tbuckley/cabot-search huggingface dataset:
Role of the IgE variable heavy chain in FcεRIα and superantigen binding in allergy and immunotherapy
Authors: Wai-Heng Lua, Chinh Tran-To Su, Joshua Yi Yeo, Jun-Jie Poh, Wei-Li Ling, Ser-Xian Phua, Samuel Ken-En Gan
Journal: Journal of Allergy and Clinical Immunology (2019)

Variable heavy chain (VH) family frameworks (FWRs) have been reported to affect antibody receptor and superantigen binding; however, such effects in IgE remain largely unknown. Given that VH family biases have been previously reported in IgE of certain allergies, there is a need to investigate this phenomenon for biotechnological and therapeutic purposes.We sought to investigate the effects of VH families on IgE interaction with FcεRIα, anti-IgE omalizumab, antigen, and superantigen protein A (spA) by using the pertuzumab and trastuzumab IgE models.Pertuzumab VH1-VH7 family variants of IgE with the same complementarity-determining regions were investigated with regard to their binding interactions to FcεRIα, Her2, omalizumab, and spA. Notable FcεRIα-IgE observations were cross-checked against appropriate trastuzumab IgE VH variants. Computational structural modeling and simulations were also performed for insight into the mechanism of interactions with various VH FWRs.The pertuzumab VH5 IgE variant, but not the trastuzumab VH5 IgE, was found to interact with FcεRIα significantly longer than the respective VH family variants within each model antibody. No significant differences in interaction were found between IgE and omalizumab for the pertuzumab VH variants. Although trastuzumab VH3 interacted with spA, none of our pertuzumab VH variants, including VH3, associated with spA.We found unexpected varying allosteric communications caused by the VH family FWRs to the FcεRIα-, Her2-, and spA-binding regions of pertuzumab IgE, with implications for use of IgE/anti-IgE therapeutics to treat allergy and IgE therapeutics in allergo-oncology.
Squamousness: Next-generation sequencing to reveal shared molecular features across squamous tumor types.
Authors: Maria Clemence Schwaederle, Sheryl Krevsky Elkin, Brett N. Tomson, Jennifer Carter, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2015)

11099 Background: In order to gain a better understanding of the underlying biology of squamous cell carcinoma (SCC), we tested the hypothesis that SCC originating from different organs may possess common molecular alterations. Methods: SCC samples (N = 361) were examined using clinical-grade targeted next-generation sequencing (NGS) (182 or 236 cancer-related genes). Results: The most frequent SCC tumor types were head and neck, lung, cutaneous, gastrointestinal and genitourinary. The most common gene alterations were TP53 (64.5% of patients), PIK3CA (28.5%), CDKN2A (24.4%), SOX2 (17.7%), and CCND1 (15.8%). By comparing NGS results of our SCC cohort to a non-SCC cohort (N = 277), we found that CDKN2A, SOX2, NOTCH1, TP53, PIK3CA, CCND1, and FBXW7 were significantly more frequently altered, unlike KRAS, which was less frequently altered in SCC specimens (all P < 0.05; multivariable analysis). Therefore, we identified “squamousness” gene signatures (TP53, PIK3CA, CCND1, CDKN2A, SOX2, NOTCH 1, and FBXW7 aberrations, and absence of KRAS alterations) that were significantly more frequent in SCC versus non-SCC histologies. A multivariable co-alteration analysis established two SCC subgroups: (i) patients in whom TP53 and cyclin pathway (CDKN2A and CCND1) alterations strongly correlated but in whom PIK3CA aberrations were less frequent; and (ii) patients with PIK3CA alterations in whom TP53 mutations were less frequent (all P ≤ 0.001, multivariable analysis). Conclusions: We identified a set of eight genes altered with significantly different frequencies when SCC and non-SCC were compared, suggesting the existence of patterns for “squamousness.” Targeting the PI3K-AKT-mTOR and/or cyclin pathway components in SCC may be warranted.
Abstract P001: Life′s Simple 7 in Middle-age and Prognosis After Myocardial Infarction in Later Life
Authors: Yejin Mok, Yingying Sang, Shoshana H Ballew, Casey M Rebholz, Gerardo Heiss, Aaron Folsom, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2017)

