ABSTRACT
The overall size and timing of monsoon floods in Bangladesh are challenging to measure. The inundated area is extensive in low-lying Bangladesh, and observations of water storage are key to understanding floods. Laser-ranging instruments on Gravity Recovery and Climate Experiment (GRACE) Follow-On spacecraft detected the peak water storage anomaly of 75 gigatons across Bangladesh in late July 2020. This is in addition to, and three times larger than, the maximum storage anomaly in soil layers during the same period. A flood propagation model suggested that the water mass, as shown in satellite observations, is largely influenced by slow floodplain and groundwater flow processes. Independent global positioning system measurements confirmed the timing and total volume of the flood water estimates. According to land surface models, the soils were saturated a month earlier than the timing of the peak floodplain storage observed by GRACE Follow-On. The cyclone Amphan replenished soils with rainfall just before the monsoon rains started, and consequently, excessive runoff was produced and led to the early onset of the 2020 flooding. This study demonstrated how antecedent soil moisture conditions can influence the magnitude and duration of flooding. Continuous monitoring of storage change from GRACE Follow-On gravity measurements provides important information complementary to river gauges and well levels for enhancing hydrologic flood forecasting models and assisting surface water management.
ABSTRACT
Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting ß cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.
Subject(s)
Cell Encapsulation/methods , Drug Delivery Systems/methods , Insulin-Secreting Cells/metabolism , Animals , Cell Survival/drug effects , Convection , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Drug Delivery Systems/instrumentation , Insulin/metabolism , Insulin Secretion/drug effects , Insulin Secretion/physiology , Insulin-Secreting Cells/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans Transplantation/methods , Male , RatsABSTRACT
Pharyngeal muscle changes occur in patients with Parkinson's disease and related disorders (PRD); however, the association between the structural alterations in the pharynx and the symptoms of dysphagia remains unclear. We assessed structural changes and contractile forces by measuring pharyngeal wall thickness and width. We aimed to define the pharyngeal measurements and determine their value as diagnostic tools for dysphagia. The pharyngeal wall thickness (PWT), pharyngeal width at rest (PWR), and shortest pharyngeal width at swallowing (PWS) were measured using lateral neck roentgenograms and videofluoroscopic swallowing study. We compared the PWR and PWT between the PRD and control groups using an independent t-test. The Kendall correlation test was performed on the radiological data of the pharynx (PWT, PWR and PWS), dysphagia scales (Penetration-Aspiration scale [PAS] and Dysphagia Outcome and Severity Scale [DOSS]), and Hoehn and Yahr scale (HY scale). The PWT was smaller and the PWR greater in the PRD than in the control group (p < 0.05). The dysphagia scales (PAS and DOSS) were correlated with the radiological data (PWT and PWS) and the HY scale (p < 0.05). The HY scale score also correlated with the PWT (p < 0.05). The optimal cutoff points of the PWT and PWR for predicting aspiration were 4.05 and 16.05 mm in the PRD group, respectively. Using the PWT, PWR and PWS, muscle atrophy and contractile strength of the pharynx can be estimated. The combination of the PWT and PWR can be a simple indicator for predicting swallowing disorders at the bedside.
ABSTRACT
Background: The coronavirus disease 2019 pandemic has expanded noncontact health care systems worldwide. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technology that enables treatment monitoring under remote supervision. We investigated the factors affecting patients' decision to participate in telerehabilitation (TR) using tDCS for motor function recovery after suffering a stroke. Materials and Methods: Four medical institutions surveyed 156 patients with poststroke paralysis. The participants were asked whether they would participate in TR therapy using tDCS in the future. We performed logistic regression analysis to examine the factors-demographic data, stroke characteristics, arm function, gait, and cognitive function-that influenced participants' decisions. Results: Of the participants, 66% (103/156) reported that they would participate in TR using tDCS in the future. Participants' monthly salary was a single significant independent factor influencing their decision to participate. Those earning greater than 5 million KRW (4,000 USD) were more likely to engage in TR via tDCS than those earning less than 1 million KRW (800 USD). The most common barriers to participation in telemedicine included the preference for face-to-face treatment and unfamiliarity. The expected medical expenses of TR using tDCS were 46,154 KRW (37 USD) per session. Conclusions: Most participants with poststroke paralysis responded positively to TR using tDCS for hand function recovery. For telemedicine to work effectively in a situation wherein face-to-face rehabilitation is impossible, prior discussion at the governmental level is essential for determining medical finances.
