tbuckley/cabot-search huggingface dataset:
Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers
Authors: Suzanne J. Forrest, Alyaa Al-Ibraheemi, Duong Doan, Abigail Ward, Catherine M. Clinton, Juan Putra, R. Seth Pinches, Cigall Kadoch, Susan N. Chi, Steven G. DuBois, Patrick J. Leavey, Nicole R. LeBoeuf, Elizabeth Mullen, Natalie Collins, Alanna J. Church, Katherine A. Janeway
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors. Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing. Results: SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors. Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
Somatic mutations of EGFR and KRAS in pure bronchioloalveolar carcinomas and adenocarcinomas of the lung with bronchioloalveolar features
Authors: I. J. Dahabreh, S. Murray, H. T. Spiliadi, E. A. Karagiani, A. Stamatelopoulos, K. Vassilikos, G. Zanos, J. Janinis, J. Dahabreh
Journal: Journal of Clinical Oncology (2007)

21111 Background: EGFR mutations are more common in lung cancers from female, non-smoking patients of Asian ethnicity with adenocarcinoma histology. We investigated the relationship between clinicopathologic parameters and mutations of EGFR and KRAS in patients with pure bronchioloalveolar carcinomas (BACs) and adenocarcinomas (ADCs) with BAC features, not previously treated with EGFR inhibitors. Methods: We retrospectively reviewed the files of patients who were diagnosed with pure BACs or ADCs with BAC features between February 2001 and May 2005. Demographics, stage and smoking histories were recorded. Paraffin embedded tissue blocks were retrieved and re-examined using the WHO 1999/2004 histological criteria for lung cancers. EGFR expression, detected by immunohistochemistry, was scored from 0 to +3. Expression was considered positive when the score was +1, or higher. DNA was isolated from paraffin blocks (containing at least 75% tumor cell content) and exons 18–21 of the EGFR gene and exon 2 of the KRAS gene were amplified by PCR and bi-directionally sequenced. The chi-squared test and regression analysis were used to identify parameters correlating with EGFR or KRAS mutations. Results: A total of 46 patients were eligible for this study. Tissue was available from 43 patients, 19 with pure BAC and 24 with ADC with BAC features. There were 27 (62.8%) males and 16 (37.2%) females, all of Greek descent. Mean age was 62.7 years (range, 41–79). There were 34 smokers and former smokers (79%) and 9 never-smokers (21%). Tumors were classified as mucinous (20), non- mucinous (19) or mixed (4). We detected somatic EGFR mutations in 7 patients (including common mutations, delEx19, L858R, G719C), and KRAS codon 12 mutations in 13 patients. EGFR and KRAS mutations were mutually exclusive. No clinicopathologic parameters correlated with the presence of EGFR or KRAS mutations. Conclusions: Among Greek lung cancer patients with pure BACs or ADCs with BAC features, unselected for response to EGFR inhibitors, the incidence of KRAS or EGFR mutations was 30.2% and 16.3% respectively. EGFR and KRAS mutations were mutually exclusive but no clinicopathologic factor predicted the presence of mutations in either gene. Further molecular analysis is ongoing. No significant financial relationships to disclose.
Abstract P3-08-11: The application of machine learning techniques to standardize breast cancer grading and develop multivariate risk outcome models
Authors: Marcel Prastawa, Abishek Sainath Madduri, Brandon Veremis, Alexander Shtabsky, Bahram Marami, Jack Zeineh, Michael Joseph Donovan, Gerardo Fernandez
Journal: Cancer Research (2020)

