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Cancer Letters Jun 2024In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery,...
In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.
PubMed: 38925361
DOI: 10.1016/j.canlet.2024.217063 -
European Journal of Radiology Jun 2024To develop and validate an artificial intelligence (AI) application in a clinical setting to decide whether dynamic contrast-enhanced (DCE) sequences are necessary in...
PURPOSE
To develop and validate an artificial intelligence (AI) application in a clinical setting to decide whether dynamic contrast-enhanced (DCE) sequences are necessary in multiparametric prostate MRI.
METHODS
This study was approved by the institutional review board and requirement for study-specific informed consent was waived. A mobile app was developed to integrate AI-based image quality analysis into clinical workflow. An expert radiologist provided reference decisions. Diagnostic performance parameters (sensitivity and specificity) were calculated and inter-reader agreement was evaluated.
RESULTS
Fully automated evaluation was possible in 87% of cases, with the application reaching a sensitivity of 80% and a specificity of 100% in selecting patients for multiparametric MRI. In 2% of patients, the application falsely decided on omitting DCE. With a technician reaching a sensitivity of 29% and specificity of 98%, and resident radiologists reaching sensitivity of 29% and specificity of 93%, the use of the application allowed a significant increase in sensitivity.
CONCLUSION
The presented AI application accurately decides on a patient-specific MRI protocol based on image quality analysis, potentially allowing omission of DCE in the diagnostic workup of patients with suspected prostate cancer. This could streamline workflow and optimize time utilization of healthcare professionals.
PubMed: 38925042
DOI: 10.1016/j.ejrad.2024.111581 -
EBioMedicine Jun 2024The 5-year survival rate of oesophageal squamous cell carcinoma (ESCC) is approximately 20%. The prognosis and drug response exhibit substantial heterogeneity in ESCC,...
BACKGROUND
The 5-year survival rate of oesophageal squamous cell carcinoma (ESCC) is approximately 20%. The prognosis and drug response exhibit substantial heterogeneity in ESCC, impeding progress in survival outcomes. Our goal is to identify a signature for tumour subtype classification, enabling precise clinical treatments.
METHODS
Utilising pre-treatment multi-omics data from an ESCC dataset (n = 310), an enhancer methylation-eRNA-target gene regulation network was constructed and validated by in vitro experiments. Four machine learning methods collectively identified core target genes, establishing an Enhancer Demethylation-Regulated Gene Score (EDRGS) model for classification. The molecular function of EDRGS subtyping was explored in scRNA-seq (n = 60) and bulk-seq (n = 310), and the EDRGS's potential to predict treatment response was assessed in datasets of various cancer types.
FINDINGS
EDRGS stratified ESCCs into EDRGS-high/low subtypes, with EDRGS-high signifying a less favourable prognosis in ESCC and nine additional cancer types. EDRGS-high exhibited an immune-hot but immune-suppressive phenotype with elevated immune checkpoint expression, increased T cell infiltration, and IFNγ signalling in ESCC, suggesting a better response to immunotherapy. Notably, EDRGS outperformed PD-L1 in predicting anti-PD-1/L1 therapy effectiveness in ESCC (n = 42), kidney renal clear cell carcinoma (KIRC, n = 181), and bladder urothelial carcinoma (BLCA, n = 348) cohorts. EDRGS-low showed a cell cycle-activated phenotype with higher CDK4 and/or CDK6 expression, demonstrating a superior response to the CDK4/6 inhibitor palbociclib, validated in ESCC (n = 26), melanoma (n = 18), prostate cancer (n = 15) cells, and PDX models derived from patients with pancreatic cancer (n = 30).
INTERPRETATION
Identification of EDRGS subtypes enlightens ESCC categorisation, offering clinical insights for patient management in immunotherapy (anti-PD-1/L1) and CDK4/6 inhibitor therapy across cancer types.
FUNDING
This study was supported by funding from the National Key R&D Program of China (2021YFC2501000, 2020YFA0803300), the National Natural Science Foundation of China (82030089, 82188102), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2022-I2M-2-001, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091).
