faced varied risks of perioperative mortality and complications depending on the type of surgery they underwent. Data were collected on March 22, 2017.Life-years, quality-adjusted life-years (QALYs), costs (in 2017 $US), and incremental cost-effectiveness ratios (ICERs) were calculated.Demographic characteristics of the patient population were based on a previously published prospective study (n = 161). Patients in the model were 41.0% female, and the base case age was 54 years. Compared with usual care, SG was associated with an increase in QALYs of 0.263 to 1.180 (bounds of ranges represent overweight to severe obesity); GB, 0.263 to 1.207; and ILI, 0.004 to 0.216. Sleeve gastrectomy was also associated with an increase in life-years of 0.693 to 1.930; GB, 0.694 to 1.947; and ILI, 0.012 to 0.114. With usual care, expected life-years in overweight, mild obesity, moderate obesity, and severe obesity were 12.939, 11.949, 10.976, and 10.095, respectively. With usual care, QALY in overweight was 6.418; mild obesity, 5.790; moderate obesity, 5.186; and severe obesity, 4.577. Sleeve gastrectomy was the most cost-effective option for patients across all weight classes assessed: ICER for SG in patients with overweight was $66 119 per QALY; mild obesity, $18 716 per QALY; moderate obesity, $10 274 per QALY; and severe obesity, $6563 per QALY. A threshold analysis on the procedure cost of GB found that for GB to be cost-effective, the cost of the surgery must be decreased from its baseline value of $28 734 by $4889 for mild obesity, by $3189 for moderate obesity, and by $2289 for severe obesity. In overweight patients, GB involved fewer QALYs than SG, and thus decreasing the cost of surgery would not result in cost-effectiveness.Bariatric surgery could be highly cost-effective in patients with NASH compensated cirrhosis and obesity or overweight. The findings from this analysis suggest that it can inform clinical trials evaluating the effect of bariatric procedures in patients with NASH cirrhosis, including those with a lower body mass index.
A Nationwide Epidemiologic Study for Disease Transformation and Secondary Cancers in Korean Patients with Myeloproliferative Neoplasms
Authors: Junshik Hong, Ju Hyun Lee, Ja Min Byun, Ji Yun Lee, Hyun Jung Lee, Sang Mee Hwang, Byung-Su Kim, Hyo Jung Kim, Jung Lim Lee, Dong-Yeop Shin, Youngil Koh, Sung-Soo Yoon, Soo-Mee Bang
Journal: Blood (2018)
High-Annealing-Temperature PCR (HAT-PCR) Enables Sensitive Quantification of Minimal Residual Disease (MRD) in Blood in Acute Lymphoblastic Leukaemia (ALL)
Authors: Alexander A Morley, Sue Latham, Elizabeth Hughes, Bradley Budgen, Matthew Greenwood, Kenneth F Bradstock, Luciano Dalla-Pozza, Tamara Law, Louise Doculara, Nicola Venn, Rosemary Sutton
Journal: Blood (2018)
Mechanisms of Temozolomide resistance in pediatric glioblastoma multiforme
Authors: Daniel Wu, Bo Cui, Stewart Johnson, Stephen Keir, Jill Maxwell, Darell Bigner, Henry Friedman
Journal: Cancer Research (2007)

LB-324  PURPOSE: Temozolomide (TMZ) has become the standard of care for the treatment of adult anaplastic astrocytoma and glioblastoma multiforme (GBM). However, in the pediatric population, this DNA alkylating agent has not fared as well. The known mechanisms of resistance to TMZ in the adult population are expression of O6-alkylguanine-DNA alkyltransferase (AGT), an enzyme that removes the cytotoxic O6-methylguanine adduct generated by TMZ, and defective mismatch repair (MMR), which allows cells to tolerate the O6-methylguanine lesion. We attempted to elucidate if these mechanisms of resistance to TMZ occur in a pediatric GBM model.  METHODS: The activity of TMZ on a panel of six pediatric GBM xenografts was evaluated in athymic nude mice bearing the subcutaneous tumors. TMZ was administered daily for a total of five days at 0.75 LD10 (262.5 mg/kg). Xenograft response was assessed by growth delay, calculated as T-C, which is the difference in days between the median time for tumors of treated (T) and control (C) mice to reach a volume five times greater than the volume at the time of initial treatment and/or to reach a final volume of 1000 mm3. The xenografts were analyzed for AGT activity and microsatellite instability (MSI), as high MSI is a surrogate marker for mismatch repair deficiency. Western blotting was performed on all xenografts to evaluate the expression of the MMR proteins, hMLH1, hMSH2, hMSH6, and hPMS2.  >RESULTS: TMZ demonstrated marked activity (T-C > 45 days) in three of the xenografts (D-645, SJ-BT56, SJ-GBM2), all of which demonstrated low AGT activity, no MSI, and no MMR protein deficiency. SJ-BT39 had a T-C value of 6.0 days and demonstrated high AGT activity. Treatment of SJ-BT39 with O6-benzylguanine (O6BG), an pseudosubstract inactivator of AGT, prior to administration of a single dose of TMZ resulted in a significant increase in growth delay (T-C = 19.6 days for TMZ/O6BG versus T-C = 4.9 days for TMZ alone). D-212 and D-456 had a T-C values of 4.7 and 11.0 days, respectively, and were found to be deficient in hMLH1. D-212 was microsatellite stable (MSS), while D-456 demonstrated high MSI.  >CONCLUSIONS: In pediatric GBM, TMZ resistance may, in part, be explained by the presence of high AGT activity or defective MMR. These results demonstrate the importance of determining AGT levels and MMR status as a prelude for TMZ therapy in pediatric GBM and the need for further investigations of additional mechanisms of TMZ resistance in these tumors.
Higher incidence of acute lymphoblastic leukemia among adult hispanics in the Unites States.
Authors: Sheeja Pullarkat, Kathleen Danley, Wendy Cozen, Leslie Bernstein, Russell Brynes
Journal: Cancer Research (2007)

