Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition.

BACKGROUND: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk. METHODS: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics. RESULTS: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade. CONCLUSIONS: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Radical prostatectomy using the Hinotori robot-assisted surgical system: Docking-free design may contribute to reduction in postoperative pain.

BACKGROUND: The docking-free design of the Japanese Hinotori surgical robotic system allows the robotic arm to avoid trocar grasping, thereby minimising excessive abdominal wall stress. The aim of this study was to evaluate the safety and efficacy of robotic-assisted radical prostatectomy (RARP) using the Hinotori system and to explore the potential contribution of its docking-free design to postoperative pain reduction. METHODS: This study reviewed the clinical records of 94 patients who underwent RARP: 48 patients in the Hinotori group and 46 in the da Vinci Xi group. RESULTS: Hinotori group had significantly longer operative and console times (p = 0.030 and p = 0.029, respectively). Perioperative complications and oncologic outcomes did not differ between the two groups. On postoperative day 4, the rate of decline from the maximum visual analogue scale score was marginally significant in the Hinotori group (p = 0.062). CONCLUSIONS: The docking-free design may contribute to reducing postoperative pain.

Mendelian randomization evidence based on European ancestry for the causal effects of leukocyte telomere length on prostate cancer.

BACKGROUND: Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC). METHODS: Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls). RESULTS: Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs. CONCLUSION: This study provides potential intervention measures for preventing LTL-induced PCs.

Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment.

Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake-associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834.

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

Multimodal, PSMA-Targeted, PAMAM Dendrimer-Drug Conjugates for Treatment of Prostate Cancer: Preclinical Evaluation.

Introduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response. Methods: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts. Results: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity. Conclusion: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Managing prostate cancer after proctocolectomy and ileal pouch-anal anastomosis: feasibility and outcomes of single-port transvesical robot-assisted radical prostatectomy.

INTRODUCTION: Patients with proctocolectomy and ileal pouch-anal anastomosis (PC-IPAA) face unique challenges in managing prostate cancer due to their hostile abdomens and heightened small bowel mucosa radiosensitivity. In such cases, external beam radiation therapy (EBRT) is contraindicated, and while brachytherapy provides a safer option, its oncologic effectiveness is limited. The Single-Port Transvesical Robot-Assisted Radical Prostatectomy (SP TV-RARP) offers promise by avoiding the peritoneal cavity. Our study aims to evaluate its feasibility and outcomes in patients with PC-IPAA. METHODS: A retrospective evaluation was done on patients with PC-IPAA who had undergone SP TV-RARP from June 2020 to June 2023 at a high-volume center. Outcomes and clinicopathologic variables were analyzed. RESULTS: Eighteen patients underwent SP TV-RARP without experiencing any complications. The median hospital stay was 5.7 h, with 89% of cases discharged without opioids. Foley catheters were removed in an average of 5.5 days. Immediate urinary continence was seen in 39% of the patients, rising to 76 and 86% at 6- and 12-month follow-ups. Half of the cohort had non-organ confined disease on final pathology. Two patients with ISUP GG3 and GG4 exhibited detectable PSA post-surgery and required systemic therapy; both had SVI, multifocal ECE, and large cribriform pattern. Positive surgical margins were found in 44% of cases, mostly Gleason pattern 3, unifocal, and limited. After 11.1 months of follow-up, no pouch failure or additional BCR cases were found. CONCLUSION: Patients with PC-IPAA often exhibit aggressive prostate cancer features and may derive the greatest benefit from surgical interventions, particularly given that radiation therapy is contraindicated. SP TV-RARP is a safe option for this group, reducing the risk of bowel complications and promoting faster recovery.

Evaluation of the clinical application value of cytokine expression profiles in the differential diagnosis of prostate cancer.

