tbuckley/cabot-search huggingface dataset:
RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment
Authors: Han-Hee Park, Hwa-Ryeon Kim, Sang-Yeong Park, Sung-Min Hwang, Sun Mi Hong, Sangwook Park, Ho Chul Kang, Michael J. Morgan, Jong-Ho Cha, Dakeun Lee, Jae-Seok Roe, You-Sun Kim
Journal: Molecular Cancer (2021)

Abstract Background Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes. Methods We employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8 + T cells or dendritic cells (DC) in all TCGA tumors. Results We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses. Conclusion Our data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.
26188 Recurrence status, perineural invasion, lymphovascular invasion, and hypothyroidism are independently associated with lymph node metastasis in cutaneous squamous cell carcinoma of the head and neck: A matched case-control study
Authors: Marissa Lobl, Heng Jiang, Joshua Abels, Shera Feinstein, Shauna Higgins, Omeed Ahadiat, Erica Lee, Makenzie Hawkins, Myles Cockburn, Adam Sutton, Ashley Wysong
Journal: Journal of the American Academy of Dermatology (2021)
Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention
Authors: Daniel Chandramohan, Issaka Zongo, Issaka Sagara, Matthew Cairns, Rakiswendé-Serge Yerbanga, Modibo Diarra, Frédéric Nikièma, Amadou Tapily, Frédéric Sompougdou, Djibrilla Issiaka, Charles Zoungrana, Koualy Sanogo, Alassane Haro, Mahamadou Kaya, Abdoul-Aziz Sienou, Seydou Traore, Almahamoudou Mahamar, Ismaila Thera, Kalifa Diarra, Amagana Dolo, Irene Kuepfer, Paul Snell, Paul Milligan, Christian Ockenhouse, Opokua Ofori-Anyinam, Halidou Tinto, Abdoulaye Djimde, Jean-Bosco Ouédraogo, Alassane Dicko, Brian Greenwood
Journal: New England Journal of Medicine (2021)

Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa.We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes.We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively.Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).
First Oral Blood Thinner Is Approved for Children
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

The FDA approved dabigatran etexilate as the first oral blood thinner for children aged 3 months to 11 years who have venous thromboembolism and received injectable blood thinners for at least 5 days. Previously, the only anticoagulant approved for children was an injectable formulation.
AB0905-HPR TELEMEDICINE IN RHEUMATOLOGY AT TIME OF COVID PANDEMIC
Authors: G. Cuomo, F. Masini, K. Gjeloshi, D. Lubrano, L. E. Adinolfi, C. Romano
Journal: Annals of the Rheumatic Diseases (2021)

Background: The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has imposed considerable restrictions on people’s mobility in order to limit infection transmission. Before the COVID -19 pandemic tele-rheumatology was proposed to patients living in remote areas. Currently, the use of telemedicine has increased significantly. We report on the implementation of a telemedicine program for the evaluation and treatment of patients with rheumatic diseases (1). Objectives: The aim of the study is to evaluate telemedicine as a viable approach for routine follow-up and management of rheumatic disease. Methods: Sixty-six patients were evaluated online by the remote rheumatologist in four weeks. The population of rheumatology patients was evaluated using a IARPLUS platform Information collected included demographic information consisting of age, gender, and primary rheumatologic diagnosis. Results: The average age of patients who were seen was 54 years and 85% of patients were women. The most common disorders included rheumatoid arthritis (22, 33%), axial spondyloarthropathies (7, 11%), and psoriatic arthritis (15,23%), systemic sclerosis (13, 20%), lupus (6, 9%), UCTD (2,3%), Sjogren and fibromyalgia (1, 1.5%). Results: All patients were given recommendations on COVID-19 vaccine administration. Therapy was remodeled in 13 patients (in particular in 5 patients with anemia intravenous iron infusion was scheduled; 1 started immunosuppressant therapy for proteinuria, 4 increased methotrexate for disease activity, 2 discontinued Methotrexate for adverse events (hypertransaminasemia), 1 suspended OH-chloroquine due to retinal accumulation; 2 biologic-naive patients, after a three-month of waiting due to inability to come to the hospital, started the biologic drug; 22 patients received a renewal of the therapeutic plan; 25 patients had a regular six-month follow up; 2 ticket exemption for illness; 13 consultations and/or laboratory tests (1 pneumological consultation, 1 ophthalmological consultation, 1 request for sacro-iliac MRI, 3 nailfold videocapillaroscopies, 3 FKT, 1 musculotendinous ultrasound, 1 antibodies for celiac disease, 2 antibodies anti Sars-CoV-2). Conclusion: Telemedicine is becoming more prevalent. We report the successful use of this service in evaluation and management of rheumatic diseases in a period with limited access to rheumatologic care. We have shown that patients can be seen, evaluated, and successfully treated with a variety of medications, including biologic agents, and evaluated for both chronic inflammatory arthropaties and connective tissue diseases. References: [1]Rheumatology Care Using Telemedicine Michael M. Rezaian; Telemedicine and e-Health, 2020. Disclosure of Interests: None declared
The Prognostic Impact of Tumor Differentiation on Recurrence and Survival after Resection of Hepatocellular Carcinoma Is Dependent on Tumor Size
Authors: Hiroji Shinkawa, Shogo Tanaka, Daijiro Kabata, Shigekazu Takemura, Ryosuke Amano, Kenjiro Kimura, Masahiko Kinoshita, Shoji Kubo
Journal: Liver Cancer (2021)