Subject(s)
COVID-19 , Stroke , Telerehabilitation , Transcranial Direct Current Stimulation , Humans , COVID-19/epidemiology , Stroke/complications , Stroke/therapy , ParalysisABSTRACT
ABSTRACT: A child with acute abdomen with gross hematuria occasionally visits the emergency department (ED). Usually, such a condition is subject to differential diagnosis for stones, injuries, or sometimes malignancies in the urinary tract. Here we introduce an unusual case of a 9-year-old girl who presented to ED with acute lower abdominal pain and gross hematuria. She had no medical history. An urgent computed tomographic image revealed a renal vein thrombosis. Laboratory tests for autoimmune diseases and coagulaopathies were performed, and the results were within normal ranges. At the time, she did not fulfil the criteria for systemic lupus erythematosus or antiphospholipid syndrome. Later at follow-up, however, she had a recurrent episode of renal vein thrombosis. A kidney biopsy was performed to reveal histology of membranous lupus nephropathy. The case emphasizes the importance for both ED physicians and pediatricians to have a clinical suspicion of autoimmune diseases in cases with major vessel thrombosis, even when the patient is seronegative.
Subject(s)
Abdominal Pain/etiology , Hematuria/etiology , Lupus Erythematosus, Systemic , Child , Female , Humans , Lupus Erythematosus, Systemic/diagnosis , Venous Thrombosis/diagnostic imagingABSTRACT
BACKGROUND: The American College of Surgeons Commission on Cancer has incorporated documentation of critical elements outlined in Operative Standards for Cancer Surgery into revised standards for cancer center accreditation. This study assessed the current documentation of critical elements in partial mastectomy (PM) and sentinel lymph node biopsy (SLNB) operative reports. MATERIALS AND METHODS: Operative reports for PM + SLNB at a single academic institution from 2013 to 2018 were reviewed for compliance and surveyor interobserver reliability with the Oncologic Elements of Operative Record defined in Operative Standards and compared with a nonredundant American Society of Breast Surgeons Mastery of Breast Surgery (MBS) quality measure for specimen orientation. RESULTS: Ten reviewers each evaluated 66 PM + SLNB operative reports for 13 Oncologic Elements and one MBS measure. No operative records reported all critical elements for PM + SLNB or PM alone. Residents completed 36.4% of operative reports: Element documentation was similar for PM but varied significantly for SLNB between resident and attending authorship. Combined reporting performance and interrater reliability varied across all elements and was highest for the use of SLNB tracer (97.1% and κ = 0.95, respectively) and lowest for intraoperative assessment of SLNB (30.6%, κ = 0.43). MBS specimen orientation had both high proportion reported (87.0%) and interrater reliability (κ = 0.84). CONCLUSIONS: Adherence to reporting critical elements for PM and SLNB varied. Whether differential compliance was tied to discrepancies in documentation or reviewer abstraction, clarification of synoptic choices may improve reporting consistency. Evolving techniques or technologies will require continuous appraisal of mandated reporting for breast surgery.
