tbuckley/cabot-search huggingface dataset:
Editor's Note: Therapeutic Targeting of ATP7B in Ovarian Carcinoma
Authors: Lingegowda S. Mangala, Vesna Zuzel, Rosemarie Schmandt, Erik S. Leshane, Jyotsna B. Halder, Guillermo N. Armaiz-Pena, Whitney A. Spannuth, Takemi Tanaka, Mian M.K. Shahzad, Yvonne G. Lin, Alpa M. Nick, Christopher G. Danes, Jeong-Won Lee, Nicholas B. Jennings, Pablo E. Vivas-Mejia, Judith K. Wolf, Robert L. Coleman, Zahid H. Siddik, Gabriel Lopez-Berestein, Svetlana Lutsenko, Anil K. Sood
Journal: Clinical Cancer Research (2021)

The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]): in Fig. 5A, the representative images for "empty liposome" and "control siRNA-DOPC" were both from the "empty liposome" group. MD Anderson's Office of Research Oversight and Integrity
Roles of physical exercise in neurodegeneration: reversal of epigenetic clock
Authors: Miao Xu, JiaYi Zhu, Xian-Dong Liu, Ming-Ying Luo, Nan-Jie Xu
Journal: Translational Neurodegeneration (2021)

Abstract The epigenetic clock is defined by the DNA methylation (DNAm) level and has been extensively applied to distinguish biological age from chronological age. Aging-related neurodegeneration is associated with epigenetic alteration, which determines the status of diseases. In recent years, extensive research has shown that physical exercise (PE) can affect the DNAm level, implying a reversal of the epigenetic clock in neurodegeneration. PE also regulates brain plasticity, neuroinflammation, and molecular signaling cascades associated with epigenetics. This review summarizes the effects of PE on neurodegenerative diseases via both general and disease-specific DNAm mechanisms, and discusses epigenetic modifications that alleviate the pathological symptoms of these diseases. This may lead to probing of the underpinnings of neurodegenerative disorders and provide valuable therapeutic references for cognitive and motor dysfunction.
Prevalence of UBA1 mutations in MDS/CMML patients with systemic inflammatory and auto-immune disease
Authors: Lin-Pierre Zhao, Berenice Schell, Marie Sébert, Rathana Kim, Pierre Lemaire, Maxime Boy, Stephanie Mathis, Lise Larcher, Clémentine Chauvel, Mohamed Bedis Dhouaieb, Valéria Bisio, Claude Preudhomme, Alice Marceau-Renaut, Raphaël Itzykson, Arsène Mekinian, Olivier Fain, Antoine Toubert, Pierre Fenaux, Nicolas Dulphy, Emmanuelle Clappier, Lionel Adès
Journal: Leukemia (2021)
Gene Editing — A Cure for Transthyretin Amyloidosis?
Authors: Mathew S. Maurer
Journal: New England Journal of Medicine (2021)

Imagine that you had several family members with transthyretin amyloidosis. In their sixth decade of life, numbness developed, initially in their hands and feet, that progressed proximally over a period of years. This numbness came with associated muscle weakness, and then symptoms of autonomic dysfunction developed, including profound dizziness with changes in posture and alternating constipation and diarrhea that hindered their ability to engage socially. With disease progression, a syndrome of heart failure with worsening fatigue, shortness of breath, and edema developed. They initially needed an assistive device to walk, and ultimately they could not ambulate at all, losing their . . .
汎癌計算組織病理学は突然変異,腫瘍組成および予後を明らかにする【JST・京大機械翻訳】
Authors: Fu Yu, W Jung Alexander, Torne Ramon Vinas, Gonzalez Santiago, Vohringer Harald, Shmatko Artem, R Yates Lucy, Jimenez-Linan Mercedes, Moore Luiza, Gerstung Moritz
Journal: Nature Cancer (2020)
Changing the implied consent model for investigations is not easy
Authors: Santhanam Sundar
Journal: BMJ (2021)

Lessing highlights the significant distress that can result from unexpected incidental findings on follow-up imaging.1

Unnecessary distress can be caused by expected but unwanted findings, since early detection of disease relapse, at an asymptomatic stage, is not always beneficial. For example, a Cochrane meta-analysis found that more intensive follow‐up of cancer survivors made little or no difference …
The gRASs Is Greener: Potential New Therapies in Lung Cancer with Acquired Resistance to KRASG12C Inhibitors
Authors: Marika Pinnelli, Livio Trusolino
Journal: Cancer Discovery (2021)

