tbuckley/cabot-search huggingface dataset:
Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells
Authors: Elisabeth R. Wilson, Nichole M. Helton, Sharon E. Heath, Robert S. Fulton, Jacqueline E. Payton, John S. Welch, Matthew J. Walter, Peter Westervelt, John F. DiPersio, Daniel C. Link, Christopher A. Miller, Timothy J. Ley, David H. Spencer
Journal: Leukemia (2021)

Abstract Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4000 focal regions that were uniquely hypermethylated in IDH mut samples vs. normal CD34+ cells and other AMLs. These regions had modest hypermethylation in AMLs with biallelic TET2 mutations, and levels of 5-hydroxymethylation that were diminished in IDH and TET -mutant samples, indicating that this hypermethylation results from inhibition of TET-mediated demethylation. Focal hypermethylation in IDH mut AMLs occurred at regions with low methylation in CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3A R882 mutations were significantly less hypermethylated, suggesting that IDH mut -associated hypermethylation is mediated by DNMT3A. IDH mut -specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6 . These results suggest that focal hypermethylation in IDH -mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis.
Selected Articles from This Issue
Journal: Clinical Cancer Research (2021)

Dysregulation of TGF-ß signaling occurs in many cancer subtypes.Preclinical studies of the TGF-ßR1 inhibitor LY3200882 have suggested that this agent may translate well to the clinic.To this end, Yap and colleagues conducted a first-inhuman phase I study of LY3200882 in patients with advanced cancer.LY3200882 was well tolerated as monotherapy and in combination with other agents.When combined with gemcitabine and nab-paclitaxel in patients with treatment-na€ ve pancreatic adenocarcinoma, LY3200882 led to a RECIST v1.1 partial response in 6/12 patients and stable disease in 3/12 patients, an overall disease control rate of 75%.Encouraging response data was observed in patients with grade 4 glioma as well.These results are encouraging and suggest that further clinical assessment of LY3200882 is warranted, especially in patients with pancreatic adenocarcinoma.
Postimplant Phosphodiesterase-5 Inhibitor Use in Centrifugal Flow Left Ventricular Assist Devices
Authors: Andrew Xanthopoulos, Kathy Wolski, Qiuqing Wang, Eugene H. Blackstone, Varinder Kaur Randhawa, Edward G. Soltesz, James B. Young, Steven E. Nissen, Jerry D. Estep, Filippos Triposkiadis, Randall C. Starling
Journal: JACC Heart Failure (2021)
Outcomes Stratified by Adapted Inclusion Criteria After Mitral Edge-to-Edge Repair
Authors: Benedikt Koell, Mathias Orban, Jessica Weimann, Mohammad Kassar, Nicole Karam, Michael Neuss, Aniela Petrescu, Christos Iliadis, Matthias Unterhuber, Marianna Adamo, Cristina Giannini, Bruno Melica, Sebastian Ludwig, Steffen Massberg, Fabien Praz, Roman Pfister, Holger Thiele, Ralph Stephan von Bardeleben, Stephan Baldus, Christian Butter, Philipp Lurz, Stephan Windecker, Marco Metra, Anna Sonia Petronio, Jörg Hausleiter, Edith Lubos, Daniel Kalbacher
Journal: Journal of the American College of Cardiology (2021)
CTNI-38. PriCoTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Sied Kebir, Daniela Pierscianek, Martin Proescholdt, Peter Hau, Anca-Ligia Grosu, Dietmar Krex, Ulrich Sure, Björn Scheffler, Martin Stuschke, Martin Glas
Journal: Neuro-Oncology (2021)

Abstract TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). Preclinical studies showed that combination of TTFields and radiotherapy synergistically impaired glioblastoma cell growth. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. Following surgery and wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with. We will present initial practical experiences as well as preliminary safety and tolerance data. There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.
SARS‐CoV‐2 Omicron variant: Characteristics and prevention
Authors: Xuemei He, Weiqi Hong, Xiangyu Pan, Guangwen Lu, Xiawei Wei
Journal: MedComm (2021)

