tbuckley/cabot-search huggingface dataset:
Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer
Authors: Yingjie Li, Liangliang Bai, Huichuan Yu, Du Cai, Xiaolin Wang, Baoyuan Huang, Shaoyong Peng, Meijin Huang, Guangwen Cao, Andrew M. Kaz, William M. Grady, Jianping Wang, Yanxin Luo
Journal: Cancer Research (2020)

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. SIGNIFICANCE: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.
Initial pilot testing of a smartphone app for detection of chemotherapy-induced peripheral neuropathy.
Authors: Daniel Louis Hertz, Ciao-Sin Chelsea Chen, Judith Louis Kim, Harsha Guntupalli, Michael Dorsch, Brian Callaghan, Noemi Garg, Reshma Jagsi, Jennifer J. Griggs, Michael S. Sabel
Journal: Journal of Clinical Oncology (2020)

176 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that manifests in the hands or feet primarily as numbness or tingling but can also have motor or painful components. CIPN monitoring is typically conducted by patients self-reporting symptoms during appointments or via questionnaires. Objective CIPN testing may improve early detection but is not typical during treatment, perhaps due to the need for specialized equipment and personnel. The objective of this pilot study was to conduct initial testing of a smartphone app that collects patient-reported and objective CIPN data. Methods: NeuroDetect V1.0 (available in iOS app store) includes a patient-reported CIPN questionnaire (EORTC CIPN20) and two functional assessments available within ResearchKit, the Gat and Balance and 9-Hole Peg tests. Patients who had completed neurotoxic chemotherapy were enrolled to complete NeuroDetect assessments one time. Study participants were classified as CIPN cases if they answered ≥ 3 for at least one of the first four CIPN20 questions, which ask about numbness or tingling in the hands or feet on a 1-4 scale. User acceleration data features were extracted with two open source tools, mhealthtools and pdkit. The results of the functional assessments were compared between CIPN cases and controls in principal component analysis and partial least squares discriminant analysis. Results: Twenty-four patients who had completed neurotoxic chemotherapy enrolled and completed the NeuroDetect assessments. Integration across all 87 features measured in the gait and balance test explained 42% of the difference between CIPN cases (n = 14) and controls (n = 10) and 9 individual features were significantly different between cases and controls (all p &lt; 0.05). In the 9-hole Peg Test, hand speed explained 77% of the difference between CIPN cases and controls. CIPN cases took longer to complete the 9-hole peg test though the difference was not statistically significant (dominant hand mean 407.3 vs. 406.2 ms, p = 0.075). Conclusions: App-based functional assessment may detect evidence of CIPN. We are developing additional CIPN functional assessments for NeuroDetect V2.0 to test CIPN detection in a longitudinal study of patients undergoing neurotoxic chemotherapy.
Contemporary Population-Based Analysis of Bone Mineral Density Testing in Men Initiating Androgen Deprivation Therapy for Prostate Cancer
Authors: Jason Hu, Armen G. Aprikian, Marie Vanhuyse, Alice Dragomir
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Androgen deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer (PCa); however, it accelerates the loss of bone mineral density (BMD), which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to assess baseline fracture risk properly. The objective of this study was to examine the proportion of BMD testing in men initiating ADT in Quebec and to identify factors associated with receipt of this testing. Methods: The study cohort consisted of men extracted from Quebec public healthcare insurance administrative databases who initiated continuous ADT from 2000 to 2015 for &gt;12 months. The primary study outcome was receipt of BMD testing in the period from 6 months before through 12 months after ADT initiation. Multivariable generalized linear mixed regression modeling with a logit link was performed to identify variables associated with BMD testing. Results: We identified 22,033 patients, of whom 3,910 (17.8%) underwent BMD testing. Rates of BMD testing increased from 4.1% in 2000 to 23.4% in 2015. After multivariable analyses, prior history of osteoporosis (odds ratio [OR], 1.84; 95% CI, 1.32–2.57; P &lt;.001), rheumatoid arthritis (OR, 1.64; 95% CI, 1.15–2.34; P =.006), use of bisphosphonates (OR, 1.47; 95% CI, 1.25–1.73; P &lt;.001), and long-term corticosteroid use (OR, 1.63; 95% CI, 1.15–2.31; P =.006) were associated with higher odds of BMD testing. Patient age &gt;80 years (OR, 0.67; 95% CI, 0.59–0.76; P &lt;.001), metastases (OR, 0.79; 95% CI, 0.70–0.89; P &lt;.001), higher Charlson comorbidity score (OR, 0.65; 95% CI, 0.51–0.81; P &lt;.001), and rural residence (OR, 0.77; 95% CI, 0.68–0.87; P &lt;.001) were associated with lower odds of BMD testing. Conclusions: In our study population, BMD testing rates in men initiating ADT were low, although they increased over the years especially in the years after the publication of recommendations for BMD testing in these patients. Potential gaps identified include being older, more comorbid, and rural areas. Overall, additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.
Characteristics Associated with Adults Remembering to Wash Hands in Multiple Situations Before and During the COVID-19 Pandemic — United States, October 2019 and June 2020
Authors: Julia C. Haston, Gabrielle F. Miller, David Berendes, Ashley Andújar, Brittany Marshall, Jennifer Cope, Candis M. Hunter, Brittany M. Robinson, Vincent R. Hill, Amanda G. Garcia-Williams
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Washing hands often, especially during times when one is likely to acquire and spread pathogens,* is one important measure to help prevent the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), as well as other pathogens spread by respiratory or fecal-oral transmission (1,2). Studies have reported moderate to high levels of self-reported handwashing among adults worldwide during the COVID-19 pandemic (3-5)†; however, little is known about how handwashing behavior among U.S. adults has changed since the start of the pandemic. For this study, survey data from October 2019 (prepandemic) and June 2020 (during pandemic) were compared to assess changes in adults' remembering to wash their hands in six situations.§ Statistically significant increases in reported handwashing were seen in June 2020 compared with October 2019 in four of the six situations; the odds of remembering to wash hands was 2.3 times higher among respondents after coughing, sneezing, or blowing their nose, 2.0 times higher before eating at a restaurant, and 1.7 times higher before eating at home. Men, young adults aged 18-24 years, and non-Hispanic White (White) adults were less likely to remember to wash hands in multiple situations. Strategies to help persons remember to wash their hands frequently and at important times should be identified and implemented, especially among groups reporting low prevalence of remembering to wash their hands.
Using Data to Achieve Organ Procurement Organization Accountability—Reply
Authors: Seth J. Karp, Greg Segal, D. J. Patil
Journal: JAMA Surgery (2020)