Abstract Background: The 2019 NCCN guidelines and the College of American Pathology (CAP) endorse consistent, unambiguous comprehensive pathology reporting for invasive breast cancer. Challenges surrounding inter-pathologist variability and the lack of quantitative, standardized approaches to histologic grade are significant and critical to patient management. We developed an automated multi-network machine learning platform for histologic grading and examined performance with clinical outcome. Methods: Using the Cancer Genome Atlas (TCGA) breast cancer (BCA) image dataset and clinical data as a training cohort, we evaluated 420 conventional H&amp;E images (one slide per patient). An artificial intelligent (AI) / deep-learning based workflow is used to normalize staining differences, identify regions of tumor vs. normal and characterize individual cellular attributes of breast cancer grading systems including overall gland structure, nuclear morphology, and mitotic figures. Individual features were correlated with overall survival using the concordance index (c-index). Support vector models and Kaplan-Meier incidence curves were used to further understand feature importance. Results: Using the AI platform, 88 image features representing BCA gland morphology and cellular-nuclear attributes were generated from 420 patients with 36 events including metastasis and or death with a median overall survival (OS) of 5-years. Three clinical variables were available including AJCC stage, grade and age at diagnosis. Image features were prioritized on C-index &amp;lt;0.5 or &amp;gt;0.5 which reflects increased or reduced risk of poor outcome, respectively. A training model consisting of image features + clinical data produced a C-index of 0.85, Hazards ratio 11, p&amp;lt;0.001. Only 1 clinical feature (stage) and 9 imaging features (all with individual c-indices &amp;lt;0.5) representing nuclear shape, size, number and mitotic figure activity were selected. Conclusions: Our innovative lab-based AI / deep-learning platform produced accurate BCA risk models to predict metastasis and OS through automated H&amp;E BCA grading. Future analyses include a multi-site validation study to confirm these initial training results. Citation Format: Marcel Prastawa, Abishek Sainath Madduri, Brandon Veremis, Alexander Shtabsky, Bahram Marami, Jack Zeineh, Michael Joseph Donovan, Gerardo Fernandez. The application of machine learning techniques to standardize breast cancer grading and develop multivariate risk outcome models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-11.
Unilateral Leptomeningeal Enhancement in Myelin Oligodendrocyte Glycoprotein Immunoglobulin G–Associated Disease
Authors: Adrian Budhram, Amy C. Kunchok, Eoin P. Flanagan
Journal: JAMA Neurology (2020)

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Associations Between Racial and Ethnic Groups and Foot Self-Inspection in People With Diabetes
Authors: Alyson J. Littman, Catherine J. Knott, Edward J. Boyko, Stephen E. Hawes
Journal: Diabetes Care (2020)

OBJECTIVE Daily foot self-inspection may permit earlier detection and treatment of a foot lesion, reducing the risk of infection and lower-limb amputation (LLA). Though race and ethnicity are strongly associated with LLA risk, with higher risk seen in African Americans (AA), American Indians/Alaska Natives (AI/AN), and Native Hawaiians/Pacific Islanders (NH/PI), associations between foot self-inspection and racial and ethnic groups are inconsistent. We aimed to assess differences in foot self-inspection among people with diabetes by race/ethnicity. RESEARCH DESIGN AND METHODS Using national, cross-sectional data from the 2015–2017 Behavioral Risk Factor Surveillance System surveys and including 88,424 individuals with diabetes, we estimated prevalence ratios (PRs) and associated 95% CIs of daily foot checking for sores or irritation by racial and ethnic groups using log-binomial linear regression models, after accounting for survey weights. RESULTS Compared with whites (who had a weighted prevalence [P] of daily foot self-inspection of 57%), AA (P 67%, PR 1.18 [95% CI 1.14, 1.23]), AI/AN (P 66%, PR 1.15 [95% CI 1.07, 1.25]), and NH/PI (P 71%, PR 1.25 [95% CI 1.03, 1.52]) had higher prevalences of daily foot self-inspection. The prevalence of daily foot inspection was significantly lower among Asians (P 35%, PR 0.62 [95% CI 0.48, 0.81]) and Hispanics (P 53%, PR 0.93 [95% CI 0.88, 0.99]) compared with whites. Associations did not vary importantly by insulin use, years since diabetes diagnosis, or having received diabetes self-management education. CONCLUSIONS The higher frequency of foot self-inspection in racial and ethnic groups at elevated risk of diabetes-related LLA is not sufficient to eliminate LLA disparities; additional interventions are needed to achieve this aim.
Understanding the challenges faced by adolescents and young adults with allergic conditions: A systematic review
Authors: Marta Vazquez‐Ortiz, Elizabeth Angier, Katharina Blumchen, Pasquale Comberiati, Bettina Duca, Audrey DunnGalvin, Claudia Gore, Valérie Hox, Britt Jensen, Helena Pite, Alexandra F. Santos, Silvia Sanchez, Cherry Alviani, Teresa Garriga‐Baraut, Rebecca Knibb, Charlotte G. Mortz, M. Hazel Gowland, Frans Timmermans, Graham Roberts
Journal: Allergy (2020)

