tbuckley/cabot-search huggingface dataset:
Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting
Authors: Mayssam Nehme, Olivia Braillard, François Chappuis, Delphine S. Courvoisier, Idris Guessous
Journal: Annals of Internal Medicine (2021)

With millions of SARS-CoV-2 infections worldwide, increasing numbers of patients are coming forward with long-term clinical effects of the disease lasting several weeks to months.
Emerging Role of Genomic Analysis in Clinical Evaluation of Lean Individuals With NAFLD
Authors: Sílvia Vilarinho, Veeral Ajmera, Melanie Zheng, Rohit Loomba
Journal: Hepatology (2021)

Whereas the rising prevalence of nonalcoholic fatty liver disease (NAFLD) is closely related with the global obesity epidemic, up to 10-20% of individuals with NAFLD are lean as defined by a body mass index of < 25 kg/m 2 , or < 23 kg/m 2 in Asians.This entity designated as "lean NAFLD" is estimated to affect 8 to 10 million individuals in the United States alone.Here, we review the emerging data on the epidemiology, natural history and prognosis of lean NAFLD and put forward a diagnostic approach that combines detailed clinical phenotyping with genomic analysis.We propose two subtypes of lean NAFLD referred to as type 1: individuals with visceral adiposity and insulin resistance but normal BMI; and type 2: lean individuals with hepatic steatosis secondary to a known or unknown monogenic disease.We envision that incorporation of genomic analysis in the diagnostic algorithm of lean patients with NAFLD will elucidate the contribution of common genetic variants through the calculation of NAFLD polygenic risk score and also characterize the diverse array of rare monogenic diseases that can lead to triglyceride accumulation in the cytoplasm of hepatocytes.Collectively, the integration of a molecular diagnosis in the clinical evaluation of patients with lean NAFLD will provide an accurate diagnosis, with possible targeted therapies and may uncover novel molecular mechanisms with potential broader therapeutic implications.
HDAC1: an environmental sensor regulating endothelial function
Authors: Luke S Dunaway, Jennifer S Pollock
Journal: Cardiovascular Research (2021)

The histone deacetylases (HDACs) are a family of enzymes that catalyse lysine deacetylation of both histone and non-histone proteins. Here, we review, summarize, and provide perspectives on the literature regarding one such HDAC, HDAC1, in endothelial biology. In the endothelium, HDAC1 mediates the effects of external and environmental stimuli by regulating major endothelial functions such as angiogenesis, inflammatory signalling, redox homeostasis, and nitric oxide signalling. Angiogenesis is most often, but not exclusively, repressed by endothelial HDAC1. The regulation of inflammatory signalling is more complex as HDAC1 promotes or suppresses inflammatory signalling depending upon the environmental stimuli. HDAC1 is protective in models of atherosclerosis where loss of HDAC1 results in increased cytokine and cell adhesion molecule (CAM) abundance. In other models, HDAC1 promotes inflammation by increasing CAMs and repressing claudin-5 expression. Consistently, from many investigations, HDAC1 decreases antioxidant enzyme expression and nitric oxide production in the endothelium. HDAC1 decreases antioxidant enzyme expression through the deacetylation of histones and transcription factors, and also regulates nitric oxide production through regulating both the expression and activity of nitric oxide synthase 3. The HDAC1-dependent regulation of endothelial function through the deacetylation of both histone and non-histone proteins ultimately impacts whole animal physiology and health.
Abstract 1666: Tumor-specificity of tumor-infiltrating CD8+ t cells determines the potential of immune checkpoint inhibitors in breast cancer
Authors: Jee Ye Kim, Yong Joon Lee, Seung hyuck Jeon, Heejin Nam, Jae Hyung Jung, Seung Il Kim, Eui-Cheol Shin
Journal: Cancer Research (2021)