Abstract Coronavirus disease 2019 (COVID‐19) has brought about a great threat to global public health. Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variant B.1.1.529 has been reported in South Africa and induced a rapid increase in COVID‐19 cases. On November 24, 2021, B.1.1.529 named Omicron was designated as a variant under monitoring (VUM) by World Health Organization (WHO). Two days later, the Omicron variant was classified as a variant of concern (VOC). This variant harbors a high number of mutations, including 15 mutations in the receptor‐binding domain (RBD) of spike. The Omicron variant also shares several mutations with the previous VOC Alpha, Beta, and Gamma variants, which immediately raised global concerns about viral transmissibility, pathogenicity, and immune evasion. Here we described the discovery and characteristics of the Omicron variant, compared the mutations of the spike in the five VOCs, and further raised possible strategies to prevent and overcome the prevalence of the Omicron variant.
Іmmunological disorders and colonic dysbiosis inpatients with biliary lesions in type 2 diabetes mellitus and obesity
Authors: Ye.S. Sirchak, M.M. Nastych
Journal: GASTROENTEROLOGY (2021)

Background. The microbiome plays a crucial role in maintaining homeostasis. The purpose of the research was to study the peculiarities of changes in immunological status and their relationship with colonic dysbiosis in patients with biliary lesions on the background of type 2 diabetes mellitus (DM) and obesity. Materials and methods. The study included 54 patients with type 2 DM and obesity of varying severity, who underwent a comprehensive examination. Two groups of those examined for type 2 DM and obesity were formed, depending on the type of lesion of the biliary system. Thus, group I included 24 patients with chronic acalculous cholecystitis, and group II consisted of 30 patients with gallstone disease. Results. The results of the analysis of the quantitative and qualitative composition of the colonic microflora indicate dysbiotic changes in patients with type2 DM, obesity, and lesions of the biliary system. More pronounced disorders in the quantitative and qualitative composition of colonic microflora were diagnosed in patients of group II (with type 2 DM and obesity in combination with gallstone disease). The patients of group II significantly more often developed an increase in the number of Enterobacter (14.2%; p&lt;0.05), Citrobacter (31.8%; p&lt;0.01), Staphylococcus (16.7%; p&lt;0.05), and Clostridium (11.8%; p&lt;0.05) compared with the data of group I. More pronounced increase in all immunoglobulin parameters was found in patients with gallstone disease associated with type 2 DM and obesity. At the same time, the increase in IgA and IgG levels, which is indisputable evidence of activation of the humoral part of the body’s immunocompetent system, was found in patients with biliary lesions and type 2 DM and obesity. Conclusions. In patients with type2 DM and obesity in combination with lesions of the biliary system (mainly gallstone disease), changes in the quantitative and qualitative composition of the colonic microflora (a decrease in the number of Bifidobacterium and Lactobacillus and an increase in the concentration of Clostridium, Staphylococci, Proteus, and Klebsiella) were detected. Impairment of immunological status in patients with type 2 DM and obesity in combination with lesions of the biliary tract was diagnosed, which manifested in increased levels of IgA, IgG, IgM, IgG and a decrease in serum C3 and C4 in patients with gallstone disease. The increase in IgA and IgG directly depends on the change in the number of Bifidobacterium and Lactobacillus, Staphylococcus, Clostridium, Proteus in the microbiological examination of feces in patients with type 2 DM and obesity in combination with the biliary system (mainly gallstone disease).
Sertaconazole provokes proapoptotic autophagy via stabilizing TRADD in nonsmall cell lung cancer cells
Authors: Wenhui Zhang, Li Zhou, Siyuan Qin, Jingwen Jiang, Zhao Huang, Zhe Zhang, Xiyu Zhang, Zheng Shi, Jie Lin
Journal: MedComm (2021)

