tbuckley/cabot-search huggingface dataset:
Association of<i>MGMT</i>Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide
Authors: Erica H. Bell, Peixin Zhang, Barbara J. Fisher, David R. Macdonald, Joseph P. McElroy, Glenn J. Lesser, Jessica Fleming, Arup R. Chakraborty, Ziyan Liu, Aline P. Becker, Denise Fabian, Kenneth D. Aldape, Lynn S. Ashby, Maria Werner-Wasik, Eleanor M. Walker, Jean-Paul Bahary, Young Kwok, H. Michael Yu, Nadia N. Laack, Christopher J. Schultz, Heidi J. Gray, H. Ian Robins, Minesh P. Mehta, Arnab Chakravarti
Journal: JAMA Oncology (2018)

The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported.To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes.Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses.Progression-free survival (PFS) and overall survival (OS).Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02).In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status.ClinicalTrials.gov Identifier: NCT00114140.
Abstract 5686: Utilization of fluorescent multiplex IHC and digital image analysis for studying LAG-3, CD3 and CD8 positive TIL subsets in NSCLC tissue
Authors: Malik Khenkhar, Daniel Biljes, Nickels Winkler, Philipp C. Uhlig, Hartmut Juhl, Alison L. Bigley, Lorcan Sherry
Journal: Cancer Research (2018)

Abstract Targeting checkpoint molecules expressed on immune cells has shown promising results in the treatment of non-small cell lung cancer (NSCLC). One interesting molecule that is frequently expressed on exhausted tumor-infiltrating lymphocytes (TIL) is lymphocyte activation gene-3 (LAG-3). We recently implemented chromogenic anti-LAG-3/CD3 dual immunohistochemistry (IHC) and digital image analysis to quantify LAG-3 positive T cells in NSCLC tissue. Here, we extended this work by establishing an anti-LAG-3/CD3/CD8/pan-Cytokeratin (pan-CK) fluorescent multiplex IHC (mIHC) assay followed by digital image analysis to examine the composition of T cells infiltrating NSCLC tissue in more detail. Tyramide signal amplification (TSA) based fluorescent 5-color mIHC (LAG-3/CD3/CD8/pan-CK + DAPI) was developed by Indivumed on the Leica BOND RX automated staining platform and applied to formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples. Image analysis was performed by OracleBio. Tumor and stroma regions of interest (ROI) were classified according to the pan-CK and DAPI signals. LAG-3, CD3 and CD8 single positive cells, as well as dual and triple positive cells, were then quantified in the tumor and stroma ROIs. Fluorescent mIHC allowed for a specific quantification of LAG-3, CD3 and CD8 single, LAG-3/CD3, LAG-3/CD8, CD3/CD8 dual and LAG-3/CD3/CD8 triple labeled cells in the tumor and stroma ROIs of the analyzed NSCLC samples. As part of the assay validation, similar ratios of the differently labeled cells, in particular LAG-3 positive T cells (LAG-3/CD3 dual positive), were observed with fluorescent mIHC and chromogenic IHC, demonstrating a good concordance between the two approaches. Among the analyzed NSCLC samples, different ratios of LAG-3 positive TILs in adeno- and non-adenocarcinoma samples were detected. Determining the ratios of dual or triple positive TIL subsets by mIHC in combination with digital image analysis allows for a clearer understanding of the lymphocyte composition within NSCLC tissue than a simple quantification of LAG-3, CD3 and CD8 single positive cells. Furthermore, such information will contribute to a deeper understanding of the role of LAG-3 positive immune cell sub-populations in the progression and treatment of NSCLC. Citation Format: Malik Khenkhar, Daniel Biljes, Nickels Winkler, Philipp C. Uhlig, Hartmut Juhl, Alison L. Bigley, Lorcan Sherry. Utilization of fluorescent multiplex IHC and digital image analysis for studying LAG-3, CD3 and CD8 positive TIL subsets in NSCLC tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5686.
Abstract 4176: Abrogation of desmoglein 2-mediated c-met activation as a novel therapeutic strategy for reducing anaplastic thyroid cancer metastasis
Authors: Dong G. Lee, Jeong-Ki Min
Journal: Cancer Research (2018)