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Autosomal Recessive Bestrophinopathy
Authors: Giuseppe Casalino, Kamron N. Khan, Monica Armengol, Genevieve Wright, Nikolas Pontikos, Michalis Georgiou, Andrew R. Webster, Anthony G. Robson, Parampal S. Grewal, Michel Michaelides
Journal: Ophthalmology (2020)

To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults.Retrospective case series.Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center.Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing.Visual acuity (VA), retinal imaging, and electrophysiologic changes over time.Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results.Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human <i>TNNT2</i> Variants
Authors: Anthony M. Pettinato, Feria A. Ladha, David J. Mellert, Nicholas Legere, Rachel Cohn, Robert Romano, Ketan Thakar, Yu-Sheng Chen, J. Travis Hinson
Journal: Circulation (2020)

Background: Pathogenic TNNT2 variants are a cause of hypertrophic and dilated cardiomyopathies, which promote heart failure by incompletely understood mechanisms. The precise functional significance for 87% of TNNT2 variants remains undetermined, in part, because of a lack of functional genomics studies. The knowledge of which and how TNNT2 variants cause hypertrophic and dilated cardiomyopathies could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, and provide new insights into cardiomyopathy pathogenesis, as well. Methods: We created a toolkit of human induced pluripotent stem cell models and functional assays using CRISPR/Cas9 to study TNNT2 variant pathogenicity and pathophysiology. Using human induced pluripotent stem cell–derived cardiomyocytes in cardiac microtissue and single-cell assays, we functionally interrogated 51 TNNT2 variants, including 30 pathogenic/likely pathogenic variants and 21 variants of uncertain significance. We used RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants and adapted CRISPR/Cas9 to engineer a transcriptional reporter assay to assist prediction of TNNT2 variant pathogenicity. We also studied variant-specific pathophysiology using a thin filament–directed calcium reporter to monitor changes in myofilament calcium affinity. Results: Hypertrophic cardiomyopathy–associated TNNT2 variants caused increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction. TNNT2 variant–dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, including MAPK (mitogen-activated protein kinase) signaling targets, HOPX , and NPPB . We distinguished pathogenic TNNT2 variants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenous NPPB locus. On the basis of a combination of NPPB reporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 variants of uncertain significance. Conclusions: Our study found that hypertrophic cardiomyopathy–associated TNNT2 variants increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and can be used to predict TNNT2 variant pathogenicity.
Multiple myeloma (MM) therapy within a Medicare-insured patient population: Role of care setting and oncologist sub-specialization in hematologic malignancies.
Authors: Amy J. Davidoff, Jessica B. Long, Scott F. Huntington
Journal: Journal of Clinical Oncology (2020)