Subject(s)
Accreditation/standards , Breast Neoplasms/surgery , Documentation/standards , Lymph Node Excision/statistics & numerical data , Mastectomy, Segmental/statistics & numerical data , Academic Medical Centers/organization & administration , Academic Medical Centers/standards , Academic Medical Centers/statistics & numerical data , Breast/pathology , Breast/surgery , Breast Neoplasms/pathology , Cancer Care Facilities/organization & administration , Cancer Care Facilities/standards , Cancer Care Facilities/statistics & numerical data , Documentation/statistics & numerical data , Female , Guideline Adherence/standards , Guideline Adherence/statistics & numerical data , Humans , Lymph Node Excision/instrumentation , Lymph Node Excision/methods , Lymph Node Excision/standards , Mastectomy, Segmental/instrumentation , Mastectomy, Segmental/methods , Mastectomy, Segmental/standards , Practice Patterns, Physicians'/organization & administration , Practice Patterns, Physicians'/standards , Practice Patterns, Physicians'/statistics & numerical data , Quality Indicators, Health Care/standards , Quality Indicators, Health Care/statistics & numerical data , Reproducibility of Results , Sentinel Lymph Node Biopsy/standards , Sentinel Lymph Node Biopsy/statistics & numerical dataABSTRACT
PURPOSE: To characterize burnout, as defined by high emotional exhaustion (EE) or depersonalization (DP), among interventional radiologists using a validated assessment tool. MATERIALS AND METHODS: An anonymous 34-question survey was distributed to interventional radiologists. The survey consisted of demographic and practice environment questions and the 22-item Maslach Burnout Inventory-Human Services Survey (MBI). Interventional radiologists with high scores on EE (≥ 27) or DP (≥ 10) MBI subscales were considered to have a manifestation of career burnout. RESULTS: Beginning on January 7, 2019, 339 surveys were completed over 31 days. Of respondents, 263 (77.6%) identified as male, 75 (22.1%) identified as female, and 1 (0.3%) identified as trans-male. The respondents were interventional radiology attending physicians (298; 87.9%), fellows (20; 5.9%), and residents (21; 6.2%) practicing at academic (136; 40.1%), private (145; 42.8%), and hybrid (58; 17.1%) centers. Respondents worked < 40 hours (15; 4.4%), 40-60 hours (225; 66.4%), 60-80 hours (81; 23.9%), and > 80 hours (18; 5.3%) per week. Mean MBI scores for EE, DP, and personal achievement were 30.0 ± 13.0, 10.6 ± 6.9, and 39.6 ± 6.6. Burnout was present in 244 (71.9%) participants. Identifying as female (odds ratio 2.4; P = .009) and working > 80 hours per week (odds ratio 7.0; P = .030) were significantly associated with burnout. CONCLUSIONS: Burnout is prevalent among interventional radiologists. Identifying as female and working > 80 hours per week were strongly associated with burnout.
Subject(s)
Attitude of Health Personnel , Burnout, Professional/etiology , Health Knowledge, Attitudes, Practice , Physicians, Women/psychology , Radiography, Interventional , Radiologists/psychology , Workload/psychology , Adult , Burnout, Professional/diagnosis , Burnout, Professional/psychology , Depersonalization/etiology , Depersonalization/psychology , Humans , Middle Aged , Psychological Distress , Risk Factors , Sex Factors , Surveys and Questionnaires , Time FactorsABSTRACT
BACKGROUND: Assessment tools for early cystic fibrosis (CF) lung disease are limited. Detecting early pulmonary disease is crucial to increasing life expectancy by starting interventions to slow the progression of the pulmonary disease with the many treatment options available. OBJECTIVE: To compare the utility of lung T1-mapping MRI with ultrashort echo time (UTE) MRI in children with cystic fibrosis in detecting early stage lung disease and monitoring pulmonary exacerbations. MATERIALS AND METHODS: We performed a prospective study in 16 children between September 2017 and January 2018. In Phase 1, we compared five CF patients with normal spirometry (mean 11.2 years) to five age- and gender-matched healthy volunteers. In Phase 2, we longitudinally evaluated six CF patients (median 11 years) in acute pulmonary exacerbation. All children had non-contrast lung T1-mapping and UTE MRI and spirometry testing. We compared the mean normalized T1 value and percentage lung volume without T1 value in CF patients and healthy subjects in Phase 1 and during treatment in Phase 2. We also performed cystic fibrosis MRI scoring. We evaluated differences in continuous variables using standard statistical tests. RESULTS: In Phase 1, mean normalized T1 values of the lung were significantly lower in CF patients in comparison to healthy controls (P=0.02) except in the right lower lobe (P=0.29). The percentage lung volume without T1 value was also significantly higher in CF patients (P=0.006). UTE MRI showed no significant differences between CF patients and healthy volunteers (P=0.11). In Phase 2, excluding one outlier case who developed systemic disease in the course of treatment, the whole-lung T1 value increased (P=0.001) and perfusion scoring improved (P=0.02) following therapy. We observed no other significant changes in the MRI scoring. CONCLUSION: Lung T1-mapping MRI can detect early regional pulmonary CF disease in children and might be helpful in the assessment of acute pulmonary exacerbations.
