tbuckley/cabot-search huggingface dataset:
CXCR6 is required for antitumor efficacy of intratumoral CD8<sup>+</sup>T cell
Authors: Binglin Wang, Yi Wang, Xiaofan Sun, Guoliang Deng, Wei Huang, Xingxin Wu, Yanghong Gu, Zhigang Tian, Zhimin Fan, Qiang Xu, Hongqi Chen, Yang Sun
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Increasing infiltration of CD8 + T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8 + T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases. Methods Combination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6 −/− mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6 + CD8 + T cells. Transgenic Cxcr6 −/− OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response. Results We identified that CXCR6 was exclusively expressed on intratumoral CD8 + T cell. CXCR6 + CD8 + T cells were more immunocompetent, and chimeras with specific deficiency on CD8 + T cells showed weaker antitumor activity. In addition, Cxcr6 −/− mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6 + CD8 + T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression. Conclusions This study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8 + T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.
An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks
Authors: Julia Ramírez-Moya, Christos Miliotis, Allison R. Baker, Richard I. Gregory, Frank J. Slack, Pilar Santisteban
Journal: Molecular Cancer (2021)

Abstract Background Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined. Methods We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis. Results We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A &gt; G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation. Conclusions Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers.
A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study
Authors: Christine M. Bestvina, Kelli B. Pointer, Theodore Karrison, Hania Al-Hallaq, Philip C. Hoffman, Michael J. Jelinek, Aditya Juloori, James M. Melotek, Septimiu Murgu, Julien Partouche, Everett E. Vokes, Ralph R. Weichselbaum, Sean P. Pitroda, Jyoti D. Patel, Steven J. Chmura
Journal: Journal of Thoracic Oncology (2021)
Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia
Authors: Marisa J. L. Aitken, Farhad Ravandi, Keyur P. Patel, Nicholas J. Short
Journal: Journal of Hematology & Oncology (2021)

Abstract Quantification of measurable residual disease (MRD) provides critical prognostic information in acute myeloid leukemia (AML). A variety of platforms exist for MRD detection, varying in their sensitivity and applicability to individual patients. MRD detected by quantitative polymerase chain reaction, multiparameter flow cytometry, or next-generation sequencing has prognostic implications in various subsets of AML and at various times throughout treatment. While it is overwhelmingly evident that minute levels of remnant disease confer increased risk of relapse and shortened survival, the therapeutic implications of MRD remain less clear. The use of MRD as a guide to selecting the most optimal post-remission therapy, including hematopoietic stem cell transplant or maintenance therapy with hypomethylating agents, small molecule inhibitors, or immunotherapy is an area of active investigation. In addition, whether there are sufficient data to use MRD negativity as a surrogate endpoint in clinical trial development is controversial. In this review, we will critically examine the methods used to detect MRD, its role as a prognostic biomarker, MRD-directed therapeutics, and its potential role as a study endpoint.
Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort
Authors: Tracey G Simon, Bjorn Roelstraete, Hannes Hagström, Johan Sundström, Jonas F Ludvigsson
Journal: Gut (2021)

Objective Some data suggest a positive association between non-alcoholic fatty liver disease (NAFLD) and incident major adverse cardiovascular events (MACEs). However, data are lacking from large cohorts with liver histology, which remains the gold standard for staging NAFLD severity. Design This population-based cohort included all Swedish adults with histologically confirmed NAFLD and without cardiovascular disease (CVD) at baseline (1966–2016, n=10 422). NAFLD was defined from prospectively recorded histopathology and categorised as simple steatosis, non-fibrotic steatohepatitis, non-cirrhotic fibrosis and cirrhosis. Patients with NAFLD were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year and county (n=46 517). Using Cox proportional hazards modelling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs for MACE outcomes (ie, ischaemic heart disease (IHD), stroke, congestive heart failure (CHF) or cardiovascular (CV) mortality). Results Over a median of 13.6 years, incident MACE was confirmed in 2850 patients with NAFLD and 10 648 controls. Patients with NAFLD had higher incidence of MACE than controls (24.3 vs 16.0/1000 person-years (PY); difference=8.3/1000 PY; aHR 1.63, 95% CI 1.56 to 1.70), including higher rates of IHD (difference=4.2/1000 PY; aHR 1.64, 95% CI 1.54 to 1.75), CHF (difference=3.3/1000 PY; aHR 1.75, 95% CI 1.63 to 1.87), stroke (difference=2.4/1000 PY; aHR 1.58, 95% CI 1.46 to 1.71) and CV mortality (difference=1.2/1000 PY; aHR 1.37, 95% CI 1.27 to 1.48). Rates of incident MACE increased progressively with worsening NAFLD severity (p trend =0.02), with the highest incidence observed with cirrhosis (difference vs controls=27.2/1000 PY; aHR 2.15, 95% CI 1.77 to 2.61). Conclusion Compared with matched population controls, patients with biopsy-proven NAFLD had significantly higher incidence of MACE, including IHD, stroke, CHF and CV mortality. Excess risk was evident across all stages of NAFLD and increased with worsening disease severity.
Characteristics of Registered Clinical Trials Evaluating the Role of e-Cigarettes in Cessation or Reduction of Cigarette Smoking
Authors: Felicia Hung, Joshua D. Wallach, Stephanie S. O’Malley, Krysten W. Bold
Journal: JAMA Psychiatry (2021)

