tbuckley/cabot-search huggingface dataset:
Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function
Authors: Qianyi Wu, Azman Akhter, Shashank Pant, Eunjoo Cho, Jin Xin Zhu, Alastair Garner, Tomoko Ohyama, Emad Tajkhorshid, Donald J. van Meyel, Renae M. Ryan
Journal: Journal of Clinical Investigation (2022)

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl- channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.
118P Impact of grade ≥2 pneumonitis (G2+ PNS) on patient reported outcomes (PROs) with durvalumab (D) after chemoradiotherapy (CRT) in unresectable stage III NSCLC
Authors: R. Hui, J. Naidoo, M.C. Garassino, H. Broadhurst, N. Patel, M. Newton, P. Thiyagarajah, J.F. Vansteenkiste
Journal: Annals of Oncology (2022)
The Lancet Commission on diabetes: using data to transform diabetes care and patient lives
Authors: Juliana C N Chan, Lee-Ling Lim, Nicholas J Wareham, Jonathan E Shaw, Trevor J Orchard, Ping Zhang, Eric S H Lau, Björn Eliasson, Alice P S Kong, Majid Ezzati, Carlos A Aguilar-Salinas, Margaret McGill, Naomi S Levitt, Guang Ning, Wing-Yee So, Jean Adams, Paula Bracco, Nita G Forouhi, Gabriel A Gregory, Jingchuan Guo, Xinyang Hua, Emma L Klatman, Dianna J Magliano, Boon-Peng Ng, David Ogilvie, Jenna Panter, Meda Pavkov, Hui Shao, Nigel Unwin, Martin White, Constance Wou, Ronald C W Ma, Maria I Schmidt, Ambady Ramachandran, Yutaka Seino, Peter H Bennett, Brian Oldenburg, Juan José Gagliardino, Andrea O Y Luk, Philip M Clarke, Graham D Ogle, Melanie J Davies, Rury R Holman, Edward W Gregg
Journal: The Lancet (2020)
HIV pre-exposure prophylaxis was associated with no impact on sexually transmitted infection prevalence in a high-prevalence population of predominantly men who have sex with men, Germany, 2018 to 2019
Authors: Hendrik Streeck, Klaus Jansen, Trevor A Crowell, Allahna Esber, Heiko K Jessen, Christiane Cordes, Stefan Scholten, Stephan Schneeweiss, Norbert Brockmeyer, Christoph D Spinner, Markus Bickel, Stefan Esser, Jukka Hartikainen, Albrecht Stoehr, Clara Lehmann, Ulrich Marcus, Jörg Janne Vehreschild, Alexandra Knorr, Anna-Lena Brillen, Carsten Tiemann, Merlin L Robb, Nelson L Michael
Journal: Eurosurveillance (2022)

Introduction Despite increased use of pre-exposure prophylaxis (PrEP) in Germany, HIV infection rates are not declining and little is known about how this prevention method affects the prevalence of sexually transmitted infections (STI) among men who have sex with men (MSM). Aim We studied, in a large multicentre cohort, STI point prevalence, co-infection rates, anatomical location and influence of PrEP. Methods The BRAHMS study was a prospective cohort study conducted at 10 sites in seven major German cities that enrolled MSM reporting increased sexual risk behaviour. At screening visits, MSM were tested for Mycoplasma genitalium (MG), Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT) and Treponema pallidum (TP) , and given a behavioural questionnaire. With binomial regression, we estimated prevalence ratios (PR) and 95% confidence intervals (CI) for the association of PrEP and STI. Results We screened 1,043 MSM in 2018 and 2019, with 53.0% currently using PrEP. At screening, 370 participants (35.5%) had an STI. The most common pathogen was MG in 198 (19.0%) participants, followed by CT (n = 133; 12.8%), NG (n = 105; 10.1%) and TP (n = 37; 3.5%). Among the 370 participants with at least one STI, 14.6% (n = 54) reported STI-related symptoms. Infection prevalence was highest at anorectal site (13.4% MG, 6.5% NG, 10.2% CT). PrEP use was not statistically significant in adjusted models for STI (PR: 1.10; 95% CI: 0.91–1.32), NG/CT, only NG or only CT. Conclusions Prevalence of asymptomatic STI was high, and PrEP use did not influence STI prevalence in MSM eligible for PrEP according to national guidelines.
Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies
Authors: Makoto Hibino, Yoichiro Otaki, Elsa Kobeissi, Han Pan, Hiromi Hibino, Henock Taddese, Azeem Majeed, Subodh Verma, Tsuneo Konta, Kunihiro Yamagata, Shouichi Fujimoto, Kazuhiko Tsuruya, Ichiei Narita, Masato Kasahara, Yugo Shibagaki, Kunitoshi Iseki, Toshiki Moriyama, Masahide Kondo, Koichi Asahi, Tsuyoshi Watanabe, Tetsu Watanabe, Masafumi Watanabe, Dagfinn Aune
Journal: Circulation (2021)