Background: The AHA recommends focusing on seven traditional risk factors (Life’s Simple 7) for cardiovascular health promotion, primarily based on their impact on the risk of incident cardiovascular disease. However, the contribution of Life’s simple 7 in mid-life to prognosis after myocardial infarction (MI) in later life is unknown. Methods: In 13,500 participants from the Atherosclerosis Risk in Communities (ARIC) study (age 45-64 years) at Visit 1 (1987-1989), a 14-point score of Life’s simple 7 was constructed according to the status of each of seven factors (smoking, body mass index, physical activity, dietary quality, total cholesterol, blood pressure, and fasting glucose). We quantified the association between this score and adverse outcomes after validated incident hospitalized MI occurring during ARIC follow-up, using Cox proportional hazards models adjusting for age at MI, gender, race, and year of MI occurrence. Results: 1,341 participants had a definite or probable hospitalized MI after the ARIC baseline visit (median elapsed time between baseline and MI occurrence, 24.4 years [IQR 17.5-25.4]). Of these, 807 (60%) had cardiovascular outcomes of interest after MI during a median follow-up of 3.0 years. Higher Life’s Simple 7 score (better cardiovascular health) in middle-age was associated with lower risk of adverse outcomes after MI in later life (Table). For example, individuals with Life’s Simple 7 score ≥10 had 50-80% lower risk of cardiovascular mortality, recurrent MI, and heart failure compared to those with score ≤3. The associations were largely consistent across years of MI occurrence and when we restricted the follow-up after MI to 1-3 years. Conclusion: A better AHA Life’s Simple 7 in middle-age was associated not only with lower incidence but also with a lower risk of adverse outcomes after MI in later life. Our findings suggest a secondary prevention benefit of striving for ideal CV health status in mid-life, further supporting AHA promotion of Life’s Simple 7.
SAT-276-Point shear wave elastography by ElastPQ accurately stages hepatic fibrosis in patients with NAFLD: A prospective, multicentric study
Authors: David JM Bauer, Dr. Vladimir Matic, Dr. Ruxandra Mare, Dr. Laura Maiocchi, David Chromy, Theresa Bucsics, Sanda Mustapic, loan Sporea, Giovanna Ferraioli, Thomas Reiberger, Ivica Grgurevic
Journal: Journal of Hepatology (2019)
Direct-to-Consumer Genetic Testing and Potential Loopholes in Protecting Consumer Privacy and Nondiscrimination
Authors: Rachele M. Hendricks-Sturrup, Anya E. R. Prince, Christine Y. Lu
Journal: JAMA (2019)

This Viewpoint discusses privacy and discrimination issues raised when direct-to-consumer (DTC) genetic testing companies give law enforcement agencies access to their data, and gaps in nondiscrimination and HIPAA regulations protecting consumers of DTC genetic testing more generally.
Characterization of bacteremia and healthcare cost burden in ALL patients admitted with febrile neutropenia at a children’s hospital.
Authors: Brenna Eldridge, Elizabeth D Knackstedt, E. Kent Korgenski, Chris Stockmann, Elizabeth A. Raetz, Richard S. Lemons, Joshua David Schiffman, Anne Blaschke
Journal: Journal of Clinical Oncology (2015)