P < .001),Latino adults had comparable odds of MDE persistence and severity, while Asian adults had similar odds of MDE persistence and lower odds of MDE severity (odds ratio, 0.5; 95% CI, 0.4-0.7;P < .010).Discussion | This nationally representative data analysis identified that Black adults continue to experience greater MDE persistence and severity, Latino adults experience comparable MDE persistence and severity, and Asian adults had comparable MDE persistence but lower severity compared with White adults.Consistent with prior research, minoritized racial and ethnic groups had lower MDE prevalence than White adults.Our findings update prior research, 3,4 raising concern about the continued disease burden experienced by Black adults.Greater experiences of discrimination, racism, and disparities in access to and quality of mental health treatment may partly explain our findings. 6These pathways are amenable to clinical and policy intervention that could buffer the links between mental illness, disability, and premature death. 6his study has some limitations.The National Survey on Drug Use and Health excludes persons institutionalized or lacking a permanent address.Data are cross sectional and based on survey respondents' self-report. 5ulturally responsive and nondiscriminatory outreach is needed to improve mental health service use among individuals from minoritized racial and ethnic groups. 6Clinicians practicing patient-centered treatment that support active patient participation and openness to understanding patient experiences with and interpretation of mental illness can improve mental health care.It is important that clinicians acknowledge and be sensitive to patients' prior experiences with discrimination and trauma stemming from medical system interactions, which may contribute to treatment nonadherence and exacerbation of mental illness. 6These considerations are especially salient as we continue to endure the COVID-19 pandemic, which has disproportionately affected minoritized racial and ethnic groups and elevated their need for mental health treatment.
Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1–Deficient Polycystic Kidney Disease in Animal Model
Authors: Jinzhao He, Shun Zhang, Zhiwei Qiu, Xiaowei Li, Huihui Huang, William Jin, Yue Xu, Guangying Shao, Liang Wang, Jia Meng, Shuyuan Wang, Xiaoqiang Geng, Yingli Jia, Min Li, Baoxue Yang, Hua A. Jenny Lu, Hong Zhou
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement Focal adhesion kinase (FAK) has been widely studied and shown to have a crucial effect on tumor progression. Although autosomal dominant polycystic kidney disease (ADPKD) shares numerous commonalities with tumors, it is undetermined whether FAK is involved in cyst development. Our study demonstrates that inhibiting FAK activity using small molecule FAK inhibitor VS-4718 ameliorates ADPKD progression and improves renal function. Inhibiting FAK and its downstream Src signaling suppresses cAMP-mediated aberrant proliferation of cystic epithelial cells in ADPKD animals. This study highlights the therapeutic potential of small molecule FAK inhibitors in treating patients with ADPKD. Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. Methods We established the forskolin (FSK)-induced three-dimensional (3D) Madin–Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate–stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst–lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein–tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct–specific Pkd1 knockout mouse models. Results FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. Conclusions Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA–regulated proliferation.
Author Correction: Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement
Authors: Ream Al-Hasani, Raajaram Gowrishankar, Gavin P. Schmitz, Christian E. Pedersen, David J. Marcus, Sofia E. Shirley, Taylor E. Hobbs, Abigail J. Elerding, Sophie J. Renaud, Miao Jing, Yulong Li, Veronica A. Alvarez, Julia C. Lemos, Michael R. Bruchas
Journal: Nature Neuroscience (2021)
Domestic Violence Police Reporting and Resources During the 2020 COVID-19 Stay-at-Home Order in Chicago, Illinois
