tbuckley/cabot-search huggingface dataset:
PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression
Authors: Liu Yang, Da-wei Ma, Yue-peng Cao, Dong-zheng Li, Xin Zhou, Ji-feng Feng, Jun Bao
Journal: Theranostics (2021)

Background: Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that symmetrically di-methylates arginine residues on both histone and non-histone protein substrates. Accumulating evidence suggests that PRMT5 exerts its oncogenic properties in a wide spectrum of human malignancies. However, the underlying mechanisms by which PRMT5 contributes to the progression of colorectal cancer (CRC) remain to be defined. Methods: Western blot and real-time PCR were used to analyze the expression of CDKN2B. Co-immunoprecipitation (Co-IP), immunofluorescence and GST pulldown assays were employed to investigate the interaction between PRMT5 and EZH2. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to validate CDKN2B as a direct target of PRMT5/EZH2. DNA methylation status at the CpG islands of promoter region of CDKN2B gene was analyzed by bisulfite sequencing. The effect of PRMT5/EZH2 on malignant phenotypes was examined through in vitro and in vivo assays. PRMT5 and EZH2 protein expression levels in CRC tissues were analyzed by immunohistochemistry (IHC) staining. Results: We observed that PRMT5-deficient CRC cells exhibit proliferation defects in vitro. PRMT5 was identified as a major transcriptional repressor of CDKN2B (p15INK4b) for determining CRC progression. Mechanistically, PRMT5-mediated histone marks H4R3me2s and H3R8me2s were predominantly deposited at the promoter region of CDKN2B gene in CRC cells. Knockdown of PRMT5 in CRC cells decreased the accumulation of H4R3me2s and H3R8me2s marks and reduced the CpG methylation level of CDKN2B promoter, then re-activated CDKN2B expression. Strikingly, silencing of CDKN2B partially abrogated the proliferation defects caused by PRMT5 depletion in vitro and in vivo. Furthermore, we proved that PRMT5 interacted with Enhancer of zeste homolog 2 (EZH2), leading to enhanced EZH2 binding and H3K27me3 deposition together with decreased transcriptional output of CDKN2B gene. Importantly, we found that the combined interventions exerted a synergistic inhibitory effect of combined treatment with PRMT5i (GSK591) and EZH2i (GSK126) on the growth of CRC cells/xenografts in vitro and in vivo. Moreover, PRMT5 and EZH2 were found to be significantly elevated and associated with poor prognosis in CRC patients. Conclusion: PRMT5 functionally associates with EZH2 to promote CRC progression through epigenetically repressing CDKN2B expression. Thus, our findings raise the possibility that combinational intervention of PRMT5 and EZH2 may be a promising strategy for CRC therapy.
Outcomes after liver transplantation in Korea: Incidence and risk factors from Korean transplantation registry
Authors: Jong Man Kim, Deok Gie Kim, Jihyun Kim, Keunsung Lee, Kwang-Woong Lee, Je Ho Ryu, Bong-Wan Kim, Dong Lak Choi, Young Kyoung You, Dong-Sik Kim, Yang Won Nah, Koo Jeong Kang, Jai Young Cho, Geun Hong, Hee Chul Yu, Ju Ik Moon, Dongho Choi, Shin Hwang, Myoung Soo Kim
Journal: Clinical and Molecular Hepatology (2021)

Background/Aims: To analyze the incidence and risk factors of outcomes after liver transplantation (LT) in the Korean population.Methods: This study analyzed data from the liver cohort of Korean Organ Transplantation Registry (KOTRY) who had LT between May 2014 and December 2017. Study measures included the incidence of post-LT outcomes in recipients of living donor LT (LDLT) and deceased donor LT (DDLT). Cox multivariate proportional hazards model was used to determine the potential risk factors predicting the outcomes.Results: A total of 2,563 adult recipients with LT (LDLT, n=1,956; DDLT, n=607) were included, with mean±standard deviation age of 53.9±8.9 years, and 72.2% were male. The post-LT outcomes observed in each LDLT and DDLT recipients were death (4.0% and 14.7%), graft loss (5.0% and 16.1%), rejection (7.0% and 12.0%), renal failure (2.7% and 13.8%), new onset of diabetes (12.5% and 15.4%), and hepatocellular carcinoma (HCC) recurrence (both 6.7%). In both LDLT and DDLT recipients, the most common post-LT complications were renal dysfunction (33.6% and 51.4%), infection (26.7% and 48.4%), and surgical complication (22.5% and 23.9%). Incidence of these outcomes were generally higher among recipients of DDLT than LDLT. Multivariate analysis indicated recipient age and DDLT as significant risk factors associated with death and graft loss. DDLT and ABO incompatible transplant were prognostic factors for rejection, and HCC beyond Milan criteria at pre-transplant was a strong predictor of HCC recurrence.Conclusions: This study is a good indicator of the post-LT prognosis in the Korean population and suggests a significant burden of post-LT complications.
Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated <i>Trp53</i> and <i>Pten</i> in Proximal Tubular Kidney Epithelial Cells
Authors: Xunian Zhou, Fei Xiao, Hikaru Sugimoto, Bingrui Li, Kathleen M. McAndrews, Raghu Kalluri
Journal: Cancer Research (2021)