Background: Hypertension or elevated blood pressure (BP) is an important risk factor for aortic dissection (AD); however, few prospective studies on this topic have been published. We investigated the association between hypertension/elevated BP and AD in 2 cohorts and conducted a meta-analysis of published prospective studies, including these 2 studies. Methods: We analyzed data from the J-SHC study (Japan-Specific Health Checkups) and UK Biobank, which prospectively followed up 534 378 and 502 424 participants, respectively. Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for the association of hypertension/elevated BP with AD incidence in the UK Biobank and AD mortality in the J-SHC Study. In the meta-analysis, summary relative risks were calculated with random-effects models. A potential nonlinear dose-response relationship between BP and AD was tested with fractional polynomial models, and the best-fitting second-order fractional polynomial regression model was determined. Results: In the J-SHC study and UK Biobank, there were 84 and 182 ADs during the 4- and 9-year follow-up, and the adjusted hazard ratios of AD were 3.57 (95% CI, 2.17–6.11) and 2.68 (95% CI, 1.78–4.04) in hypertensive individuals, 1.33 (95% CI, 1.05–1.68) and 1.27 (95% CI, 1.11–1.48) per 20–mm Hg increase in systolic BP (SBP), and 1.67 (95% CI, 1.40–2.00) and 1.66 (95% CI, 1.46–1.89) per 10-mm Hg increase in diastolic BP (DBP), respectively. In the meta-analysis, the summary relative risks were 3.07 (95% CI, 2.15–4.38, I 2 =76.7%, n=7 studies, 2818 ADs, 4 563 501 participants) for hypertension and 1.39 (95% CI, 1.16–1.66, I 2 =47.7%, n=3) and 1.79 (95% CI: 1.51–2.12, I 2 = 57.0%, n=3) per 20–mm Hg increase in SBP and per 10–mm Hg increase in DBP, respectively. The AD risk showed a strong, positive dose-response relationship with SBP and even more so with DBP. The risk of AD in the nonlinear dose-response analysis was significant at SBP &gt;132 mm Hg and DBP &gt;75 mm Hg. Conclusions: Hypertension and elevated SBP and DBP are associated with a high risk of AD. The risk of AD was positively dose dependent, even within the normal BP range. These findings provide further evidence for the optimization of BP to prevent AD.
Single-cell immune signature for detecting early-stage HCC and early assessing anti-PD-1 immunotherapy efficacy
Authors: Jiawei Shi, Junwei Liu, Xiaoxuan Tu, Bin Li, Zhou Tong, Tian Wang, Yi Zheng, Hongyu Shi, Xun Zeng, Wei Chen, Weiwei Yin, Weijia Fang
Journal: Journal for ImmunoTherapy of Cancer (2022)