BACKGROUND: The significance of tumor-secreted cytokines in tumor development has gained substantial attention. Nevertheless, the precise role of tumor-related inflammatory cytokines in prostate cancer (PCa) remains ambiguous. OBJECTIVES: To gain deeper insights into the inflammatory response in the process of PCa. METHODS: A total of 233 cases were collected, including 80 cases of prostate hyperplasia as disease control, 65 cases of postoperative prostate cancer and 36 cases of prostate cancer as PCa group. Additionally, 52 patients undergoing physical examinations during the same period were collected as the healthy control. The levels of 12 inflammatory cytokines in peripheral blood samples were analyzed using flow cytometric bead array technology. The levels of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) in peripheral blood samples were analyzed using electrochemiluminescence technology. RESULTS: Our findings revealed significant increases in serum IL-8 levels in PCa group compared to the healthy control group. Additionally, IL-6, IL-10, IFN-γ and IL-12p70 levels were markedly elevated in the PCa group compared to the disease control group (all p < 0.05). Conversely, the level of IL-4, TNF-α, IL-1ß, IL-17A and IFN-α were lower in the PCa group compared to those in control group. Following surgery, the concentration of IL-6 decreased; whereas, the concentrations of IL-4, TNF-α, IL-17A, IL-1ß, IL-12p70, and IFN-α increased, demonstrating significant differences (p < 0.05). The differential upregulation of IL-6 or downregulation of IL-17A in peripheral blood exhibited diagnostic efficacy in PCa patients. Moreover, we observed a significant increase in IL-17A levels, accompanied by decreased of IL-2, IL-4, IL-10, TNF-a, IFN-γ, IL-1ß, and IL-12P70 in patients with distant metastasis. CONCLUSION: The peripheral blood cytokines are closely associated with the occurrence and development of prostate cancer, especially the serum levels of IL-6 and IL-17A may be useful as potential predictors of PCa diagnosis.

Effects of exercise during active surveillance for prostate cancer: A systematic review and meta-analysis.

PURPOSE: The efficacy of exercise in men with prostate cancer (PCa) on active surveillance (AS) remains unclear. In this meta-analysis, we aimed to examine the effects of exercise in PCa patients on AS. METHODS: A literature search was conducted in PubMed, EMBASE, and the Cochrane Library using search terms, including exercise, PCa, AS, and randomized controlled trials (RCTs). The means and standard deviations for peak oxygen consumption (VO2peak), prostate-specific antigen (PSA) levels, and quality of life (QoL) were extracted for the intervention and control groups. A random-effects model was used to summarize the effects of exercise. RESULTS: Of the 158 identified studies, six RCTs with 332 patients were included. The interventions included lifestyle modifications (aerobic exercise + diet) in three studies and different exercise modalities in three studies. The intervention duration was 2-12 months; three interventions were supervised and three were self-directed. The pooled weighted mean difference between exercise and usual care for VO2peak was 1.42 mL/kg/min (95% confidence interval [CI]: 0.30 to 2.54, P ≤ 0.001). A non-significant effect was observed for QoL (pooled standardized mean difference [SMD]: 0.24, 95% CI: - 0.03 to 0.51, P = 0.08) which became statistically significant and stronger after excluding one outlier study (P < 0.001). Exercise also had a positive effect on PSA levels (pooled SMD: - 0.43, 95% CI: - 0.87 to 0.01, P = 0.05). CONCLUSION: Exercise improves cardiorespiratory fitness and may improve QoL and PSA levels in men with PCa on AS. Further studies with larger sample sizes are warranted to obtain more reliable results.

Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting.

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure: Nonmetastatic PCa. Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Access to Prostate-Specific Antigen Testing and Mortality Among Men With Prostate Cancer.