Abstract Tissue-resident memory CD8+ T cells (TRMs), marked by expression of CD103, are considered to play a key role as anti-tumor immune response in breast cancer. However, prognostic value of TRMs and heterogeneity in CD103+ TRMs of breast cancer in terms of tumor-specificity needs further understanding to establish immuno-therapeutic implications. Here, we isolated tumor-infiltrating CD103+TRMs in breast cancer samples and matched peripheral blood mononuclear cells (PBMCs) which were prospectively collected from 127 patients who underwent surgical resection between July 2016 and May 2020 at Severance Hospital, Seoul, Republic of Korea. Multi-color flow cytometry analyses were performed.CD103+TRMs consist of both tumor-antigen specific CD8+ T cells and bystander CD8+ T cells, such as viral antigen-specific CD8+ T cells. Dissection of CD103+TRMs with CD39 expression reveals a clonally-distinct subpopulation exhibiting tumor-antigen specificity and reactivity with transcriptionally and phenotypically exhaustive features. CD39+CD103+ TRMs were enriched in HER2 enriched and triple-negative breast cancer(TNBC) subtypes, but not in Hormone receptor(HR) positive/HER2 not enriched subtypes, implying that the role of tumor-infiltrating CD8+ T cells in eliciting anti-tumor immune response differ among molecular subtypes. In line with early-exhaustive features of CD39+CD103+TRMs, inhibition of either PD-1 alone or both PD-1 and CTLA-4 reinvigorate the proliferation and the cytokine production of CD8+ TILs in HER2 and TNBC subtypes. Our findings indicate that different immuno-therapeutic strategies should be considered to different subtypes of breast cancer. Citation Format: Jee Ye Kim, Yong Joon Lee, Seung hyuck Jeon, Heejin Nam, Jae Hyung Jung, Seung Il Kim, Eui-Cheol Shin. Tumor-specificity of tumor-infiltrating CD8+ t cells determines the potential of immune checkpoint inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1666.
Abstract LB261: BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma
Authors: Tianyi Liu, Linli Zhou, Yuhang Zhang
Journal: Cancer Research (2021)

Abstract The tumor stroma and its cellular components are known to play important roles in tumor resilience towards treatment but remain to be urgently characterized in melanoma targeted therapy. By performing a paired-analysis of melanoma tissue samples collected from the patients before and after combined BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) treatment, we discovered that the number of intratumoral cancer-associated fibroblasts (CAFs) increased significantly in BRAFi/MEKi-treated melanoma stroma comparing with the samples before the therapy. Those intratumoral CAFs exhibit increased amounts of nuclear β-catenin under BRAFi/MEKi therapy. Further studies show that BRAFi not only leads to increased β-catenin nuclear accumulation in CAFs and enhances their biological properties, suggesting BRAFi induces a new resistant phenotype in CAFs. In both in vitro and in vivo models, depleting β-catenin in CAFs abolishes their ability to elicit melanoma cell growth and drug resistance. BRAFi induces BRAF and CRAF dimerization and subsequently the activation of MEK/ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. RNA-Seq data reveals that nuclear β-catenin is a major regulator of CAF phenotype. We identify matricellular protein periostin (POSTN) as a downstream effector of β-catenin. In melanoma, POSTN is uniquely expressed in CAFs, and BRAFi can specifically upregulate POSTN production in CAFs but not in melanoma cells. Recombinant POSTN contributes to melanoma cell BRAFi/MEKi resistance and can compensate for the loss of β-catenin in CAFs. By reactivating ERK pathway in melanoma cells through PI3K/AKT signaling, POSTN compensates for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. In summary, our data reveal a novel resistance mechanism in melanoma that is elicited by BRAFi-induced non-canonical nuclear β-catenin signaling in CAFs and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma. Citation Format: Tianyi Liu, Linli Zhou, Yuhang Zhang. BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB261.
PROGRESS (Patient Reported Outcomes in Genital Reconstructive Surgeries): A validated patient reported outcome measure questionnaire to assess post-operative functional improvement following feminising genital reconstructive surgery
Authors: A. Kanthabalan, F. Hosking Jervis, A. Dusoye, C. Charlotte Dunford, H. Gresty, K.A. Bell, K. Sahota, M. Bertoncelli Tanaka, M. Hyder Junejo, N. Bedi, P. Jan Eyskens, R.L. Oliver, R. Crawford, T. Yap, U. Walters, T. Rashid
Journal: European Urology (2021)
Abstract 1189: Association of RAS pathway mutations with lower CD8+ T cell infiltration and 2-year survival rate in Stage-III colorectal adenocarcinoma patients
Authors: Zhipeng Jiang, Feilong Zhao, Hui Chen, Xiaochen Zhao, Yuezong Bai
Journal: Cancer Research (2021)