PubMed: 38924839
DOI: 10.1016/j.ebiom.2024.105177 -
Journal of Medical Internet Research Jun 2024Sexual minority men with HIV are at increased risk of cardiovascular disease (CVD) and have been underrepresented in behavioral research and in clinical trials.
Perceptions on HIV-related Comorbidities and Usability of a Virtual Environment as CVD Prevention Education in Sexual Minority Men with HIV: Formative Phases of a Pilot RCT.
BACKGROUND
Sexual minority men with HIV are at increased risk of cardiovascular disease (CVD) and have been underrepresented in behavioral research and in clinical trials.
OBJECTIVE
To explore perceptions about HIV-related comorbidities and assess the interest and usability of a virtual environment as CVD prevention education in Black and Latinx sexual minority men with HIV.
METHODS
This is a 3-phase pilot randomized control behavioral trial. We report on formative phases 1 and 2 that informed virtual environment content and features using qualitative interviews, usability testing, and beta testing with 25 individuals. In Phase 1, 15 participants completed interviews exploring HIV-related illnesses of concern that would be used to tailor the virtual environment. In Phase 2, usability and beta testing were conducted with 10 participants to assess interest, features, and content.
RESULTS
In Phase 1, we found CVD risk factors included high blood pressure, heart attack, stroke, and diabetes. Cancer (prostate, colon, and others) was a common concern and so were the development of mental health conditions. In Phase 2, all participants completed the 12-item usability checklist with favorable feedback within 30 to 60 minutes. Beta-testing interviews suggested: 1) Mixed perceptions about health and HIV, 2) High risk for comorbid conditions, 3) Virtual environment features were promising, and 4) need for diverse avatar representations.
CONCLUSIONS
We identified several comorbid conditions of concern and findings carry significant implications for mitigating barriers to preventative health screenings given the shared risk factors between HIV and related comorbidities. Highly rated aspects of the virtual environment were anonymity, meeting others who identify as gay or bisexual with HIV, validating LGBTQ+ images and content, and accessibility to CVD prevention education. Critical end-user feedback from beta-testing suggested more options for avatar customization in skin, hair, body representation. Our next phase will test the virtual environment as a new approach to advancing cardiovascular health equity in ethnic and racial sexual minority men with HIV.
CLINICALTRIAL
clinicaltrials.gov (NCT04061915).
INTERNATIONAL REGISTERED REPORT
RR2-10.2196/38348.
PubMed: 38924481
DOI: 10.2196/57351 -
Immunity, Inflammation and Disease Jun 2024Systemic immune-inflammation index (SII) provides convincing evaluation of systemic immune and inflammatory condition in human body. Its correlation with prostate cancer...
BACKGROUND
Systemic immune-inflammation index (SII) provides convincing evaluation of systemic immune and inflammatory condition in human body. Its correlation with prostate cancer (PCa) risk remains uncharted. The principal objective of this investigation was to elucidate the association between SII and the risk for PCa in middle-aged and elderly males.
MATERIALS AND METHODS
Analysis entailed multivariate linear and logistic regression, generalized additive model, and smoothing curve fitting using resource from 2007 to 2010 National Health and Nutrition Examination Survey (NHANES). To ascertain robustness and consistency of this association across different demographic strata, we conducted rigorous subgroup analyses and interaction tests.
RESULTS
Among 3359 participants, those with elevated SII displayed higher total prostate-specific antigen (tPSA) levels, higher risk for PCa, and lower free/total PSA (f/t PSA) ratio. Specifically, each unit increase of log (SII) was associated with a 0.22 ng/mL increase in tPSA (β: 0.22, 95% confidence intervals [CI] 0.05-0.38), a 2.22% decline in f/t PSA ratio (β: -2.22, 95% CI -3.20 to -1.23), and a 52% increased odds of being at high risk for PCa (odds ratio [OR]: 1.52, 95% CI 1.13-2.04). People in the top quartile of log (SII) exhibited 0.55 ng/mL increased tPSA (β: 0.55, 95% CI 0.19-0.90), 4.39% reduced f/t PSA ratio (β: -4.39, 95% CI -6.50 to -2.27), and 168% increased odds of being at high risk for PCa (OR: 2.68, 95% CI 1.32-5.46) compared to those in the bottom quartile.