Authors: Louisa Baidoo, Tanya L. Zakrison, Gillian Feldmeth, Stacy Tessler Lindau, Elizabeth L. Tung
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Domestic violence (DV) has become a growing public health concern during the COVID-19 pandemic because individuals may be sheltering in place with abusers and facing mounting economic and health-related stresses. <h3>Objective</h3> To analyze associations of the 2020 COVID-19 stay-at-home (SH) order with DV police reporting and resource availability, including differences by community area racial/ethnic composition. <h3>Design, Setting, and Participants</h3> This longitudinal cohort study assessed DV police reports (January-June 2020) obtained from the Chicago, Illinois, Police Department and DV resource availability (March and August 2020) obtained from the NowPow community resource database, both for 77 community areas in Chicago. Data were analyzed July through December 2020. <h3>Exposures</h3> The COVID-19 SH order effective March 21, 2020. <h3>Main Outcomes and Measures</h3> Monthly rates of DV police reports and DV resource availability per 100 000 persons. <h3>Results</h3> Of 77 community areas in Chicago, 28 (36.4%) were majority Black, 19 (24.7%) majority Hispanic/Latinx, 18 (23.4%) majority White, and 12 (15.6%) a different or no majority race/ethnicity, representing an estimated population of 2 718 555 individuals. For each community area, the SH order was associated with a decrease in the rate of DV police reports by 21.8 (95% CI, −30.48 to −13.07) crimes per 100 000 persons per month relative to the same months in 2019. Compared with White majority community areas, Black majority areas had a decrease in the rate of DV police reports by 40.8 (95% CI, −62.93 to −18.75) crimes per 100 000 persons per month relative to the same months in 2019. The SH order was also associated with a decrease in DV resource availability at a rate of 5.1 (95% CI, −7.55 to −2.67) resources per 100 000 persons, with the largest decreases for mental health (−4.3 [95% CI, −5.97 to −2.66] resources per 100 000 persons) and personal safety (−2.4 [95% CI, −4.40 to −0.41] resources per 100 000 persons). The Black majority south side of Chicago had a larger decrease in resource availability (−6.7 [95% CI, −12.92 to −0.46] resources per 100 000 persons) than the White majority north side. <h3>Conclusions and Relevance</h3> In this longitudinal cohort study, the rate of DV police reports decreased after the SH order was implemented in Chicago. This decrease was largely observed in Black majority communities, whereas there was no significant change in White majority communities. These findings may reflect decreased DV incidence but may also reflect an exacerbation of underreporting. In addition, DV resource availability decreased disproportionately on the predominantly Black south side of Chicago.
Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic
Authors: Jordi Riera, Roberto Roncon-Albuquerque, María Paz Fuset, Sara Alcántara, Pablo Blanco-Schweizer, Jordi Riera, Camilo Bonilla, Roberto Roncon-Albuquerque, Ana Vaz, María Paz Fuset, Stephani María Luna, Philip Fortuna, Pedro Eduardo Silva, Carlos Luis Albacete, Daniel Pérez, Pablo Blanco-Schweizer, Marta García, Pablo Millán, Javier Veganzones, Pilar Ricart, Sergi Martínez, María Victoria Boado, Roberto Voces, Sara Alcántara, Héctor Villanueva-Fernández, Aaron Blandino, Patricia Santa-Teresa, Elena Sandoval, Pablo Ruiz de Gopegui, Alfredo González-Pérez, Jorge Duerto, Ricardo Gimeno, Joaquín Colomina, Vanesa Gómez, Helena Pérez-Chomón, Gloria Renedo, Manuel Alfonso García, José Ricardo Naranjo, Emilio Rodríguez-Ruiz
Journal: Intensive Care Medicine (2021)
Call for emergency action to limit global temperature increases, restore biodiversity and protect health
Authors: Lukoye Atwoli, Abdullah H Baqui, Thomas Benfield, Raffaella Bosurgi, Fiona Godlee, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Carlos Augusto Monteiro, Ian Norman, Kirsten Patrick, Nigel Praities, Marcel GM Olde Rikkert, Eric J Rubin, Peush Sahni, Richard Smith, Nicholas J Talley, Sue Turale, Damián Vázquez
Journal: Journal of the Royal Society of Medicine (2021)