Abstract Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations found in RCC have been lacking. In this study, we crossed Trp53 and Pten conditional knockout mice with Ggt1-Cre mice to generate a Ggt1-Cre; Trp53LoxP/LoxP; PtenLoxP/LoxP; YFPLoxP/LoxP (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC), with only approximately 25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated Vhl knockout in these mice increased the frequency of dysplasia, but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without Vhl knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, noninjured kidney with 100% penetrance at a younger age, but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from preestablished dysplastic precursor lesions. Significance: These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC.
Systematic memory B cell archiving and random display shape the human splenic marginal zone throughout life
Authors: Artur Kibler, Bettina Budeus, Ekaterina Homp, Kevin Bronischewski, Victoria Berg, Ludger Sellmann, Florian Murke, Andreas Heinold, Falko M. Heinemann, Monika Lindemann, Isabelle Bekeredjian-Ding, Peter A. Horn, Carsten J. Kirschning, Ralf Küppers, Marc Seifert
Journal: The Journal of Experimental Medicine (2021)

Human memory B cells (MBCs) are generated and diversified in secondary lymphoid tissues throughout the organism. A paired immunoglobulin (Ig)-gene repertoire analysis of peripheral blood (PB) and splenic MBCs from infant, adult, and elderly humans revealed that throughout life, circulating MBCs are comprehensively archived in the spleen. Archive MBC clones are systematically preserved and uncoupled from class-switching. Clonality in the spleen increases steadily, but boosts at midlife, thereby outcompeting small clones. The splenic marginal zone (sMZ) represents a primed MBC compartment, generated from a stochastic exchange within the archive memory pool. This is supported by functional assays, showing that PB and splenic CD21+ MBCs acquire transient CD21high expression upon NOTCH2-stimulation. Our study provides insight that the human MBC system in PB and spleen is composed of three interwoven compartments: the dynamic relationship of circulating, archive, and its subset of primed (sMZ) memory changes with age, thereby contributing to immune aging.
Deep metric learning-based image retrieval system for chest radiograph and its clinical applications in COVID-19
Authors: Aoxiao Zhong, Xiang Li, Dufan Wu, Hui Ren, Kyungsang Kim, Younggon Kim, Varun Buch, Nir Neumark, Bernardo Bizzo, Won Young Tak, Soo Young Park, Yu Rim Lee, Min Kyu Kang, Jung Gil Park, Byung Seok Kim, Woo Jin Chung, Ning Guo, Ittai Dayan, Mannudeep K. Kalra, Quanzheng Li
Journal: Medical Image Analysis (2021)
Near-Equivalence: Generating Evidence to Support Alternative Cost-Effective Treatments
Authors: Ian F. Tannock, Mark J. Ratain, Daniel A. Goldstein, Allen S. Lichter, Gary L. Rosner, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2021)

The cost of cancer drugs is a challenge to patients and healthcare systems.Here, we propose a new paradigm of near-equivalence, which combines various types of evidence to support acceptability of alternative treatments (ALTs) relative to standard-of-care (SOC).Nearequivalence facilitates cost-effective therapies but differs from cost-effectiveness analysis in emphasizing near-equivalent outcomes over cost and includes analysis of pharmacokinetic and pharmacodynamic data to support near-equivalent outcomes.Demonstration of near-equivalence does not require large noninferiority randomized controlled trials (RCTs).Rather, it is supported by the new discipline of interventional pharmacoeconomics. 1,2The utilitarian approach of near-equivalence aims to provide the greatest good for the greatest number of patients under real-world constraints; it can increase access to treatment and reduce financial toxicity, with minimal impact on efficacy and often with decreased toxicity.Various approaches to demonstrate near-equivalence, with examples, are described below and in the Table 1.
Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial
Authors: Kristian Reich, Kim A Papp, Andrew Blauvelt, Richard G Langley, April Armstrong, Richard B Warren, Kenneth B Gordon, Joseph F Merola, Yukari Okubo, Cynthia Madden, Maggie Wang, Christopher Cioffi, Veerle Vanvoorden, Mark Lebwohl
Journal: The Lancet (2021)
Compositional Variability and Mutation Spectra of Monophyletic SARS-CoV-2 Clades
Authors: Xufei Teng, Qianpeng Li, Zhao Li, Yuansheng Zhang, Guangyi Niu, Jingfa Xiao, Jun Yu, Zhang Zhang, Shuhui Song
Journal: Genomics Proteomics & Bioinformatics (2020)