e21036 Background: Febrile neutropenia (FN) is a potentially life-threatening complication of chemotherapy in children. Few large analyses have described the etiology, prevalence, outcomes and healthcare costs of bacteremia in children with acute lymphoblastic leukemia/lymphoma (ALL) admitted with FN. Methods: We performed a retrospective study of children with ALL admitted to Primary Children’s Hospital (Salt Lake City, UT) with FN between January 1, 2009 and October 1, 2013. Our FN cohort was identified through the Intermountain Healthcare cancer registry and Enterprise Data Warehouse. An FN episode required an absolute neutrophil count < 500/µL, and blood culture obtained with administration of an anti-pseudomonal antibiotic within one day of hospital admission. Patients with infantile leukemia and relapsed disease were excluded. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) are reported for all regression model results. Results: 374 episodes of FN were identified in 180 children, aged 1-24 years. Positive blood cultures were identified in 37 FN episodes (10%). The most common pathogens identified were S. aureus (19%), E. coli (19%) and Viridans streptococci (14%). P. aeruginosa was detected in 2 episodes (5%). PICU admission was required in 31 (8%) of FN cases, of which 10 (27%) had positive blood cultures. Compared to children with negative blood cultures, children with bacteremia were more likely to be taking steroids (OR: 2 [95% CI: 1.4-4.8]), require PICU admission (OR: 4.3 [95% CI: 2.2-8.5]), have a longer length of stay (OR: 2.2 [95% CI: 1.7-2.9]), have increased hospital costs (OR: 2.3 [95% CI: 1.5-3.4]), and die (OR: 4.6 [95% CI: 0.4-49.9]). During Induction therapy, there were 30 re-admissions for FN, and 13 (43%) cases of bacteremia. Conclusions: Among children with ALL admitted with FN, those with bacteremia experienced more serious clinical outcomes and greater financial burden than those without bacteremia. Steroid use was more common in patients that developed bacteremia. Induction therapy carried an unexpectedly high rate of bacteremia, highlighting the risk of infection during this phase of treatment.
Impact of socioeconomic status (SES) and ethnicity on melanoma presentation and recurrence in Caucasian patients.
Authors: Christine Salvaggio, Sung Won Han, Kathryn Martires, Eric M. Robinson, Reshmi Madankumar, Priyanka Gumaste, David Polsky, Jennifer Stein, Russell S. Berman, Richard L. Shapiro, Judy Zhong, Iman Osman
Journal: Journal of Clinical Oncology (2015)

e20098 Background: Melanoma is most prevalent in Caucasians of higher SES. While several studies have reported survival disparities in minority melanoma patients compared to Caucasians, the impact of ethnicity and SES among Caucasians are not well studied. Methods: We studied a prospectively enrolled cohort of patients presenting to NYU with primary melanoma. Ethnicity was self-reported by all patients and patients with unknown ethnic background were excluded from the study. SES data was obtained from the United States’ Census Bureau. Patient’s zip codes were matched with the corresponding median household income (MHI). As Ashkenazi Jewish (AJ) patients represent a significant proportion of our patient population, we evaluated the associations between ethnicity classified as AJ versus Caucasian non-AJ, SES classified as below versus above the MHI for the cohort, and baseline tumor characteristics using Chi-square test. We also compared the distributions of time-to-recurrence between groups using Kaplan-Meier and Log rank tests. Results: Of the 1,366 patients included, AJ represented 31% (n = 421). Apart from AJ patients being older in age at presentation (p < 0.001), no significant differences were observed in baseline characteristics or recurrence rate between AJ and Caucasian non-AJ. There was no association between ethnicity and MHI. Patients with lower than the MHI for the cohort ( < 90K) were significantly more likely to present with thicker and ulcerated tumors (p < 0.001), mitoses (p = 0.002), positive lymph nodes (p = 0.006) and more advanced stages (p < 0.001) as compared to patients with higher than the MHI. Shorter time to recurrence was observed in the lower versus higher income patients (469 vs. 559 days, p = 0.05). Conclusions: Our data suggest that disparities in melanoma presentation in Caucasians stratify according to income independent of ethnic background. Established methodology of measuring SES with respect to the US median income may fail to capture the impact of SES within higher socioeconomic groups at greatest risk for melanoma. More work is needed to better understand the variables contributing to melanoma disparities within higher income Caucasian groups.
Variability in Antinuclear Antibody Testing to Assess Patient Eligibility for Clinical Trials of Novel Treatments for Systemic Lupus Erythematosus
Authors: David S. Pisetsky, Dana Kathryn Thompson, Joseph Wajdula, Annette Diehl, Sudhakar Sridharan
Journal: Arthritis & Rheumatology (2019)

