tbuckley/cabot-search huggingface dataset:
Modulation of histone methylation by hexavalent chromium
Authors: Hong Sun, Xue Zhou, Haobin Chen, Qin Li, Max Costa
Journal: Cancer Research (2008)

6  Hexavalent chromium is a mutagen and carcinogen, and occupational exposure could lead to lung cancer and other adverse health effects. Genetic change resulting from DNA damage has been proposed as an important mechanism that mediates chromium induced genotoxicity and carcinogenicity. Interestingly, recent studies indicated the involvement of DNA methylation in chromium silenced tumor suppressor genes (e.g. p16, hMLH1) suggesting that potential epigenetic effects may also contribute to chromium’s carcinogenicity. DNA methylation occurs in cooperation with other epigenetic modifications, such as histone methylation of histone 3 lysine 9 (H3K9). However, little is known about whether Cr(VI) can induce changes in histone marks. Here, we report that chromate can modulate various histone methylation profiles. Exposure of human lung carcinoma A549 cells to potassium chromate (5-10 µM) increased the global levels of the gene silencing mark dimethylated H3K9 (H3K9me2), a mark known to be crucial for DNA methylation. In addition, increasing the cellular level of the primary reductant required for Cr(VI) metabolism, ascorbate (1 mM), partially reversed the Cr(VI)-increased H3K9me2 level, suggesting that the epigenetic effects involve the Cr(VI) reduction process. Moreover, both protein and mRNA level of G9a, the primary enzyme involved in di-methylating H3K9 were also increased upon Cr(VI) exposure, which may in part contribute to the increased H3K9me2 in cells. Furthermore, our ongoing study of Cr(VI)-induced H3K9me2 in hMLH1 and p16 gene promoters via CHIP assays will address whether Cr(VI)-increased histone methylation accounts for the silencing of specific tumor suppressor genes. Thus, our studies suggest a new mechanism whereby hexavalent chromate may modulate histone modification and sequentially promote DNA methylation and silence tumor suppressor genes. (This work was supported by grants ES00260, ES014454, ES005512, ES010344, and T32-ES07324 from the National Institutesof Environmental Health Sciences, and grant CA16087 from the NationalCancer Institute.)
Asthma in combination with rhinitis and eczema is associated with a higher degree of type‐2 inflammation and symptom burden than asthma alone
Authors: Viiu Blöndal, Janson Christer, Sundbom Fredrik, Borres Magnus P., Hallgren Jenny, Tsolakis Nikolaos, Alving Kjell, Malinovschi Andrei
Journal: Allergy (2021)
Case 27-2021: A 16-Year-Old Boy Seeking Human Immunodeficiency Virus Prophylaxis
Authors: Anne M. Neilan, Sheila Salvant Valentine, Amelia S. Knopf
Journal: New England Journal of Medicine (2021)

A 16-year-old boy was seen in the infectious disease clinic for consideration of preexposure prophylaxis against human immunodeficiency virus infection. He identified as a cisgender male and reported having had more than 10 male sexual partners. He requested that the content of the visit remain confidential. Management decisions were made.
Early cross-coronavirus reactive signatures of humoral immunity against COVID-19
Authors: Paulina Kaplonek, Chuangqi Wang, Yannic Bartsch, Stephanie Fischinger, Matthew J. Gorman, Kathryn Bowman, Jaewon Kang, Diana Dayal, Patrick Martin, Radoslaw P. Nowak, Alexandra-Chloé Villani, Ching-Lin Hsieh, Nicole C. Charland, Anna L.K. Gonye, Irena Gushterova, Hargun K. Khanna, Thomas J. LaSalle, Kendall M. Lavin-Parsons, Brendan M. Lilley, Carl L. Lodenstein, Kasidet Manakongtreecheep, Justin D. Margolin, Brenna N. McKaig, Maricarmen Rojas-Lopez, Brian C. Russo, Nihaarika Sharma, Jessica Tantivit, Molly F. Thomas, Moshe Sade-Feldman, Jared Feldman, Boris Julg, Eric J. Nilles, Elon R. Musk, Anil S. Menon, Eric S. Fischer, Jason S. McLellan, Aaron Schmidt, Marcia B. Goldberg, Michael R. Filbin, Nir Hacohen, Douglas A. Lauffenburger, Galit Alter
Journal: Science Immunology (2021)

Preexisting cross-coronavirus immunity influences the early development of SARS-CoV-2 humoral immunity after COVID-19.
Economic impact of tuberculosis mortality in 120 countries and the cost of not achieving the Sustainable Development Goals tuberculosis targets: a full-income analysis
Authors: Sachin Silva, Nimalan Arinaminpathy, Rifat Atun, Eric Goosby, Michael Reid
Journal: The Lancet Global Health (2021)