2504  The incidence of childhood Acute Lymphoblastic Leukemia (ALL) in United States varies among different ethnic groups and has been shown to be highest in Hispanics. However little information has been published on the incidence of ALL in adults in the United States. We use data from the SEER registry (1990-2003) and California Cancer Registry (1998-2002) programs to document incidence of ALL among various ethnic groups.  Materials and Methods: Both age-specific (5-year age groups) and age-adjusted incidence rates (AAIR) were calculated by gender and race/ethnicity using SEER registry data for the period 1990-2003. AAIR were also calculated for each year by gender and race/ethnicity for broad age groups (0-19 years, 20-54 years, 55 years or older). AAIR were calculated by socio-economic status (SES) and gender for the period 1998-2002 using California data.  Results: During 1990-2003, AAIRs of ALL were higher in males than females and higher among Hispanic whites than other racial/ethnic groups overall, and across broad age groups. Overall incidence rates per 100,000 population were as follows: Hispanic White males 2.33, Hispanic White females 1.90, non-Hispanic white males 1.66 cases, non-Hispanic white females 1.23, Black males 0.94, and Black females 0.73. Age specific rates were highest among children 0-19 years for each racial/ethnic group. For each year during the 1990-2003 year period, AAIRs overall and by age-group were higher among Hispanic whites than among Blacks or non-Hispanic Whites. These results were consistent across SES categories within the California data with incidence rates highest among Hispanic whites in each SES group. Incidence rates per 100,000 population were 2.54 among male Hispanics of the highest SES, 2.38 among those of intermediate SES, and 2.47among Hispanics of the lowest SES. In comparison, AAIRs of ALL among non-Hispanic Whites at high, intermediate and low SES ranged between 1.73 and 1.45 cases per 100,000 population.  Conclusion: Utilizing population-based data from the California Cancer Registry (1998-2002) and the SEER program (1990-2003), Hispanic Whites had higher risk of ALL than Blacks or non-Hispanic Whites regardless of socio-economic status or year of diagnosis. Of note, Hispanic whites not only have the highest incidence rates of ALL among children, but they also have the highest rates of adult onset ALL. The causes of most types of ALL remain elusive but are likely to involve an interaction between inherited susceptibility, environment, and hematopoietic development . Studies are needed to determine whether variation in exposure and polymorphisms in the genes that are important in the detoxifying pathway for environmental mutagens account for the higher risk among Hispanic adults.
Abstract 5764: Oncogenic role of GAEC1 and its potential modulation with p53 in pathogenesis of colon cancer
Authors: Riajul Wahab, Farhadul Islam, Vinod Gopalan, Alfred King-Yin Lam
Journal: Cancer Research (2017)

