tbuckley/cabot-search huggingface dataset:
Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells
Authors: Zhixin Qiu, Linjie Zhao, Jia Z. Shen, Zhengyu Liang, Qiulian Wu, Kailin Yang, Lihua Min, Ryan C. Gimple, Qiyuan Yang, Shruti Bhargava, Chunyu Jin, Cheryl Kim, Denise Hinz, Deobrat Dixit, Jean A. Bernatchez, Briana C. Prager, Guoxin Zhang, Zhen Dong, Deguan Lv, Xujun Wang, Leo J.Y. Kim, Zhe Zhu, Katherine A. Jones, Ye Zheng, Xiuxing Wang, Jair L. Siqueira-Neto, Lukas Chavez, Xiang-Dong Fu, Charles Spruck, Jeremy N. Rich
Journal: Cancer Discovery (2022)

Abstract Glioblastoma (GBM) is the most lethal primary brain cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSC). Here, we interrogated gene expression and whole-genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated GBM cells (DGC), and neural stem cells (NSC) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II–mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance in vitro and in vivo. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacologic targeting of the YY1–CDK9 complex elicited RNA m6A modification–dependent interferon responses, reduced regulatory T-cell infiltration, and augmented efficacy of immune checkpoint therapy in GBM. Collectively, these results suggest that YY1–CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in GBM. Significance: Effective strategies to rewire immunosuppressive microenvironment and enhance immunotherapy response are still lacking in GBM. YY1-driven transcriptional elongation machinery represents a druggable target to activate interferon response and enhance anti–PD-1 response through regulating the m6A modification program, linking epigenetic regulation to immunomodulatory function in GBM. This article is highlighted in the In This Issue feature, p. 275
Abstract P189: Leveraging Existing Cohort Study Infrastructure And Community Trust To Promote Covid Vaccination In Rural Mississippi: Experience From NHLBI’s RURAL Cohort Study
Authors: Keith O Cobb, Frances C Henderson, Kristie A Alvarez, Tammy T Taylor-Bufford, Sue H Simmons, Emily L Landrum, Vasan S Ramachandran, Ervin R Fox
Journal: Circulation (2022)

Background: The current surge in COVID-19 infections in the rural south is primarily due to the large number of unvaccinated individuals. Increasing the number of individuals getting vaccinated in rural areas remains a challenge due to multiple factors including education, vaccine literacy and hesitancy, and access to vaccination sites. Objective: Investigators in the Risk Underlying Rural Areas Longitudinal (RURAL) Study used existing community partnerships with local advisory boards and with state organizations to promote vaccinations in a pair of low-risk and high-risk rural counties in Mississippi. Methods: The Mississippi Core of the RURAL Study is responsible for community engagement, forming community advisory boards and promoting the RURAL Study among residents of Oktibbeha and Panola Counties. We partnered with community advisory board (CAB) members to identify geographic sites that have a need for increasing vaccinations and assessed the willingness of the facilities to serve as a site for ‘popup’ vaccination clinics. We partnered with the Mississippi State Medical Association and the Mississippi Department of Health to identify COVID 19 vaccination providers in these rural areas. Working with physicians on the CAB and local county hospitals, we secured staffing, vaccines and equipment and scheduled dates and times for popup vaccination clinics at 4 sites in Panola County and 5 sites in Oktibbeha County. Popup clinics were promoted locally by physicians and churches, and through RURAL investigators using both social media and news media. Investigators evaluated: 1) the success of popup clinics; 2) number of persons vaccinated at each clinic; and 3) sex, age range and race of those receiving vaccinations collected. Findings: All nine of the COVID19 popup vaccinations clinics were successfully set up and run. A total of 77 individuals received vaccinations (32 in Panola County and 45 in Oktibbeha County). In Panola County more men than women received vaccinations and all age ranges (12-19, 20-29, 30-39,40-49, 50-59, 60-69, ≥ 70 years) were represented. The majority of those receiving vaccinations in Panola County were Non-Hispanic Black Americans. In Oktibbeha County more men than women received vaccinations and older age ranges (&gt; 50 years) predominated. In Oktibbeha County there was a more even balance of Non-Hispanic Black and White Americans among those receiving vaccinations. Panola County vaccinations were mostly first-time vaccinations and Oktibbeha County vaccinations were mostly booster doses. Conclusion: Existing cohort study infrastructure and human resources offer a unique opportunity to leverage existing community collaborations to promote vaccinations in a national pandemic.
Abstract MP60: Sleep Fragmentation, Sleep Medications, And Incident Heart Failure And Subtypes In Post-menopausal Women
Authors: Miremad Moafi-Madani, Michael Stephens, Mary Roberts, Charles Eaton
Journal: Circulation (2022)