Subject(s)
Cystic Fibrosis/diagnostic imaging , Lung Diseases/diagnostic imaging , Magnetic Resonance Imaging/methods , Adolescent , Case-Control Studies , Child , Cross-Sectional Studies , Cystic Fibrosis/physiopathology , Disease Progression , Female , Humans , Male , Pilot Projects , Prospective Studies , Respiratory Function TestsABSTRACT
Glioblastoma (GBM) is the most aggressive and common form of brain cancer in adults. GBM is characterized by poor survival and remarkably high tumors heterogeneity (both intertumoral and intratumoral), and lack of effective therapies. Recent high-throughput data revealed heterogeneous genetic/genomic/epigenetic features and led to multiple methods aiming to classify tumors according to the key molecular events that drive the most aggressive cellular components so that targeted therapies can be developed for individual subtypes. However, GBM molecular subtypes have not led to improvement of patients outcomes. Targeted or tailored therapies for specific mutations or subtypes largely failed due to the complexities arising from intratumoral molecular heterogeneity. Most tumors develop resistance to treatment and soon recur. GBM stem cells (GSCs) have been identified. Recent single cell sequencing studies of GBM suggest that intratumoral cellular heterogeneity can be partially explained by tumor cell hierarchy arising from GBM stem cells. Therefore, the molecular subtypes based on patient derived GSCs may potentially lead to more effective subtype-specific treatments. In this paper, we review the molecular alterations of GBM and molecular subtyping methods as well as subtype plasticity in primary and recurrent tumors emphasizing the clinical relevance of potential targets for further drug development.
Subject(s)
Brain Neoplasms/genetics , Epigenomics/methods , Genomics/methods , Glioblastoma/genetics , Neoplastic Stem Cells/metabolism , Adult , Brain Neoplasms/classification , Brain Neoplasms/therapy , Gene Expression Profiling/methods , Glioblastoma/classification , Glioblastoma/therapy , Humans , Immunotherapy/methods , Immunotherapy/trends , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trendsABSTRACT
Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.
Subject(s)
Gene Regulatory Networks , Quantitative Trait Loci , Saccharomyces cerevisiae Proteins/genetics , Transcription Factors/genetics , Algorithms , Basic-Leucine Zipper Transcription Factors/genetics , Gene Expression Regulation, Fungal , Gene Ontology , Genes, Mating Type, Fungal/genetics , Models, Genetic , Mutation , Promoter Regions, Genetic , Reproducibility of Results , Saccharomyces cerevisiae/geneticsABSTRACT
We consider a functional linear Cox regression model for characterizing the association between time-to-event data and a set of functional and scalar predictors. The functional linear Cox regression model incorporates a functional principal component analysis for modeling the functional predictors and a high-dimensional Cox regression model to characterize the joint effects of both functional and scalar predictors on the time-to-event data. We develop an algorithm to calculate the maximum approximate partial likelihood estimates of unknown finite and infinite dimensional parameters. We also systematically investigate the rate of convergence of the maximum approximate partial likelihood estimates and a score test statistic for testing the nullity of the slope function associated with the functional predictors. We demonstrate our estimation and testing procedures by using simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Our real data analyses show that high-dimensional hippocampus surface data may be an important marker for predicting time to conversion to Alzheimer's disease. Data used in the preparation of this article were obtained from the ADNI database (adni.loni.usc.edu).