CONCLUSION
Systemic immune and inflammatory condition, as represented by SII, is independently and positively associated with tPSA levels and the risk for PCa, as well as independently and negatively associated with f/t PSA ratio among middle-aged and older US males. These findings may enhance the effectiveness of PCa screening in predicting positive biopsy results.
Topics: Humans; Male; Prostatic Neoplasms; Middle Aged; Aged; Inflammation; United States; Prostate-Specific Antigen; Nutrition Surveys; Risk Factors
PubMed: 38923408
DOI: 10.1002/iid3.1327 -
JAMA Network Open Jun 2024One in 3 US adults uses multivitamins (MV), with a primary motivation being disease prevention. In 2022, the US Preventive Services Task Force reviewed data on MV...
IMPORTANCE
One in 3 US adults uses multivitamins (MV), with a primary motivation being disease prevention. In 2022, the US Preventive Services Task Force reviewed data on MV supplementation and mortality from randomized clinical trials and found insufficient evidence for determining benefits or harms owing, in part, to limited follow-up time and external validity.
OBJECTIVE
To estimate the association of MV use with mortality risk, accounting for confounding by healthy lifestyle and reverse causation whereby individuals in poor health initiate MV use.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data from 3 prospective cohort studies in the US, each with baseline MV use (assessed from 1993 to 2001), and follow-up MV use (assessed from 1998 to 2004), extended duration of follow-up up to 27 years, and extensive characterization of potential confounders. Participants were adults, without a history of cancer or other chronic diseases, who participated in National Institutes of Health-AARP Diet and Health Study (327 732 participants); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (42 732 participants); or Agricultural Health Study (19 660 participants). Data were analyzed from June 2022 to April 2024.
EXPOSURE
Self-reported MV use.
MAIN OUTCOMES AND MEASURES
The main outcome was mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.
RESULTS
Among 390 124 participants (median [IQR] age, 61.5 [56.7-66.0] years; 216 202 [55.4%] male), 164 762 deaths occurred during follow-up; 159 692 participants (40.9%) were never smokers, and 157 319 participants (40.3%) were college educated. Among daily MV users, 49.3% and 42.0% were female and college educated, compared with 39.3% and 37.9% among nonusers, respectively. In contrast, 11.0% of daily users, compared with 13.0% of nonusers, were current smokers. MV use was not associated with lower all-cause mortality risk in the first (multivariable-adjusted HR, 1.04; 95% CI, 1.02-1.07) or second (multivariable-adjusted HR, 1.04; 95% CI, 0.99-1.08) halves of follow-up. HRs were similar for major causes of death and time-varying analyses.
CONCLUSIONS AND RELEVANCE
In this cohort study of US adults, MV use was not associated with a mortality benefit. Still, many US adults report using MV to maintain or improve health.
Topics: Humans; Female; Male; Middle Aged; United States; Prospective Studies; Vitamins; Aged; Dietary Supplements; Mortality; Cohort Studies; Adult; Risk Factors
PubMed: 38922615
DOI: 10.1001/jamanetworkopen.2024.18729 -
Nanomaterials (Basel, Switzerland) Jun 2024Solid lipid nanoparticles (SLNs) represent promising nanostructures for drug delivery systems. This study successfully synthesized SLNs containing different proportions...
Solid lipid nanoparticles (SLNs) represent promising nanostructures for drug delivery systems. This study successfully synthesized SLNs containing different proportions of babassu oil (BBS) and copaiba oleoresin (COPA) via the emulsification-ultrasonication method. Before SLN synthesis, the identification and quantification of methyl esters, such as lauric acid and β-caryophyllene, were performed via GC-MS analysis. These methyl esters were used as chemical markers and assisted in encapsulation efficiency experiments. A 2 factorial design with a center point was employed to assess the impact of stearic acid and Tween 80 on particle hydrodynamic diameter (HD) and polydispersity index (PDI). Additionally, the effects of temperature (8 ± 0.5 °C and 25 ± 1.0 °C) and time (0, 7, 15, 30, 40, and 60 days) on HD and PDI values were investigated. Zeta potential (ZP) measurements were utilized to evaluate nanoparticle stability, while transmission electron microscopy provided insights into the morphology and nanometric dimensions of the SLNs. The in vitro cytotoxic activity of the SLNs (10 µg/mL, 30 µg/mL, 40 µg/mL, and 80 µg/mL) was evaluated using the MTT assay with PC-3 and DU-145 prostate cancer cell lines. Results demonstrated that SLNs containing BBS and COPA in a 1:1 ratio exhibited a promising cytotoxic effect against prostate cancer cells, with a percentage of viable cells of 68.5% for PC-3 at a concentration of 30 µg/mL and 48% for DU-145 at a concentration of 80 µg/mL. These findings underscore the potential therapeutic applications of SLNs loaded with BBS and COPA for prostate cancer treatment.