Importance: Prostate-specific antigen (PSA) screening for prostate cancer is controversial but may be associated with benefit for certain high-risk groups. Objectives: To evaluate associations of county-level PSA screening prevalence with prostate cancer outcomes, as well as variation by sociodemographic and clinical factors. Design, Setting, and Participants: This cohort study used data from cancer registries based in 8 US states on Hispanic, non-Hispanic Black, and non-Hispanic White men aged 40 to 99 years who received a diagnosis of prostate cancer between January 1, 2000, and December 31, 2015. Participants were followed up until death or censored after 10 years or December 31, 2018, whichever end point came first. Data were analyzed between September 2023 and January 2024. Exposure: County-level PSA screening prevalence was estimated using the Behavior Risk Factor Surveillance System survey data from 2004, 2006, 2008, 2010, and 2012 and weighted by population characteristics. Main Outcomes and Measures: Multivariable logistic, Cox proportional hazards regression, and competing risks models were fit to estimate adjusted odds ratios (AOR) and adjusted hazard ratios (AHR) for associations of county-level PSA screening prevalence at diagnosis with advanced stage (regional or distant), as well as all-cause and prostate cancer-specific survival. Results: Of 814 987 men with prostate cancer, the mean (SD) age was 67.3 (9.8) years, 7.8% were Hispanic, 12.2% were non-Hispanic Black, and 80.0% were non-Hispanic White; 17.0% had advanced disease. There were 247 570 deaths over 5 716 703 person-years of follow-up. Men in the highest compared with lowest quintile of county-level PSA screening prevalence at diagnosis had lower odds of advanced vs localized stage (AOR, 0.86; 95% CI, 0.85-0.88), lower all-cause mortality (AHR, 0.86; 95% CI, 0.85-0.87), and lower prostate cancer-specific mortality (AHR, 0.83; 95% CI, 0.81-0.85). Inverse associations between PSA screening prevalence and advanced cancer were strongest among men of Hispanic ethnicity vs other ethnicities (AOR, 0.82; 95% CI, 0.78-0.87), older vs younger men (aged ≥70 years: AOR, 0.77; 95% CI, 0.75-0.79), and those in the Northeast vs other US Census regions (AOR, 0.81; 95% CI, 0.79-0.84). Inverse associations with all-cause mortality were strongest among men of Hispanic ethnicity vs other ethnicities (AHR, 0.82; 95% CI, 0.78-0.85), younger vs older men (AHR, 0.81; 95% CI, 0.77-0.85), those with advanced vs localized disease (AHR, 0.80; 95% CI, 0.78-0.82), and those in the West vs other US Census regions (AHR, 0.89; 95% CI, 0.87-0.90). Conclusions and Relevance: This population-based cohort study of men with prostate cancer suggests that higher county-level prevalence of PSA screening was associated with lower odds of advanced disease, all-cause mortality, and prostate cancer-specific mortality. Associations varied by age, race and ethnicity, and US Census region.

The Role of the Advanced Practice Provider in Bone Health Management for the Prostate Cancer Population.

Androgen deprivation therapy (ADT) is standard, first-line therapy for many aspects of prostate cancer treatment. Although ADT can be an effective treatment to inhibit androgen-fueled cell growth in prostate cancer, suppressi.

Efficacy of educational stepwise robot-assisted radical prostatectomy procedure for urology residents.

OBJECTIVE: To evaluate the effectiveness of an educational stepwise robot-assisted radical prostatectomy (RARP) procedure for urology residents. METHODS: We performed a detailed evaluation of 42 RARP procedures performed by a single urology resident from July 2019 to February 2022. The RARP procedures were divided into the following nine steps: (1) bladder dissection, (2) endopelvic fascia dissection, (3) bladder neck dissection, (4) seminal vesicle dissection, (5) Denonvilliers' fascia dissection, (6) dorsal vascular complex ligation, (7) dissection of the prostatic apex, (8) posterior anastomosis, and (9) urethro-vesical anastomosis. The procedures were further subcategorized as anatomical understanding, spatial recognition, and technical skills for evaluation of resident training. The surgeries were divided into first and second halves, and patient characteristics and operative outcomes were statistically analyzed. The operative time of each of the nine steps and the reasons for proctor intervention were compared. RESULTS: Among 42 patients, there were no significant differences in operative outcomes between the two groups. The median operative time was 169 min (164 vs. 179 min, p = .12), and the median console time was 128 min (127 vs. 130 min, p = .74). Although there were no significant differences in the time of the nine steps, the resident significantly overcame (7) dissection of the prostatic apex and (8) posterior anastomosis based on the evaluation of the proctored reasons for intervention. CONCLUSIONS: Urology residents can safely perform and efficiently learn RARP with this stepwise educational system. This educational stepwise RARP procedure can effectively help residents to develop their skills.

