tbuckley/cabot-search huggingface dataset:
Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula
Authors: Alvaro Nuno-Perez, Massimo Trusel, Arnaud L. Lalive, Mauro Congiu, Denise Gastaldo, Anna Tchenio, Salvatore Lecca, Mariano Soiza-Reilly, Claudia Bagni, Manuel Mameli
Journal: Neuron (2021)

Weighing alternatives during reward pursuit is a vital cognitive computation that, when disrupted by stress, yields aspects of neuropsychiatric disorders. To examine the neural mechanisms underlying these phenomena, we employed a behavioral task in which mice were confronted by a reward and its omission (i.e., error). The experience of error outcomes engaged neuronal dynamics within the lateral habenula (LHb), a subcortical structure that supports appetitive behaviors and is susceptible to stress. A high incidence of errors predicted low strength of habenular excitatory synapses. Accordingly, stressful experiences increased error choices while decreasing glutamatergic neurotransmission onto LHb neurons. This synaptic adaptation required a reduction in postsynaptic AMPA receptors (AMPARs), irrespective of the anatomical source of glutamate. Bidirectional control of habenular AMPAR transmission recapitulated and averted stress-driven cognitive deficits. Thus, a subcortical synaptic mechanism vulnerable to stress underlies behavioral efficiency during cognitive performance.
Comorbid Conditions and Medical History Among Patients with Refractory or Unexplained Chronic Cough in Two Phase 3 Clinical Trials (COUGH-1 and COUGH-2)
Authors: Peter Dicpinigaitis, Surinder Birring, Lorcan McGarvey, Alyn Morice, Ian Pavord, Jaclyn Smith, Carmen La Rosa, Qing Li, Allison Martin Nguyen, Jonathan Schelfhout, Anjela Tzontcheva, David Muccino
Journal: Journal of Allergy and Clinical Immunology (2021)
Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia
Authors: Rajkumar Ganesan, Vijaykumar Chennupati, Balaji Ramachandran, Michael Riis Hansen, Sanjaya Singh, Iqbal S. Grewal
Journal: Leukemia (2021)

Abstract Despite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3 + T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2 + γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9 + γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9 + γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9 + γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9 + γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.
Prevalence of Normal Coronary Arteries by Coronary Computed Tomography Angiography (CCTA) in Patients with Type 2 Diabetes Mellitus from Semaglutide Treatment on Coronary Plaque Progression (STOP) Trial
Authors: Divya Birudaraju, April Kinninger, Lavanya Cherukuri, Suvasini Lakshmanan, Ahmed K. Ghanem, Vahid Rezvanizadeh, Ferdinand Flores, Sajad Hamal, Rayan G. Pozon, Nishitha Adudodla, Suraj Dahal, John A. Tayek, Sion K. Roy, Matthew J. Budoff
Journal: Metabolism (2021)
Immune cartography of macrophage activation syndrome in the COVID-19 era
Authors: Dennis McGonagle, Athimalaipet V. Ramanan, Charlie Bridgewood
Journal: Nature Reviews Rheumatology (2021)

A hyperinflammatory 'cytokine storm' state termed macrophage activation syndrome (MAS), culminating from a complex interplay of genetics, immunodeficiency, infectious triggers and dominant innate immune effector responses, can develop across disparate entities including systemic juvenile idiopathic arthritis (sJIA) and its counterpart adult-onset Still disease (AOSD), connective tissue diseases, sepsis, infection, cancers and cancer immunotherapy. Classifying MAS using the immunological disease continuum model, with strict boundaries that define the limits of innate and adaptive immunity, at one boundary is MAS with loss of immune function, as occurs in the 'perforinopathies' and some cases of sJIA–AOSD. Conversely, at the other boundary, immune hypersensitivity with gain of immune function in MHC class II-associated sJIA–AOSD and with chimeric antigen receptor (CAR) T cell therapy also triggers MAS. This provides a benchmark for evaluating severe inflammation in some patients with COVID-19 pneumonia, which cripples primary type I interferon immunity and usually culminates in a lung-centric 'second wave' cytokine-driven alveolitis with associated immunothrombosis; this phenomenon is generally distinct from MAS but can share features with the proposed 'loss of immune function' MAS variant. This loss and gain of function MAS model offers immune cartography for a novel mechanistic classification of MAS with therapeutic implications. In this Review, the authors discuss macrophage activation syndrome (MAS) in relation to other cytokine storm scenarios, and provide a framework for understanding MAS within the spectrum of innate and adaptive immunity in the context of gain or loss of immune function.
Biomarker Discovery and Validation: Statistical Considerations
Authors: Fang-Shu Ou, Stefan Michiels, Yu Shyr, Alex A. Adjei, Ann L. Oberg
Journal: Journal of Thoracic Oncology (2021)