Abstract Introduction: GAEC1 (Gene amplified in esophageal cancer 1), is frequently amplified and overexpressed in colon cancer tissues. In the present study, we aimed to unveil the oncogenic potential of GAEC1 in carcinogenesis of colon cancer by studying the underlying cellular functions and molecular interactions by in vitro and in vivo experiments. Method: Transient overexpression of GAEC1 with pcDNA3.1-GAEC1 and silencing with GAEC1-siRNA was performed and several downstream assays were done such as migration, clonogenic and apoptotic assay. Analysis of cell kinetics was done using flow cytometry and cell counting kit-8 was used for cell proliferation assay. Immunofluorescence and Western blot assay were used to determine the expression of different target proteins. Co-immunoprecipitation was used to confirm the protein-protein interaction. For xenotransplantation the severely combined immunodeficient (SCID) mice (4 groups, 6 in each group) were injected subcutaneously with GAEC1 shRNA and control shRNA transfected (stable) SW480 and SW48 colon cancer cells. Result: The overexpression of GAEC1 increased cell proliferation, migration, reduced apoptosis in colon cancer cells. Also, these cells showed cell cycle arrest at the synthetic phase, activation of Bcl-2, K-ras, pAKT proteins as well as inhibition of p53, PUMA, p21 and BAX proteins. Conversely, knockdown of GAEC1 reduced cell proliferation, migration, decreased the phosphorylation of AKT, and induced apoptosis, G2/M phase arrest and cleavage of poly (ADP-ribose) polymerase (PARP). Co-immunoprecipitation revealed GAEC1’s interaction with p53. In addition ectopic over expression and silencing of GAEC1 lead to reciprocal effects of p53 protein expression. Moreover, knockdown of GAEC1 reduced the nuclear translocation of murine double minute 2 protein (mdm2) indicating that GAEC1 is responsible for the degradation of p53 through the direct interaction between mdm2-p53 in nucleus. Furthermore, our in vivo data demonstrate that the loss of GAEC1 inhibits the tumor formation in xenograft model. Conclusion: Collectively our study demonstrates that GAEC1 exhibits the oncogenic role in colon cancer by reducing expression of p53 through protein-protein interaction which leads to the inhibition of PUMA, p21, BAX, and activation of Bcl-2, K-ras and pAKT protein expression. Note: This abstract was not presented at the meeting. Citation Format: Riajul Wahab, Farhadul Islam, Vinod Gopalan, Alfred King-Yin Lam. Oncogenic role of GAEC1 and its potential modulation with p53 in pathogenesis of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5764. doi:10.1158/1538-7445.AM2017-5764
Abstract 3156: Construction and validation of an activating and inhibitory chimeric antigen receptor (CAR) system
Authors: Leonardo Chicaybam, Martin H. Bonamino
Journal: Cancer Research (2015)

Abstract Introduction: Chimeric antigen receptors (CARs) consists a promising type of adoptive immunotherapy. CARs consist of an antigen recognition unit (scFv), a transmembrane (TM) region and an intracellular activation domain. However, on target/off tumor responses due to target recognition in normal cells limits the widespread application of this therapy. In B-cell precursor acute lymphoblastic leukemia, lymphocytes expressing anti-CD19 CARs (19BBz) are being used in the clinical setting. However, the expression of CD19 as a pan-B marker can lead to undesired side effects such as depletion of mature B cells. As mature B cells express both CD19 and CD20 antigens, we propose the creation of an inhibitory anti-CD20 CAR, that when used in combination with 19BBz would be able to discriminate between leukemic blasts and normal B cells. Methods and results: Three inhibitory CARs were constructed containing signaling domains of CTLA-4, PD-1 or BTLA. Jurkat T cells expressing the plasmid pGL4.30 - expressing luciferase controlled by a NFAT responsive promoter - were generated. K562 cell line was used as target cells and modified to express CD19 (K5-19), CD20 (K5-20) or CD19 and CD20 (K5-19/20). In coculture experiments, Jurkat cells expressing 19BBz showed induction of luciferase activity when cultured with K5-19 or K5-19/20. However, Jurkat expressing both activation and inhibitory CAR showed inhibition of luciferase activity when incubated with K5-19/20 while maintained high activity when cultured with K5-19 cells. Furthermore, all three inhibitory CARs were able to inhibit the expression of the activation marker CD69 induced by 19BBz. In primary human T lymphocytes, the 20PD1 CAR did not inhibit proliferation or cytotoxicity induced by 19BBz. Surprisingly, T cells expressing 19BBz and 20PD1 showed preferential lysis of NALM6 CD19+ CD20+ cells, suggesting that the addition of PD1 domain may increase T-cell function in specific contexts. This effect was partially reversed by using a mutant PD1 domain where the tyrosines were replaced by phenylalanine and was completely reversed by using an anti-CD20 CAR truncated at the TM region, suggesting that this phenomenon is dependent of signaling. Conclusions: Additional experiments are needed to evaluate the activity of 20PD1 in primary human T cells. Experiments with inhibitory CARs 20LAG3 and 20PD1LAG3 are ongoing and can serve as an alternative to CAR 20PD1 in the construction of a conditional response system. Citation Format: Leonardo Chicaybam, Martin H. Bonamino. Construction and validation of an activating and inhibitory chimeric antigen receptor (CAR) system. [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 3156. doi:10.1158/1538-7445.AM2015-3156
AB0695 Cardiac Involvement in Ankylosing Spondylitis in A Tunisien Population
Authors: F. Ajili, A. Laanani, N. Boussetta, S. Sayhi, I. Gharsallah, L. Metoui, N. Ben Abdelhafidh, B. Louzir, S. Othmani
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Cardiac involvement in ankylosing spondylitis is uncommon. We have tried through this study to analyze the cardiovascular events among 50 patients with ankylosing spondylitis. <h3>Methods</h3> A retrospective study including 50 patients with ankylosing spondylitis. all patients underwent a complete physical examination with a heart and lung auscultation and an electro-cardiogram (ECG). Transthoracic ultrasound was performed whenever there was an abnormal physical examination and/or ECG. <h3>Results</h3> The study included 47 men and 3 women, the sex ratio is 15.6. The average age of onset was 26±7 years. The mode of onset is axial in 95% of cases (low back pain and/or buttock). The extra-articular manifestations are present in 54% of cases. Cardiac involvement is present in 9 cases (18% of cases). The reason for consultation is dyspnea in 2 patients. In other cases, cardiac involvement was discovered incidentally. Aortic regurgitation was noted in 4 patients. Mitral insufficiency was found in 3 cases. Two patients have predominantly septal hypertrophic cardiomyopathy and one patient presented an array of pulmonary insufficiency. The average time of onset of cardiac involvement was 8±5 years. All patients were put under special medical treatment of their heart, with good clinical outcome. <h3>Conclusions</h3> Cardiac involvement in ankylosing spondylitis is seen more frequently in men, especially in the old cases. A close relationship between time to onset of aortic insufficiency and duration of disease progression was found. It would be responsible for one third of deaths of patients. It was significantly more frequent in HLA B27 positive patients (especially complete atrioventricular block and aortic insufficiency). Cardiac involvement should be sought routinely in patients with APS because it presents a poor prognosis that can be life-threatening. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5835
Doctor who qualified in China is struck off after repeated incompetence
Authors: Clare Dyer
Journal: BMJ (2019)