Abstract Nonsmall cell lung cancer (NSCLC) is one of the most commonly diagnosed and lethal cancers characterized by relatively low overall cure and poor survival rates with great challenge for consistent effective clinical treatment. Here we demonstrated that the antifungal sertaconazole displays potent anti‐NSCLC effect by promoting apoptosis in vitro and in vivo. Further studies found that sertaconazole induces complete autophagic flux, which contributes to sertaconazole‐induced apoptosis and subsequent growth suppression in NSCLC cells. Further studies demonstrated that sertaconazole provokes TNF receptor type 1 associated death domain protein (TRADD) expression via stabilizing it from ubiquitination‐mediated degradation, which results in Akt dephosphorylation and thereby triggers proapoptotic autophagy in NSCLC cells. Moreover, we found that TRADD suppression reverses sertaconazole‐induced proapoptotic autophagy and relieves growth suppression, indicating the vital role of TRADD‐regulated proapoptotic autophagy in the anti‐NSCLC activity of sertaconazole. In summary, our findings suggest that sertaconazole could be a highly promising anti‐NSCLC drug by triggering proapoptotic autophagy via stabilizing TRADD, which may provide a new potential therapeutic option for patients with NSCLC.
Recurrent Germline Variant in the Cohesin Complex Gene <i>RAD21</i> Predisposes Children to Lymphoblastic Leukemia and Lymphoma
Authors: Anne Schedel, Ulrike Anne Friedrich, Rabea Wagener, Juha Mehtonen, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter, Peter Horak, Nagarajan Paramasivam, Grazia Fazio, Stefan Fröhling, Martin Dugas, Daniela Richter, Hanno Glimm, Merja Heinäniemi, Rolf Jessberger, Giovanni Cazzaniga, Arndt Borkhardt, Julia Hauer, Franziska Auer
Journal: Blood (2021)
Mammary Tumor–Derived Transplants as Breast Cancer Models to Evaluate Tumor–Immune Interactions and Therapeutic Responses
Authors: Jade Moore, Lin Ma, Ann A. Lazar, Mary Helen Barcellos-Hoff
Journal: Cancer Research (2021)

Abstract In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, cancers with abundant tumor-infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, whereas those in which CD8+ T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology. Here we established mammary tumor–derived transplants (mTDT) from 12 Trp53-null mammary tumors in syngeneic BALB/cJ mice and examined the stability of their growth rate, TIL distribution, and transcriptomic profiles. All mTDTs were estrogen receptor negative. Half of the parental tumors were classified as infiltrated, and the rest were divided between excluded and desert phenotypes. After two orthotopic passages, most (70%) mTDT from infiltrated parents recapitulated this pattern, whereas the desert or excluded parental patterns were maintained in about half of daughter mTDT. Approximately 30% of mTDT gave rise to lung or liver metastases, although metastasis was not associated with a TIL phenotype. Unsupervised transcriptomic analysis clustered mTDT according to their TIL spatial patterns. Infiltrated mTDT transplanted subcutaneously or orthotopically were resistant to anti–PD-L1. Profiling implicated prolonged antigen stimulation and loss of effector function of lymphocytes rather than T-cell exhaustion in the lack of response of infiltrated mTDT to checkpoint blockade. In summary, the molecular diversity and immune complexity of mTDT should facilitate the dissection of mechanisms of breast cancer response to immunotherapies. Significance: A set of diverse preclinical models of breast cancer is characterized to enable mechanistic dissection of tumor–immune interactions and to improve the efficacy of immunotherapies.
Engineering naphthalimide-cyanine integrated near-infrared dye into ROS-responsive nanohybrids for tumor PDT/PTT/chemotherapy
Authors: Tongxia Jin, Di Cheng, Guanyu Jiang, Wenqian Xing, Peiwen Liu, Bin Wang, Weiping Zhu, Haitao Sun, Zhenrong Sun, Yufang Xu, Xuhong Qian
Journal: Bioactive Materials (2021)