COVID-19 and its causative pathogen SARS-CoV-2 have rushed the world into a staggering pandemic in a few months, and a global fight against both has been intensifying. Here, we describe an analysis procedure where genome composition and its variables are related, through the genetic code to molecular mechanisms, based on understanding of RNA replication and its feedback loop from mutation to viral proteome sequence fraternity including effective sites on the replicase-transcriptase complex. Our analysis starts with primary sequence information, identity-based phylogeny based on 22,051 SARS-CoV-2 sequences, and evaluation of sequence variation patterns as mutation spectra and its 12 permutations among organized clades. All are tailored to two key mechanisms: strand-biased and function-associated mutations. Our findings are listed as follows: 1) The most dominant mutation is C-to-U permutation, whose abundant second-codon-position counts alter amino acid composition toward higher molecular weight and lower hydrophobicity, albeit assumed most slightly deleterious. 2) The second abundance group includes three negative-strand mutations (U-to-C, A-to-G, and G-to-A) and a positive-strand mutation (G-to-U) due to DNA repair mechanisms after cellular abasic events. 3) A clade-associated biased mutation trend is found attributable to elevated level of negative-sense strand synthesis. 4) Within-clade permutation variation is very informative for associating non-synonymous mutations and viral proteome changes. These findings demand a platform where emerging mutations are mapped onto mostly subtle but fast-adjusting viral proteomes and transcriptomes, to provide biological and clinical information after logical convergence for effective pharmaceutical and diagnostic applications. Such actions are in desperate need, especially in the middle of the War against COVID-19.
The effect of migration on the incidence and mortality of bloodstream infection: a Danish register-based cohort study
Authors: Rikke Thoft Nielsen, Marie Norredam, Henrik Carl Schønheyder, Jørgen Holm Petersen, Jenny Dahl Knudsen, Jens Otto Jarløv, Christian Østergaard Andersen
Journal: Clinical Microbiology and Infection (2021)
Factors associated to treatment delay in women with primary breast cancer who were referred to reproductive specialists.
Authors: Atsuko Kitano, Sachiko Ohde, Kyoko Shiota, Fumi Akitani, Hideko Yamauchi, Teruo Yamauchi, Chikako Shimizu
Journal: Journal of Clinical Oncology (2018)

e12541 Background: Treatment-related infertility is known as a survivorship issues among young breast cancer patients. Cancer treatment-delay due to fertility preservation procedure can be a barrier for patients who might seek fertility preservation. This study sought to describe any association between fertility preservation and treatment-delay then to assess factors related to treatment-delay. Methods: Women diagnosed with breast cancer stages I to III between 2007 and 2015 who visited reproductive unit at our institution referred from two high-volume hospital in Japan were included. Cut-off of treatment-delay was defined as below; time to treatment (TTC) > 8weeks for patients intending to receiving to neoadjuvant chemotherapy, TTC > 12 weeks for patients intending to receiving to adjuvant chemotherapy patients, time to endocrine therapy (TTE) > 12 weeks for patients intending to receiving endocrine therapy without radiation therapy, and TTE > 20 weeks for patients intending to receiving endocrine therapy after radiation therapy. Multivariable models were constructed to examine factors associated with treatment-delay. Results: Two-hundred twenty-two patients met the inclusion criteria. Treatment-delay occurred in 18% of patients. Mean TTC among patients who received neoadjuvant chemotherapy or adjuvant chemotherapy was 30.7 days (SD = 29.3) and 65.6 days (SD = 29.5) respectively. Mean TTE without radiation therapy or with radiation therapy was 74.0 days (SD = 51.7) and 124.0 days (SD = 67.5) respectively. Among patients receiving adjuvant chemotherapy, TTC of fertility preservation group was longer than no fertility preservation group (66.3 vs 64.9 days, p = 0.03); the treatment-delay rate was not statistically different between the two groups. Endocrine therapy undertaken was related to treatment-delay (OR, 4.45; 95%CI: [1.01-19.57]; p = 0.048), but fertility preservation was not (OR, 1.82 95%CI: [0.88-3.76], p = 0.10). Conclusions: Fertility preservation-underwent was not related to treatment-delay. Early referral to reproductive specialist is required especially for patients intending to receive endocrine therapy.
Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression
Authors: Yutaka Kurebayashi, Colleen P. Olkowski, Kelly C. Lane, Olga V. Vasalatiy, Biying C. Xu, Ryuhei Okada, Aki Furusawa, Peter L. Choyke, Hisataka Kobayashi, Noriko Sato
Journal: Cancer Research (2021)