Real-world treatment patterns and clinical outcomes in patients with prostate cancer.: A single institution experience in Saudi Arabia.

OBJECTIVES: To describe the current real-world treatment landscape, sequence of therapies, and outcomes in patients with prostate cancer (PC). METHODS: A retrospective cohort study for PC patients diagnosed at King Abdullah Medical City Cancer Center in Makkah, Saudi Arabia, between January 2011 and December 2021. Data extracted from electronic medical records. RESULTS: A total of 282 patients with PC, with a mean age of 70 years and body mass index of 27. Among them, 274 (99%) had no family history of cancer, while 164 (58%) had hypertension and 125 (44%) had diabetes mellitus. Adenocarcinoma was the most common histology, found in 275 (97%) patients, with 99 (35%) having a Gleason score of 9. Notably, 184 (65%) patients presented with metastatic disease, and 147 (52%) with bone metastasis. While 198 (70%) patients underwent surgery, 184 (65%) did not receive radiotherapy. The most common first-line metastatic therapy was abiraterone in 23 (8%) patients, followed by enzalutamide in 7 (2.5%). During the study period, 167 (59%) patients survived, with an average treatment duration of 2.5 years. CONCLUSION: This study provides insights into real-world treatment patterns and clinical outcomes in patients with PC. The findings of this study highlight the importance of adhering to treatment standards and making informed clinical decisions.

shRNA-mediated gene silencing of HDAC11 empowers CAR-T cells against prostate cancer.

Epigenetic mechanisms are involved in several cellular functions, and their role in the immune system is of prime importance. Histone deacetylases (HDACs) are an important set of enzymes that regulate and catalyze the deacetylation process. HDACs have been proven beneficial targets for improving the efficacy of immunotherapies. HDAC11 is an enzyme involved in the negative regulation of T cell functions. Here, we investigated the potential of HDAC11 downregulation using RNA interference in CAR-T cells to improve immunotherapeutic outcomes against prostate cancer. We designed and tested four distinct short hairpin RNA (shRNA) sequences targeting HDAC11 to identify the most effective one for subsequent analyses. HDAC11-deficient CAR-T cells (shD-NKG2D-CAR-T) displayed better cytotoxicity than wild-type CAR-T cells against prostate cancer cell lines. This effect was attributed to enhanced activation, degranulation, and cytokine release ability of shD-NKG2D-CAR-T when co-cultured with prostate cancer cell lines. Our findings reveal that HDAC11 interference significantly enhances CAR-T cell proliferation, diminishes exhaustion markers PD-1 and TIM3, and promotes the formation of T central memory TCM populations. Further exploration into the underlying molecular mechanisms reveals increased expression of transcription factor Eomes, providing insight into the regulation of CAR-T cell differentiation. Finally, the shD-NKG2D-CAR-T cells provided efficient tumor control leading to improved survival of tumor-bearing mice in vivo as compared to their wild-type counterparts. The current study highlights the potential of HDAC11 downregulation in improving CAR-T cell therapy. The study will pave the way for further investigations focused on understanding and exploiting epigenetic mechanisms for immunotherapeutic outcomes.

Multiplex, high-throughput method to study cancer and immune cell mechanotransduction.