Objective In the development of novel therapies for systemic lupus erythematosus, antinuclear antibody ( ANA ) positivity represents a criterion for trial eligibility. Since as many as 30% of patients enrolled in trials have been ANA negative, we evaluated the performance characteristics of immunofluorescence assays ( IFA s) for ANA determinations for screening. Methods This study used 5 commercially available IFA s to assess the ANA status of 181 patients enrolled in a phase II clinical trial for an anti–interleukin‐6 antibody. Enrollment included a detailed review of medical records to verify a historical ANA value. IFA results were related to various clinical and serologic features at enrollment. Results While the frequency of ANA negativity assessed by the central laboratory was 23.8% in a cohort of 181 patients, the evaluated IFA kits demonstrated frequencies of negativity from 0.6 to 27.6%. With 2 IFA kits showing a significant frequency of ANA negativity, positive and negative samples differed in levels of anti–double‐stranded DNA , C3, and presence of other ANA s as well as the frequency of high interferon ( IFN ) expression. Conclusion These findings indicate that, when used for screening, IFA s can vary because of performance characteristics of kits and thus can affect determination of trial eligibility. With kits producing a significant frequency of ANA negativity, ANA status can be associated with other serologic measures as well as the presence of the IFN signature, potentially affecting responsiveness to a trial agent.
THU-259-The gene signature-MELD score and alcohol consumption determine long-term prognosis of patients with severe alcoholic hepatitis
Authors: Pierre Deltenre, Eric Trepo, Naoto Fujiwara, Nicolas Goossens, Astrid Marot, Margaux Dubois, Laurent Spahr, Jean Henrion, Christophe Moreno, Yujin Hoshida
Journal: Journal of Hepatology (2019)
Imaging fibrosis in inflammatory diseases: targeting the exposed extracellular matrix
Authors: Nicolas Beziere, Kerstin Fuchs, Andreas Maurer, Gerald Reischl, Jürgen Brück, Kamran Ghoreschi, Birgit Fehrenbacher, Daniel Carvajal Berrio, Katja Schenke-Layland, Ursula Kohlhofer, Leticia Quintanilla-Martinez, Meinrad Gawaz, Manfred Kneilling, Bernd Pichler
Journal: Theranostics (2019)

In a variety of diseases, from benign to life-threatening ones, inflammation plays a major role. Monitoring the intensity and extent of a multifaceted inflammatory process has become a cornerstone in diagnostics and therapy monitoring. However, the current tools lack the ability to provide insight into one of its most crucial aspects, namely, the alteration of the extracellular matrix (ECM). Using a radiolabeled platelet glycoprotein VI-based ECM-targeting fusion protein (GPVI-Fc), we investigated how binding of GPVI-Fc on fibrous tissue could uncover the progression of several inflammatory disease models at different stages (rheumatoid arthritis, cutaneous delayed-type hypersensitivity, lung inflammation and experimental autoimmune encephalomyelitis). Methods: The fusion protein GPVI-Fc was covalently linked to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and subsequently labeled with 64Cu. We analyzed noninvasively in vivo64Cu-GPVI-Fc accumulation in murine cutaneous delayed-type hypersensitivity, anti-glucose-6-phosphate isomerase serum-induced rheumatoid arthritis, lipopolysaccharide-induced lung inflammation and an experimental autoimmune encephalomyelitis model. Static and dynamic Positron Emission Tomography (PET) of the radiotracer distribution was performed in vivo, with ex vivo autoradiography confirmation, yielding quantitative accumulation and a distribution map of 64Cu-GPVI-Fc. Ex vivo tissue histological staining was performed on harvested samples to highlight the fusion protein binding to collagen I, II and III, fibronectin and fibrinogen as well as the morphology of excised tissue. Results:64Cu-GPVI-Fc showed a several-fold increased uptake in inflamed tissue compared to control tissue, particularly in the RA model, with a peak 24 h after radiotracer injection of up to half the injected dose. Blocking and isotype control experiments indicated a target-driven accumulation of the radiotracer in the case of chronic inflammation. Histological analysis confirmed a prolonged accumulation at the inflammation site, with a pronounced colocalization with the different components of the ECM (collagen III and fibronectin notably). Binding of the fusion protein appeared to be specific to the ECM but unspecific to particular components. Conclusion: Imaging of 64Cu-GPVI-Fc accumulation in the ECM matrix appears to be a promising candidate for monitoring chronic inflammation. By binding to exposed fibrous tissue (collagen, fibronectin, etc.) after extravasation, a new insight is provided into the fibrotic events resulting from a prolonged inflammatory state.
Impaired Chylomicron Assembly Modifies Hepatic Metabolism Through Bile Acid–Dependent and Transmissible Microbial Adaptations
Authors: Yan Xie, Hitoshi Matsumoto, Susan Kennedy, Elizabeth P. Newberry, William Moritz, Brian J. DeBosch, Kelle H. Moley, Deborah C. Rubin, Brad W. Warner, Andrew L. Kau, Phillip I. Tarr, Todd N. Wylie, Kristine M. Wylie, Nicholas O. Davidson
Journal: Hepatology (2019)