Abstract Background: The oncogenic pathways, including WNT, TP53, RAS, PI3K and TGFβ, were associated with tumor progression in colorectal adenocarcinomas (CRC). However, a majority of CRC patients have mutations from multiple pathways simultaneously, which makes it difficult to identify the key pathway influencing prognosis of CRC. Herein, we aimed to evaluate the novel dominant pathway-typing method in predicting the prognosis of Stage-III CRC. Methods: Clinicopathologic and molecular variation data of Stage-III CRC patients (n=152) were obtained from The Cancer Genome Atlas database (TCGA). Immune cell infiltration level of the tumor was calculated by xCell (https://xcell.ucsf.edu/). Oncogenic pathway genes were classified according to a TCGA study (PMID: 29625050). In each patient, the dominant pathway-typing were based on which pathway the genes with the highest variant-allele-frequency (VAF) belongs to. Results: In all, 124/152 (82%) patients had mutation on at least one of the oncogenic pathway genes and 120/124 (97%) patients harbored mutations from two or more pathways simultaneously. According to their dominant pathway-typing method, the patients were classified into five groups: WNT (n=45), RAS (n=26), TP53 (n=36), PI3K (n=8) and TGFβ (n=9) groups. There was no significant difference in OS among the five groups. However, the two-year survival rate of RAS group was significantly lower than that of WNT (p=0.042) and TP53 (p=0.035) groups. Further, we found that the infiltration of CD8+ T cell was significantly lower in RAS group compared to WNT group (with median infiltration score: 0.005 vs 0.013, p=0.024). Importantly, we found that among the RAS group without CD8+ T-cell infiltration, 63% (5/8) patients were died within two years after diagnosis. While the two-year death rate of WNT and TP53 groups without CD8+ T cell infiltration were zero (0/6) and 14% (1/7). And the two-year death rate of RAS, WNT and TP53 groups with CD8+ T cell infiltration were 17% (1/6), 11% (3/27) and 8% (1/13), respectively. Conclusion: RAS pathway mutation may be associated with low CD8+ T cell infiltration and promote the two-year death rate of stage-III CRC patients using dominant pathway-typing method. And further larger cohorts are needed to validate these findings and the underlying mechanisms. Citation Format: Zhipeng Jiang, Feilong Zhao, Hui Chen, Xiaochen Zhao, Yuezong Bai. Association of RAS pathway mutations with lower CD8+ T cell infiltration and 2-year survival rate in Stage-III colorectal adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1189.
scLink: Inferring Sparse Gene Co-Expression Networks from Single-Cell Expression Data
Authors: Wei Vivian Li, Yanzeng Li
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract A system-level understanding of the regulation and coordination mechanisms of gene expression is essential for studying the complexity of biological processes in health and disease. With the rapid development of single-cell RNA sequencing technologies, it is now possible to investigate gene interactions in a cell type-specific manner. Here we propose the scLink method, which uses statistical network modeling to understand the co-expression relationships among genes and construct sparse gene co-expression networks from single-cell gene expression data. We use both simulation and real data studies to demonstrate the advantages of scLink and its ability to improve single-cell gene network analysis. The scLink R package is available at https://github.com/Vivianstats/scLink.
Definition and impact on oncologic outcomes of persistently elevated PSA after salvage lymph node dissection for node-only recurrent prostate cancer after radical prostatectomy: Clinical Implications for multi-modal therapy
Authors: C.A. Bravi, N. Fossati, G. Gandaglia, G. Motterle, R.J. Karnes, D. Pfister, A. Heidenreich, A. Kretschmer, A. Buchner, C. Stief, G. Devos, S. Joniau, H. Van Poppel, D. Osmonov, K-P. Jueneman, B. Grubmuller, S. Shariat, A. Hiester, P. Albers, D. Tilki, M. Graefen, I.S. Gill, A. Mottrie, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 9376: Cardiac-Specific Very Long Chain Acyl-CoA Dehydrogenase Deficiency Induces Dilated Cardiomyopathy and Cold Intolerance in Mice
Authors: Dingding Xiong, Zaza Khuchua, Chonan Tokunaga, Kathryn Rafferty, Sarkies Ruben Mattheus Martherus, Anne-Cecile Huby, Hanna Osinska, Enkhsaikhan Purevjav, Jeanne James, Jeffrey Towbin, Arnold Strauss
Journal: Circulation (2011)