A trainee doctor who scored some of the lowest marks ever seen by his General Medical Council clinical performance assessor has been struck off the UK medical register.

Haseeb Azam left the UK to train in China and qualified from Weifang Medical College, in Shandong province, in 2014, after which he returned to the UK and obtained provisional GMC registration. He went back to China for a year to undertake a clinical attachment before again returning to the UK and obtaining full GMC registration.

In December 2016 he was hired by the Northern Health and Social Care Trust in Northern Ireland as a foundation year 1 …
Effects of Age and Immune Landscape on Outcome in HER2-Positive Breast Cancer in the NCCTG N9831 (Alliance) and NSABP B-31 (NRG) Trials
Authors: Saranya Chumsri, Daniel J. Serie, Zhuo Li, Katherine L. Pogue-Geile, Aixa E. Soyano-Muller, Afshin Mashadi-Hossein, Sarah Warren, Yanyan Lou, Gerardo Colon-Otero, Keith L. Knutson, Edith A. Perez, Alvaro Moreno-Aspitia, E. Aubrey Thompson
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P &amp;lt; 0.001; and age &amp;gt; 40; HR, 0.56; 95% CI, 0.45–0.69; P &amp;lt; 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P &amp;lt; 0.001; and age &amp;gt; 40; HR, 0.42; 95% CI, 0.33–0.54; P &amp;lt; 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.
Abstract 20226: Heparin-Induced Thrombocytopenia and In-Hospital Outcomes in Patients Receiving Ventricular Assist Devices
Authors: Srikanth Yandrapalli, Sohaib Tariq, Tanush Gupta, Sahil Khera, Wilbert S Aronow, Chhaya Aggarwal, Howard A Cooper, Gregg M Lanier, Julio A Panza, Alan L Gass
Journal: Circulation (2017)

Background: Unfractionated heparin (UFH) is commonly used as an anticoagulation strategy in patients receiving ventricular assist devices (VADs) to reduce pump thrombosis. Heparin-induced thrombocy...
Comprehensive Integration of Whole Genome, Transcriptome and Methylation Profiling Reveals Novel Gene Dysregulation Including IL15, SOCS6 and CARD11 Associated with MYD88 and CXCR4 Genotype Status in WM
Authors: Zachary R Hunter, Gloria G Chan, Cristina Jimenez, Nickolas Tsakmaklis, Lian Xu, Jiaji G Chen, Maria Demos, Amanda Kofides, Manit Munshi, Maria Luisa Guerrera, Xia Liu, Guang Yang, Jorge J. Castillo, Ari M Melnick, Steven P Treon
Journal: Blood (2018)
Infographic. Relative energy deficiency in sport: an infographic guide
Authors: Nicola Keay, Alan Rankin
Journal: British Journal of Sports Medicine (2019)

Relative energy deficiency in sport (RED-S)1 is a clinical syndrome encompassing adverse health and performance (figure 1) consequences of low energy availability (LEA)2 in male3 and female exercisers of all ages and all levels from recreational to elite. LEA is a situation where energy intake is insufficient to cover the combined energy demands of training and baseline physiological processes to maintain health. LEA can arise unintentionally or intentionally (figure 2). Unintentional LEA results from …