tbuckley/cabot-search huggingface dataset:
Pseudofolliculitis Barbae
Authors: Tejesh S. Patel, Yoseph Dalia
Journal: JAMA Dermatology (2022)

Pseudofolliculitis BarbaePseudofolliculitis barbae (PFB) is also called razor, shaving, or barber's bumps.It is relatively common in people who have naturally curly hair and occurs in up to 60% of Black men.It can also rarely affect women. CausesPseudofolliculitis barbae is caused when hairs curve back and either re-enter or grow under the skin after shaving.This is more likely in people with naturally curly hair.This leads to a reaction resulting in painful inflammation and scarring.Pseudofolliculitis barbae typically occurs in the beard area, but may also occur in the armpits, groin, or other areas of shaving.
Utility of PET to Appropriately Select Patients for PSMA-Targeted Theranostics
Authors: Anna Eshghi, Matthew F. Covington, Naghmehossadat Eshghi, Phillip H. Kuo
Journal: Clinical Nuclear Medicine (2022)

The majority of aggressive prostate cancers overexpress the transmembrane protein prostate-specific membrane antigen (PSMA). PSMA is, therefore, an attractive target for drug development. Over the last decade, numerous PSMA-targeted radiopharmaceuticals for imaging and therapy have been developed and investigated in theranostic combination. PSMA-targeted radiopharmaceuticals for imaging have been primarily developed for PET. PSMA PET provides whole-body evaluation of the degree of PSMA expression on tumors and potentially provides a method to better select patients for PSMA-targeted therapy. Numerous PSMA-targeted therapeutic agents using β- or α-particle emitters are under study in clinical trials. In particular, the β-particle-emitting radioisotope 177Lu bound to PSMA-targeted small molecules have ongoing and completed late-stage clinical trials in metastatic castration-resistant prostate cancer. To define the most appropriate patient group for PSMA-targeted therapeutics, multiple studies have investigated PSMA and FDG PET/CT to establish PET parameters as predictive and prognostic biomarkers. This article discusses recent clinical trials that examine the optimal use of PET for the selection of patients for PSMA-targeted therapeutics and provides an integrative overview of choice of PET tracer(s), targeting molecule, therapeutic radioisotope, nonradioactive therapy, and cancer type (prostate or nonprostate).
Fully Automatic Quantitative Measurement of 18F-FDG PET/CT in Thymic Epithelial Tumors Using a Convolutional Neural Network
Authors: Sangwon Han, Jungsu S. Oh, Yong-il Kim, Seung Yeon Seo, Geun Dong Lee, Min-Jae Park, Sehoon Choi, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Jin-Sook Ryu
Journal: Clinical Nuclear Medicine (2022)

Objectives The aim of this study was to develop a deep learning (DL)–based segmentation algorithm for automatic measurement of metabolic parameters of 18 F-FDG PET/CT in thymic epithelial tumors (TETs), comparable performance to manual volumes of interest. Patients and Methods A total of 186 consecutive patients with resectable TETs and preoperative 18 F-FDG PET/CT were retrospectively enrolled (145 thymomas, 41 thymic carcinomas). A quasi-3D U-net architecture was trained to resemble ground-truth volumes of interest. Segmentation performance was assessed using the Dice similarity coefficient. Agreements between manual and DL-based automated extraction of SUV max , metabolic tumor volume (MTV), total lesion glycolysis (TLG), and 63 radiomics features were evaluated via concordance correlation coefficients (CCCs) and linear regression slopes. Diagnostic and prognostic values were compared in terms of area under the receiver operating characteristics curve (AUC) for thymic carcinoma and hazards ratios (HRs) for freedom from recurrence. Results The mean Dice similarity coefficient was 0.83 ± 0.34. Automatically measured SUV max (slope, 0.97; CCC, 0.92), MTV (slope, 0.94; CCC, 0.96), and TLG (slope, 0.96; CCC, 0.96) were in good agreement with manual measurements. The mean CCC and slopes were 0.88 ± 0.06 and 0.89 ± 0.05, respectively, for the radiomics parameters. Automatically measured SUV max , MTV, and TLG showed good diagnostic accuracy for thymic carcinoma (AUCs: SUV max , 0.95; MTV, 0.85; TLG, 0.87) and significant prognostic value (HRs: SUV max , 1.31 [95% confidence interval, 1.16–1.48]; MTV, 2.11 [1.09–4.06]; TLG, 1.90 [1.12–3.23]). No significant differences in the AUCs or HRs were found between automatic and manual measurements for any of the metabolic parameters. Conclusions Our DL-based model provides comparable segmentation performance and metabolic parameter values to manual measurements in TETs.
Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma
Authors: James M. Cleary, Brian M. Wolpin, Stephanie K. Dougan, Srivatsan Raghavan, Harshabad Singh, Brandon Huffman, Nilay S. Sethi, Jonathan A. Nowak, Geoffrey I. Shapiro, Andrew J. Aguirre, Alan D. D'Andrea
Journal: Clinical Cancer Research (2021)