Abstract Anaplastic thyroid cancer (ATC) is a fast growing and highly metastatic cancer with limited therapeutic options. Thus, targeted therapies need to be developed. This study aims to determine desmoglein 2 (Dsg2) expression in ATC and to elucidate its biological role and potential as a therapeutic target in ATC. Dsg2 expression was low or abnormal in ATC tissues. The ATC patients with reduced Dsg2 expression also had distant metastasis. Dsg2 depletion significantly increased cell migration and invasion, with relatively little effect on ATC cell proliferation in vitro, and increased distant metastasis in vivo. Dsg2 knockdown induced cell motility through the hepatocyte growth factor receptor (HGFR, c-Met)/Src/Rac1 signaling axis, with no alterations in the expression of EMT-related molecules. Further, specific targeting of c-Met significantly inhibited the motility of shDsg2-depleted ATC cells. Decreased membrane expression of Dsg2 increases the metastatic potential of ATC cells. Dsg2 plays an important role in migration and invasiveness in cell lines derived from ATC. Therapies targeting c-Met might be effective for ATC patients with decreased membrane expression of Dsg2. Thus, analysis of Dsg2 expression may provide a novel therapeutic strategy for ATC treatment. Keywords Anaplastic Thyroid Cancer, Desmoglein 2, Metastasis, c-Met, Tivantinib Citation Format: Dong G. Lee, Jeong-Ki Min. Abrogation of desmoglein 2-mediated c-met activation as a novel therapeutic strategy for reducing anaplastic thyroid cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4176.
Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours
Authors: Bumwhee Lee, Kunwoo Lee, Shree Panda, Rodrigo Gonzales-Rojas, Anthony Chong, Vladislav Bugay, Hyo Min Park, Robert Brenner, Niren Murthy, Hye Young Lee
Journal: Nature Biomedical Engineering (2018)
System pressures should be considered in gross negligence manslaughter cases, says BMA
Authors: Gareth Iacobucci
Journal: BMJ (2018)

System pressures and failures should be taken into account by the law when considering individual responsibility in gross negligence manslaughter (GNM) cases following the Bawa-Garba case, the BMA has said.

Doctors unanimously passed a motion backing the move at the BMA’s annual representative meeting Brighton on 28 June. They also unanimously backed calls for an independent body to be given a remit to provide “confidential, professional, no-fault safety incident investigation” in medical cases, in line with how the aviation industry …
Expression profile of the amino acid transporters <scp>SLC</scp> 7A5, <scp>SLC</scp> 7A7, <scp>SLC</scp> 7A8 and the enzyme <scp>TDO</scp> 2 in basal cell carcinoma
Authors: E. Tina, S. Prosén, S. Lennholm, G Gasparyan, M. Lindberg, A. Göthlin Eremo
Journal: British Journal of Dermatology (2018)

The incidence of basal cell carcinoma (BCC) is increasing and the costs for care rising. Therefore, the need for simplified and cost-effective treatment choices is substantial. Aberrant signalling in several pathways, induced by ultraviolet radiation, is of importance in the development of BCC. Alterations in tumour metabolic activity are part of general carcinogenesis; however, these alterations are only partially recognized in skin cancer.To study expression profiles in BCCs compared with individually matched nontumour skin, with a focus on finding differences associated with tumour metabolism.Gene expression in biopsies from BCCs (n = 14) compared with biopsies from nontumour gluteal skin was analysed with microarrays (n = 4 + 4) and/or quantitative real-time polymerase chain reaction (qPCR, n = 14 + 14). Protein expression and localization was assessed using immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded BCC samples.Microarray analysis revealed increased expression of the amino acid transporters SLC7A5, SLC7A7 and SLC7A8 as well as the cytosolic enzyme tryptophan 2,3-dioxygenase (TDO) 2 in BCC. Higher expression of SLC7A5 (P < 0·001), SLC7A8 (P < 0·001) and TDO2 (P = 0·002), but not SLC7A7 (P = 0·50), was confirmed by qPCR, and IHC demonstrated correlating tumour cell protein expression of SLC7A5 and SLC7A8. Protein expression of SLC7A7 was observed in the stratum granulosum, and TDO2 in immune cells.This study highlights the upregulation of SLC7A5, SLC7A8 and TDO2 in BCC compared with nontumour skin. Our findings imply that amino acid transporters may be further explored as potential targets for future medical treatment.
Associations Between Gun Shows and Firearm Deaths and Injuries
Authors: Seth Breitbart
Journal: Annals of Internal Medicine (2018)