The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.
Abstract 16946: Accuracy of Cardiovascular (cv) Risk Stratification by Canadian Primary Care Physicians: Preliminary Results From the Primary Care Audit of Global Risk Management (PARADIGM) Study
Authors: Milan Gupta, Mahesh Kajil, Sheriar Hirjikaka, Michelle Tsigoulis, G. B. John Mancini, Rosane Nisenbaum, Muhammad Mamdani, Subodh Verma
Journal: Circulation (2010)

Background: Optimal clinical management requires proper CV risk stratification. Guidelines recommend the use of validated tools (eg. Framingham Risk Score (FRS)) but such tools are not widely adopt...
<scp>PAPASH</scp> , Ps <scp>APASH</scp> and <scp>PASS</scp> autoinflammatory syndromes: phenotypic heterogeneity, common biological signature and response to immunosuppressive regimens
Authors: J. Gottlieb, M. Madrange, C. Gardair, E. Sbidian, A. Frazier, P. Wolkenstein, G. Hickman, P. Schneider, C. Baudry, P. Claudepierre, P. Bertheau, P. Richette, A. Smahi, H. Bachelez
Journal: British Journal of Dermatology (2019)
THU-467-Comparison of the immune tumour microenvironment between primary and metastatic hepatocellular carcinoma: Implication for biomarker research of immunotherapy
Authors: Da-Liang Ou, Chia-Lang Hsu, Yung-Ming Jeng, Li-Yuan Bai, Ann-Lii Cheng, Chiun Hsu
Journal: Journal of Hepatology (2019)
Intensive Models of Hepatitis C Care for People Who Inject Drugs Receiving Opioid Agonist Therapy
Authors: Matthew J. Akiyama, Brianna L. Norton, Julia H. Arnsten, Linda Agyemang, Moonseong Heo, Alain H. Litwin
Journal: Annals of Internal Medicine (2019)

Background: Many people who inject drugs (PWID) are denied treatment for hepatitis C virus (HCV) infection, even if they are receiving opioid agonist therapy (OAT). Research suggests that HCV in PWID may be treated effectively, but optimal models of care for promoting adherence and sustained virologic response (SVR) have not been evaluated in the direct-acting antiviral (DAA) era. Objective: To determine whether directly observed therapy (DOT) and group treatment (GT) are more effective than self-administered individual treatment (SIT) in promoting adherence and achieving SVR among PWID receiving OAT. Design: Three-group, randomized controlled trial conducted from October 2013 to April 2017. (ClinicalTrials.gov: NCT01857245) Setting: Three OAT programs in Bronx, New York. Participants: Persons aged 18 years and older with genotype 1 HCV infection who were willing to receive HCV therapy on site in the OAT program. Of 190 persons screened, 158 were randomly assigned to a study group and 150 initiated treatment: DOT (n = 51), GT (n = 48), and SIT (n = 51). Intervention: 2 intensive interventions (DOT and GT) and 1 control condition (SIT). Measurements: Primary: adherence, measured by using electronic blister packs. Secondary: HCV treatment completion and SVR 12 weeks after treatment completion. Results: Mean age was 51 years; 65% of participants had positive results on urine drug testing during the 6 months before treatment, and 75% reported ever injecting drugs. Overall adherence, estimated from mixed-effects models using the daily timeframe, was 78% (95% CI, 75% to 81%) and was greater among participants randomly assigned to DOT (86% [CI, 80% to 92%]) than those assigned to SIT (75% [CI, 70% to 81%]; difference, 11% [CI, 5% to 18%]; Bonferroni-corrected P = 0.001). No significant difference in adherence was observed between participants randomly assigned to GT (80% [CI, 74% to 86%]) and those assigned to SIT (difference, 4.7% [CI, −2% to 11%]; Bonferroni-corrected P = 0.29). The HCV treatment completion rate was 97%, with no differences among groups (P = 0.53). Overall SVR was 94% (CI, 89% to 97%); the SVR rate was 98% in the DOT group, 94% in the GT group, and 90% in the SIT group (P = 0.152). Limitation: These findings may not be generalizable to PWID not enrolled in OAT programs. Conclusion: All models of onsite HCV care delivered to PWID in OAT programs resulted in high SVR, despite ongoing drug use. Directly observed therapy was associated with greater adherence than SIT. Primary Funding Source: National Institute on Drug Abuse and Gilead Sciences.