Subject(s)
Linear Models , Proportional Hazards Models , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Likelihood Functions , Models, Statistical , Neuroimaging , Principal Component Analysis , Time FactorsABSTRACT
Over the past 40 years, the discharge in South America's Paraná River basin has increased despite no evidence of significant rainfall increases in the basin. In this analysis, we show that the observed multi-decadal increase in discharge can be explained by concomitant changes in land cover that have occurred within the basin during this period. Our analysis also indicates that the peak discharge timing may have shifted concurrently from January/February in the 1970s to March in more recent decades. While land-use effect dominantly alters the long-term temporal dynamics of the river discharge over multi-decades, the change in the seasonality of the discharge can be attributable to the combined effect of the land-use and climate variability. This study suggests that the mean annual discharge is likely to change in the other South American River basins where land transformation is currently taking place, and the shift of the month of peak discharge needs to be taken into consideration to forecast the hydropower generation under changing climate and land conversion.
ABSTRACT
BACKGROUND: Chronic hepatitis B virus (HBV) infection leads to liver fibrosis, which is a major risk factor in hepatocellular carcinoma (HCC) and an independent risk factor of recurrence after HCC tumor resection. The HBV genome can be inserted into the human genome, and chronic inflammation may trigger somatic mutations. However, how HBV integration and other genomic changes contribute to the risk of tumor recurrence with regards to the different degree of liver fibrosis is not clearly understood. METHODS: We sequenced mRNAs of 21 pairs of tumor and distant non-neoplastic liver tissues of HBV-HCC patients and performed comprehensive genomic analyses of our RNAseq data and public available HBV-HCC sequencing data. RESULTS: We developed a robust pipeline for sensitively identifying HBV integration sites based on sequencing data. Simulations showed that our method outperformed existing methods. Applying it to our data, 374 and 106 HBV host genes were identified in non-neoplastic liver and tumor tissues, respectively. When applying it to other RNA sequencing datasets, consistently more HBV integrations were identified in non-neoplastic liver than in tumor tissues. HBV host genes identified in non-neoplastic liver samples significantly overlapped with known tumor suppressor genes. More significant enrichment of tumor suppressor genes was observed among HBV host genes identified from patients with tumor recurrence, indicating the potential risk of tumor recurrence driven by HBV integration in non-neoplastic liver tissues. We also compared SNPs of each sample with SNPs in a cancer census database and inferred samples' pathogenic SNP loads. Pathogenic SNP loads in non-neoplastic liver tissues were consistently higher than those in normal liver tissues. Additionally, HBV host genes identified in non-neoplastic liver tissues significantly overlapped with pathogenic somatic mutations, suggesting that HBV integration and somatic mutations targeting the same set of genes are important to tumorigenesis. HBV integrations and pathogenic mutations showed distinct patterns between low and high liver fibrosis patients with regards to tumor recurrence. CONCLUSIONS: The results suggest that HBV integrations and pathogenic SNPs in non-neoplastic tissues are important for tumorigenesis and different recurrence risk models are needed for patients with low and high degrees of liver fibrosis.