Background: Women, specifically post-menopausal women, have poorer sleep quality and an increased risk for insomnia relative to men. Insomnia is more prevalent among patients with heart failure, and prior research has shown a dose-dependent association between the severity of insomnia and the risk of heart failure. However, it is unclear which aspects of insomnia are most associated with heart failure, and whether any associations exist between sleep medication use and incident heart failure subtypes. Methods: This is a prospective cohort study of 42,832 post-menopausal women from the Women’s Health Initiative (WHI). Insomnia was assessed using the validated WHI Insomnia Rating Scale (WHIIRS) which includes sleep fragmentation, trouble falling asleep, waking up early, difficulty in falling back asleep upon waking up, and perceived sleep quality. Sleep medication use was asked and arranged into three categories. Association between insomnia components and sleep medication use and incident HF and its subtypes were evaluated using Cox proportional hazard models. Results: In our multivariable-adjusted model, Sleep fragmentation for more than two nights per week is associated with incident overall HF (HR=1.32, 95% CI: 1.19 - 1.46) and HFpEF (HR=1.43, 95% CI: 1.24 - 1.65). Sleep medications use for more than two nights per week was associated with HF (HR=1.46, 95% CI: 1.28 - 1.67), HFpEF (HR=1.40, 95% CI: 1.16- 1.68), and HFrEF (HR=1.44, 95% CI: 1.12 - 1.85). There were no significant associations between HF and the remaining insomnia components. Conclusions: In postmenopausal women, sleep fragmentation is associated with an increased risk of incident HF and HFpEF. Sleep medication use for more than two nights per week is associated with an increased risk of incident HF, HFpEF, and HFrEF among postmenopausal women. Whether interventions to decrease the frequency of sleep fragmentation and sleep medication use in older adults will reduce HF risk warrants further study.
Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs
Authors: Sven Fengler, Birgit Kurkowsky, Sanjeev Kumar Kaushalya, Wera Roth, Eugenio Fava, Philip Denner
Journal: Biomaterials (2022)

Optimizing drug candidates for blood-brain barrier (BBB) penetration remains one of the key challenges in drug discovery to finally target brain disorders including neurodegenerative diseases which do not have adequate treatments so far. It has been difficult to establish state-of-the-art stem cell derived in vitro models that mimic physiological barrier properties including a 3D microvasculature in a format that is scalable to screen drugs for BBB penetration. To address this challenge, we established human induced pluripotent stem cell (iPSC)-derived brain endothelial microvessels in a standardized and scalable multi-well plate format. iPSC-derived brain microvascular endothelial cells (BMECs) were supplemented with primary cell conditioned media and grew to microvessels in 10 days. Produced microvessels show typical BBB endothelial protein expression, tight-junctions and polarized localization of efflux transporter. Microvessels exhibited physiological relevant trans-endothelial electrical resistance (TEER), were leak-tight for 10 kDa dextran-Alexa 647 and strongly limited the permeability of sodium fluorescein (NaF). Permeability tests with reference compounds confirmed the suitability of our model as platform to identify potential BBB penetrating anti-inflammatory drugs. The here presented platform recapitulates physiological properties and allows rapid screening of BBB permeable anti-inflammatory compounds that has been suggested as promising substances to cure so far untreatable neurodegenerative diseases.
Epigenetic and Transcriptional Regulation of Innate Immunity in Cancer
Authors: Chuan Chen, Na Man, Fan Liu, Gloria Mas Martin, Hidehiro Itonaga, Jun Sun, Stephen D. Nimer
Journal: Cancer Research (2022)

Innate immune cells participate in the detection of tumor cells via complex signaling pathways mediated by pattern-recognition receptors, such as Toll-like receptors and nucleotide-binding and oligomerization domain-like receptors. These pathways are finely tuned via multiple mechanisms, including epigenetic regulation. It is well established that hematopoietic progenitors generate innate immune cells that can regulate cancer cell behavior, and the disruption of normal hematopoiesis in pathologic states may lead to altered immunity and the development of cancer. In this review, we discuss the epigenetic and transcriptional mechanisms that underlie the initiation and amplification of innate immune signaling in cancer. We also discuss new targeting possibilities for cancer control that exploit innate immune cells and signaling molecules, potentially heralding the next generation of immunotherapy.
BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age
Authors: Shuang-Fang Fang, Nan Liu, Hou-Wei Du
Journal: New England Journal of Medicine (2022)