The tuberculosis targets for the UN Sustainable Development Goals (SDGs) call for a 90% reduction in tuberculosis deaths by 2030, compared with 2015, but meeting this target now seems highly improbable. To assess the economic impact of not meeting the target until 2045, we estimated full-income losses in 120 countries, including those due to excess deaths resulting from COVID-19-related disruptions to tuberculosis services, for the period 2020-50.Annual mortality risk changes at each age in each year from 2020 to 2050 were estimated for 120 countries. This risk change was then converted to full-income risk by calculating a population-level mortality risk change and multiplying it by the value of a statistical life-year in each country and year. As a comparator, we assumed that current rates of tuberculosis continue to decline through the period of analysis. We calculated the full-income losses, and mean life expectancy losses per person, at birth and at age 35 years, under scenarios in which the SDG targets are met in 2030 and in 2045. We defined the cost of inaction as the difference in full-income losses and tuberculosis mortality between these two scenarios.From 2020 to 2050, based on the current annual decrease in tuberculosis deaths of 2%, 31·8 million tuberculosis deaths (95% uncertainty interval 25·2 million-39·5 million) are estimated to occur, corresponding to an economic loss of US$17·5 trillion (14·9 trillion-20·4 trillion). If the SDG tuberculosis mortality target is met in 2030, 23·8 million tuberculosis deaths (18·9 million-29·5 million) and $13·1 trillion (11·2 trillion-15·3 trillion) in economic losses can be avoided. If the target is met in 2045, 18·1 million tuberculosis deaths (14·3 million-22·4 million) and $10·2 trillion (8·7 trillion-11·8 trillion) can be avoided. The cost of inaction of not meeting the SDG tuberculosis mortality target until 2045 (vs 2030) is, therefore, 5·7 million tuberculosis deaths (5·1 million-8·1 million) and $3·0 trillion (2·5 trillion-3·5 trillion) in economic losses. COVID-19-related disruptions add $290·3 billion (260·2 billion-570·1 billion) to this cost.Failure to achieve the SDG tuberculosis mortality target by 2030 will lead to profound economic and health losses. The effects of delay will be greatest in sub-Saharan Africa. Affected countries, donor nations, and the private sector should redouble efforts to finance tuberculosis programmes and research because the economic dividend of such strategies is likely to be substantial.None.
Non-cancer-related pathogenic germline variants and expression consequences in ten-thousand cancer genomes
Authors: Zishan Wang, Xiao Fan, Yufeng Shen, Meghana S Pagadala, Rebecca Signer, Kamil J. Cygan, William G. Fairbrother, Hannah Carter, Wendy K. Chung, Kuan-lin Huang
Journal: Genome Medicine (2021)

Abstract Background DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear. Methods We analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers. Results The affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay. Conclusions Our results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations.
Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart
Authors: Golam M. Uddin, Qutuba G. Karwi, Simran Pherwani, Keshav Gopal, Cory S. Wagg, Dipsikha Biswas, Mariam Atnasious, Yikuan Wu, Guoqing Wu, Liyan Zhang, Kim L. Ho, Thomas Pulinilkunnil, John R. Ussher, Gary D. Lopaschuk
Journal: Metabolism (2021)
Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of <i>EGFR</i> -mutant lung cancer
Authors: Pınar Özden Eser, Raymond M. Paranal, Jieun Son, Elena Ivanova, Yanan Kuang, Heidi M. Haikala, Ciric To, Jeffrey J. Okoro, Kshiti H. Dholakia, Jihyun Choi, Yoonji Eum, Atsuko Ogino, Pavlos Missios, Dalia Ercan, Man Xu, Michael J. Poitras, Stephen Wang, Kenneth Ngo, Michael Dills, Masahiko Yanagita, Timothy Lopez, Mika Lin, Jeanelle Tsai, Nicolas Floch, Emily S. Chambers, Jennifer Heng, Rana Anjum, Alison D. Santucci, Kesi Michael, Alwin G. Schuller, Darren Cross, Paul D. Smith, Geoffrey R. Oxnard, David A. Barbie, Lynette M. Sholl, Magda Bahcall, Sangeetha Palakurthi, Prafulla C. Gokhale, Cloud P. Paweletz, George Q. Daley, Pasi A. Jänne
Journal: Science Translational Medicine (2021)

A subset of drug-resistant EGFR -mutant MET -amplified lung cancer switches oncogenic dependence to MET and is treatable with MET inhibitor monotherapy.
Association Between Exposure Characteristics and the Risk for COVID-19 Infection Among Health Care Workers With and Without BNT162b2 Vaccination
Authors: Yonatan Oster, Shmuel Benenson, Limor Yochi Harpaz, Inon Buda, Ran Nir-Paz, Jacob Strahilevitz, Matan J. Cohen
Journal: JAMA Network Open (2021)
Polycythemia vera: historical oversights, diagnostic details, and therapeutic views
Authors: Ayalew Tefferi, Alessandro M. Vannucchi, Tiziano Barbui
Journal: Leukemia (2021)