Letters3 July 2018Associations Between Gun Shows and Firearm Deaths and InjuriesSeth Breitbart, MDSeth Breitbart, MDEnglewood Hospital, Englewood, New Jersey (S.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0103 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:As Xu correctly states in a previous comment on Matthay and colleagues' article (1), it is already a federal crime for both private individuals and businesses to sell a firearm across state borders without a background check. It is also illegal for a person to buy a gun in a state where he or she does not maintain a residence. Again, as Xu correctly states, a California resident cannot drive to Nevada, buy a firearm, and then travel back to California: Such a transaction is already illegal.If, for example, a California resident wants to buy a ...Reference1. Matthay EC, Galin J, Rudolph KE, Farkas K, Wintemute GJ, Ahern J. In-state and interstate associations between gun shows and firearm deaths and injuries: a quasi-experimental study. Ann Intern Med. 2017;167:837-44. [PMID: 29059689]. doi:10.7326/M17-1792 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Englewood Hospital, Englewood, New Jersey (S.B.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0103. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoIn-State and Interstate Associations Between Gun Shows and Firearm Deaths and Injuries Ellicott C. Matthay , Jessica Galin , Kara E. Rudolph , Kriszta Farkas , Garen J. Wintemute , and Jennifer Ahern Associations Between Gun Shows and Firearm Deaths and Injuries Alan R. Ertle Associations Between Gun Shows and Firearm Deaths and Injuries Ellicott C. Matthay , Jessica Galin , Kriszta Farkas , Kara Rudolph , Garen Wintemute , and Jennifer Ahern Associations Between Gun Shows and Firearm Deaths and Injuries Michael Xu Metrics 3 July 2018Volume 169, Issue 1Page: 65KeywordsConflicts of interestCrimeDisclosureFirearm injuries ePublished: 3 July 2018 Issue Published: 3 July 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Prevalence and Predictors of Provider-Initiated HIV Test Offers Among Heterosexual Persons at Increased Risk for Acquiring HIV Infection — Virginia, 2016
Authors: Karen L. Diepstra, Tina Cunningham, Anne G. Rhodes, Lauren E. Yerkes, Celestine A. Buyu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Since 2006, CDC has recommended routine, provider-initiated human immunodeficiency virus (HIV) screening (i.e., HIV screening at least once in lifetime) for all patients aged 13-64 years in all health care settings (1). Whereas evidence related to the frequency of HIV testing is available, less is known about the prevalence and predictors of providers' HIV test offers to patients (2). National HIV Behavioral Surveillance (NHBS) data from Virginia were used to examine the prevalence and predictors of provider-initiated HIV test offers to heterosexual adults aged 18-60 years at increased risk for HIV acquisition. In a sample of 333 persons who visited a health care provider in the 12 months before their NHBS interview, 194 (58%) reported not receiving an HIV test offer during that time, approximately one third of whom (71, 37%) also reported never having had an HIV test in their lifetime. In multivariable analysis, the prevalence of HIV test offers was significantly lower among men than among women (adjusted prevalence ratio [aPR] = 0.72; 95% confidence interval [CI] = 0.53-0.97). Provider-initiated HIV test offers are an important strategy for increasing HIV testing among heterosexual populations; there is a need for increased provider-initiated HIV screening among heterosexual adults who are at risk for acquiring HIV, especially men, who were less likely than women to be offered HIV screening in this study.
WIC Participation and Blood Lead Levels among Children 1–5 Years: 2007–2014
Authors: Yutaka Aoki, Debra J. Brody
Journal: Environmental Health Perspectives (2018)