Abstract Background Adolescence represents a vulnerable time for individuals with asthma and allergic conditions. They suffer an unexpected degree of morbidity. This systematic review aimed to understand the challenges faced by adolescents and young adults with these conditions. Methods A systematic literature search was undertaken across eight databases. References were checked by two reviewers for inclusion. Study data were extracted, and their quality was assessed in duplicate. A narrative meta‐synthesis was undertaken. Results A total of 108 papers describing 106 studies were retrieved, most focused on asthma. Five themes were identified across studies: (a) Health‐related quality of life—impairment was associated with poor disease control, psychosocial issues, adolescent‐onset allergic disease and female sex; (b) Psychological factors—asthma and food allergy were associated with anxiety and depression, atopic dermatitis was associated with suicidal ideation, and that parental emotional support may be protective; (c) Adherence—suboptimal adherence was associated with older age, barriers to medication usage, poor symptom perception and failure to take responsibility, and positive factors were routines, simpler treatment regimes, better knowledge and perceptions about medications; (d) Self‐management—facilitated by education, knowledge and a positive attitude; and (e) Supportive relationships—families could modify barriers to adherence and foster positive views about self‐management, adolescents suggested that their peers should be more involved in supporting them, and adolescents also wished to have support from nonjudgemental healthcare professionals. Conclusions We have some understanding of the challenges faced by adolescents with asthma, less so for other allergic conditions. This knowledge will be used to support guidelines for managing adolescents.
Ets1 regulates the differentiation and function of iNKT cells through both Pointed domain-dependent and domain-independent mechanisms
Authors: Tzong-Shyuan Tai, Hsiao-Wei Tsao, Wan-Chu Chuang, Chih-Chun Liu, Yu-Wen Huang, Peter Oettgen, Ya-Ting Chuang, I-Cheng Ho
Journal: Cellular and Molecular Immunology (2020)
Abstract 17: Comparative Effectiveness of Implementation Strategies on Cardiovascular Risk Factor Control in Patients With Diabetes: The D4C Cluster Randomized Trial
Authors: Jiang He, Xiulin Shi, Mingzhu Lin, Changqin Liu, Bing Yan, Haiqu Song, Caihong Wang, Fangsen Xiao, Peiying Huang, Liying Wang, Mulin Zhang, Yinxiang Huang, Weihua Li, Shuyu Yang, Guanhua Yao, Xuejun Li
Journal: Circulation (2020)