Biomarkers have various applications including disease detection, diagnosis, prognosis, prediction of response to intervention, and disease monitoring. In this era of precision medicine, having validated biomarkers to inform clinical decision making is more important than ever. In this article, we discuss best the practices and potential issues in biomarker discovery and validation. We encourage team science partnerships to bring cutting-edge discovery from bench to bedside, leading to improved patient care and outcomes.
Remote Data Collection Through the ASTHMAXcel Mobile Application, and Lessons Learned During the COVID-19 Pandemic
Authors: Brian Hsia, Anjani Singh, Obumneme Njeze, Emine Cosar, Savneet Kaur, Sunit Jariwala
Journal: Journal of Allergy and Clinical Immunology (2021)

The ASTHMAXcel mobile application has been associated with improvements in clinical outcomes and healthcare utilization through on-site use at designated study visits. Remote testing and data collection may streamline and transform clinical trials for mobile health (mHealth) interventions. ASTHMAXcel is a novel, guideline-based smartphone application freely available on the iOS/Android app marketplaces. Within the app, users answered surveys on initial (prior to navigating content) use and after first-time use. Pre-intervention questions included user demographics and baseline knowledge. Post-intervention questions addressed attitude changes after completion of all content. Between April 15 and August 13, 2020, 96 users (F: 60%, mean age: 38.8 ± 14.9, range: 19-77) completed the pre-intervention survey. 56% of users completed college or a higher program. 83% of users primarily spoke English, 6% primarily Spanish, and 11% another language. Common comorbidities included seasonal allergies (37%), anxiety/depression (37%), eczema (16%), food allergies (12%), and diabetes mellitus (9%). At baseline, the following proportion of users reported: 41% had an asthma action plan; 60% knew the difference between a rescue vs controller medication; 32% had a peak flow meter; and 38% had a spacer. 23 users completed the post-intervention survey. 72% reported knowing the importance of an asthma action plan; 81% reported knowing the difference between a rescue vs controller medication; 87% reported knowing the importance of a spacer; and 81% reported knowing the importance of a peak flow meter. Remote data collection through mHealth interventions may serve as a viable method for conducting clinical trials, especially during the COVID-19 pandemic.
Racial and Ethnic Disparities in the Prevalence of Stress and Worry, Mental Health Conditions, and Increased Substance Use Among Adults During the COVID-19 Pandemic — United States, April and May 2020
Authors: Lela R. McKnight-Eily, Catherine A. Okoro, Tara W. Strine, Jorge Verlenden, NaTasha D. Hollis, Rashid Njai, Elizabeth W. Mitchell, Amy Board, Richard Puddy, Craig Thomas
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In 2019, approximately 51 million U.S. adults aged ≥18 years reported any mental illness,* and 7.7% reported a past-year substance use disorder† (1). Although reported prevalence estimates of certain mental disorders, substance use, or substance use disorders are not generally higher among racial and ethnic minority groups, persons in these groups are often less likely to receive treatment services (1). Persistent systemic social inequities and discrimination related to living conditions and work environments, which contribute to disparities in underlying medical conditions, can further compound health problems faced by members of racial and ethnic minority groups during the coronavirus disease 2019 (COVID-19) pandemic and worsen stress and associated mental health concerns (2,3). In April and May 2020, opt-in Internet panel surveys of English-speaking U.S. adults aged ≥18 years were conducted to assess the prevalence of self-reported mental health conditions and initiation of or increases in substance use to cope with stress, psychosocial stressors, and social determinants of health. Combined prevalence estimates of current depression, initiating or increasing substance use, and suicidal thoughts/ideation were 28.6%, 18.2%, and 8.4%, respectively. Hispanic/Latino (Hispanic) adults reported a higher prevalence of psychosocial stress related to not having enough food or stable housing than did adults in other racial and ethnic groups. These estimates highlight the importance of population-level and tailored interventions for mental health promotion and mental illness prevention, substance use prevention, screening and treatment services, and increased provision of resources to address social determinants of health. How Right Now (Qué Hacer Ahora) is an evidence-based and culturally appropriate communications campaign designed to promote and strengthen the emotional well-being and resiliency of populations adversely affected by COVID-19-related stress, grief, and loss (4).
Disparities of GERD treatment and Gastroenterology Care in Black Children with Food Allergy in FORWARD Cohort
Authors: Mary Tobin, Jamie Fierstein, Jialing Jiang, Aame Andy-Nweye, Susan Fox, Mahboobeh Mahdavinia, Andrea Pappalardo, Annika Chura, Amal Assa'ad, Adam Robinson, Hemant Sharma, Amaziah Coleman, Lucy Bilaver, Christopher Warren, Pamela Newmark, Alexandria Bozen, Jacqueline Pongracic, Ruchi Gupta
Journal: Journal of Allergy and Clinical Immunology (2021)
Gain of HIF1 Activity and Loss of miRNA <i>let-7d</i> Promote Breast Cancer Metastasis to the Brain via the PDGF/PDGFR Axis
Authors: Christof B. Wyss, Nathalie Duffey, Sanam Peyvandi, David Barras, Amaïa Martinez Usatorre, Oriana Coquoz, Pedro Romero, Mauro Delorenzi, Girieca Lorusso, Curzio Rüegg
Journal: Cancer Research (2021)