The present study aimed to evaluate the effect of poor differentiation and tumor size on survival outcome after hepatic resection of hepatocellular carcinoma (HCC).A total of 1,107 patients who underwent initial and curative hepatic resection for HCC without macroscopic vascular invasion participated in the study. Using the multivariable Cox proportional hazards regression model, we evaluated changes in hazard ratios (HRs) for the association between tumor differentiation and survival based on tumor size.In patients with poorly (Por) differentiated HCCs, the adjusted HRs of reduced overall survival (OS), recurrence-free survival (RFS), early RFS, and early extrahepatic RFS were 1.31 (95% confidence interval [CI]; 1.07-1.59), 1.07 (95% CI 0.89-1.28), 1.31 (95% CI 1.06-1.62), and 1.81 (95% CI 1.03-3.17), respectively. Moreover, based on an analysis of the effect modification of tumor differentiation according to tumor size, Por HCC was found to be associated with a reduced OS (p = 0.033). The HRs of Por HCCs sharply increased in patients with tumors measuring up to 5 cm. The adjusted HRs of reduced OS in patients with Por HCCs measuring <2, ≥2 and <5, and ≥5 cm were 1.22 (95% CI 0.69-2.14), 1.33 (95% CI 1.02-1.73), and 1.58 (95% CI 1.04-2.42), respectively. The corresponding adjusted HRs of reduced early RFS were 0.85 (95% CI 0.46-1.57), 1.34 (95% CI 1.01-1.8), and 1.57 (95% CI 1.03-2.39), respectively. The adjusted HRs of reduced early extrahepatic RFS were 1.89 (95% CI 0.83-4.3) in patients with tumors measuring ≥2 and <5 cm and 2.33 (95% CI 0.98-5.54) in those with tumors measuring ≥5 cm.Por HCC measuring ≥2 cm was associated with early recurrence. Hence, it had negative effects on OS. After surgery, patients with Por HCC measuring ≥5 cm should be cautiously monitored for early extrahepatic recurrence. These findings will help physicians devise treatment strategies for patients with HCC.
Targeted Transcriptome and <i>KRAS</i> Mutation Analysis Improve the Diagnostic Performance of EUS-FNA Biopsies in Pancreatic Cancer
Authors: Joanne Lundy, Hugh Gao, William Berry, Samar Masoumi-Moghoddam, Brendan J. Jenkins, Daniel Croagh
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, and current diagnostic tests have suboptimal sensitivity. Incorporating standard cytology with targeted transcriptomic and mutation analysis may improve upon the accuracy of diagnostic biopsies, thus reducing the burden of repeat procedures and delays to treatment initiation. Experimental Design: We reviewed the accuracy of 308 endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) diagnostic PDAC biopsies using a large multicenter clinical and biospecimen database, then performed RNA sequencing on 134 EUS-FNA biopsies spanning all stages of disease. We identified a transcriptomic diagnostic gene signature that was validated using external datasets and 60 further diagnostic EUS-FNAs. KRAS digital droplet PCR (ddPCR) analysis was performed and correlated with signature gene expression. Results: The sensitivity of EUS-FNA cytology in diagnosing solid pancreatic masses in our retrospective cohort of 308 patients was 78.6% (95% confidence interval, 73.2%–83.2%). KRAS mutation analysis and our custom transcriptomic signature significantly improved upon the diagnostic accuracy of standard cytology to 91.3% in external validation sets and 91.6% in our validation cohort (n = 60). Exploratory ddPCR analysis of KRAS-mutant allele fraction (MAF%) correlated closely to signature performance and may represent a novel surrogate marker of tumor cellularity in snap-frozen EUS-FNA biopsies. Conclusions: Our findings support snap-frozen EUS-FNA biopsies as a feasible tissue source for the integrated genomic and transcriptomic analysis of patients presenting with PDAC from all tumor stages, including cases with nondiagnostic cytology. Our transcriptome-derived genetic signature in combination with tissue KRAS mutation analysis significantly improves upon the diagnostic accuracy of current standard procedures, and has potential clinical utility in improving the speed and accuracy of diagnosis for patients presenting with PDAC.
Unmet clinical needs in the management of CALR-mutated essential thrombocythaemia: a consensus-based proposal from the European LeukemiaNet
Authors: Alberto Alvarez-Larrán, Emanuela Sant'Antonio, Claire Harrison, Jean-Jacques Kiladjian, Martin Griesshammer, Ruben Mesa, Jean Christophe Ianotto, Francesca Palandri, Juan Carlos Hernández-Boluda, Gunnar Birgegård, Jyoti Nangalia, Steffen Koschmieder, Elisa Rumi, Tiziano Barbui
Journal: The Lancet Haematology (2021)
Mitochondrial dysfunction leads to NADPH oxidase (NOX) activation and sensitization of cancer cells to NOX inhibitor
Authors: Weiqin Lu, Zhao Chen, Helene pelicano, Li Feng, Peng Huang
Journal: Cancer Research (2008)