BACKGROUND: Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of fatty acids with chain lengths of 14 to 20 carbons. Patients with VLCAD deficiency present with hypoketotic hypoglycemia, cardiomyopathy and sudden death that can be exacerbated by the stresses of fasting and cold. Global VLCAD knockout (KO) mice recapitulate these phenotypes. However, the contribution of cardiac VLCAD in the development of cardiomyopathy and the response to the environmental stressors is unclear. In this study, we assessed the hypothesis that cardiac-specific VLCAD deficiency is sufficient to induce cardiomyopathy and cold intolerance. METHODS AND RESULTS: A cardiac-specific homozygous VLCAD KO (csVLCAD KO) mouse was generated by crossing a VLCAD floxed-allele mouse with a transgenic mouse expressing Cre recombinase under the control of the α-myosin heavy chain promoter. Echocardiographic analysis at 6 months of age demonstrated left ventricular dilation and decreased fractional shortening (FS) in csVLCAD KO mice (for FS, 21±1% vs 29±4% in wild-type mice, p&lt;0.05). Ultrastructural analysis of ventricular myocardium showed widening of the sarcomeric I band, increased sarcomere length and substantial lipid deposits in csVLCAD KO mice. To test if cardiac VLCAD deficiency leads to susceptibility to death caused by cold stress, csVLCAD-KO mice and controls were placed at 4°C. All csVLCAD-KO mice (n=9) became moribund within 4-10 hours, whereas only 1/9 hemizygous and 1/9 wild-type mice died. Unlike global VLCAD KO mice, csVLCAD KO mice did not develop hypoglycemia. To determine if VLCAD deficiency alters mitochondrial fatty acid oxidation in cardiomyocytes, oxygen consumption rates in response to palmitate and glutamate administration were measured. The results indicated that while mitochondrial function was largely preserved, the fatty acid oxidation rate was markedly reduced in csVLCAD-KO mice, measuring 10-15% of WT. CONCLUSIONS: Cardiac-specific VLCAD deficiency is sufficient to induce ventricular dilation and cardiac dysfunction as well as cold intolerance, which may be related to reduced fatty acid oxidation and increased lipid deposition in cardiomyocytes.
A Randomized Clinical Trial of Cognitive-Behavioral Therapy for Insomnia to Augment Posttraumatic Stress Disorder Treatment in Survivors of Interpersonal Violence
Authors: Wilfred R. Pigeon, Hugh F. Crean, Catherine Cerulli, Autumn M. Gallegos, Todd M. Bishop, Kathi L. Heffner
Journal: Psychotherapy and Psychosomatics (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Individuals exposed to interpersonal violence (IPV) commonly develop posttraumatic stress disorder (PTSD) with co-occurring depression and insomnia. Standard PTSD interventions such as cognitive processing therapy (CPT) do not typically lead to remission or improved insomnia. Cognitive behavioral therapy for insomnia (CBTi) improves insomnia in individuals with PTSD, but PTSD severity remains elevated. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To determine whether sequential treatment of insomnia and PTSD is superior to treatment of only PTSD. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In a 20-week trial, 110 participants exposed to IPV who had PTSD, depression and insomnia were randomized to CBTi followed by CPT or to attention control followed by CPT. Primary outcomes following CBTi (or control) were the 6-week change in score on the Insomnia Severity Index (ISI), the Clinician-Administered PTSD Scale (CAPS), and the Hamilton Rating Scale for Depression (HAM-D). Primary outcomes following CPT were the 20-week change in scores. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; At 6 weeks, the CBTi condition had greater reductions in ISI, HAM-D, and CAPS scores than the attention control condition. At 20 weeks, participants in the CBTi+CPT condition had greater reductions in ISI, HAM-D, and CAPS scores compared to control+CPT. Effects were larger for insomnia and for depression than for PTSD. Similar patterns were observed with respect to clinical response and remission. A tipping point sensitivity analyses supported the plausibility of the findings. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The sequential delivery of CBTi and CPT had plausible, significant effects on insomnia, depression, and PTSD compared to CPT alone. The effects for PTSD symptoms were moderate and clinically meaningful.
Abstract 2321: Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage
Authors: Khoa Dang Pham, Bradley Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2021)