Years of AgeTo the Editor: Walter et al. (Jan.6 issue) 1 report the results of a randomized, controlled trial showing that two doses of the messenger RNA (mRNA) vaccine BNT162b2 against Covid-19 were safe, immunogenic, and efficacious in children 5 to 11 years of age.However, this trial was not powered to detect potential serious side effects of mRNA vaccines.Here, we present the pooled results of the trial conducted by Walter et al. and two other randomized, controlled trials 2,3 (through November 15, 2021).Our analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 4The risks of injection-related and total adverse events after the first or second injection (Fig. 1A and1B) were significantly higher after vaccination with an mRNA vaccine than after injection of placebo.However, the risks of serious adverse events (risk ratio, 1.63; 95% confidence interval [CI], 0.45 to 5.88) (Fig. 1C) and the risks of any adverse event leading to nonreceipt of the second injection (risk ratio, 2.99; 95% CI, 0.36 to 24.93) (Fig. 1D) did not differ significantly between the vaccine and placebo groups.Two doses of mRNA vaccine effectively prevented the occurrence of Covid-19 in participants with previous severe SARS-CoV-2 infection and in those without previous infection (Fig. 1E and1F).No cases of severe Covid-19, multisystem inflammatory syndrome in children, or death were reported.Our findings provide support for the use of mRNA vaccines against Covid-19 in children and adolescents.
BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma
Authors: Tianyi Liu, Linli Zhou, Yao Xiao, Thomas Andl, Yuhang Zhang
Journal: Cancer Research (2022)

The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)-induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fibroblasts (CAF). Treatment with BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhanced biological properties. This CAF subpopulation is essential for melanoma cells to proliferate and acquire resistance to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in CAFs, leading to inactivation of the β-catenin destruction complex. RNA-seq identified periostin (POSTN) as a major downstream effector of β-catenin in CAFs. POSTN compensates for the loss of β-catenin in CAFs and mediates melanoma cell BRAFi/MEKi resistance. In melanoma cells, POSTN activates phosphoinositide 3-kinase (PI3K)/AKT signaling and subsequently reactivates the ERK pathway that was inhibited by BRAFi/MEKi. Collectively, these data underscore the role of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells. SIGNIFICANCE: β-Catenin activation in cancer-associated fibroblasts in response to BRAF inhibitors stimulates POSTN secretion to promote resistance in cancer cells, revealing POSTN as a potential matrix target in cancer therapy.
Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer
Authors: Ruozheng Wei, Yuning Zhou, Chang Li, Piotr Rychahou, Shulin Zhang, William B. Titlow, Greg Bauman, Yuanyuan Wu, Jinpeng Liu, Chi Wang, Heidi L. Weiss, B. Mark Evers, Qingding Wang
Journal: Cancer Research (2022)

The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression.This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.
Minocycline-Induced Hyperpigmentation
Authors: Sho Katayama, Mitsuhito Ota
Journal: New England Journal of Medicine (2021)

A 75-year-old woman with long-term minocycline use presented with darkening facial skin that spared an area of skin grafted from her chest wall. She received a diagnosis of type III minocycline-induced hyperpigmentation, in which areas of the skin exposed to the sun have an elevated density of melanocytes, which produce excess melanin under the influence of minocycline.
CIRCULATING TUMOR CELLS
Authors: Bruno Paiva
Journal: HemaSphere (2022)