The early diagnosis of hepatocellular carcinoma (HCC) can greatly improve patients' 5-year survival rate, and the early efficacy assessment is important for oncologists to harness the anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced HCC. The lack of effective predicting biomarkers not only leads to delayed detection of the disease but also results in ineffective immunotherapy and limited clinical survival benefit.We exploited the single-cell approach (cytometry by time of flight (CyTOF)) to analyze peripheral blood mononuclear cells from multicohorts of human samples. Immune signatures for different stages of patients with HCC were systematically profiled and statistically compared. Furthermore, the dynamic changes of peripheral immune compositions for both first-line and second-line patients with HCC after anti-PD-1 monotherapy were also evaluated and systematically compared.We identified stage-specific immune signatures for HCC and constructed a logistic AdaBoost-SVM classifier based on these signatures. The classifier provided superior performance in predicting early-stage HCC over the commonly used serum alpha-fetoprotein level. We also revealed the treatment stage-specific immune signatures from peripheral blood and their dynamical changing patterns, all of which were integrated to achieve early discrimination of patients with non-durable benefit for both first-line and second-line anti-PD-1 monotherapies.Our newly identified single-cell peripheral immune signatures provide promising non-invasive biomarkers for early detection of HCC and early assessment for anti-PD-1 immunotherapy efficacy in patients with advanced HCC. These new findings can potentially facilitate early diagnosis and novel immunotherapy for patients with HCC in future practice and further guide the utility of CyTOF in clinical translation of cancer research.NCT02576509 and NCT02989922.
Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial
Authors: Francesca Gay, Pellegrino Musto, Delia Rota-Scalabrini, Luca Bertamini, Angelo Belotti, Monica Galli, Massimo Offidani, Elena Zamagni, Antonio Ledda, Mariella Grasso, Stelvio Ballanti, Antonio Spadano, Michele Cea, Francesca Patriarca, Mattia D'Agostino, Andrea Capra, Nicola Giuliani, Paolo de Fabritiis, Sara Aquino, Angelo Palmas, Barbara Gamberi, Renato Zambello, Maria Teresa Petrucci, Paolo Corradini, Michele Cavo, Mario Boccadoro
Journal: The Lancet Oncology (2021)
Subsequent Primary Cancer Risk Among 5-Year Survivors of Adolescent and Young Adult Cancers
Authors: Hyuna Sung, Rebecca L Siegel, Noorie Hyun, Kimberly D Miller, K Robin Yabroff, Ahmedin Jemal
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background A comprehensive examination of the incidence and mortality of subsequent primary cancers (SPCs) among adolescent and young adult (AYA) cancer survivors in the United States is lacking. Methods Cancer incidence and mortality among 170 404 cancer survivors of 5 or more years who were aged 15-39 years at first primary cancer diagnosis during 1975-2013 in 9 Surveillance, Epidemiology, and End Results registries were compared with those in the general population using standardized incidence ratio (SIR), absolute excess incidence (AEI), standardized mortality ratio (SMR), and absolute excess mortality (AEM). Results During a mean follow-up of 14.6 years, 13 420 SPC cases and 5008 SPC deaths occurred among survivors (excluding the same site as index cancer), corresponding to 25% higher incidence (95% confidence interval [CI] = 1.23 to 1.27, AEI = 10.8 per 10 000) and 84% higher mortality (95% CI = 1.79 to 1.89, AEM = 9.2 per 10 000) than that in the general population. Overall, SPC risk was statistically significantly higher for 20 of 29 index cancers for incidence and 26 for mortality, with the highest SIR among female Hodgkin lymphoma survivors (SIR = 3.05, 95% CI = 2.88 to 3.24, AEI = 73.0 per 10 000) and the highest SMR among small intestine cancer survivors (SMR = 6.97, 95% CI = 4.80 to 9.79, AEM = 64.1 per 10 000). Type-specific SPC risks varied substantially by index cancers; however, SPCs of the female breast, lung, and colorectum combined constituted 36% of all SPC cases and 39% of all SPC deaths, with lung cancer alone representing 11% and 24% of all cases and deaths, respectively. Conclusion AYA cancer survivors are almost twice as likely to die from a new primary cancer as the general population, highlighting the need for primary care clinicians to prioritize cancer prevention and targeted surveillance strategies in these individuals.
Inhaled corticosteroids for outpatients with COVID-19: a meta-analysis
Authors: Todd C. Lee, Émilie Bortolussi-Courval, Sara Belga, Nick Daneman, Adrienne K. Chan, Ryan Hanula, Nicole Ezer, Emily G. McDonald
Journal: European Respiratory Journal (2022)