Abstract Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. In other cancers, high-level expression of MYC increase glutamine transport and fuels the TCA cycle, supporting cell growth and proliferation. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of xenografts of human MYC-amplified medulloblastoma tumors. We found that glucose was the main carbon source for TCA cycle. We also found that glutaminase ii pathway was the main pathway utilizing glutamine. In orthotopic xenografts, glutathione was the most abundant upregulated metabolite in tumor compared to normal brain. Glutamine derived glutathione was synthesized through glutamine transaminase K (GTK) enzyme in vivo, and it was significantly inhibited by glutamine analog 6-diazo-5-oxo-l-norleucine (DON). We engineered a DON prodrug with higher lipophilicity (JHU395) and found that JHU395 suppressed medulloblastoma growth in vitro and induced apoptosis. A single dose of JHU395 induced apoptosis in orthotopic D425 MED tumors but not in normal cerebellum or cortex. Twice weekly 15mg/kg dosing of JHU395 significantly extended the survival of the mice with D425 MED orthotopic xenografts (p&amp;lt;0.001 by log-rank test comparing treated vs vehicle control). Glutamine antagonists exploit MYC-amplified medulloblastoma's reliance on glutamine metabolism and may have therapeutic applications in human patients. Citation Format: Khoa Dang Pham, Bradley Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2321.
Pseudomembranous Invasive Tracheobronchial Aspergillosis
Authors: Shinshu Katayama, Ken Tonai, Daisuke Minakata, Shin Nunomiya
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Pseudomembranous Invasive Tracheobronchial Aspergillosis." American Journal of Respiratory and Critical Care Medicine, 205(3), pp. e6–e7
Dismantling Structural Discrimination in Global Health
Authors: Bolajoko O. Olusanya
Journal: JAMA Pediatrics (2021)

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Acute scrotum in children: Management and costs at the emergency room
Authors: A. Bernal Gomez, F. Gómez Palomo, R. Rogel Bertó, A. Polo Rodrigo, M.Á. Conca Baenas, J.A. March Villalba, L. Rodríguez Caraballo, I. Sáez Moreno, O. Dagà Martínez, J.O. Colet Guitert, J. Ortiz Salvador, J. Bolón Marset, A. Serrano Durbá
Journal: European Urology (2021)
Transcriptome-based estimation of immune cell populations is prognostic for risk of relapse in localized renal cell carcinoma
Authors: E. Roussel, L. Kinget, A. Verbiest, J. Zucman-Rossi, G. Couchy, S. Caruso, M. Baldewijns, S. Joniau, H. Van Poppel, M. Albersen, B. Beuselinck
Journal: European Urology (2021)