Bone marrow (BM) aspirates are the gold standard for patient prognostication and genetic characterization in multiple myeloma (MM). However, they represent an important limitation for periodic disease monitoring because it entails an aggressive procedure. Moreover, recent findings are showing that a single BM aspirate is unable to reflect the complex MM heterogeneity. Recent advances in flow cytometry, microfluidics and “omics” technologies have made possible the detection and isolation of circulating tumor cells (CTCs), which offers a promising and minimally invasive alternative for tumor assessment and metastasis study. CTCs are detectable in premalignant and active MM states and its enumeration has strong prognostic value, to an extent that it is challenging current stratification systems. In addition, CTCs reflect with high precision both intra and extramedullary disease at the phenotypic, genomic and transcriptomic levels. Despite the high resemblance between tumor clones in distinct locations, some subtle (not random) differences might shed some light onto the metastatic process. Thus, it has been suggested that a hypoxic and pro-inflammatory microenvironment could induce an arrest in proliferation forcing tumor cells to recirculate. In my presentation, I will summarize data on the characterization of MM CTCs as well as their clinical and research potential.
Androgen Receptor Pathway in Salivary Gland Cancer
Authors: Alan L. Ho
Journal: Journal of Clinical Oncology (2021)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Abiraterone Acetate in Patients With Castration-Resistant, Androgen Receptor–Expressing Salivary Gland Cancer: A Phase II Trial. October 01, 2021 ARTICLE CITATION DOI: 10.1200/JCO.21.01983 Journal of Clinical Oncology - published online before print October 1, 2021 PMID: 34597118 Androgen Receptor Pathway in Salivary Gland Cancer Alan L. Ho , MD, PhD1,2xAlan L. HoSearch for articles by this author Show More 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY2Department of Medicine Weill Cornell Medical College, New York City, NY https://doi.org/10.1200/JCO.21.01983 First Page Full Text PDF Figures and Tables © 2021 by American Society of Clinical OncologySUPPORTA.L.H. is supported by the NIH/NCI Cancer Center Support Grant P30CA008748, NIH/NCI R01DE027738, and the Geoffrey Beene Cancer Research Center at Memorial Sloan Kettering Cancer Center.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAndrogen Receptor Pathway in Salivary Gland CancerThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Alan L. HoConsulting or Advisory Role: Bristol Myers Squibb, Eisai, Genzyme, Merck, Novartis, Sun Pharma, Regeneron, TRM Oncology, Ayala Pharmaceuticals, AstraZeneca, Sanofi, CureVac, Prelude Therapeutics, Kura Oncology, McGivney Global Advisors, Rgenta, AffyImmune Therapeutics, Exelixis, InxmedSpeakers' Bureau: Medscape, Omniprex America, NovartisResearch Funding: Lilly, Genentech/Roche, AstraZeneca, Bayer, Kura Oncology, Kolltan Pharmaceuticals, Eisai, AstraZeneca, Bristol Myers Squibb, Astellas Pharma, Novartis, Merck, Pfizer, Ayala Pharmaceuticals, Allos Therapeutics, Daiichi Sankyo, Elevar TherapeuticsTravel, Accommodations, Expenses: Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals, Klus PharmaNo other potential conflicts of interest were reported. Companion Abiraterone Acetate in Patients With Castration-Resistant, Androgen Receptor–Expressing Salivary Gland Cancer: A Phase II Trial
STopTox: An <i>in Silico</i> Alternative to Animal Testing for Acute Systemic and Topical Toxicity
Authors: Joyce V.B. Borba, Vinicius M. Alves, Rodolpho C. Braga, Daniel R. Korn, Kirsten Overdahl, Arthur C. Silva, Steven U.S. Hall, Erik Overdahl, Nicole Kleinstreuer, Judy Strickland, David Allen, Carolina Horta Andrade, Eugene N. Muratov, Alexander Tropsha
Journal: Environmental Health Perspectives (2022)

Background: Modern chemical toxicology is facing a growing need to Reduce, Refine, and Replace animal tests (Russell 1959) for hazard identification. The most common type of animal assays for acute toxicity assessment of chemicals used as pesticides, pharmaceuticals, or in cosmetic products is known as a “6-pack” battery of tests, including three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) end points. Methods: We compiled, curated, and integrated, to the best of our knowledge, the largest publicly available data sets and developed an ensemble of quantitative structure–activity relationship (QSAR) models for all six end points. All models were validated according to the Organisation for Economic Co-operation and Development (OECD) QSAR principles, using data on compounds not included in the training sets. Results: In addition to high internal accuracy assessed by cross-validation, all models demonstrated an external correct classification rate ranging from 70% to 77%. We established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for 6-pack assays. Conclusions: We developed STopTox, a comprehensive collection of computational models that can be used as an alternative to in vivo 6-pack tests for predicting the toxicity hazard of small organic molecules. Models were established following the best practices for the development and validation of QSAR models. Scientists and regulators can use the STopTox portal to identify putative toxicants or nontoxicants in chemical libraries of interest. https://doi.org/10.1289/EHP9341