Photodynamic (PDT) and photothermal therapies (PTT) are emerging treatments for tumour ablation. Organic dyes such as porphyrin, chlorin, phthalocyanine, boron-dipyrromethene and cyanine are the clinically or preclinically used photosensitizer or photothermal agents. Development of structurally diverse near-infrared dyes with long absorption wavelength is of great significance for PDT and PTT. Herein, we report a novel near-infrared dye ML880 with naphthalimide modified cyanine skeleton. The introduction of naphthalimide moiety results in stronger electron delocalization and larger redshift in emission compared with IR820. Furthermore, ML880 is co-loaded with chemotherapeutic drug into ROS-responsive mesoporous organosilica (RMON) to construct nanomedicine NBD&ML@RMON, which exhibits remarkable tumor inhibition effects through PDT/PTT/chemotherapy in vivo.
Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties
Authors: Zhangcheng Chen, Luyu Fan, Huan Wang, Jing Yu, Dengyu Lu, Jianzhong Qi, Fen Nie, Zhipu Luo, Zhen Liu, Jianjun Cheng, Sheng Wang
Journal: Nature Neuroscience (2021)
RADT-30. MULTISESSION RADIOSURGERY ALONE FOR TREATMENT OF PRESUMED MENINGIOMAS: AN INTERIM REPORT FROM A SINGLE INSTITUTION PROTOCOL
Authors: Michael Carrasquilla, Alexander Tai, Matthew Forsthoefel, Edina Wang, Siyuan Lei, Lloyd Campbell, Simeng Suy, Breant Harris, Norio Azumi, Frank Berkowitz, Jean-Marc Voyadzis, Christopher Kalhorn, Walter Jean, Kevin McGrail, Sean Collins, Brian Collins
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Meningiomas are the most commonly diagnosed primary intracranial tumor. Resection and single-fraction radiosurgery are treatment options with well-established long-term outcomes data. Multisession radiosurgery is an alternative treatment option with promising early results. However, mature outcomes literature does not yet exist. In this study, we report our institution’s interim results on the efficacy and safety of 5-fraction radiosurgery alone for radiographically diagnosed meningiomas. MATERIALS AND METHODS Between 2005-2015 all patients who completed treatment on a single institution protocol utilizing 5-fraction robotic radiosurgery alone for the treatment of progressing radiographically diagnosed meningiomas were eligible for inclusion. Local control was calculated using the Kaplan-Meier Method. RESULTS Forty-four consecutive predominately female patients (84%) ranging in age from 33-85 (median: 59) were included in the present study. Median tumor volume was 4.05mm3 (range: 0.94-15.4mm3) and the majority of tumors were located at the base of skull (66%). A median dose of 25Gy (range: 25Gy-35Gy), was delivered to a median isodose line of 82%, (range: 70%-90%) over a median of 7 days (range: 5-11 days). Acute toxicity was minimal with 7 patients (15%) requiring a short course of steroids for symptomatic edema during treatment. Of 16 patients who presented with a cranial nerve deficit, symptom improvement was noted in 11 patients (69%). No permanent treatment related toxicity was noted in our cohort. The median radiographic follow-up was 6.9 years (range: 0.5-14.8 years). The 5 and 8-year local control rates were 100% and 95%. The median time to local failure (n=2) in our cohort was 8.2 years. CONCLUSIONS The treatment of radiographically diagnosed meningiomas with 5-fraction robotic radiosurgery provides excellent local control to date, with low rates of acute and late toxicity. However, with late failures noted in our series, continued follow-up is needed to determine the optimal dose required for long-term tumor control.
When is a Christmas party not a Christmas party? When it’s in Downing Street
Authors: Andy Cowper
Journal: BMJ (2021)