Objectives: Uncontrolled blood glucose, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) are major risk factors for premature death and cardiovascular disease (CVD) in patients with diabetes. We compared the effectiveness of team-based care (TBC) with clinical decision support systems (CDSS) versus TBC alone on CVD risk factor control among patients with diabetes in China. Methods: In the Diabetes Complication Control in Community Clinics (D4C) cluster randomized trial, 38 community health centers were randomly assigned to TBC-CDSS (primary care physician-health educator-diabetes specialist collaborative care plus guideline-based treatment protocol implemented in CDSS) or TBC alone in Xiamen City, China. A total of 11,132 patients (5378 in TBC-CDSS and 5754 in TBC) aged ≥50 years with uncontrolled diabetes and additional risk factors (dyslipidemia, hypertension, or clinical CVD) were recruited. The intervention lasted for 18 months, and study data were collected at 6, 12, and 18 months after baseline. Results: Mean baseline age (62.6 vs. 63.1 years), body mass index (24.9 vs. 24.9 kg/m 2 ), HbA1c (8.8 vs. 8.7%), LDL-C (121.2 vs. 121.1 mg/dL), systolic BP (136.6 vs. 136.9 mm Hg) and diastolic BP (79.7 vs. 79.8 mmHg) were comparable between TBC-CDSS and TBC alone groups. About 87.1% of participants in the TBC-CDSS group and 84.1% in the TBC alone group completed the 18-month intervention. Both TBC-CDSS and TBC alone significantly reduced HbA1c, LDL-C, and BP over the 18-month follow-up (all P&lt;0.0001). Furthermore, the proportions of controlled HbA1c, LDL-C, and BP, as well as all 3 risk factors, were significantly higher in the TBC-CDSS group compared to the TBC alone group (Table). Conclusions: As compared with team-based care alone, team-based care plus a guideline-based treatment protocol implemented in clinical decision support systems further reduces CVD risk factors in patients with diabetes. (ClinicalTrials.gov number, NCT02835287)
Glutamine transporters as pharmacological targets: From function to drug design
Authors: Mariafrancesca Scalise, Lorena Pochini, Michele Galluccio, Lara Console, Cesare Indiveri
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Among the different targets of administered drugs, there are membrane transporters that play also a role in drug delivery and disposition. Moreover, drug-transporter interactions are responsible for off-target effects of drugs underlying their toxicity. The improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption, delivery and side effect production. A peculiar group of proteins with great relevance to pharmacology is constituted by the membrane transporters responsible for managing glutamine traffic in different body districts. The interest around glutamine metabolism lies in its physio-pathological role; glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous synthesis. Then, glutamine transporters provide cells with this special nutrient. Among the glutamine transporters, SLC1A5, SLC6A14, SLC6A19, SLC7A5, SLC7A8 and some members of SLC38 family are the best characterized, so far, in both physiological and pathological conditions. Few 3D structures have been solved by CryoEM; other structural data on these transporters have been obtained by computational analysis. Interactions with drugs have been described for several transporters of this group. For some of them, the studies are at an advanced stage, for others, the studies are still in nuce and novel biochemical findings open intriguing perspectives.
Molecular remission to imatinib-IFN-alpha combination or imatinib monotherapy in chronic myeloid leukemia (CML) patients
Authors: A. Liberati, M. Schippa, D. Luzi, L. Falchi, R. Emili, V. Capparella, P. Cerroni, E. Gentileschi, E. Gottardi, G. Saglio
Journal: Journal of Clinical Oncology (2007)

17512 Background: Continously improving results have been obtained in the control of Philadelphia chromosome (Ph’) positive CML. However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. Evaluation of the rate of complete molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests over a period of 3 mths or more) to imatinib or to imatinib-IFNa combination as first, second or subsequent line of therapy. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, 21 patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 13 patients were treated with the imatinib-IFNa combination as second (7,G4) or third (6,G5) line therapy, but in two cases IFNa was discontinuated after one month because of intolerance to treatment. Methods: Molecular response was evaluated by NESTED/RT-PCR (Guo JQ et al.; Leukemia:2002;15:2447–53) and RQ-PCR (Gabert J et al. Leukemia:2003;17:2318–57) at time intervals of 3–6 months from the beginning of therapy. Results: Complete molecular remission lasting 3 months or more (range 3–34) was obtained in 15 of 44 evaluable patients (therapy duration = 11 mths, range 11–73).The response rate was higher in patients receiving imatinib- IFNa combination given as first or second line therapy (5/13) than in those given imatinib monotherapy (9/37). In 7 of the 15 complete responders, remission duration lasted more than 12 mths (range 12–34) with 6/7 pts still continuous remission. In further 6 cases continuous remission duration ranged from 3–8 mths while in one case fluctuating negative-positive NESTED/RT-PCR tests have been observed over a period of 65 months. Conclusions: It is not possible to draw any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’positive clone control. No significant financial relationships to disclose.
Abstract 12561: Family History of Premature Myocardial Infarction Modifies the Association Between Bilateral Oophorectomy and Heart Disease Mortality in a National Cohort of Postmenopausal Women
Authors: Duke Appiah, Chike C Nwabuo, Damilola R Owoade, Jaffer Samad, Imo Ebong, Stephen Winters
Journal: Circulation (2019)