PubMed: 38921890
DOI: 10.3390/nano14121014 -
Marine Drugs Jun 2024Cyclic pentapeptide compounds have garnered much attention as a drug discovery resource. This study focused on the characterization and anti-benign prostatic hyperplasia...
Cyclic pentapeptide compounds have garnered much attention as a drug discovery resource. This study focused on the characterization and anti-benign prostatic hyperplasia (BPH) properties of avellanin A from fungus in marine sediment samples collected in the Beibu Gulf of Guangxi Province in China. The antiproliferative effect and molecular mechanism of avellanin A were explored in testosterone propionate (TP)-induced RWPE-1 cells. The transcriptome results showed that avellanin A significantly blocked the ECM-receptor interaction and suppressed the downstream PI3K-Akt signalling pathway. Molecular docking revealed that avellanin A has a good affinity for the cathepsin L protein, which is involved in the terminal degradation of extracellular matrix components. Subsequently, qRT-PCR analysis revealed that the expression of the genes , , , , , , , and was significantly downregulated after avellanin A intervention. The Western blot results also confirmed that it not only reduced ITGB3 and FAK/p-FAK protein expression but also inhibited PI3K/p-PI3K and Akt/p-Akt protein expression in the PI3K-Akt signalling pathway. Furthermore, avellanin A downregulated Cyclin D1 protein expression and upregulated Bax, p21, and p53 proapoptotic protein expression in TP-induced RWPE-1 cells, leading to cell cycle arrest and inhibition of cell proliferation. The results of this study support the use of avellanin A as a potential new drug for the treatment of BPH.
Topics: Humans; Proto-Oncogene Proteins c-akt; Signal Transduction; Cell Proliferation; Phosphatidylinositol 3-Kinases; Molecular Docking Simulation; Cell Line; Male; Apoptosis
PubMed: 38921586
DOI: 10.3390/md22060275 -
Current Issues in Molecular Biology Jun 2024The aim of the current study is to review potential molecular biomarker substances selected so far as useful for assessing the quality of dog semen. Proteins, lipids,... (Review)
Review
The aim of the current study is to review potential molecular biomarker substances selected so far as useful for assessing the quality of dog semen. Proteins, lipids, carbohydrates, and ions can serve as molecular biomarkers of reproductive functions (BRFs) for evaluating male reproductive health and identifying potential risk factors for infertility or reproductive disorders. Evaluation of BRF levels in semen samples or reproductive tissues may provide insights into the underlying causes of infertility, such as impaired sperm function, abnormal sperm-egg interaction, or dysfunction of the male reproductive tract. Molecular biomarker proteins may be divided into two groups: proteins that are well-studied, such as A-kinase anchoring proteins (AKAPs), albumins (ALBs), alkaline phosphatase (ALPL), clusterin (CLU), canine prostate-specific esterase (CPSE), cysteine-rich secretory protein 2 (CRISP2), lactotransferrin (LTF), metalloproteinases (MMPs), and osteopontin (OPN) and proteins that are not well-studied. Non-protein markers include lipid-based substances (fatty acids, phosphatidylcholine), carbohydrates (glycosaminoglycans), and ions (zinc, calcium). Assessing the levels of BRFs in semen samples may provide valuable information for breeding management and reproductive assessments in dogs. This review systematizes current knowledge that could serve as a starting point for developing practical tests with the use of biomarkers of canine reproductive functions and their predictive value for assisted reproductive technique outcomes and semen preservation.
PubMed: 38921038
DOI: 10.3390/cimb46060367