Abstract Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA let-7d concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM2), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM2 and MDA231-BrM2). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM2 model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis. Significance: These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities.
Posttraumatic Scab on 131I Whole-Body Scan—A False-Positive Finding
Authors: Abdul Waheed Chowdhary, Anwin Joseph Kavanal, Ashwani Sood, Sarika Prashar, Ritesh Upadhyay, Anish Bhattacharya, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2021)

131I scan plays a crucial role in the management of patients with differentiated thyroid cancer for the evaluation of remnant thyroid tissue, residual/recurrent metastatic disease, posttherapy tracer distribution, and response assessment to high-dose 131I therapy. Different causes secondary to physiological, pathological, and anatomical variations have been described for false-positive findings in the whole-body planar images. This case report of a patient of differentiated thyroid cancer with undocumented trauma to the left knee region a day before receiving the high-dose radioiodine therapy showed an interesting image finding of tracer uptake at unusual site in the posttherapy whole-body 131I scan.
Prone Position Reduces Spontaneous Inspiratory Effort in Patients with Acute Respiratory Distress Syndrome: A Bicenter Study
Authors: Takeshi Yoshida, Aiko Tanaka, Rollin Roldan, Rocío Quispe, Hiroki Taenaka, Akinori Uchiyama, Yuji Fujino
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Prone Position Reduces Spontaneous Inspiratory Effort in Patients with Acute Respiratory Distress Syndrome: A Bicenter Study." American Journal of Respiratory and Critical Care Medicine, 203(11), pp. 1437–1440
History and Status of Prolonged Grief Disorder as a Psychiatric Diagnosis
Authors: Holly G. Prigerson, Sophia Kakarala, James Gang, Paul K. Maciejewski
Journal: Annual Review of Clinical Psychology (2021)