Abstract Pancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicative stress, and DNA damage-mediated immune activation through targeted inhibition of DNA repair regulatory proteins.
Electrostatic sheathing of lipoprotein lipase is essential for its movement across capillary endothelial cells
Authors: Wenxin Song, Anne P. Beigneux, Anne-Marie L. Winther, Kristian K. Kristensen, Anne L. Grønnemose, Ye Yang, Yiping Tu, Priscilla Munguia, Jazmin Morales, Hyesoo Jung, Pieter J. de Jong, Cris J. Jung, Kazuya Miyashita, Takao Kimura, Katsuyuki Nakajima, Masami Murakami, Gabriel Birrane, Haibo Jiang, Peter Tontonoz, Michael Ploug, Loren G. Fong, Stephen G. Young
Journal: Journal of Clinical Investigation (2022)

GPIHBP1, an endothelial cell (EC) protein, captures lipoprotein lipase (LPL) within the interstitial spaces (where it is secreted by myocytes and adipocytes) and transports it across ECs to its site of action in the capillary lumen. GPIHBP1's 3-fingered LU domain is required for LPL binding, but the function of its acidic domain (AD) has remained unclear. We created mutant mice lacking the AD and found severe hypertriglyceridemia. As expected, the mutant GPIHBP1 retained the capacity to bind LPL. Unexpectedly, however, most of the GPIHBP1 and LPL in the mutant mice was located on the abluminal surface of ECs (explaining the hypertriglyceridemia). The GPIHBP1-bound LPL was trapped on the abluminal surface of ECs by electrostatic interactions between the large basic patch on the surface of LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the surface of ECs. GPIHBP1 trafficking across ECs in the mutant mice was normalized by disrupting LPL-HSPG electrostatic interactions with either heparin or an AD peptide. Thus, GPIHBP1's AD plays a crucial function in plasma triglyceride metabolism; it sheathes LPL's basic patch on the abluminal surface of ECs, thereby preventing LPL-HSPG interactions and freeing GPIHBP1-LPL complexes to move across ECs to the capillary lumen.
Abstract P167: Soluble CD14 Level And Incident Diabetes Mellitus Risk: The Reasons For Geographic And Racial Differences In Stroke (REGARDS) Study
Authors: Kaileen Cruden, Insu Koh, Debora Kamin Mukaz, Timothy B Plante, Alex P Reiner, Neil A Zakai, April P Carson, Leann Long, Mary Cushman, Nels C Olson
Journal: Circulation (2022)