When is a Christmas party not a Christmas party?When it's in Downing Street Andy Cowper editorChristmas is a time for traditions, and one of our great British traditions is bad jokes.Whether it's the groan-inducing fare of pantomime scripts, or the hackneyed humour found inside Christmas crackers, "so bad it's good" humour is a key part of this season's rituals.
Clinical characteristics of antiepileptic-induced liver injury in patients from the DILIN prospective study
Authors: Naga Chalasani, Herbert L. Bonkovsky, Jonathan G. Stine, Jiezhun Gu, Huiman Barnhart, Elin Jacobsen, Einar Björnsson, Robert J. Fontana, David E. Kleiner, Jay H. Hoofnagle
Journal: Journal of Hepatology (2021)
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy
Authors: Enyong Dai, Zhi Zhu, Shudipto Wahed, Zhaoxia Qu, Walter J. Storkus, Zong Sheng Guo
Journal: Molecular Cancer (2021)

Abstract Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.
Abstract 10707: The Impact of the COVID-19 Pandemic on Incidence and Outcomes from Out-of-Hospital Cardiac Arrest (OHCA) in Texas
Authors: Summer Chavez, Ryan Huebinger, Joseph Gill, Lynn White, Hei Kit Chan, Normandy W Villa, Jeffrey L Jarvis, Veer D Vithalani, Lloyd Tannenbaum, Bentley Bobrow
Journal: Circulation (2021)

Introduction: Nationally, the COVID-19 pandemic was associated with worse OHCA outcomes. Whether these trends persist or were consistent between states is unclear. Purpose: To determine the impact of COVID-19 on OHCA incidence and outcomes in Texas between 2019-2020. Methods: We analyzed adult OHCAs in Texas from the Cardiac Arrest Registry to Enhance Survival (CARES) during a matched period (March 11-December 31 from 2019 through 2020). We excluded cases witnessed by 9-1-1 responders and arrests occurring at healthcare facilities. Outcomes were rates of BCPR, AED use, sustained ROSC, prehospital termination of resuscitation (TOR), survival to hospital, survival to hospital discharge, good neurological outcomes and Utstein bystander survival. We created a mixed effects logistic regression model analyzing the effect of the pandemic on outcomes, using EMS agency as the random intercept. We adjusted for age, gender, race/ethnicity, witnessed arrest, initial rhythm type and location type. Results: There were 8,070 OHCA cases, with 4,443 (55.1%) in the pandemic period (March 11 - December 31, 2020) and 3,627 (44.5%) from March 11 - December 31 2019, a relative 18.4% increase. There was a significantly decreased odds of BCPR (46.2% v 42.2%, aOR = 0.87, 95% CI 0.79-0.95), AED use (13.0% v 7.3%, aOR = 0.53, 95% CI 0.36-0.78), and sustained ROSC (28.8% v 21.2%, aOR = 0.67, 95% CI 0.60-0.74) during the pandemic. Survival to hospital (27.1% v 20.9%, aOR = 0.72, 95% CI 0.65-0.80) and survival to hospital discharge (10.0% v 7.4%, aOR = 0.71, 95% CI 0.64-0.89) also decreased. Prehospital TOR increased (37.3% v 46.7%, aOR = 1.51, 95% CI 1.35-1.67). The pandemic was associated with a lower Utstein bystander survival rate (58.5% v 52.5%, aOR = 0.79, 95% CI 0.6-0.97). Conclusion: In Texas during the COVID-19 pandemic, there was a greater number of OHCA events, with lower overall survival and increased prehospital TOR.
RBC-hitchhiking chitosan nanoparticles loading methylprednisolone for lung-targeting delivery
Authors: Yaning Ding, Bai Lv, Jinpeng Zheng, Caihong Lu, Jingzhou Liu, Yaran Lei, Meiyan Yang, Yuli Wang, Zhiping Li, Yang Yang, Wei Gong, Jing Han, Chunsheng Gao
Journal: Journal of Controlled Release (2021)