> Wealthy nations must do much more, much faster.

The United Nations General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference (Conference of the Parties (COP)26) in Glasgow, UK. Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature and protect health.

Health is already being harmed by global temperature increases and the destruction of the natural world, a state of affairs health professionals have been bringing attention to for decades.1 The science is unequivocal; a global increase of 1.5°C above the preindustrial average and the continued loss of biodiversity risk catastrophic harm to health that will be impossible to reverse.2 3 Despite the world’s necessary preoccupation with COVID-19, we cannot wait for the pandemic to pass to rapidly reduce emissions.

Reflecting the severity of the moment, this editorial appears in health journals across the world. We are united in recognising that only fundamental and equitable changes to societies will reverse our current trajectory.

The risks to health of increases above 1.5°C are now well established.2 Indeed, no temperature rise is ‘safe’. In the past 20 years, heat-related mortality among people aged over 65 has increased by more than 50%.4 Higher temperatures have brought increased dehydration and renal function loss, dermatological malignancies, tropical infections, adverse mental health outcomes, pregnancy complications, allergies, and cardiovascular and pulmonary morbidity and mortality.5 6 Harms disproportionately affect the most vulnerable, including children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2 4 

Global heating is also contributing to the decline in …
Extracellular Matrix‐Mimetic Hydrogels for Treating Neural Tissue Injury: A Focus on Fibrin, Hyaluronic Acid, and Elastin‐Like Polypeptide Hydrogels
Authors: Derek W. Nelson, Ryan J. Gilbert
Journal: Advanced Healthcare Materials (2021)

Abstract Neurological and functional recovery is limited following central nervous system injury and severe injury to the peripheral nervous system. Extracellular matrix (ECM)‐mimetic hydrogels are of particular interest as regenerative scaffolds for the injured nervous system as they provide 3D bioactive interfaces that modulate cellular response to the injury environment and provide naturally degradable scaffolding for effective tissue remodeling. In this review, three unique ECM‐mimetic hydrogels used in models of neural injury are reviewed: fibrin hydrogels, which rely on a naturally occurring enzymatic gelation, hyaluronic acid hydrogels, which require chemical modification prior to chemical crosslinking, and elastin‐like polypeptide (ELP) hydrogels, which exhibit a temperature‐sensitive gelation. The hydrogels are reviewed by summarizing their unique biological properties, their use as drug depots, and their combination with other biomaterials, such as electrospun fibers and nanoparticles. This review is the first to focus on these three ECM‐mimetic hydrogels for their use in neural tissue engineering. Additionally, this is the first review to summarize the use of ELP hydrogels for nervous system applications. ECM‐mimetic hydrogels have shown great promise in preclinical models of neural injury and future advancements in their design and use can likely lead to viable treatments for patients with neural injury.
State Public Option Plans — Too Modest to Improve Affordability?
Authors: Erin C. Fuse Brown, Katherine L. Gudiksen, Jaime S. King
Journal: New England Journal of Medicine (2021)

Interview with Prof. Erin Fuse Brown on lessons from U.S. states that have enacted public option health plans (11:46)Download Facing daunting political, legal, and fiscal challenges, the public option health plans recently enacted by Washington State, Nevada, and Colorado have been narrowed to such an extent that they may fail to meet their affordability and coverage goals.
An intramedullary mass
Authors: Jun-Song Yang, Lei Chu, Liang Yan, Ding-Jun Hao
Journal: BMJ (2021)

A man in his 30s presented with one month of progressive bilateral numbness and paralysis in the lower extremities. He had a history of pulmonary tuberculosis two years earlier, which resolved after treatment with isoniazid, rifampicin, and ethambutol. Physical examination showed hypoesthesia below the level of T10; grade I strength in the bilateral iliopsoas, quadriceps femoris, and tibialis anterior muscles; and bilateral lower extremity hyperreflexia. Gadolinium enhanced magnetic resonance imaging (MRI) detected a mass in the thoracic canal (fig 1).



Fig 1 
Gadolinium enhanced MRI of the thoracic spine (sagittal plane) showing a “target” sign—a ring enhancing intramedullary lesion with a clear border measuring 0.8 cm×3.0 cm×0.8 cm (red arrows) …
Axillary Lymphadenopathy After Coronavirus Disease 2019 Vaccinations in Patients With Thoracic Malignancy: Incidence, Predisposing Factors, and Imaging Characteristics
Authors: Mizuki Nishino, Hiroto Hatabu, Biagio Ricciuti, Victor Vaz, Kesi Michael, Mark M. Awad
Journal: Journal of Thoracic Oncology (2021)