Introduction: CD14 is a pattern recognition receptor that plays important roles in the inflammatory response. Circulating soluble CD14 (sCD14) is generated by hepatocyte secretion during the acute phase response and by cleavage from immune cell surfaces, and levels are higher in White than Black individuals. CD14 is implicated in adipose tissue-mediated inflammation and insulin resistance in experimental animal models and in some cross-sectional cohort studies. Prospective studies of sCD14 and incidence of diabetes mellitus (DM) are limited. We evaluated the prospective association of sCD14 with incident DM risk in participants of the REGARDS study. Methods: At the baseline study examination in 2003-07, REGARDS recruited 30,239 Black and White participants aged 45-years and older from across the contiguous U.S. A second in-home visit occurred in 2013-16. sCD14 was measured by ELISA in baseline serum samples among participants of the REGARDS Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study, a nested race- and sex-stratified random sample of 4400 participants who completed the first and second REGARDS visits. Poisson regression models estimated risk ratios (RR) of incident DM per 1-SD increment higher sCD14, with tiered adjustment for risk factors. We tested a priori for a sCD14-by-race interaction (p interaction significance threshold &lt;0.10). Results: Among REGARDS BioMedioR participants there were 475 cases of incident DM over a mean follow-up of 9.5 years. Adjusting for age, sex, and body mass index, the sCD14-by-race interaction term was statistically significant (p-interaction=0.05). In analyses stratified by race, higher sCD14 was associated with incident DM in White (RR: 1.18; 95% CI: 1.04, 1.35) but not Black participants (RR: 0.97; 95% CI: 0.86, 1.09). In models additionally adjusted for education, income, lipids, hypertension, and physical activity, the association of higher sCD14 with DM risk was attenuated among White participants (RR: 1.10; 95% CI: 0.95, 1.27) and slightly accentuated among Black participants (RR: 0.89; 95% CI: 0.80, 1.00), although these associations were not statistically significant. Conclusions: sCD14 is differentially associated with risk of DM by race with higher levels associated with increased risk among White but not Black adults. Observed associations were explained by other risk factors, providing clues as to potentially novel mechanisms of their association with DM.
Artificial Intelligence-Assisted Serial Analysis of Clinical Cancer Genomics Data Identifies Changing Treatment Recommendations and Therapeutic Targets
Authors: Catherine G. Fischer, Aparna Pallavajjala, LiQun Jiang, Valsamo Anagnostou, Jessica Tao, Emily Adams, James R. Eshleman, Christopher D. Gocke, Ming-Tseh Lin, Elizabeth A. Platz, Rena R. Xian
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Given the pace of predictive biomarker and targeted therapy development, it is unknown whether repeat annotation of the same next-generation sequencing data can identify additional clinically actionable targets that could be therapeutically leveraged. In this study, we sought to determine the predictive yield of serial reanalysis of clinical tumor sequencing data. Experimental Design: Using artificial intelligence (AI)-assisted variant annotation, we retrospectively reanalyzed sequencing data from 2,219 patients with cancer from a single academic medical center at 3-month intervals totaling 9 months in 2020. The yield of serial reanalysis was assessed by the proportion of patients with improved strength of therapeutic recommendations. Results: A total of 1,775 patients (80%) had ≥1 potentially clinically actionable mutation at baseline, including 243 (11%) patients who had an alteration targeted by an FDA-approved drug for their cancer type. By month 9, the latter increased to 458 (21%) patients mainly due to a single pan-cancer agent directed against tumors with high tumor mutation burden. Within this timeframe, 67 new therapies became available and 45 were no longer available. Variant pathogenicity classifications also changed leading to changes in treatment recommendations for 124 patients (6%). Conclusions: Serial reannotation of tumor sequencing data improved the strength of treatment recommendations (based on level of evidence) in a mixed cancer cohort and showed substantial changes in available therapies and variant classifications. These results suggest a role for repeat analysis of tumor sequencing data in clinical practice, which can be streamlined with AI support.
18F-FDG-Detected Brown Tumor Confined to the Maxillary Bone With Parathyroid Adenoma
Authors: Emi Yamaga, Tomoyuki Fujioka, Takahiro Asakage, Keiko Miura, Ukihide Tateishi
Journal: Clinical Nuclear Medicine (2021)

Abstract Brown tumor is a reactive osteolytic lesion associated with hyperparathyroidism and an extremely rare form of a single lesion in the maxilla. We report the case of a 57-year-old woman with renal dysfunction, nasal obstruction, and hypercalcemia. MRI and CT revealed a huge osteolytic lesion in the maxilla. 18 F-FDG PET/CT demonstrated marked FDG uptake within the mass and the lower-left lobe of the thyroid gland. 99m Tc-methoxy-isobutyl-isonitrile scintigraphy suggested that this accumulation was a parathyroid adenoma. Parathyroid adenoma resection was performed, and the maxillary tumor was diagnosed as brown tumor. FDG PET/CT was helpful in evaluating brown tumor and detecting parathyroid adenoma.
Abstract P039: Low-density Lipoprotein Management In Patients With Peripheral Artery Disease With And Without Severe Hypercholesterolemia In A Largely Rural Population
Authors: Lauren Ross, Nicole Groth, Catherine P Benziger
Journal: Circulation (2022)

Background: Elevated low-density lipoprotein cholesterol (LDL) is associated with increased risk for peripheral artery disease (PAD) and major limb or adverse cardiovascular events. We aimed to compare the prevalence and appropriate lipid-lowering treatment of patients diagnosed with PAD with and without prior phenotypic severe hypercholesterolemia (SH) in a large, rural healthcare system. Methods: Retrospective study of ambulatory adults with a lipid panel at Essentia Health clinics obtained between 7/1/2016-6/30/2019 (MN, WI, and ND, USA) with PAD on the problem list (defined based on ICD-9/10 codes). Patients were divided into two groups, PAD only and PAD with SH. Phenotypic SH was defined as any prior LDL ≥ 190 mg/dL. Patients were excluded if they were currently pregnant (n=232) or if they did not have repeat LDL &gt; 30 days apart (n=1684). High-intensity statin was considered atorvastatin 40mg or 80mg or rosuvastatin 20mg or 40mg daily. Results: A total of 10,874 patients were previously diagnosed with PAD (mean age 40.4 + 10.9, 43.3% female (N=4711), 58.1% rural (N=6319). A total of 13.6% (N=1484) had SH. Patients with PAD and SH were more likely to be female, urban, have prior acute limb ischemia, stroke/transient ischemic attack, and were less likely to have diabetes or chronic limb ischemia than patients with PAD only. Patients with PAD and SH were more likely to be on a high intensity statin than those with PAD only (65.8% (N=977) vs. 51.3% (N=4813); p&lt;0.001). Very few patients received no lipid-lowering therapy (PAD with SH 0.7% (N=10) vs. PAD alone 2.1% (N=234). More patients with PAD and SH received PCKS9 inhibitors (2.5% (N=37) vs 0.4% (N=39); p&lt;0.001) and ezetimibe (23.4% (N=347) vs. 8.1% (N=760); p&lt;0.001) than patients with PAD only. Approximately 50% (N=749) of PAD with SH patients achieved a 50% lowering from peak LDL compared to 28.9% (N=2717) with PAD only. Mean LDL in the PAD with SH was 113.9 + 43.4 mg/dL compared to 81.8 + 29.1 mg/dL in patients with PAD without SH. However, fewer patients with PAD and SH achieved a LDL &lt;70 mg/dL compared to those with PAD only (13.3% (N=197) vs 37.1% (N=3487), p&lt; 0.001). Conclusion: One in 10 patients with PAD has a history of SH and majority are not achieving target LDL&lt;70mg/dL. There is an urgent need for more aggressive lipid-lowering therapy for all patients with PAD.
Macrophages, Metabolism and Heterophagy in the Heart
Authors: José A. Nicolás-Ávila, Laura Pena-Couso, Pura Muñoz-Cánoves, Andrés Hidalgo
Journal: Circulation Research (2022)