Introduction: The association of bilateral salpingo-oophorectomy (BSO) and coronary heart disease (CHD) is controversial. Women who undergo BSO at an earlier age (< 45 years) tend to have a higher ...
Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells
Authors: Ken-Ichi Suehiro, Akira Suto, Kensuke Suga, Hiroki Furuya, Arifumi Iwata, Taro Iwamoto, Shigeru Tanaka, Takahiro Kageyama, Kotaro Suzuki, Koichi Hirose, Véronique Lefebvre, Hiroshi Nakajima
Journal: Cellular and Molecular Immunology (2020)
Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia
Authors: Robert J. Autry, Steven W. Paugh, Robert Carter, Lei Shi, Jingjing Liu, Daniel C. Ferguson, Calvin E. Lau, Erik J. Bonten, Wenjian Yang, J. Robert McCorkle, Jordan A. Beard, John C. Panetta, Jonathan D. Diedrich, Kristine R. Crews, Deqing Pei, Christopher J. Coke, Sivaraman Natarajan, Alireza Khatamian, Seth E. Karol, Elixabet Lopez-Lopez, Barthelemy Diouf, Colton Smith, Yoshihiro Gocho, Kohei Hagiwara, Kathryn G. Roberts, Stanley Pounds, Steven M. Kornblau, Wendy Stock, Elisabeth M. Paietta, Mark R. Litzow, Hiroto Inaba, Charles G. Mullighan, Sima Jeha, Ching-Hon Pui, Cheng Cheng, Daniel Savic, Jiyang Yu, Charles Gawad, Mary V. Relling, Jun J. Yang, William E. Evans
Journal: Nature Cancer (2020)
Abstract P195: Lipoprotein and Metabolite Biomarkers for Coronary and Peripheral Artery Disease: Blood Biomarker Profiling of 32,000 Individuals From Five Prospective Studies
Authors: Emmi Tikkanen, Linda Mustelin, Viljami Aittomaki, Maria Kalimeri, Pekka Jousilahti, Markus Perola, Mika J Ala-Korpela, Veikko V Salomaa, Peter Würtz
Journal: Circulation (2020)

Background: Coronary artery disease (CAD) and peripheral artery disease (PAD) share pathogenesis, but the evidence of metabolic risk factors underlying PAD risk is limited. We conducted detailed metabolic profiling of incident CAD and PAD to identify novel risk factors and clarify pathogenesis for these diseases. Methods: We measured circulating blood biomarkers using an NMR metabolomics in four large prospective studies from Finland (national FINRISK and Health 2000 studies, total n = 32,607). We used Cox proportional hazard modelling to estimate associations between biomarkers and incident CAD and PAD ( n events = 2010 and 464, respectively, during the median follow-up time of 14 years). Results: High VLDL-C increased the risk for CAD (HR=1.30, 95% CI 1.24-1.35 per SD-change), but not PAD (HR=1.09, 95% CI 0.99-1.21). Moreover, LDL-C and apolipoprotein B were only associated with CAD (HR=1.13, 95% CI 1.08-1.19; HR=1.29, 95% CI 1.23-1.35), whereas high triglycerides in LDL and VLDL increased the risk for both endpoints. Glycolysis-related metabolites (glucose, lactate, pyruvate and glycerol), amino acids (phenylalanine, alanine and glutamine) and inflammation biomarker glycoprotein acetyls (GlycA) showed stronger associations with PAD. Biomarker score showed stronger risk discrimination of high-risk individuals for incident PAD when compared to traditional CVD risk factors, suggesting that measuring these biomarkers could help to detect high-risk individuals better than currently used risk factors. Conclusions: We identified novel biomarkers for cardiovascular endpoints showed that the associations of these biomarkers were actually stronger for PAD compared to the CAD. Novel biomarkers could be used to guide the development of new therapies and improve the detection of high-risk individuals for these diseases. Figure. Associations between metabolic biomarkers and incident PAD and CAD.