38 Background: Dramatic increases in oncology practice consolidation with hospitals may affect care setting and whether patients see oncologists that specialize in their cancer, with downstream effects on treatment patterns. This may be particularly true for MM, where approval of new immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), coupled with evidence supporting PI-IMiD combinations, maintenance (MT), and stem cell transplant (SCT) among fit patients, have expanded options, complexity and lines of therapy (LOT). Methods: We selected adults with MM diagnosis (dx) between 07/07-12/15 from the SEER-Medicare linked database. We required continuous Medicare Parts A and B enrollment and no HMO/PPO coverage from 12 months prior to dx (1 month prior for Part D) through death or end of study (12/16) and MM therapy initiation w/in 12 months post dx. Outcomes including LOT1 PI-IMiD combination, SCT, MT, and any LOT2, 3 or 4 were constructed using claims indicators for oral and IV drugs and receipt dates. Provider setting was assigned as academic and/or NCI cancer center, non-teaching hospital, or community (non-hospital) based on the most recent oncologist E and M visit prior to LOT1 initiation. Percentage of patient panel with hematologic malignancies (Heme%) was calculated for each oncologist, using a pooled sample of 11 major cancer sites reported in SEER-Medicare. Multivariable logistic regressions included care setting, %Heme, with controls for demographics, health status, and diagnosis year. Results: The cohort (n = 4930) was 14% Black, and 51% age ≥75 years. Care setting was 23% academic, 14% non-teaching hospital, and 63% community; community setting decreased from 72 to 58% during observation period (2007 to 2015). Mean Heme% (31% overall) was higher in academic hospitals (44%) compared with community practices (27%; p &lt; .001). LOT1 PI-IMiD, LOT 2, 3 and 4 were received by 21%, 55%, 31% and 18% respectively, with 53% MT, and 7% SCT. Higher %Heme was associated with increased likelihood of LOT1 PI-IMiD, SCT, LOT3, and LOT4. Relative to academic/NCI, community care was associated with higher adjusted odds for LOT1 PI-IMiD: aOR 1.33, p &lt; .001; but lower odds for any LOT4: aOR .67, p = .001). Conclusions: Using a novel measure of oncologist sub-specialization in hematologic malignancies, we found positive associations with receipt of initial PI-IMiD therapy and ongoing LOTs in a Medicare insured population treated for MM. Surprisingly, care in a community setting was associated with recommended initial PI-IMiD therapy, but fewer LOTs.
Maximum Uptake and Hypermetabolic Volume of 18F-FDOPA PET Estimate Molecular Status and Overall Survival in Low-Grade Gliomas
Authors: Hiroyuki Tatekawa, Jingwen Yao, Talia C. Oughourlian, Akifumi Hagiwara, Chencai Wang, Catalina Raymond, Albert Lai, Timothy F. Cloughesy, Phioanh L. Nghiemphu, Linda M. Liau, Noriko Salamon, Benjamin M. Ellingson
Journal: Clinical Nuclear Medicine (2020)

We evaluated F-FDOPA PET and MRI characteristics in association with the molecular status and overall survival (OS) in a large number of low-grade gliomas (LGGs).Eighty-six patients who underwent F-FDOPA PET and MRI and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 noncodeleted, 37 codeleted). After segmentation of the hyperintense area on fluid-attenuated inversion recovery image (FLAIRROI), the following were calculated: normalized SUVmax (nSUVmax) of F-FDOPA relative to the striatum, F-FDOPA hypermetabolic volume (tumor-to-striatum ratios >1), FLAIRROI volume, relative cerebral blood volume, and apparent diffusion coefficient within FLAIRROI. Receiver operating characteristic curve and Cox regression analyses were performed.PET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76% and specificities of 100% and 94%, respectively. Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006). The nSUVmax (HR = 151.6) for newly diagnosed LGGs and the F-FDOPA hypermetabolic volume (HR = 1.038) for recurrent LGGs demonstrated significant association with OS.Combining F-FDOPA PET and MRI with age proved useful for predicting the molecular status in patients with LGGs, whereas the nSUVmax and F-FDOPA hypermetabolic volume may be useful for prognostication.
Long non-coding RNAs in liver diseases: Focusing on nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease
Authors: Sen Han, Ting Zhang, Praveen Kusumanchi, Nazmul Huda, Yanchao Jiang, Zhihong Yang, Suthat Liangpunsakul
Journal: Clinical and Molecular Hepatology (2020)

Long non-coding RNAs (lncRNAs), a class of transcribed RNA molecules with the lengths exceeding 200 nucleotides, are not translated into protein. They can modulate protein-coding genes by controlling transcriptional and posttranscriptional processes. The dysregulation of lncRNAs has been related to various pathological disorders. In this review, we summarized the current knowledge of lncRNAs and their implications in the pathogenesis of three common liver diseases: nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease. Future studies to further define the role of lncRNAs and their mechanisms in various types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting specific lncRNAs for the treatment of liver diseases.