Studying cellular mechanoresponses during cancer metastasis is limited by sample variation or complex protocols that current techniques require. Metastasis is governed by mechanotransduction, whereby cells translate external stimuli, such as circulatory fluid shear stress (FSS), into biochemical cues. We present high-throughput, semi-automated methods to expose cells to FSS using the VIAFLO96 multichannel pipetting device custom-fitted with 22 G needles, increasing the maximum FSS 94-fold from the unmodified tips. Specifically, we develop protocols to semi-automatically stain live samples and to fix, permeabilize, and intracellularly process cells for flow cytometry analysis. Our first model system confirmed that the pro-apoptotic effects of TRAIL therapeutics in prostate cancer cells can be enhanced via FSS-induced Piezo1 activation. Our second system implements this multiplex methodology to show that FSS exposure (290 dyn cm-2) increases activation of murine bone marrow-derived dendritic cells. These methodologies greatly improve the mechanobiology workflow, offering a high-throughput, multiplex approach.

Optimizing clinico-genomic disease prediction across ancestries: a machine learning strategy with Pareto improvement.

BACKGROUND: Accurate prediction of an individual's predisposition to diseases is vital for preventive medicine and early intervention. Various statistical and machine learning models have been developed for disease prediction using clinico-genomic data. However, the accuracy of clinico-genomic prediction of diseases may vary significantly across ancestry groups due to their unequal representation in clinical genomic datasets. METHODS: We introduced a deep transfer learning approach to improve the performance of clinico-genomic prediction models for data-disadvantaged ancestry groups. We conducted machine learning experiments on multi-ancestral genomic datasets of lung cancer, prostate cancer, and Alzheimer's disease, as well as on synthetic datasets with built-in data inequality and distribution shifts across ancestry groups. RESULTS: Deep transfer learning significantly improved disease prediction accuracy for data-disadvantaged populations in our multi-ancestral machine learning experiments. In contrast, transfer learning based on linear frameworks did not achieve comparable improvements for these data-disadvantaged populations. CONCLUSIONS: This study shows that deep transfer learning can enhance fairness in multi-ancestral machine learning by improving prediction accuracy for data-disadvantaged populations without compromising prediction accuracy for other populations, thus providing a Pareto improvement towards equitable clinico-genomic prediction of diseases.

Predictive significance of intraprostatic volumetric parameters derived from early and standard time 68Ga-PSMA PET/CT images in newly diagnosed prostate cancer patients.

OBJECTIVE: To investigate the relationship between intraprostatic 68Ga-prostate-specific membrane antigen (PSMA) uptake values and volumetric parameters derived from early pelvic and standard-time whole-body 68Ga-PSMA PET/computed tomography (CT) images in untreated prostate cancer (PCa) patients, and to assess the predictive significance of these data in relation to disease prognosis, comparing them with the Gleason score, clinical risk classification and the presence of metastatic disease detected in 68Ga-PSMA PET/CT imaging. METHODS: Eighty-one newly diagnosed PCa patients underwent early phase pelvic imaging at the 5th minute and standard time whole-body imaging at the 60th minute. Various threshold values were used in intraprostatic delineations to compute maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), intraprostatic PSMA tumor volume and intraprostatic total lesion PSMA uptake. Correlations between early and standard time measurements, as well as changes in SUV parameters over time, were examined. The association of these values with Gleason score, clinical risk status (National Comprehensive Cancer Network), and metastatic disease was explored. RESULTS: SUVmax measurements from both early and standard time images distinguished all three groups (clinical risk scores, Gleason score and metastatic group), with standard imaging demonstrating statistical superiority in receiver operating characteristic analyses. Strong correlations were observed between early and standard-time PET parameters. Changes in intraprostatic SUVmax and SUVmean values over time did not exhibit predictive value. CONCLUSION: Although intraprostatic PSMA PET parameters generally aligned at both early and standard times, parameters obtained from standard time images showed more robust correlations with clinical risk scores, Gleason score and metastasis status in newly diagnosed, untreated PCa patients.