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1.
Nature ; 619(7971): 844-850, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37380778

ABSTRACT

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.


Subject(s)
Brain Neoplasms , Carcinogenesis , Glioma , Neurons , Tumor Microenvironment , Humans , Brain/pathology , Brain Neoplasms/pathology , Brain Neoplasms/physiopathology , Carcinogenesis/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic/pathology , Glioblastoma/pathology , Glioblastoma/physiopathology , Glioma/pathology , Glioma/physiopathology , Neurons/pathology , Cell Proliferation , Synapses , Disease Progression , Animals , Mice , Axons , Corpus Callosum/pathology , Neural Pathways
2.
FASEB J ; 38(4): e23484, 2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38407380

ABSTRACT

The transcription factor RUNX2 is a key regulator of chondrocyte phenotype during development, making it an ideal target for prevention of undesirable chondrocyte maturation in cartilage tissue-engineering strategies. Here, we engineered an autoregulatory gene circuit (cisCXp-shRunx2) that negatively controls RUNX2 activity in chondrogenic cells via RNA interference initiated by a tunable synthetic Col10a1-like promoter (cisCXp). The cisCXp-shRunx2 gene circuit is designed based on the observation that induced RUNX2 silencing after early chondrogenesis enhances the accumulation of cartilaginous matrix in ATDC5 cells. We show that the cisCXp-shRunx2 initiates RNAi of RUNX2 in maturing chondrocytes in response to the increasing intracellular RUNX2 activity without interfering with early chondrogenesis. The induced loss of RUNX2 activity in turn negatively regulates the gene circuit itself. Moreover, the efficacy of RUNX2 suppression from cisCXp-shRunx2 can be controlled by modifying the sensitivity of cisCXp promoter. Finally, we show the efficacy of inhibiting RUNX2 in preventing matrix loss in human mesenchymal stem cell-derived (hMSC-derived) cartilage under conditions that induce chondrocyte hypertrophic differentiation, including inflammation. Overall, our results demonstrated that the negative modulation of RUNX2 activity with our autoregulatory gene circuit enhanced matrix synthesis and resisted ECM degradation by reprogrammed MSC-derived chondrocytes in response to the microenvironment of the degenerative joint.


Subject(s)
Chondrogenesis , Gene Regulatory Networks , Humans , Chondrogenesis/genetics , Core Binding Factor Alpha 1 Subunit/genetics , Chondrocytes , Cell Differentiation/genetics
3.
Int J Mol Sci ; 25(2)2024 Jan 13.
Article in English | MEDLINE | ID: mdl-38256095

ABSTRACT

Astrocytes are the most abundant glial cell type in the central nervous system, and they play a crucial role in normal brain function. While gliogenesis and glial differentiation occur during perinatal cerebellar development, the processes that occur during early postnatal development remain obscure. In this study, we conducted transcriptomic profiling of postnatal cerebellar astrocytes at postnatal days 1, 7, 14, and 28 (P1, P7, P14, and P28), identifying temporal-specific gene signatures at each specific time point. Comparing these profiles with region-specific astrocyte differentially expressed genes (DEGs) published for the cortex, hippocampus, and olfactory bulb revealed cerebellar-specific gene signature across these developmental timepoints. Moreover, we conducted a comparative analysis of cerebellar astrocyte gene signatures with gene lists from pediatric brain tumors of cerebellar origin, including ependymoma and medulloblastoma. Notably, genes downregulated at P14, such as Kif11 and HMGB2, exhibited significant enrichment across all pediatric brain tumor groups, suggesting the importance of astrocytic gene repression during cerebellar development to these tumor subtypes. Collectively, our studies describe gene expression patterns during cerebellar astrocyte development, with potential implications for pediatric tumors originating in the cerebellum.


Subject(s)
Brain Neoplasms , Cerebellar Neoplasms , Child , Female , Pregnancy , Humans , Astrocytes , Gene Expression Profiling , Brain , Transcriptome , Cerebellum
4.
NMR Biomed ; : e4992, 2023 Jul 04.
Article in English | MEDLINE | ID: mdl-37401341

ABSTRACT

The global disparity of magnetic resonance imaging (MRI) is a major challenge, with many low- and middle-income countries (LMICs) experiencing limited access to MRI. The reasons for limited access are technological, economic and social. With the advancement of MRI technology, we explore why these challenges still prevail, highlighting the importance of MRI as the epidemiology of disease changes in LMICs. In this paper, we establish a framework to develop MRI with these challenges in mind and discuss the different aspects of MRI development, including maximising image quality using cost-effective components, integrating local technology and infrastructure and implementing sustainable practices. We also highlight the current solutions-including teleradiology, artificial intelligence and doctor and patient education strategies-and how these might be further improved to achieve greater access to MRI.

5.
Mod Pathol ; 34(6): 1185-1193, 2021 06.
Article in English | MEDLINE | ID: mdl-33462368

ABSTRACT

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p < 0.001], respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , BRCA2 Protein/genetics , Genomic Instability/genetics , Prostatic Neoplasms/genetics , Adult , Aged , Allelic Imbalance/genetics , Biomarkers, Tumor/genetics , Germ-Line Mutation/genetics , Humans , Loss of Heterozygosity/genetics , Male , Middle Aged
6.
Prostate ; 80(12): 1012-1023, 2020 09.
Article in English | MEDLINE | ID: mdl-32649013

ABSTRACT

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Subject(s)
Neuroendocrine Cells/pathology , Neuroendocrine Tumors/pathology , Prostatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Carcinoma, Small Cell/genetics , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , Cell Differentiation/physiology , Cohort Studies , Humans , Immunohistochemistry , Male , Middle Aged , Neuroendocrine Cells/metabolism , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Androgen/biosynthesis , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Retinoblastoma Binding Proteins/genetics , Retinoblastoma Binding Proteins/metabolism , Retrospective Studies , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
7.
Am J Physiol Heart Circ Physiol ; 315(4): H910-H924, 2018 10 01.
Article in English | MEDLINE | ID: mdl-29775406

ABSTRACT

Extracellular matrix (ECM) proteins have been shown to play important roles regulating multiple biological processes in an array of organ systems, including the cardiovascular system. Using a novel bioinformatics text-mining tool, we studied six categories of cardiovascular disease (CVD), namely, ischemic heart disease, cardiomyopathies, cerebrovascular accident, congenital heart disease, arrhythmias, and valve disease, anticipating novel ECM protein-disease and protein-protein relationships hidden within vast quantities of textual data. We conducted a phrase-mining analysis, delineating the relationships of 709 ECM proteins with the 6 groups of CVDs reported in 1,099,254 abstracts. The technology pipeline known as Context-Aware Semantic Online Analytical Processing was applied to semantically rank the association of proteins to each CVD and all six CVDs, performing analyses to quantify each protein-disease relationship. We performed principal component analysis and hierarchical clustering of the data, where each protein was visualized as a six-dimensional vector. We found that ECM proteins display variable degrees of association with the six CVDs; certain CVDs share groups of associated proteins, whereas others have divergent protein associations. We identified 82 ECM proteins sharing associations with all 6 CVDs. Our bioinformatics analysis ascribed distinct ECM pathways (via Reactome) from this subset of proteins, namely, insulin-like growth factor regulation and interleukin-4 and interleukin-13 signaling, suggesting their contribution to the pathogenesis of all six CVDs. Finally, we performed hierarchical clustering analysis and identified protein clusters predominantly associated with a targeted CVD; analyses of these proteins revealed unexpected insights underlying the key ECM-related molecular pathogenesis of each CVD, including virus assembly and release in arrhythmias. NEW & NOTEWORTHY The present study is the first application of a text-mining algorithm to characterize the relationships of 709 extracellular matrix-related proteins with 6 categories of cardiovascular disease described in 1,099,254 abstracts. Our analysis informed unexpected extracellular matrix functions, pathways, and molecular relationships implicated in the six cardiovascular diseases.


Subject(s)
Cardiovascular Diseases/metabolism , Data Mining/methods , Extracellular Matrix Proteins/metabolism , Extracellular Matrix/metabolism , Machine Learning , Pattern Recognition, Automated/methods , Big Data , Biomarkers/metabolism , Databases, Factual , Humans , Principal Component Analysis , Protein Interaction Maps
8.
J Vitreoretin Dis ; 8(3): 307-311, 2024.
Article in English | MEDLINE | ID: mdl-38770077

ABSTRACT

Purpose: To describe the clinical course of 3 patients with Stickler syndrome found on fluorescein angiography (FA) to have nonperfusion of the peripheral retina. Methods: Three patients with confirmed Stickler syndrome were examined under anesthesia. Genetic testing and FA were performed. Results: Each patient had characteristic ocular findings of Stickler syndrome, including high myopia with vitreoretinal degeneration. FA was performed on each patient and showed 360 degrees of nonperfusion of the retinal periphery in all eyes, with mild leakage in Case 3. Conclusions: The current series presents evidence of peripheral retinal nonperfusion in 3 consecutive patients with Stickler syndrome. Based on these findings, the authors recommend adopting FA as a standard imaging modality and using laser photocoagulation to treat the areas of retinal nonperfusion for all patients with Stickler syndrome.

9.
Cureus ; 16(1): e52824, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38406078

ABSTRACT

Background Limited information exists regarding the research productivity of matched ophthalmology applicants given that ophthalmology residencies do not participate in the National Residency Match Program. Objectives This study determines the research productivity characteristics of matched ophthalmology applicants and variables associated with matching to higher-tier ophthalmology residency programs. Methods Medical school, matched residency program, and applicant-specific PubMed-indexed research productivity (including consideration for first-author publications, relevance to ophthalmology, and acceptance before application submission date) for 2020-2021 matched ophthalmology applicants were collected from publicly available websites. Statistical analysis was conducted using chi-squared tests and t-tests to compare research productivity between groups (gender, medical school tier, and ophthalmology residency program Doximity rank). Multivariate regression was used to analyze research factors associated with matching at the top 20 Doximity-ranked ophthalmology residency programs. Results Three hundred ninety-three matched ophthalmology applicants for the 2020-2021 academic year were analyzed with an average of 2.4 ± 3.1 (median: 1 {0-3}) publications, 1.0 ± 2.1 (median: 0 {0-1}) ophthalmic publications, 0.8 ± 1.4 (median: 0 {0-1}) first-author publications, and 0.5 ± 1.1 (median: 0 {0-1}) ophthalmic first-author publications. The applicants who matched at the top 20 Doximity-ranked ophthalmology residency programs were more likely to matriculate from the top 40 medical schools (63% versus 22%, p < 0.001), have more first-author publications at the time of application submission (1.1 ± 1.6 versus 0.7 ± 1.3, p = 0.044), and have more projects resulting in publications after submission (2.0 ± 2.5 versus 1.4 ± 2.3, p = 0.048). In multivariate regression, attendance at a top 40 medical school (adjusted odds ratio {aOR} = 6.07, 95% confidence interval {CI}: 3.56-10.5, p < 0.001) was a significant predictor of matching at a top 20 Doximity ophthalmology residency program, and no variables associated with research productivity were significant predictors. Conclusions There has been a consistent increase in research productivity among matched ophthalmology applicants. However, in multivariate analysis, the medical school tier was the only significant variable for matching at top-tier programs. More nuanced studies regarding the effect of research productivity on ophthalmology applicants are needed.

10.
BMJ Open ; 13(8): e074009, 2023 08 22.
Article in English | MEDLINE | ID: mdl-37607794

ABSTRACT

INTRODUCTION: Multiparametric MRI (mpMRI) has transformed the prostate cancer diagnostic pathway, allowing for improved risk stratification and more targeted subsequent management. However, concerns exist over the interobserver variability of images and the applicability of this model long term, especially considering the current shortage of radiologists and the growing ageing population. Artificial intelligence (AI) is being integrated into clinical practice to support diagnostic and therapeutic imaging analysis to overcome these concerns. The following report details a protocol for a systematic review and meta-analysis investigating the accuracy of AI in predicting primary prostate cancer on mpMRI. METHODS AND ANALYSIS: A systematic search will be performed using PubMed, MEDLINE, Embase and Cochrane databases. All relevant articles published between January 2016 and February 2023 will be eligible for inclusion. To be included, articles must use AI to study MRI prostate images to detect prostate cancer. All included articles will be in full-text, reporting original data and written in English. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. The QUADAS-2 score will assess the quality and risk of bias across selected studies. ETHICS AND DISSEMINATION: Ethical approval will not be required for this systematic review. Findings will be disseminated through peer-reviewed publications and presentations at both national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42021293745.


Subject(s)
Multiparametric Magnetic Resonance Imaging , Prostatic Neoplasms , Male , Humans , Artificial Intelligence , Systematic Reviews as Topic , Meta-Analysis as Topic , Prostatic Neoplasms/diagnostic imaging
11.
JCI Insight ; 8(3)2023 02 08.
Article in English | MEDLINE | ID: mdl-36752203

ABSTRACT

The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically treated cohort of 145 self-identified Black (BL) and 145 self-identified White (WH) patients with genetic ancestry estimation. A generalized linear model adjusted with age, preoperative prostate-specific antigen (PSA), and Gleason Grade Group and filtered for germline copy number variations (gCNV) identified 143 loci where copy number varied significantly by percent African ancestry, clustering on chromosomes 6p, 10q, 11p, 12p, and 17p. Multivariable Cox regression models adjusted for age, preoperative PSA levels, and Gleason Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, Treg density in BL and WH patients was significantly correlated with percent genome altered, and these findings were validated in the TCGA cohort. Taken together, our findings identify specific sCNA linked to genetic ancestry and outcome in primary prostate cancer and demonstrate that Treg infiltration varies by global sCNA burden in primary disease.


Subject(s)
Prostatic Neoplasms , Humans , Male , DNA Copy Number Variations , Neoplasm Grading , Proportional Hazards Models , Prostate-Specific Antigen/genetics , Prostatic Neoplasms/ethnology , Prostatic Neoplasms/genetics , Racial Groups
12.
bioRxiv ; 2023 Mar 16.
Article in English | MEDLINE | ID: mdl-36993539

ABSTRACT

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

13.
Nat Commun ; 13(1): 6808, 2022 11 10.
Article in English | MEDLINE | ID: mdl-36357396

ABSTRACT

The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.


Subject(s)
Amino Acids , Lysosomes , Amino Acids/metabolism , Feedback , Lysosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism
14.
Eur Heart J Cardiovasc Imaging ; 23(6): e246-e260, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35157038

ABSTRACT

Cardiovascular disease continues to be a major burden facing healthcare systems worldwide. In the developed world, cardiovascular magnetic resonance (CMR) is a well-established non-invasive imaging modality in the diagnosis of cardiovascular disease. However, there is significant global inequality in availability and access to CMR due to its high cost, technical demands as well as existing disparities in healthcare and technical infrastructures across high-income and low-income countries. Recent renewed interest in low-field CMR has been spurred by the clinical need to provide sustainable imaging technology capable of yielding diagnosticquality images whilst also being tailored to the local populations and healthcare ecosystems. This review aims to evaluate the technical, practical and cost considerations of low field CMR whilst also exploring the key barriers to implementing sustainable MRI in both the developing and developed world.


Subject(s)
Cardiovascular Diseases , Cardiovascular Diseases/diagnostic imaging , Delivery of Health Care , Ecosystem , Humans , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy
15.
Nat Commun ; 12(1): 935, 2021 02 10.
Article in English | MEDLINE | ID: mdl-33568675

ABSTRACT

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.


Subject(s)
Plasma Cells/immunology , Prostatic Neoplasms/immunology , Black or African American/genetics , Aged , Cell Movement , Cohort Studies , Humans , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Killer Cells, Natural/immunology , Male , Middle Aged , Prostate/immunology , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Prostatic Neoplasms/physiopathology
16.
Clin Cancer Res ; 26(18): 4869-4881, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32694154

ABSTRACT

PURPOSE: The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized. EXPERIMENTAL DESIGN: We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes. RESULTS: ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables. CONCLUSIONS: ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/deficiency , Prostate/pathology , Prostatic Neoplasms/genetics , Adult , Aged , Ataxia Telangiectasia Mutated Proteins/genetics , Cell Line, Tumor , Datasets as Topic , Gene Expression Profiling , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Immunohistochemistry/methods , Male , Middle Aged , Neoplasm Grading , Progression-Free Survival , Prostate/surgery , Prostatectomy , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery , Retrospective Studies , Sequence Analysis, DNA , Tissue Array Analysis
17.
Clin Cancer Res ; 26(11): 2595-2602, 2020 06 01.
Article in English | MEDLINE | ID: mdl-31969336

ABSTRACT

PURPOSE: The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. EXPERIMENTAL DESIGN: Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis. RESULTS: At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non-organ confined. The median PGA was 3.7% (IQR = 0.9%-9.4%) and differed by pathologic grade (P < 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55-70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2-40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3-35.2; P = 0.026). CONCLUSIONS: Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.


Subject(s)
Biomarkers, Tumor/genetics , Black or African American/statistics & numerical data , Cyclin-Dependent Kinase Inhibitor p27/genetics , Gene Deletion , Neoplasm Recurrence, Local/pathology , Prostatectomy/methods , Prostatic Neoplasms/pathology , Follow-Up Studies , Genomics , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/surgery , Neoplasm Recurrence, Local/therapy , Prognosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/surgery , Prostatic Neoplasms/therapy , Retrospective Studies , Survival Rate , White People/statistics & numerical data
18.
J Clin Invest ; 129(12): 5584-5599, 2019 12 02.
Article in English | MEDLINE | ID: mdl-31527310

ABSTRACT

The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function fully restored MiT/TFE expression and activity. These data suggest that signaling feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling, respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.


Subject(s)
Lysosomes/physiology , Mechanistic Target of Rapamycin Complex 1/physiology , Microphthalmia-Associated Transcription Factor/physiology , Proto-Oncogene Proteins c-akt/physiology , Active Transport, Cell Nucleus , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cells, Cultured , ErbB Receptors/physiology , Mice , Promoter Regions, Genetic , Receptor, ErbB-2/physiology , Tuberous Sclerosis Complex 1 Protein/physiology
19.
Sci Data ; 5: 180258, 2018 11 20.
Article in English | MEDLINE | ID: mdl-30457569

ABSTRACT

Clinical case reports (CCRs) provide an important means of sharing clinical experiences about atypical disease phenotypes and new therapies. However, published case reports contain largely unstructured and heterogeneous clinical data, posing a challenge to mining relevant information. Current indexing approaches generally concern document-level features and have not been specifically designed for CCRs. To address this disparity, we developed a standardized metadata template and identified text corresponding to medical concepts within 3,100 curated CCRs spanning 15 disease groups and more than 750 reports of rare diseases. We also prepared a subset of metadata on reports on selected mitochondrial diseases and assigned ICD-10 diagnostic codes to each. The resulting resource, Metadata Acquired from Clinical Case Reports (MACCRs), contains text associated with high-level clinical concepts, including demographics, disease presentation, treatments, and outcomes for each report. Our template and MACCR set render CCRs more findable, accessible, interoperable, and reusable (FAIR) while serving as valuable resources for key user groups, including researchers, physician investigators, clinicians, data scientists, and those shaping government policies for clinical trials.


Subject(s)
Clinical Studies as Topic , Data Curation , Metadata , Computational Biology , Data Analysis , Data Curation/methods , Data Curation/standards , Humans , Metadata/standards
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