Prolonged grief disorder (PGD) is a diagnostic entity now included in the International Classification of Diseases 11th Revision (ICD-11) and soon to appear in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision (DSM-5-TR). A characteristic feature of PGD is distressing, disabling yearning that persists a year or more after the loss. Other characteristic symptoms include disbelief and lack of acceptance of the loss, emotional detachment from others since the loss, loneliness, identity disturbance, and sense of meaninglessness. In this review, we detail psychiatric views on grief and their evolution over the twentieth century. We then discuss the development of diagnostic formulations for disordered grief, which culminated in PGD's status as a mental disorder in the DSM. After summarizing recent evidence that may suggest that PGD is linked to the neural reward system, we suggest further areas of research. In particular, we note the need for studies that extend the evidence base concerning PGD across cultural and sociodemographic boundaries and that investigate novel treatments.
Response to: ‘Correspondence on ‘Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study’’ by Zheng
Authors: Shahab Abtahi, Johanna H M Driessen, Andrea M Burden, Patrick C Souverein, Joop P van den Bergh, Tjeerd P van Staa, Annelies Boonen, Frank de Vries
Journal: Annals of the Rheumatic Diseases (2021)

We thank Dr Zheng for his comments on our recently published article in the Annals of the Rheumatic Diseases entitled ‘Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study’.1 2 Our main goal in this study was to bring more clinical insight into the simultaneous use of these two common medications in patients with rheumatoid arthritis (RA), that is, oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), using data from a large primary care database and pharmacoepidemiological methodologies.

Our results showed that there was an interaction in the risk of osteoporotic (OP) fractures with concomitant use of oral GCs and PPIs in patients with RA. Based on the adjusted hazard ratios …
FGFR-TKI resistance in cancer: current status and perspectives
Authors: Sitong Yue, Yukun Li, Xiaojuan Chen, Juan Wang, Meixiang Li, Yongheng Chen, Daichao Wu
Journal: Journal of Hematology & Oncology (2021)

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.
Longitudinal effects of ivacaftor and medicine possession ratio in people with the<i>Gly551Asp</i>mutation: a 5-year study
Authors: Ruth Marian Mitchell, Andrew M Jones, Katie Stocking, Philip Foden, Peter J Barry
Journal: Thorax (2021)

Introduction Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying a Gly551Asp mutation were greater than previously seen in clinical trials for other therapies. Limited data are available regarding long-term outcomes and adherence to ivacaftor outside clinical trials. Methods We conducted a 5-year single-centre retrospective study of people with CF carrying the Gly 551 Asp mutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR). Results 35 people were included. After commencing ivacaftor, FEV 1 improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV 1 declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV 1 decline (1.57% pre vs 1.82% post, p=0.74). Body mass index (BMI) increased for 4 years. There was a significant reduction in inpatient and total intravenous antibiotic days sustained over 5 years. MPR remained high but declined over time (−2.5±0.9% per year, p=0.007). FEV 1 was better maintained in patients with higher MPRs. Conclusion The addition of ivacaftor provides acute benefits for people with the Gly551Asp mutation and established lung disease. We report a sustained reduction in intravenous antibiotic use but following acute improvement in lung function, decline continues, and patients will continue to require medical observation and optimisation. Strategies to maintain high adherence should be a priority to prolong the benefits of ivacaftor.
Cordycepin Ameliorates Nonalcoholic Steatohepatitis by Activation of the AMP‐Activated Protein Kinase Signaling Pathway
Authors: Tian Lan, Yang Yu, Jing Zhang, Haonan Li, Qiqing Weng, Shuo Jiang, Song Tian, Tonghao Xu, Sha Hu, Guizhi Yang, Yan Zhang, Weixuan Wang, Lexun Wang, Qing Zhu, Xianglu Rong, Jiao Guo
Journal: Hepatology (2021)

Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases.
Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology
Authors: Fading Chen, Dan B. Swartzlander, Anamitra Ghosh, John D. Fryer, Baiping Wang, Hui Zheng
Journal: Molecular Neurodegeneration (2021)

Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer's disease (AD). Both protective and risk alleles have been identified which may be associated with its expression levels. However, the physiological function of clusterin in the central nervous system remains largely unknown.