Multi-omics and single cell characterization of cancer immunosenescence landscape.

Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ ).

A multi-ancestry cerebral cortex transcriptome-wide association study identifies genes associated with smoking behaviors.

Transcriptome-wide association studies (TWAS) have provided valuable insight in identifying genes that may impact cigarette smoking. Most of previous studies, however, mainly focused on European ancestry. Limited TWAS studies have been conducted across multiple ancestries to explore genes that may impact smoking behaviors. In this study, we used cis-eQTL data of cerebral cortex from multiple ancestries in MetaBrain, including European, East Asian, and African samples, as reference panels to perform multi-ancestry TWAS analyses on ancestry-matched GWASs of four smoking behaviors including smoking initiation, smoking cessation, age of smoking initiation, and number of cigarettes per day in GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Multiple-ancestry fine-mapping approach was conducted to identify credible gene sets associated with these four traits. Enrichment and module network analyses were further performed to explore the potential roles of these identified gene sets. A total of 719 unique genes were identified to be associated with at least one of the four smoking traits across ancestries. Among those, 249 genes were further prioritized as putative causal genes in multiple ancestry-based fine-mapping approach. Several well-known smoking-related genes, including PSMA4, IREB2, and CHRNA3, showed high confidence across ancestries. Some novel genes, e.g., TSPAN3 and ANK2, were also identified in the credible sets. The enrichment analysis identified a series of critical pathways related to smoking such as synaptic transmission and glutamate receptor activity. Leveraging the power of the latest multi-ancestry GWAS and eQTL data sources, this study revealed hundreds of genes and relevant biological processes related to smoking behaviors. These findings provide new insights for future functional studies on smoking behaviors.

Night eating in timing, frequency, and food quality and risks of all-cause, cancer, and diabetes mortality: findings from national health and nutrition examination survey.

OBJECTIVE: To investigate the association of timing, frequency, and food quality of night eating with all-cause, cancer, and diabetes mortality. METHODS: This study included 41,744 participants from the US National Health and Nutrition Examination Survey (2002-2018). Night eating information was collected by 24-h dietary recall and the exposures were timing, frequency, and food quality of night eating. Food quality was assessed by latent class analysis. The outcomes were all-cause, cancer, and diabetes mortality, which were identified by the National Death Index and the International Classification of Diseases 10th Revision. Adjusted hazard ratios [aHR] with 95% confidence intervals [CI] were computed by Cox regression. RESULTS: During a median follow-up of 8.7 years, 6066 deaths were documented, including 1381 from cancer and 206 from diabetes. Compared with no night eating (eating before 22:00), the later timing of night eating was associated with higher risk of all-cause and diabetes mortality (each P-trend <0.05) rather than cancer mortality, with the highest risk of eating being 00:00-1:00 (aHR 1.38, 95% CI 1.02-1.88) and being 23:00-00:00 (aHR 2.31, 95% CI 1.21-4.40), respectively. However, the increased risks were not observed for 22:00-23:00. Likewise, one time or over frequency of night eating was associated with higher all-cause and diabetes mortality (each P < 0.05). That risks were further observed in high-dietary-energy-density group of night eating (all-cause mortality: aHR 1.21 [95% CI 1.06-1.38]; diabetes mortality: aHR 1.97 [95% CI 1.13-3.45]), but not in low-dietary-energy-density group. Finally, correlation analysis found positive associations of night eating with glycohemoglobin, fasting glucose, and OGTT. CONCLUSIONS: Night eating was associated with increased all-cause, cancer and diabetes mortality; however, reduction of excess mortality risk was observed when eating before 23:00 or low-dietary-energy-density foods.

Active DHEA uptake in the prostate gland correlates with aggressive prostate cancer.

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3ßHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3ßHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3ßHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3ßHSD1 inhibitors as early intervention.

A blood-based, metabolite and demographic characteristic markers panel for the diagnosis of Alzheimer's disease.

Aims: This work was designed to provide early diagnosis strategies for Alzheimer's disease (AD) based on the identification of blood metabolic biomarkers. Patients & methods: A total of 90 subjects aged 60 years or older were included in this study; 45 patients were assigned to the case group and control group, respectively. A total of 31 target metabolites were quantitatively analyzed by parallel reaction monitoring between the two groups. Results & conclusion: Three metabolites were screened out, including cystine, serine and alanine/sarcosine. Logistic regression and random forest analysis were used to establish AD diagnosis models, and the model combining metabolic biomarkers and demographic variables had higher detection efficiency (area under the curve = 0.869). A combination diagnostic model to provide a scientific reference for early screening and diagnosis of AD was constructed.

Meal timing of dietary total antioxidant capacity and its association with all-cause, CVD and cancer mortality: the US national health and nutrition examination survey, 1999-2018.