Subject(s)
Carcinoma, Hepatocellular/genetics , Hepatitis B virus , Hepatitis B, Chronic/genetics , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Base Sequence , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/virology , Cohort Studies , DNA, Viral , Female , Genome, Human , Hepatitis B, Chronic/complications , Humans , Liver Cirrhosis/complications , Liver Neoplasms/complications , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local , Pilot Projects , Polymorphism, Single Nucleotide , RNA, Neoplasm , Sequence Analysis, RNA , Virus IntegrationABSTRACT
MOTIVATION: MicroRNAs (miRNAs) play a key role in regulating tumor progression and metastasis. Identifying key miRNAs, defined by their functional activities, can provide a deeper understanding of biology of miRNAs in cancer. However, miRNA expression level cannot accurately reflect miRNA activity. RESULTS: We developed a computational approach, ActMiR, for identifying active miRNAs and miRNA-mediated regulatory mechanisms. Applying ActMiR to four cancer datasets in The Cancer Genome Atlas (TCGA), we showed that (i) miRNA activity was tumor subtype specific; (ii) genes correlated with inferred miRNA activities were more likely to enrich for miRNA binding motifs; (iii) expression levels of these genes and inferred miRNA activities were more likely to be negatively correlated. For the four cancer types in TCGA we identified 77-229 key miRNAs for each cancer subtype and annotated their biological functions. The miRNA-target pairs, predicted by our ActMiR algorithm but not by correlation of miRNA expression levels, were experimentally validated. The functional activities of key miRNAs were further demonstrated to be associated with clinical outcomes for other cancer types using independent datasets. For ER(-)/HER2(-) breast cancers, we identified activities of key miRNAs let-7d and miR-18a as potential prognostic markers and validated them in two independent ER(-)/HER2(-) breast cancer datasets. Our work provides a novel scheme to facilitate our understanding of miRNA. In summary, inferred activity of key miRNA provided a functional link to its mediated regulatory network, and can be used to robustly predict patient's survival. AVAILABILITY AND IMPLEMENTATION: the software is freely available at http://research.mssm.edu/integrative-network-biology/Software.html. CONTACT: jun.zhu@mssm.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Gene Regulatory Networks , MicroRNAs/metabolism , Neoplasms/genetics , Breast Neoplasms/genetics , Cell Line, Tumor , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , Molecular Sequence Annotation , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , Software , Survival RateABSTRACT
Retroviral insertional mutagenesis is a powerful tool for identifying putative cancer genes in mice. To uncover the regulatory mechanisms by which common insertion loci affect downstream processes, we supplemented genotyping data with genome-wide mRNA expression profiling data for 97 tumors induced by retroviral insertional mutagenesis. We developed locus expression signature analysis, an algorithm to construct and interpret the differential gene expression signature associated with each common insertion locus. Comparing locus expression signatures to promoter affinity profiles allowed us to build a detailed map of transcription factors whose protein-level regulatory activity is modulated by a particular locus. We also predicted a large set of drugs that might mitigate the effect of the insertion on tumorigenesis. Taken together, our results demonstrate the potential of a locus-specific signature approach for identifying mammalian regulatory mechanisms in a cancer context.
Subject(s)
Carcinogenesis/metabolism , Computational Biology/methods , DNA Damage , Gene Expression Regulation, Neoplastic/genetics , Gene Regulatory Networks/genetics , Genetic Variation , Neoplasms/genetics , Analysis of Variance , Animals , Carcinogenesis/genetics , Cluster Analysis , Enzyme Inhibitors/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Gene Ontology , High-Throughput Screening Assays/methods , Mice , Phosphoinositide-3 Kinase InhibitorsABSTRACT
Errors in sample annotation or labeling often occur in large-scale genetic or genomic studies and are difficult to avoid completely during data generation and management. For integrative genomic studies, it is critical to identify and correct these errors. Different types of genetic and genomic data are inter-connected by cis-regulations. On that basis, we developed a computational approach, Multi-Omics Data Matcher (MODMatcher), to identify and correct sample labeling errors in multiple types of molecular data, which can be used in further integrative analysis. Our results indicate that inspection of sample annotation and labeling error is an indispensable data quality assurance step. Applied to a large lung genomic study, MODMatcher increased statistically significant genetic associations and genomic correlations by more than two-fold. In a simulation study, MODMatcher provided more robust results by using three types of omics data than two types of omics data. We further demonstrate that MODMatcher can be broadly applied to large genomic data sets containing multiple types of omics data, such as The Cancer Genome Atlas (TCGA) data sets.