Inhibitors of KRASG12C that bind the target in its inactive conformation and lock it in off-mode have shown early signs of clinical activity in patients with KRAS G12C-mutant lung cancer, but responses tend to be short-lived and invariably prelude the development of acquired resistance through largely unexplored mechanisms. A new study describes the emergence of RAS-MAPK heterogeneous subclonal alterations in a patient relapsed on a KRASG12C inactive-state inhibitor and identifies a novel KRASY96D-resistant variant that is druggable by a next-generation compound capable of associating with KRASG12C in its active configuration.See related article by Tanaka et al., p. 1913.
Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome
Authors: Youmna Kfoury, Niclas Setterblad, Marwan El-Sabban, Alessia Zamborlini, Zeina Dassouki, Hiba El Hajj, Olivier Hermine, Claudine Pique, Hugues de Thé, Ali Saïb, Ali Bazarbachi
Journal: Blood (2010)
Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP
Authors: Mark Chen, Joseph P. Foster, Ian C. Lock, Nathan H. Leisenring, Andrea R. Daniel, Warren Floyd, Eric Xu, Ian J. Davis, David G. Kirsch
Journal: Cancer Research (2021)

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma. SIGNIFICANCE: Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.
Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance
Authors: Ryan A. Hlady, Xia Zhao, Louis Y. El Khoury, Aesis Luna, Kien Pham, Qunfeng Wu, Jeong‐Heon Lee, Nikolaos T. Pyrsopoulos, Chen Liu, Keith D. Robertson
Journal: Hepatology (2021)

Abstract Background and Aims Chronic HCV infection is a leading etiologic driver of cirrhosis and ultimately HCC. Of the approximately 71 million individuals chronically infected with HCV, 10%‐20% are expected to develop severe liver complications in their lifetime. Epigenetic mechanisms including DNA methylation and histone modifications become profoundly disrupted in disease processes including liver disease. Approach and Results To understand how HCV infection influences the epigenome and whether these events remain as “scars” following cure of chronic HCV infection, we mapped genome‐wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3), and open chromatin in parental and HCV‐infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene‐expression analyses following elimination of HCV in these models through treatment with interferon‐α (IFN‐α) or a direct‐acting antiviral (DAA). Our data demonstrate that HCV infection profoundly affects the epigenome (particularly enhancers); HCV shares epigenetic targets with interferon‐α targets; and an overwhelming majority of epigenetic changes induced by HCV remain as “scars” on the epigenome following viral cure. Similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of IFN‐α/DAA antiviral regimens with DNA methyltransferase inhibitor 5‐aza‐2’‐deoxycytidine synergizes in reverting aberrant DNA methylation induced by HCV. Finally, both HCV‐infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring. Conclusions Integration of epigenetic and transcriptional data elucidate key gene deregulation events driven by HCV infection and how this may underpin the long‐term elevated risk for HCC in patients cured of HCV due to epigenome scarring.
CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries
Authors: Bih H. Chendi, Hallgeir Tveiten, Candice I. Snyders, Kristian Tonby, Synne Jenum, Susanne Dam Nielsen, Malene Hove-Skovsgaard, Gerhard Walzl, Novel N. Chegou, Anne M Dyrhol-Riise
Journal: Journal of Infection (2021)

To evaluate the performance of selected host immunological biomarkers in differentiating tuberculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries.Participants with TB disease (N = 85) and LTBI (N = 150) were recruited from prospective cohorts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status.Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1+RANTES+CRP+MIP-1α) derived from a training set (n = 155) differentiated TB disease from LTBI in the test set (n = 67) with a sensitivity of 56.0% (95% CI, 34.9-75.6) and a specificity of 85.7% (95% CI, 71.5-94.6). A 5-marker signature derived from the HIV uninfected group (CCL1+RANTES+MIP-1α+procalcitonin+IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a specificity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1+TNF-α) identified in HIV-infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respectively in the test set.Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration.
Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
Authors: Yuran Qiu, Yuanhao Wang, Zongtao Chai, Duan Ni, Xinyi Li, Jun Pu, Jie Chen, Jian Zhang, Shaoyong Lu, Chuan Lv, Mingfei Ji
Journal: Acta Pharmaceutica Sinica B (2021)

RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an 'undruggable' feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.
Clinical Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Malignant Peritoneal Mesothelioma
Authors: Kanwal Raghav, Suyu Liu, Michael Overman, Ajaykumar Morani, Anneleis Willette, Keith Fournier, Gauri Varadhachary
Journal: JAMA Network Open (2021)

dedicated trials and larger cohorts to define biomarkers of response or resistance, early referral to clinical trials, and novel combinatorial strategies to enhance responses and outcomes for patients with MPeM.
SO-6 Microarchitectural changes in regional lymph nodes after chemotherapy in oesophageal cancer: Results from the UK MRC OE02 trial
Authors: M. Kloft, I. Samarska, M. Nankivell, D. Cunningham, W. Allum, R. Langley, D. Magee, H. Grabsch
Journal: Annals of Oncology (2021)
Utility of a Cancer Predisposition Screening Tool for Predicting Subsequent Malignant Neoplasms in Childhood Cancer Survivors
Authors: Noelle Cullinan, Ian Schiller, Giancarlo Di Giuseppe, Mohammed Mamun, Lara Reichman, Chantel Cacciotti, Laura Wheaton, Kimberly Caswell, Bruna Di Monte, Paul Gibson, Donna L. Johnston, Adam Fleming, Jason D. Pole, David Malkin, William D. Foulkes, Nandini Dendukuri, Catherine Goudie, Paul C. Nathan
Journal: Journal of Clinical Oncology (2021)

Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS.Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development.Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation.MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.
Coronary Computed Tomographic Angiography for Complete Assessment of Coronary Artery Disease
Authors: Patrick W. Serruys, Hironori Hara, Scot Garg, Hideyuki Kawashima, Bjarne L. Nørgaard, Marc R. Dweck, Jeroen J. Bax, Juhani Knuuti, Koen Nieman, Jonathon A. Leipsic, Saima Mushtaq, Daniele Andreini, Yoshinobu Onuma
Journal: Journal of the American College of Cardiology (2021)
An Engineered Protein Adhesive with Properties of Tissue Integration and Controlled Release for Efficient Cartilage Repair
Authors: Jinrui Zhang, Bo Li, Jianlin Zuo, Rui Gu, Bin Liu, Chao Ma, Jingjing Li, Kai Liu
Journal: Advanced Healthcare Materials (2021)

Abstract Cartilage damage is a prevalent health concern among humans. The inertness of cartilage, the absence of self‐healing properties, and the lack of appropriate repair materials that integrate into the tissue pose a significant challenge for cartilage repair. Thus, it is important to develop novel soft biomaterials with strong tissue adhesion and chondrogenic capabilities for cartilage repair. Herein, a new type of protein adhesive is reported that exhibits superior cartilage repair performance. The material is fabricated by the electrostatic combination of chondroitin sulfate (CS) and positively charged elastin‐like protein, which is derived from natural components of the extracellular matrix (ECM). The adhesive showed robust adhesion properties on different tissue substrates, offering a favorable environment for cartilage tissue integration. Noncovalent bonding between CS molecules in the glue allows for its controlled release, which is required for efficient chondrogenic differentiation. When implanted into a rat model of cartilage defect, this protein adhesive exhibited beneficial healing effects, as evidenced by enhanced chondrogenesis, sufficient ECM production, and lateral integration. Therefore, this engineered protein complex is a promising candidate for translational application in the field of cartilage repair.
A rare colonic neoplasm with submucosal bulge successfully treated by endoscopic submucosal dissection
Authors: Jun Li, Feng Liu
Journal: Endoscopy (2021)

A 47-year-old man presented to the endoscopy center for health screening. Colonoscopy revealed a mucosal neoplasm of about 2.0 × 2.0 cm in the sigmoid colon with a large submucosal bulge ([Fig. 1]). Endoscopic ultrasound showed the head of the hyperechoic structure from the first layer and the bulge predominantly hypoechoic from the third layer ([Fig. 2]). Contrast-enhanced computed tomography (CT) revealed no evidence of lymph nodes or any metastasis. Endoscopic submucosal dissection (ESD) was performed ([Video 1]). The lesion was successfully resected en bloc ([Fig. 3]). Histopathology revealed a tubular adenoma in the upper mucosa and acellular mucin pools separated by irregular fibrous septa in the stalk ([Fig. 4]). Displaced adenomatous glands are seen in the stalk ([Fig. 5], green arrow), surrounded by a rim of normal lamina propria with abundant hemosiderin ([Fig. 5], yellow arrow). The dissecting mucin encircled these glands with no epithelial fragments floating therein. A diagnosis of tubular adenoma with pseudoinvasion and dissecting mucin (stromal mucin pools) was made.
HPV-16 E6/E7 DNA tattoo vaccination using genetically optimized vaccines elicit clinical and immunological responses in patients with usual vulvar intraepithelial neoplasia (uVIN): a phase I/II clinical trial
Authors: Noor Alida Maria Bakker, Jossie Rotman, Marc Van Beurden, Henry J.M.A.A. Zijlmans, Maartje Van Ruiten, Sanne Samuels, Bastiaan Nuijen, Jos Beijnen, Karin De Visser, John Haanen, Ton Schumacher, Tanja D. De Gruijl, Ekaterina S. Jordanova, Gemma G. Kenter, Joost H. Van Den Berg, Nienke E. Van Trommel
Journal: Journal for ImmunoTherapy of Cancer (2021)

Usual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%-8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis.In this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays.Vaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response.Our results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit.NTR4607.
Philosophy on trial: examining ethics of clinical investigations
Authors: C. Marwick
Journal: JAMA (1988)

THE PARAMOUNT ETHICAL questions posed by any clinical trial include the following: Should it be done at all? What information will be elicited that is not now available? Is seeking to obtain this information justifiable in terms of the risks to the subjects that may be involved? In the view of John Fletcher, PhD, these questions override all other considerations in the protection of human subjects, including the much-publicized one of informed consent. Before going to the University of Virginia School of Medicine, Charlottesville, where he is professor of biomedical ethics, Fletcher was the resident bioethicist at the Clinical Center of the National Institutes of Health (NIH), Bethesda, Md—the first person to hold the post. Fletcher became interested in the ethical aspects of medical research when he was a student at Union Theological Seminary in New York City, where he received his doctorate. During that period, he worked as a