4343  Many cancer cells exhibit mitochondrial respiratory dysfunction due to multiple factors including mitochondrial DNA (mtDNA) mutations, hypoxia in tumor tissues, and oncogenic signals. An important consequence of mitochondrial respiration defect in cancer cells is a decrease of ATP generation in the mitochondria and an increase of aerobic glycolysis in the cytosol (the Warburg effect). However, the precise relationship between mitochondrial dysfunction and cancer cell survival remain elusive, and the potential therapeutic implications remain to be investigated. To study underlying mechanisms and test new therapeutic approaches, a novel model system harboring a dominant negative form of mitochondrial DNA polymerase gamma (POLGdn) was expressed in the T-ReX293 tetracycline inducible cell system (tet/on system). Mitochondrial dysfunctions, including a significant decrease in mtDNA content, mtDNA-encoded RNA/protein expression, and oxygen consumption, were observed upon POLGdn expression (tet/on). Increased glycolysis was also observed, as evidenced by elevated glucose uptake, lactate production, and HKII protein expression. Importantly, NOX activation was observed in this model system two days after POLGdn expression. Detail analysis revealed an increased expression of NOXA1 and p47, associated with an increase in NOX activity and increased ROS generation compared with the non-induced (tet/off) cells. Upon treatment of the cells with DPI, a NOX inhibitor, tet/on cells exhibited a decrease in glucose uptake and ATP level, but showed a slight increase in lactate production. In contrast, the tet/off cells showed no change in glucose uptake and ATP level but had a significant increase in lactate production. Tet/on cells showed resistance to gemcitabine and taxol treatment, but sensitive to DPI treatment. Further analysis by comparing immortalized ovarian epithelial T72 cells with the Ras transformed tumorigenic T72-Ras cells showed that the transformed cells had increased NOX activity, increased gene expression of NOX1, NOX2 and p47, and more sensitive to DPI treatment especially under hypoxic condition while mitochondrial respiration was suppressed. These data together suggest that mitochondrial dysfunction leads to NOX activation, and that NOX inhibition might have potential implications in cancer therapeutics.
24988 Spectrum of facial angiofibromas in 85 patients with tuberous sclerosis complex in a tertiary hospital. Retrospective study and revision of the literature
Authors: Pablo Cobo Rodríguez, Pablo Boixeda De Miquel, Iván Checa Recio, Jaime Martínez Mariscal, Raquel Cabana Navia, María Antonia Pastor Nieto, Esther Jiménez Blázquez, Adriana Martín Fuentes, Patricia González Muñoz, Consuelo Sánchez Herreros, Esther de Eusebio Murillo
Journal: Journal of the American Academy of Dermatology (2021)
27406 Dupilumab improves signs and symptoms of severe atopic dermatitis in children aged 6–11 years with and without comorbid asthma
Authors: Mark Boguniewicz, Lawrence Sher, Amy S. Paller, Elaine C. Siegfried, Weily Soong, Zhen Chen, Randy Prescilla, Brad Shumel
Journal: Journal of the American Academy of Dermatology (2021)
Normative ascent with local gaussians for unsupervised lesion detection
Authors: Xiaoran Chen, Nick Pawlowski, Ben Glocker, Ender Konukoglu
Journal: Medical Image Analysis (2021)