Subject(s)
Databases, Genetic , Genomics/methods , Molecular Sequence Annotation/methods , DNA Methylation , Female , Gene Expression Profiling , Humans , Male , Neoplasms/genetics , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Sequence Analysis, RNAABSTRACT
Epithelial-mesenchymal transition (EMT) in cancer promotes metastasis and chemotherapy resistance. A subset of triple-negative breast cancer (TNBC) exhibits a mesenchymal gene signature that is associated with poor patient outcomes. We previously identified PTK6 tyrosine kinase as an oncogenic driver of EMT in a subset of TNBC. PTK6 induces EMT by stabilizing SNAIL, a key EMT-initiating transcriptional factor. Inhibition of PTK6 activity reverses mesenchymal features of TNBC cells and suppresses their metastases by promoting SNAIL degradation via a novel mechanism. In the current study, we identify membrane-associated RING-CH2 (MARCH2) as a novel PTK6-regulated E3 ligase that promotes the ubiquitination and degradation of SNAIL protein. The MARCH2 RING domain is critical for SNAIL ubiquitination and subsequent degradation. PTK6 inhibition promotes the interaction of MARCH2 with SNAIL. Overexpression of MARCH2 exhibits tumor suppressive properties and phenocopies the effects of SNAIL downregulation and PTK6 inhibition in TNBC cells, such as inhibition of migration, anoikis resistance, and metastasis. Consistent with this, higher levels of MARCH2 expression in breast and other cancers are associated with better prognosis. We have identified MARCH2 as a novel SNAIL E3 ligase that regulates EMT and metastases of mesenchymal TNBC. SIGNIFICANCE: EMT is a process directly linked to drug resistance and metastasis of cancer cells. We identified MARCH2 as a novel regulator of SNAIL, a key EMT driver, that promotes SNAIL ubiquitination and degradation in TNBC cells. MARCH2 is oncogene regulated and inhibits growth and metastasis of TNBC. These insights could contribute to novel strategies to therapeutically target TNBC.
Subject(s)
Triple Negative Breast Neoplasms , Ubiquitin-Protein Ligases , Humans , Gene Expression Regulation , Oncogenes , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination , Membrane Proteins/genetics , Membrane Proteins/metabolismABSTRACT
RATIONALE AND OBJECTIVES: To evaluate moral injury (MI) among interventional radiologists using validated assessment tools. MATERIALS AND METHODS: An anonymous 29-question online survey was distributed to interventional radiologists using the Society of Interventional Radiology Connect Open Forum website, Twitter, Facebook, LinkedIn, and electronic mail. The survey consisted of demographic and practice environment questions, a global quality of life (QoL) scale (scored 1-100), the MI Symptom ScaleHealthcare Professional (MISS-HP) (scored 1-100), and two open-ended questions. A MISS-HP score ≥ 36 was indicative of experiencing MI. P < .05 was considered statistically significant for all two-sided tests. RESULTS: Beginning on March 30, 2023, 365 surveys were completed over 5 days. Of the respondents, 299 (81.9%) were male, 65 (17.8%) were female, and one preferred not to disclose gender. The respondents included practicing interventional radiologists (299; 81.9%) and interventional radiologists-in-training (66; 18.1%). Practice settings included academic (146; 40.0%), community (121; 33.2%), hybrid (84; 23.0%), or other (14; 3.8%) centers. Mean QoL was 71.1 ± 17.0 (range: 0-100) suggestive of "good" QoL. Mean QoL in the MI subgroup was significantly different from that for the rest of the group (67.6 ± 17.0 vs. 76.6 ± 16.0; P < 0.05). 223 (61.1%) respondents scored ≥ 36 on the MISS-HP, and thus were categorized as having profession-related MI. Mean MISS-HP was 39.9 ± 12.6 (range: 10-83). Mean MISS-HP in the MI subgroup was significantly different from that for the rest of the group (47.4 ± 9.6 vs. 28.0 ± 5.7; P < 0.05). There was a negative correlation between MI and QoL (r = -0.4; P < 0.001). Most common themes for greatest contribution to MI were ineffective leadership, barriers to patient care, corporatization of medicine, non-physician administration, performing futile procedures, turf battles, and reduced resources. Most common themes for ways to reduce MI were more autonomy, less bureaucracy, more administrative support, physician-directed leadership, adequate staffing, changes to the medical system, physician unionization, transparency with insurance companies, more time off, and leaving medicine/retirement. CONCLUSION: MI is prevalent among interventional radiologists, and it negatively correlates with QoL. Future work should investigate causative factors and mitigating solutions.