Abstract Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age &gt;60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
Enhanced bone regeneration via spatiotemporal and controlled delivery of a genetically engineered BMP-2 in a composite Hydrogel
Authors: Xin Chen, Baoyu Tan, Zhiteng Bao, Shang Wang, Rongze Tang, Zhenmin Wang, Gaoyang Chen, Shuai Chen, William W. Lu, Dazhi Yang, Songlin Peng
Journal: Biomaterials (2021)

Scaffolds functionalized with bone morphogenetic protein-2 (BMP-2) have shown great potential for bone regeneration. However, structural instability and the necessity for supra-physiological dose have thus far limited practical applications for BMP-2. Protein modification and site-specific covalent immobilization of BMP-2 to carrier materials might be optimal strategies to overcome these problems. Here, we report a broadly applicable strategy where the polyhistidine tag-T4 Lysozyme (His6-T4L) was genetically fused at the N-terminus of BMP-2 and used as a protein spacer, which on one hand enhanced protein solubility and stability, and on the other hand mediated site-specific covalent anchoring of BMP-2 upon binding to nickel-chelated nitrilotriacetic acid (Ni-NTA) microparticles (denoted as MPs-His6-T4L-BMP2) to further maximize its rescued activity. We also constructed a novel gelatin-based hydrogel that was crosslinked by transglutaminase (TG) and tannic acid (TA). This hydrogel, when incorporated with MPs-His6-T4L-BMP2, displayed excellent in-situ injectability, thermosensitivity, adhesiveness and improved mechanical properties. The effective loading mode led to a controlled and long-term sustained release of His6-T4L-BMP2, thereby resulting in enhancement of bone regeneration in a critical-sized bone defect. We believe that the protein modification strategy proposed here opens up new route not only for BMP-2 applications, but can be used to inform novel uses for other macromolecules.
Abstract 11592: Effects of Targeted Strategies in Improving Phase II Cardiac Rehabilitation Program Recruitment in an Asian Multi-ethnic Cohort
Authors: Yanhong Huang, Nur Adawiyah Yusoff, Yan Cao, Dawn Loh, Teck Bee Ang, Mei Mei Foong, Leng Geok Lim, Boon Wah Liew, Jian Jing Tan
Journal: Circulation (2019)

Introduction: Cardiac rehabilitation is a customised program of exercise and education, designed to improve the health of patients with heart diseases. Internationally, Phase II Cardiac Rehabilitat...
A subset of Kupffer cells regulates metabolism through the expression of CD36
Authors: Camille Blériot, Emelie Barreby, Garett Dunsmore, Raphaelle Ballaire, Svetoslav Chakarov, Xenia Ficht, Giorgia De Simone, Francesco Andreata, Valeria Fumagalli, Wei Guo, Guochen Wan, Gregoire Gessain, Ahad Khalilnezhad, Xiao Meng Zhang, Nicholas Ang, Ping Chen, Cecilia Morgantini, Valerio Azzimato, Wan Ting Kong, Zhaoyuan Liu, Rhea Pai, Josephine Lum, Foo Shihui, Ivy Low, Connie Xu, Benoit Malleret, Muhammad Faris Mohd Kairi, Akhila Balachander, Olivier Cexus, Anis Larbi, Bernett Lee, Evan W. Newell, Lai Guan Ng, Wint Wint Phoo, Radoslaw M. Sobota, Ankur Sharma, Shanshan W. Howland, Jinmiao Chen, Marc Bajenoff, Laurent Yvan-Charvet, Nicolas Venteclef, Matteo Iannacone, Myriam Aouadi, Florent Ginhoux
Journal: Immunity (2021)
Evaluation of Watchful Waiting and Tumor Behavior in Patients With Basal Cell Carcinoma
Authors: Marieke E. C. van Winden, Charlotte R. M. Hetterschijt, Ewald M. Bronkhorst, Peter C. M. van de Kerkhof, Elke M. G. J. de Jong, Satish F. K. Lubeek
Journal: JAMA Dermatology (2021)