Unsupervised abnormality detection is an appealing approach to identify patterns that are not present in training data without specific annotations for such patterns. In the medical imaging field, methods taking this approach have been proposed to detect lesions. The appeal of this approach stems from the fact that it does not require lesion-specific supervision and can potentially generalize to any sort of abnormal patterns. The principle is to train a generative model on images from healthy individuals to estimate the distribution of images of the normal anatomy, i.e., a normative distribution, and detect lesions as out-of-distribution regions. Restoration-based techniques that modify a given image by taking gradient ascent steps with respect to a posterior distribution composed of a normative distribution and a likelihood term recently yielded state-of-the-art results. However, these methods do not explicitly model ascent directions with respect to the normative distribution, i.e. normative ascent direction, which is essential for successful restoration. In this work, we introduce a novel approach for unsupervised lesion detection by modeling normative ascent directions. We present different modelling options based on the defined ascent directions with local Gaussians. We further extend the proposed method to efficiently utilize 3D information, which has not been explored in most existing works. We experimentally show that the proposed method provides higher accuracy in detection and produces more realistic restored images. The performance of the proposed method is evaluated against baselines on publicly available BRATS and ATLAS stroke lesion datasets; the detection accuracy of the proposed method surpasses the current state-of-the-art results.
Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model
Authors: Qinghai Liu, Kristina Shkirkova, Krista Lamorie-Foote, Michelle Connor, Arati Patel, Robin Babadjouni, Mikko Huuskonen, Axel Montagne, Hans Baertsch, Hongqiao Zhang, Jiu-Chiuan Chen, Wendy J. Mack, Brian P. Walcott, Berislav V. Zlokovic, Constantinos Sioutas, Todd E. Morgan, Caleb E. Finch, William J. Mack
Journal: Environmental Health Perspectives (2021)

Background: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood–brain barrier weakening, which may augment neurotoxic effects of PM. Objectives: This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter ≤200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS. Methods: nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) FA + BCAS, and d) nPM + BCAS. Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed. Results: The joint nPM + BCAS group exhibited synergistic effects on white matter injury (2.3× the additive nPM and FA + BCAS scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and FA + BCAS effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of nPM + BCAS than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the nPM + BCAS cohort demonstrated impaired working memory when compared to the FA + BCAS group. Discussion: Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP8792
Targeting the tumor microenvironment in B-cell lymphoma: challenges and opportunities
Authors: Yingyue Liu, Xiangxiang Zhou, Xin Wang
Journal: Journal of Hematology & Oncology (2021)

B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.
日本人集団における高血圧とCYBA,CLCNKB,およびKCNMB1の機能的遺伝子多型性の間の関連分析:吹田の研究
Authors: Kokubo Y, Iwai N, Tago N, Inamoto N, Okayama A, Yamawaki H, Naraba H, Tomoike H
Journal: Circulation (2005)