Abstract Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab′)2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies. Significance: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature.
N-glycan–mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP
Authors: Bogac Ercig, Nuno A. G. Graça, Kadri Kangro, Tom Arfman, Kanin Wichapong, Johana Hrdinová, Paul Kaijen, Floris P. J. van Alphen, Maartje van den Biggelaar, Karen Vanhoorelbeke, Agnès Veyradier, Paul Coppo, Chris Reutelingsperger, Gerry A. F. Nicolaes, Andres Männik, Jan Voorberg
Journal: Blood (2021)
How to make the most of your psychiatry placement
Authors: Afolarin Awodiya, Paul Whelan, John Pettit
Journal: BMJ (2021)

Every year, one in four people in the UK experiences mental health problems.1 As a medical student or junior doctor, you will see patients with mental illness in all branches of medicine. Seeing such patients can be daunting for students, who may worry that they do not have the skills needed to take a history containing potentially sensitive subjects, or to deal with agitated or distressed patients. During your time at medical school, however, you will have plenty of time to practise these skills in a supported manner. The communication skills learnt during your psychiatric placement will be useful throughout your career, no matter which specialty you eventually choose. During your psychiatry placement you may be exposed to upsetting histories, many including psychological trauma such as sexual abuse, and managing the feelings that arise in yourself can be challenging. It is important to build resilience to combat these difficult emotions. You may also be worried about your own safety when dealing with an agitated or distressed patient. Box 1 describes some well established methods for building emotional resilience, and a few helpful ideas for ensuring your personal safety. Box 1 ### Looking after yourself while seeing patients with mental illnessRETURN TO TEXT
Profile of Airborne Pollen in a Recently Placed Station In Madrid: Description Of Levels Of Pollen In the Last Three Years
Authors: María Cervera García, Maria Somoza Alvarez, Ana MarÃa Prieto-Moreno Pfeifer, Isabel Torres Rojas, Teresa Alfaya Arias, Diana Perez Alzate, Elisa Haroun-Diaz, Maria Vazquez de La Torre, Francisco Ruano, Paula Lopez, Natalia Blanca López, Francisco Feo Brito, Gabriela Canto
Journal: Journal of Allergy and Clinical Immunology (2021)
Assessment of Myocardial Mechanics in Patients Undergoing Pericardiectomy for Chronic Constrictive Pericarditis by Tissue Doppler Imaging and 2D Speckled Tracking Echocardiography: A Prospective Obser
Authors: Ujjwal Kumar Chowdhury, Lakshmi Kumari Sankhyan, Vikrant Yadav, Srikant Sharma, Mrigank Choubey, Niwin George, Sushamagayatri Sushamagayatri, Vishwas Malik
Journal: Clinical Cardiology and Cardiovascular Interventions (2021)

Background: This study was designed to prospectively evaluate the changes in tissue Doppler imaging (TDI) at mitral and tricuspid annuli and two dimensional speckle tracking echocardiography in patients undergoing pericardiectomy for chronic constrictive pericarditis and identify the relationship if any of the tissue Doppler imaging and speckle echocardiographic derived variables with patient’s symptomatic status following surgery. Patients and Methods: Twelve patients undergoing pericardiectomy for constrictive pericarditis aged 7 years to 70 years (median 21; IQR: 19.75-26.5 years) were studied for 2-36 months (median 19 months). They underwent Doppler flow velocity, TDI, and 2D-speckle echocardiographic studies. Friedman’ test was used to test the changes in TDI-derived mitral and tricuspid annular velocities and speckle derived parameters in postoperative period from baseline. Results: Despite congestive heart failure, all patients had normal left ventricular ejection fraction and increased medial mitral and tricuspid early diastolic septal velocity (e¢) with “annulus reversus”. This pattern of annular velocity improved maximally in the immediate postoperative period. At closing interval, 2 (16.7%) patients continued to be in New York Heart Association class II and both of them continued to remain in atrial fibrillation. There was statistical significant improvement in the Global cirumferential strain than in global longitudinal and global radial strain after pericardiectomy. Conclusions: We conclude that tissue Doppler imaging and speckle tracking echocardiography are useful investigative modalities for serial evaluation of patients undergoing pericardiectomy. It can be performed serially with a high degree of reproducibility.