The heart is a never-stopping engine that relies on a formidable pool of mitochondria to generate energy and propel pumping. Because dying cardiomyocytes cannot be replaced, this high metabolic rate creates the challenge of preserving organelle fitness and cell function for life. Here, we provide an immunologist's perspective on how the heart solves this challenge, which is in part by incorporating macrophages as an integral component of the myocardium. Cardiac macrophages surround cardiomyocytes and capture dysfunctional mitochondria that these cells eject to the milieu, effectively establishing a client cell-support cell interaction. We refer to this heterologous partnership as heterophagy. Notably, this process shares analogies with other biological systems, is essential for proteostasis and metabolic fitness of cardiomyocytes, and unveils a remarkable degree of dependence of the healthy heart on immune cells for everyday function.
YAP: The nexus between metabolism and cardiac remodeling
Authors: Chen Gao, Yibin Wang
Journal: Journal of Clinical Investigation (2022)

Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.
Loss of Long Noncoding RNA<i>NXTAR</i>in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance
Authors: Ruchi Ghildiyal, Mithila Sawant, Arun Renganathan, Kiran Mahajan, Eric H. Kim, Jingqin Luo, Ha X. Dang, Christopher A. Maher, Felix Y. Feng, Nupam P. Mahajan
Journal: Cancer Research (2021)

Abstract Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer, including castration-resistant prostate cancers (CRPC) that have developed resistance to second generation AR antagonists such as enzalutamide. In this study, we identified a long noncoding RNA (lncRNA), NXTAR (LOC105373241) that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. NXTAR bound upstream of the AR promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the NXTAR promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor (R)-9b excluded AR from the NXTAR promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing NXTAR expression. Application of an oligonucleotide derived from NXTAR exon 5 (NXTAR-N5) suppressed AR/AR-V7 expression and prostate cancer cell proliferation, indicating the translational relevance of the negative regulation of AR. In addition, pharmacologic restoration of NXTAR using (R)-9b abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein NXTAR acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates NXTAR levels, compromising enzalutamide-resistant prostate cancer. The restoration of NXTAR could serve as a new therapeutic modality for patients who have acquired resistance to second generation AR antagonists. Significance: This study identifies NXTAR as a tumor suppressive lncRNA that can epigenetically downregulate AR/AR-V7 expression and provides a therapeutic strategy to reinstate NXTAR expression for treating recurrent CRPC.
A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers
Authors: Adi Diab, Omid Hamid, John A. Thompson, Willeke Ros, Ferry A.L.M. Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Samuel J. Klempner, Bishu Ganguly, Catherine Fleener, Xiao Wang, Tenshang Joh, Ken Liao, Shahram Salek-Ardakani, Carrie Turich Taylor, Jeffrey Chou, Anthony B. El-Khoueiry
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40. Patients and Methods: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01 to 10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity and biomarker analyses. Results: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies. Conclusions: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary antitumor activity, and may serve as a partner for combination studies.
How an outbreak became a pandemic: a chronological analysis of crucial junctures and international obligations in the early months of the COVID-19 pandemic
Authors: Sudhvir Singh, Christine McNab, Rose McKeon Olson, Nellie Bristol, Cody Nolan, Elin Bergstrøm, Michael Bartos, Shunsuke Mabuchi, Raj Panjabi, Abraar Karan, Salma M Abdalla, Mathias Bonk, Margaret Jamieson, George K Werner, Anders Nordström, Helena Legido-Quigley, Alexandra Phelan
Journal: The Lancet (2021)