<b>The role of inhaled corticosteroids for outpatient COVID-19 is evolving. Meta-analysis of reported clinical trials estimated probability of any effect for symptom resolution by day 14 at 100% and hospitalisation at 89.3%, respectively.</b>https://bit.ly/3B2sDUi
Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study
Authors: Hussein A Tawbi, Peter A Forsyth, F Stephen Hodi, Alain P Algazi, Omid Hamid, Christopher D Lao, Stergios J Moschos, Michael B Atkins, Karl Lewis, Michael A Postow, Reena P Thomas, John Glaspy, Sekwon Jang, Nikhil I Khushalani, Anna C Pavlick, Marc S Ernstoff, David A Reardon, Ragini Kudchadkar, Ahmad Tarhini, Caroline Chung, Corey Ritchings, Piyush Durani, Margarita Askelson, Igor Puzanov, Kim A Margolin
Journal: The Lancet Oncology (2021)
Abstract MP04: Food Insecurity And Blood Pressure Control: The Coronary Artery Risk In Young Adults (cardia) Study
Authors: Sabira Taher, Mandy Wong, Mercedes R Carnethon, Namratha Kandula, Catarina I Kiefe, Kiarri Kershaw
Journal: Circulation (2022)

Background: Food insecurity (FI), the limited access to healthy and affordable food, is a social determinant of health that hinders blood pressure (BP) control in individuals with hypertension. Cross-sectional studies that examine this relationship do not allow for observations over time. We used longitudinal data on CARDIA Study participants with hypertension to examine the association between FI and BP control over 15 years. Methods: Generalized estimating equations were used to examine the association between FI and BP control across repeated observations on 605 participants with physician diagnosed and self-reported hypertension. Participants had some FI if they endorsed any of the following statements: “We have enough food to eat, but not always the kinds of food we want to eat”; “Sometimes we don’t have enough food to eat”; “Often we don’t have enough food to eat.” We estimated odds ratios (OR) and 95% confidence interval (CI) for control of systolic blood pressure (SBP) &lt;140 mmHg, diastolic blood pressure (DBP) &lt; 90 mmHg and combined measures of SBP and DBP. We calculated sequentially adjusted models and interaction terms based on previous research. Model 1 was adjusted for age, gender, race and field center. Model 2 was additionally adjusted for antihypertensive medication use, maximum education, marital status and household income. Model 3 was additionally adjusted for BMI, physical activity, smoking status and alcohol intake. Results: FI was reported by 21.7% of study participants (N=131). FI was reported in Black participants (N=106), and women (N=89) most. Gender modified the association of FI with BP control, whereby food insecure women were less likely to control BP Table 1. Other interactions were not significant. Conclusions: Food insecure women had more difficulty with BP control than food insecure men. Explanations for the differential influence of FI on men and women should be studied so that targeted interventions can be developed.
Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis: Erratum
Authors: Haiou Yang, Haiyang Zhang, Yuchong Yang, Xinyi Wang, Ting Deng, Rui Liu, Tao Ning, Ming Bai, Hongli Li, Kegan Zhu, Jialu Li, Qian Fan, Guoguang Ying, Yi Ba
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.44419.].
Abstract MP38: Gender Differences In Temporal Trends Of Cardiovascular Health In Young US Adults
Authors: So Mi J Cho, Sara Haidermota, Michael Honigberg, Pradeep Natarajan
Journal: Circulation (2022)