Subject(s)
Quality of Life , Stress Disorders, Post-Traumatic , Humans , Male , Female , Radiologists , Surveys and Questionnaires , Radiology, InterventionalABSTRACT
RATIONALE AND OBJECTIVES: To evaluate wellness among interventional radiologists using a multidimensional survey. MATERIALS AND METHODS: An anonymous 53-item survey, including 36 Perceived Wellness Survey (PWS) prompts, was created in Qualtrics (an online survey tool) to assess wellness among interventional radiology attendings and residents. The survey was open from June to September, 2022, 2 years into the COVID-19 Pandemic. The survey was distributed via Society of Interventional Radiology Forums, social media (Twitter, LinkedIn, and Facebook), and personal correspondence. PWS scores were categorized into Wellness Composite and subscores (physical, emotional, intellectual, psychological, social, and spiritual). RESULTS: 367 surveys were completed. 300 (81.7%) respondents were male and 67 (18.3%) were female. Respondents included attending physicians (297; 81.0%) and residents (70; 19.0%). Practice settings included academic (174; 47.4%), private (114; 31.0%), private-academic hybrid (62; 16.9%), and others (17; 4.7%). Mean Wellness Composite at academic centers (14.74 ± 3.16; range: 5.42-23.50) was significantly lower than at private (15.22 ± 3.37; range: 6.13-23.51) and hybrid (16.14 ± 2.47; range: 10.20-23.50) practices (p = 0.01). Respondents < 40 years old had significantly lower emotional wellness subscores compared to those ≥ 40 years old (4.34 ± 0.86 vs. 4.60 ± 0.87; p = 0.006). There were no significant differences between geographic regions in the United States, however, International respondents had significantly lower social and intellectual wellness (INT) subscores. Physical wellness subscore (4.00 ± 0.9) was significantly lower than the other subscores (4.59 ± 0.81) (p < .001). Overall mean Wellness Composite was 15.11 ± 3.13 (range: 5.42-23.51). CONCLUSION: Overall self-reported wellness was lower among interventional radiologists practicing at academic centers. Interventional Radiologists < 40 years old and residents had lower emotional wellness, while international respondents had lower social and INT. Overall wellness scores were lower than prior PWS studies.
Subject(s)
Burnout, Professional , COVID-19 , Humans , Male , Female , United States , Adult , Pandemics , Surveys and Questionnaires , Radiologists , Radiology, Interventional , Burnout, Professional/epidemiologyABSTRACT
Recent advancements in computer vision and neural networks have facilitated the medical imaging survival analysis for various medical applications. However, challenges arise when patients have multiple images from multiple lesions, as current deep learning methods provide multiple survival predictions for each patient, complicating result interpretation. To address this issue, we developed a deep learning survival model that can provide accurate predictions at the patient level. We propose a deep attention long short-term memory embedded aggregation network (DALAN) for histopathology images, designed to simultaneously perform feature extraction and aggregation of lesion images. This design enables the model to efficiently learn imaging features from lesions and aggregate lesion-level information to the patient level. DALAN comprises a weight-shared CNN, attention layers, and LSTM layers. The attention layer calculates the significance of each lesion image, while the LSTM layer combines the weighted information to produce an all-encompassing representation of the patient's lesion data. Our proposed method performed better on both simulated and real data than other competing methods in terms of prediction accuracy. We evaluated DALAN against several naive aggregation methods on simulated and real datasets. Our results showed that DALAN outperformed the competing methods in terms of c-index on the MNIST and Cancer dataset simulations. On the real TCGA dataset, DALAN also achieved a higher c-index of 0.803±0.006 compared to the naive methods and the competing models. Our DALAN effectively aggregates multiple histopathology images, demonstrating a comprehensive survival model using attention and LSTM mechanisms.