Few studies have examined watchful waiting (WW) in patients with basal cell carcinoma (BCC), although this approach might be suitable in patients who might not live long enough to benefit from treatment.To evaluate reasons for WW and to document the natural course of BCC in patients who chose WW and reasons to initiate later treatment.An observational cohort study was performed at a single institution between January 2018 and November 2020 studying patients with 1 or more untreated BCC for 3 months or longer.Watchful waiting was chosen by patients and proxies regardless of this study.The reasons for WW and treatment were extracted from patient files and were categorized for analyses. Linear mixed models were used to estimate tumor growth and identify covariates associated with tumor growth.Watchful waiting was chosen for 280 BCCs in 89 patients (47 men [53%] and 42 women [47%]), with a median (interquartile range [IQR]) follow-up of 9 (4-15) months. The median (IQR) age of the included patients was 83 (73-88) years. Patient-related factors or preferences (ie, prioritizations of comorbidities, severe frailty, or limited life expectancy) were reasons to initiate WW in 74 (83%) patients, followed by tumor-related factors (n = 49; 55%). Treatment-related and circumstantial reasons were important for 35% and 46% of the patients, respectively. The minority of tumors increased in size (47%). Tumor growth was associated with BCC subtype (odds ratio, 3.35; 95% CI, 1.47-7.96; P = .005), but not with initial tumor size and location. The estimated tumor diameter increase was 4.46 mm (80% prediction interval, 1.42 to 7.46 mm) in 1 year for BCCs containing at least an infiltrative/micronodular component and 1.06 mm (80% prediction interval, -1.79 to 4.28 mm) for the remaining BCCs (only nodular/superficial component/clinical diagnosis). Most common reasons to initiate treatment were tumor burden or potential tumor burden, resolved reason(s) for WW, and reevaluation of patient-related factors.In this cohort study of patients with BCC, WW was an appropriate approach in several patients, especially those with asymptomatic nodular or superficial BCCs and a limited life expectancy. Patients should be followed up regularly to determine whether a WW approach is still suitable and whether patients still prefer WW and to reconsider consequences of treatment and refraining from treatment.
The human homolog of drosophila disc large protein (hDLG) is antigenic and a potential tumor suppressor in melanoma
Authors: Pintusorn Hansakul, Brent R. Bellows, Truman Grayson, N. S. Banerjee, Thomas R. Broker, Theresa V. Strong
Journal: Cancer Research (2004)

2771  In Drosophila, the Disc large (Dlg) protein maintains epithelial cell structure and acts as a negative regulator of cell growth. Loss of dlg results in aberrant morphology, invasive growth of epithelial cells, and tumor formation. The human homologue of Dlg (hDlg) localizes to sites of intercellular contact and has been shown to bind to several cellular proteins involved in regulating cell growth and polarity. We identified hDlg as a melanoma-associated antigen by screening a cDNA expression library derived from melanoma cell lines with sera from metastatic melanoma patients undergoing immunotherapy. Analysis of the expression of hDlg mRNA in normal cells, melanoma cell lines and in primary melanomas demonstrated reduced or absent expression of hDlg in all 12 primary melanomas and in 7 of 9 melanoma cell lines compared to normal human melanocytes. Moreover, several aberrantly spliced variants of the hDlg gene were detected in melanoma cell lines and primary melanomas. The subcellular localization of hDlg protein was examined in primary melanocytes, raft cultures of primary human keratinocytes with and without melanocytes, melanoma cell lines, and primary tumors. In normal cells, hDlg was primarily localized to the membrane, particularly at points of intercellular contacts. In contrast, little or no membrane-localized hDlg was noted in melanoma cell lines and primary melanomas, with the protein exhibiting prominent cytoplasmic localization. The loss of total cellular hDlg or its aberrant localization in melanomas suggests a potential role for this protein as a tumor suppressor. We evaluated this possibility by ectopically expressing hDlg in melanoma cell lines. Ectopic expression of hDlg suppressed colony formation relative to the vector control. These results suggest that changes in the expression and cellular localization of hDlg may contribute to the malignant phenotype in melanoma.
Early-Onset Atrial Fibrillation and Heritable Heart Disease—To Test or Not to Test?
Authors: Gordon F. Tomaselli, Megan J. Roy-Puckelwartz
Journal: JAMA Cardiology (2021)

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Periodontology and pregnancy: An overview of biomedical and epidemiological evidence
Authors: Karen Raju, Lisa Berens
Journal: Periodontology 2000 (2021)

Abstract Women are particularly susceptible to developing gingival problems during pregnancy. In addition, periodontal disease in pregnant women may lead to adverse outcomes for both mother and infant, which have serious clinical and public health implications. Both scenarios have been extensively researched, helping to bring attention to pregnant women as an important and vulnerable population as it concerns periodontal health. The increase in gingival inflammation caused by hormonal changes in pregnant women is undisputed and has been studied and documented since the 1960s, although the exact etiology is not fully understood. The relationship between periodontal disease during pregnancy and adverse pregnancy outcomes is less substantiated, because of conflicting evidence. This review of the biomedical and epidemiologic literature provides an overview of both sides of this relationship and examines the potential mechanisms for developing periodontal disease during pregnancy and the proposed mechanisms by which periodontal disease leads to adverse pregnancy outcomes.