Background: The CDC recommends a targeted strategy for childhood blood lead screening based on participation in federal programs, such as Medicaid and the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Yet, there is scarcity of data on blood lead levels (BLLs) among WIC participants. Objective: Our objective was to investigate whether children participating in WIC and not enrolled in Medicaid, who have not been targeted in the historical Medicaid-focused screening strategy, have higher BLLs than children in neither of these programs. Methods: The analysis included 3,180 children 1–5 y of age in the National Health and Nutrition Examination Surveys conducted in 2007–2014. Log-binomial regression, which allows direct estimation of prevalence ratios, was used to examine associations between WIC participation (in conjunction with Medicaid enrollment) and having BLLs ≥5μg/dL with adjustment for age (1–2 vs. 3–5 y). Results: The percentage of children participating in "WIC only," "Medicaid only," "both WIC and Medicaid," and "neither" were 18.9%, 10.8%, 25.4%, and 44.9%, respectively. "WIC only," "Medicaid only," and "both WIC and Medicaid" children were more likely to have BLLs ≥5μg/dL than children who were not enrolled in either program, with adjusted prevalence ratios of 3.29 [95% confidence interval (CI): 1.19, 9.09], 4.56 (95% CI: 2.18, 9.55), and 2.58 (95% CI: 1.18, 5.63). Conclusions: Children participating in WIC but not Medicaid were more likely to have BLLs ≥5μg/dL than children who were not enrolled in either program. These findings may inform public health recommendations and clinical practice guidelines. https://doi.org/10.1289/EHP2384
Professional fees calculator to be produced by BMA
Authors: Tom Moberly
Journal: BMJ (2018)

A tool allowing doctors to calculate what they should charge for services they provide outside their NHS contract is being developed by the BMA.

Charges calculated by the new tool will be based on estimates of the time taken to complete the work, Peter Holden, chair of the BMA’s professional fees committee, said.

Doctors will input the hourly rate they want to charge, Holden told delegates at the BMA annual representative meeting in Brighton on 25 June. The tool will then …
Can We RISE to the Challenge of Youth-Onset Type 2 Diabetes?
Authors: John B. Buse, David A. D’Alessio, Matthew C. Riddle
Journal: Diabetes Care (2018)

Over the past three decades, type 2 diabetes (T2D) in adolescents has become steadily more prevalent (1), raising the specter of increasing rates of premature micro- and macrovascular disease as affected youth move into adulthood. While T2D in adolescents is clearly linked to obesity, there is otherwise no explanation for the sudden appearance of what had previously been an adult condition in young people. Despite a steadily growing body of evidence descriptive of T2D in youth (2,3), there is a paucity of information comparing diabetic phenotypes in adults and teenagers. This issue of Diabetes Care contains three papers from the Restoring Insulin Secretion (RISE) Consortium (4–6) that provide the most direct examination of this question yet, with the potential for new understanding of T2D.

Present understanding of the pathophysiology of T2D holds that insulin resistance, generally a consequence related to increased adiposity, requires hyperfunction of pancreatic β-cells to maintain glucose tolerance. People whose β-cells cannot make this compensation progress to steadily worsening states of dysglycemia over time (7). Moreover, although insulin resistance does not necessarily cause β-cell failure, hyperglycemia and its associated metabolic disturbances do, such that insufficiently treated diabetes begets more severe diabetes (8). There is evidence in adults with prediabetes that interventions to alleviate insulin resistance (9) or minimize hyperglycemia (10) reduce progression to worse glucose tolerance. Similarly, intensive glucose lowering in adults with T2D can improve hyperglycemia and mitigate the typical course of disease (11). These findings provide the rationale for the RISE Consortium’s efforts (12).

The RISE design paper, published in 2014, provides details of this project (12). Three intervention protocols were established, two in adults and one in children, all testing whether β-cell function and metabolic control could be effectively altered by specific interventions. All three studies recruited and randomized …
Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure
Authors: Oriana Ciani, Massimo Piepoli, Neil Smart, Jamal Uddin, Sarah Walker, Fiona C. Warren, Ann D. Zwisler, Constantinos H. Davos, Rod S. Taylor
Journal: JACC Heart Failure (2018)

This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL).EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (Vo2peak) or through submaximal tests, such as the 6-min walk test (6MWT).After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome.Exercise-based CR is associated with positive effects on EC measured through Vo2peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (Vo2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for Vo2peak and 80 m for 6MWT to predict a significant improvement in HRQOL.The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions.