-
MedRxiv : the Preprint Server For... Jun 2024Fine-mapping and gene-prioritisation techniques applied to the latest Genome-Wide Association Study (GWAS) results have prioritised hundreds of genes as causally...
Fine-mapping and gene-prioritisation techniques applied to the latest Genome-Wide Association Study (GWAS) results have prioritised hundreds of genes as causally associated with disease. Here we leverage these recently compiled lists of high-confidence causal genes to interrogate where in the body disease genes operate. Specifically, we combine GWAS summary statistics, gene prioritisation results and gene expression RNA-seq data from 46 tissues and 204 cell types in relation to 16 major diseases (including 8 cancers). In tissues and cell types with well-established relevance to the disease, the prioritised genes typically have higher absolute and relative (i.e. tissue/cell specific) expression compared to non-prioritised 'control' genes. Examples include brain tissues in psychiatric disorders ( -value < 1×10 ), microglia cells in Alzheimer's Disease ( -value = 9.8×10 ) and colon mucosa in colorectal cancer ( -value < 1×10 ). We also observe significantly higher expression for disease genes in multiple tissues and cell types with no established links to the corresponding disease. While some of these results may be explained by cell types that span multiple tissues, such as macrophages in brain, blood, lung and spleen in relation to Alzheimer's disease ( -values < 1×10 ), the cause for others is unclear and motivates further investigation that may provide novel insights into disease etiology. For example, mammary tissue in Type 2 Diabetes ( -value < 1×10 ); reproductive tissues such as breast, uterus, vagina, and prostate in Coronary Artery Disease ( -value < 1×10 ); and motor neurons in psychiatric disorders ( -value < 3×10 ). In the GTEx dataset, tissue type is the major predictor of gene expression but the contribution of each predictor (tissue, sample, subject, batch) varies widely among disease-associated genes. Finally, we highlight genes with the highest levels of gene expression in relevant tissues to guide functional follow-up studies. Our results could offer novel insights into the tissues and cells involved in disease initiation, inform drug target and delivery strategies, highlighting potential off-target effects, and exemplify the relative performance of different statistical tests for linking disease genes with tissue and cell type gene expression.
PubMed: 38947033
DOI: 10.1101/2024.06.20.24309121 -
Research Square Jun 2024Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline...
Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair and and tumour suppressors and . Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.
PubMed: 38947031
DOI: 10.21203/rs.3.rs-4531885/v1 -
MedRxiv : the Preprint Server For... Jun 2024Network meta-analysis, also known as mixed treatments comparison meta-analysis or multiple treatments meta-analysis, extends conventional pairwise meta-analysis by...
UNLABELLED
Network meta-analysis, also known as mixed treatments comparison meta-analysis or multiple treatments meta-analysis, extends conventional pairwise meta-analysis by simultaneously synthesizing multiple interventions in a single integrated analysis. Despite the growing popularity of network meta-analysis within comparative effectiveness research, it comes with potential challenges. For example, within-study correlations among treatment comparisons are rarely reported in the published literature. Yet, these correlations are pivotal for valid statistical inference. As demonstrated in earlier studies, ignoring these correlations can inflate mean squared errors of the resulting point estimates and lead to inaccurate standard error estimates. This paper introduces a composite likelihood-based approach that ensures accurate statistical inference without requiring knowledge of the within-study correlations. The proposed method is computationally robust and efficient, with substantially reduced computational time compared to the state-of-the-science methods implemented in R packages. The proposed method was evaluated through extensive simulations and applied to two important applications including a network meta-analysis comparing interventions for primary open-angle glaucoma, and another comparing treatments for chronic prostatitis and chronic pelvic pain syndrome.
HIGHLIGHTS
Network meta-analysis extends conventional pairwise meta-analysis by simultaneously synthesizing multiple interventions in a single integrated analysis.A significant challenge in network meta-analysis is the lack of reported within-study correlations among treatment comparisons in the published studies. We propose a new method for network meta-analysis that ensures vaild statistical inference without the need for knowledge of within-study correlations.The proposed method employs a composite likelihood and a sandwich-type robust variance estimator, offering a computationally efficient and scalable solution, particularly for network meta-analysis with a large number of treatments and studies. The proposed method can be easily applied to any univariate network meta-analysis project without requiring knowledge of within-study correlations among treatment comparisons.
PubMed: 38947001
DOI: 10.1101/2024.06.19.24309163 -
World Journal of Clinical Oncology Jun 2024Vitamin D is a hot topic nowadays, especially its relationship with cancer prevention. Normally, vitamin D is associated with bone health principally, but the new...
Vitamin D is a hot topic nowadays, especially its relationship with cancer prevention. Normally, vitamin D is associated with bone health principally, but the new research has discovered an impact on immune function and cellular signaling, even in same studies talk about a hormone, however, the most important relationship is its implication in cellular processes, inhibiting cancer growth. For now, the recent studies are oriented about a benefit and a cause-effect relationship between prostate cancer and normal levels of vitamin D. This premise opens a lot of questions in this scenario. This editorial highlighted the most important studies in this area.
PubMed: 38946829
DOI: 10.5306/wjco.v15.i6.691 -
Advanced Science (Weinheim,... Jul 2024Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to...
Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.
Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.
PubMed: 38946578
DOI: 10.1002/advs.202401095 -
Expert Review of Medical Devices Jul 2024This study focuses on the quantification of and current guidelines on the hazards related to needle positioning in prostate cancer treatment: (1) access restrictions to... (Review)
Review
INTRODUCTION
This study focuses on the quantification of and current guidelines on the hazards related to needle positioning in prostate cancer treatment: (1) access restrictions to the prostate gland by the pubic arch, so-called Pubic Arch Interference (PAI) and (2) needle positioning errors. Next, we propose solution strategies to mitigate these hazards.
METHODS
The literature search was executed in the Embase, Medline ALL, Web of Science Core Collection*, and Cochrane Central Register of Controlled Trials databases.
RESULTS
The literature search resulted in 50 included articles. PAI was reported in patients with various prostate volumes. The level of reported PAI varied between 0 and 22.3 mm, depending on the patient's position and the measuring method. Low-Dose-Rate Brachytherapy induced the largest reported misplacement errors, especially in the cranio-caudal direction (up to 10 mm) and the largest displacement errors were reported for High-Dose-Rate Brachytherapy in the cranio-caudal direction (up to 47 mm), generally increasing over time.
CONCLUSIONS
Current clinical guidelines related to prostate volume, needle positioning accuracy, and maximum allowable PAI are ambiguous, and compliance in the clinical setting differs between institutions. Solutions, such as steerable needles, assist in mitigating the hazards and potentially allow the physician to proceed with the procedure.This systematic review was performed in accordance with the PRISMA guidelines. The review was registered at Protocols.io (DOI: dx.doi.org/10.17504/protocols.io.6qpvr89eplmk/v1).
PubMed: 38946519
DOI: 10.1080/17434440.2024.2374761 -
Lab on a Chip Jul 2024Early-stage diagnosis of prostatic carcinoma is essential for successful treatment and, thus, significant prognosis improvement. In laboratory practice, the standard...
Early-stage diagnosis of prostatic carcinoma is essential for successful treatment and, thus, significant prognosis improvement. In laboratory practice, the standard non-invasive diagnostic approach is the immunochemical detection of the associated biomarker, prostate-specific antigen (PSA). Ultrasensitive detection of PSA is essential for both diagnostic and recurrence monitoring purposes. To achieve exceptional sensitivity, we have developed a microfluidic device with a flow-through cell for single-molecule analysis using photon-upconversion nanoparticles (UCNPs) as a detection label. For this purpose, magnetic microparticles (MBs) were first optimized for the capture and preconcentration of PSA and then used to implement a bead-based upconversion-linked immunoassay (ULISA) in the microfluidic device. The digital readout based on counting single nanoparticle-labeled PSA molecules on MBs enabled a detection limit of 1.04 pg mL (36 fM) in 50% fetal bovine serum, which is an 11-fold improvement over the respective analog MB-based ULISA. The microfluidic technique conferred several other advantages, such as easy implementation and the potential for achieving high-throughput analysis. Finally, it was proven that the microfluidic setup is suitable for clinical sample analysis, showing a good correlation with a reference electrochemiluminescence assay (recovery rates between 97% and 105%).
PubMed: 38946347
DOI: 10.1039/d4lc00346b -
Cancer Epidemiology, Biomarkers &... Jul 2024Inequalities in healthcare for patients with prostate cancer can result in treatment and mortality disparities. Despite Black men with prostate cancer having higher...
Inequalities in healthcare for patients with prostate cancer can result in treatment and mortality disparities. Despite Black men with prostate cancer having higher incidence and mortality from prostate cancer, the study by Hammarlund and colleagues found that they are less likely to receive appropriate treatment compared with their White counterparts. Given that Black men with prostate cancer have similar or better survival when participating in clinical trials or receiving equal treatment from an equal access to healthcare system, identifying factors contributing to inequitable treatment is essential to improve the overall health and survival of Black men with prostate cancer. See related article by Hammarlund and colleagues, Cancer Epidemiol Biomarkers Prev 2024;33:435-41.
Topics: Humans; Male; Prostatic Neoplasms; Health Services Accessibility; Healthcare Disparities; Black or African American
PubMed: 38946318
DOI: 10.1158/1055-9965.EPI-24-0397 -
Acta Oncologica (Stockholm, Sweden) Jun 2024In evaluating second primary cancers (SPCs) following External Beam Radiotherapy (EBRT), the role of lifestyle factors is frequently not considered due to data...
PURPOSE
In evaluating second primary cancers (SPCs) following External Beam Radiotherapy (EBRT), the role of lifestyle factors is frequently not considered due to data limitations. We investigated the association between smoking, comorbidities, and SPC risks within EBRT-treated patients for localized prostate cancer (PCa).
PATIENTS & METHODS
The study included 1,883 PCa survivors aged 50-79, treated between 2006 and 2013, with intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). Clinical data were combined with SPC and survival data from the Netherlands Cancer Registry with a 12-month latency period. Standardized Incidence Ratios (SIRs) were calculated comparing the EBRT cohort with the general Dutch population. To explore the effect of patient and treatment characteristics on SPCs we conducted a Cox regression analysis. Lastly, we estimated cumulative incidences of developing solid SPC, pelvis SPC, and non-pelvis SPC using a competing risk analysis.
RESULTS
Significantly increased SIRs were observed for all SPC (SIR = 1.21, 95% confidence interval [CI]: 1.08-1.34), pelvis SPC (SIR = 1.46, 95% CI: 1.18-1.78), and non-pelvis SPC (SIR = 1.18, 95% CI [1.04-1.34]). Smoking status was significantly associated with pelvic and non-pelvic SPCs. Charlson comorbidity index (CCI) ≥ 1 (Hazard Ratio [HR] = 1.45, 95% CI: 1.10-1.91), cardiovascular disease (HR = 1.41, 95% CI: 1.05-1.88), and chronic obstructive pulmonary disease (COPD) (HR = 1.91, 95% CI: 1.30-2.79) were significantly associated with non-pelvis SPC. The proportion of active smoking numbers in the cohort was similar to the general population.
INTERPRETATION
We conclude that the presence of comorbidities in the EBRT population might be a relevant factor in observed excess non-pelvis SPC risk, but not for excess pelvis SPC risk.
Topics: Humans; Male; Prostatic Neoplasms; Neoplasms, Second Primary; Aged; Middle Aged; Netherlands; Risk Factors; Incidence; Radiotherapy, Intensity-Modulated; Comorbidity; Smoking; Radiotherapy, Conformal; Neoplasms, Radiation-Induced; Registries
PubMed: 38946286
DOI: 10.2340/1651-226X.2024.24334 -
The Prostate Jun 2024The link between the prostate microbiome and prostate cancer remains unclear. Few studies have analyzed the microbiota of prostate tissue, and these have been limited by...
BACKGROUND
The link between the prostate microbiome and prostate cancer remains unclear. Few studies have analyzed the microbiota of prostate tissue, and these have been limited by potential contamination by transrectal biopsy. Transperineal prostate biopsy offers an alternative and avoids fecal cross-contamination. We aim to characterize the prostate microbiome using transperineal biopsy.
METHODS
Patients with clinical suspicion for prostate cancer who were to undergo transperineal prostate biopsy with magnetic resonance imaging (MRI) fusion guidance were prospectively enrolled from 2022 to 2023. Patients were excluded if they had Prostate Imaging Reporting and Data System lesions with scores ≤ 3, a history of prostate biopsy within 1 year, a history of prostate cancer, or antibiotic use within 30 days of biopsy. Tissue was collected from the MRI target lesions and nonneoplastic transitional zone. Bacteria were identified using 16S ribosomal RNA gene sequencing.
RESULTS
Across the 42 patients, 76% were found to have prostate cancer. Beta diversity indices differed significantly between the perineum, voided urine, and prostate tissue. There were no beta diversity differences between cancerous or benign tissue, or between pre- and postbiopsy urines. There appear to be unique genera more abundant in cancerous versus benign tissue. There were no differences in alpha diversity indices relative to clinical findings including cancer status, grade, and risk group.
CONCLUSIONS
We demonstrate a rigorous method to better characterize the prostate microbiome using transperineal biopsy and to limit contamination. These findings provide a framework for future large-scale studies of the microbiome of prostate cancer.
PubMed: 38946139
DOI: 10.1002/pros.24763