Introduction: Favorable cardiovascular health (CVH) in young adulthood has been associated with lower future cardiovascular risk. Characterizing the gender-stratified temporal trends of CVH among younger adults may better inform opportunities for earlier prevention. Therefore, we assessed persistence of gender differences in overall CVH and individual component in young US adults. Methods: Based on the National Health Examination and Nutrition Survey data 2007-2018, we identified 10,206 individuals aged 20 to 39 years. Gender and sociodemographic measures were self-reported. The CVH was assessed based on the American Heart Association’s Life’s Simple 7 metrics. Changes in the mean number of ideal CVH components (out of 7) and the ideal proportion of individual component were calculated using weighted linear regression analysis. Changes in gender differences were assessed with an interaction term between gender and calendar year. Results: The mean [SD] age of the study population was 29.3 [5.8] years, and 5,260 (51.5%) individuals were female. Between 2007 and 2018, the mean [95% CI] ideal CVH component remained unchanged in both females (4.40 [4.27-4.52] to 4.48 [4.34-4.61]; P value=0.94) and males (3.97 [3.86-4.08] to 3.93 [3.76-4.10]; P value=0.87) with stable gender differences ( P for interaction=0.94). Nonetheless, gender differences in blood pressure widened ( P for interaction &lt;0.001) as ideal blood pressure decreased (54.0% to 46.9%; P value=0.03) only in males. Concurrently, the proportion of females with ideal physical activity level declined (57.3% to 49.4; P value=0.04) whereas stagnant in males ( P for interaction=0.03). Non-smoking increased in females (64.1% to 70.5%; P value=0.05), otherwise unchanged in males ( P for interaction=0.01). Conclusions: Gender disparities in CVH have persisted with exacerbated differences in blood pressure, physical activity, and smoking. These insights provide opportunities to promote equitable CVH and to address disparities.
COVID-19 Vaccine–Induced Multisystem Inflammatory Syndrome With Polyserositis Detected by FDG PET/CT
Authors: Soo Jin Lee, Dong Won Park, Jang Won Sohn, Ho Joo Yoon, Sang-Heon Kim
Journal: Clinical Nuclear Medicine (2022)

Of the various adverse reactions to COVID-19 vaccines, fever is a common systemic symptom that often resolves spontaneously without treatment. However, rare vaccine-induced conditions that present with fever and systemic inflammation have been reported. In this case, a 65-year-old man with BNT162b2 mRNA COVID-19 vaccination underwent 18F-FDG PET/CT to evaluate prolonged fever and elevated serum C-reactive protein. PET/CT showed hypermetabolic infiltration in the pericardium and peritoneum suggesting immune-mediated pericarditis and peritonitis. After administration of high-dose corticosteroids, the patient's symptom resolved. This case suggests that multisystem inflammatory syndrome and polyserositis can be induced by the COVID-19 vaccine.
Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Trisha M. Wise-Draper, Shuchi Gulati, Sarah Palackdharry, Benjamin H. Hinrichs, Francis P. Worden, Matthew O. Old, Neal E. Dunlap, John M. Kaczmar, Yash Patil, Muhammed Kashif Riaz, Alice Tang, Jonathan Mark, Chad Zender, Ann M. Gillenwater, Diana Bell, Nicky Kurtzweil, Maria Mathews, Casey L. Allen, Michelle L. Mierzwa, Keith Casper, Roman Jandarov, Mario Medvedovic, J. Jack Lee, Nusrat Harun, Vinita Takiar, Maura Gillison
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Patients with resected, local–regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%–69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. Patients and Methods: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1–3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60–66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. Results: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). No new safety signals were identified. Conclusions: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.
Further Considerations on Early Intervention for Borderline Personality Disorder
Authors: Stephen Allison, Tarun Bastiampillai, Jeffrey C. L. Looi
Journal: JAMA Psychiatry (2022)

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