BACKGROUND: The association of the meal timing of dietary total antioxidant capacity (DAC) with mortality is unclear. We aimed to investigate the association between the meal timing of DAC and all-cause, cardiovascular disease (CVD), and cancer mortality in general adult populations. METHODS: A total of 56,066 adults who participated in the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were recruited for this study. Dietary intake (quantity and timing) was evaluated by nonconsecutive 24-h dietary recalls. The main exposure variables were the DAC across three meals (total, breakfast, lunch, and dinner; without coffee) and the difference between dinner and breakfast DAC (Δ = dinner-breakfast; without coffee). The outcomes were all-cause, CVD, and cancer mortality. The adjusted hazard ratios [aHRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. RESULTS: Among the 56,066 participants, there were 8566 deaths from any cause, including 2196 from CVD and 1984 from cancer causes. Compared to participants in the lowest quintiles of the total DAC, those in the highest quintiles had 34% and 27% decreased risks of all-cause and CVD mortality, respectively (all-cause mortality: aHRs 0.66 [95% CI 0.57-0.76]; CVD mortality: aHRs 0.73 [95% CI 0.57-0.94]). More importantly, participants in the highest quintiles of the dinner DAC, but not those in that of breakfast or lunch, had a 24% decrease in all-cause mortality (aHRs 0.76 [95% CI 0.67-0.87]) compared with those in the lowest quintiles. Inverse associations were further confirmed for Δ DAC (aHRs 0.84 [95% CI 0.74-0.96]). Above associations did not change when including DAC from snacks or tea. Mediation analysis showed that the total associations of total, dinner or Δ DACs with reduced all-cause mortality were 24%, 13% and 6%, respectively, mediated by serum CRP. Additionally, all-cause mortality was decreased by 7% in models replacing 10% breakfast DAC (aHRs 0.93 [95% CI 0.9-0.97]) with an equivalent proportion of dinner DAC. For cancer mortality, no statistical significance was detected in the adjusted models. CONCLUSIONS: The findings emphasize the putative beneficial relationship of a diet rich in antioxidants and meal timing on serum CRP and all-cause mortality.

Association of dietary total antioxidant capacity and its distribution across three meals with all-cause, cancer, and non-cancer mortality among cancer survivors: the US National Health and Nutrition Examination Survey, 1999-2018.

The effect of the antioxidant capacity of diet and its distribution across three meals on mortality risk among cancer patients remains unexplored. We aimed to prospectively investigate the association of dietary total antioxidant capacity (DAC) and its distribution across three meals with all-cause, cancer, and noncancer mortality among cancer survivors. We included 5,009 patients with cancer from the National Health and Nutrition Examination Survey conducted between 1999 and 2018. The adjusted hazard ratio (aHR) was estimated using the survey-weighted Cox proportional hazards model. During a median follow-up of 7.9 years, 1811 deaths, including 575 cancer-related deaths, were recorded. Among cancer survivors, compared with participants in the lowest quartile of total DAC from three meals, those in the highest quartile had a 24% decreased risk of noncancer mortality (aHR = 0.76, 95% confidence interval [CI]: 0.60-0.92), but not of all-cause and cancer mortality (each p trend >0.1). However, this association became insignificant for total DAC after excluding dinner DAC. In addition, higher dinner DAC rather than breakfast or lunch DAC was associated with a 21% lower risk of all-cause mortality (aHR = 0.79, 95% CI: 0.65-0.98) and 28% lower risk of noncancer mortality (aHR = 0.72, 95% CI: 0.57-0.90). Similar associations were found for ΔDAC (dinner DAC - breakfast DAC) with noncancer mortality (aHR = 0.56, 95% CI: 0.38-0.83), but DAC was not associated with cancer mortality (p trend >0.3). Among cancer survivors, total DAC from three meals was associated with reduced noncancer mortality, with the primary effect attributable to increased DAC intake from dinner. Our findings emphasize that DAC consumption from dinner should be advocated to reduce mortality risk in cancer survivors.

Celastrol recruits UBE3A to recognize and degrade the DNA binding domain of steroid receptors.

Strategies to degrade steroid receptors and their alternative splicing isoforms are critical for disease management. Here we report that celastrol recruited the ubiquitin ligase UBE3A and degraded androgen receptor (AR), AR-v7, and glucocorticoid receptor (GR) to suppress prostate cancer development. UBE3A was not an optimal endogenous AR ubiquitin ligase in mice and patients, but celastrol promoted the interaction between UBE3A and AR. Multiple domains of AR, including the DNA binding domain (DBD), were implicated into the UBE3A-AR interaction. Sharing a conserved DBD, GR, AR-v7, and other steroid receptors were recognized and degraded by UBE3A after celastrol treatment. Thus, celastrol suppressed prostate cancer cell proliferation more potently than enzalutamide. Modifying the carboxyl group of celastrol improved its anti-tumor activity. Together, our findings revealed that celastrol might be a potential molecular glue to enhance the interaction between UBE3A and steroid receptors to degrade multiple steroid receptors and splicing isoforms in prostate cancer, paving a way for further drug optimization and disease treatment.

Inhibiting 3ßHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer.

Prostate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens. In this study, mass-spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients. High doses of progesterone activate canonical and non-canonical androgen receptor (AR) target genes. Physiological levels of progesterone facilitate cell proliferation via GATA2. Inhibitors of 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) has been discovered and shown to suppress the generation of progesterone, eliminating its transient and accumulating oncogenic effects. An increase in progesterone is associated with poor clinical outcomes in patients and may be used as a predictive biomarker. Overall, we demonstrate that progesterone acts as an oncogenic hormone in prostate cancer, and strategies to eliminate its oncogenic effects may benefit prostate cancer patients.

Management of prostate cancer by targeting 3ßHSD1 after enzalutamide and abiraterone treatment.

Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3ßHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3ßHSD1, overcomes drug resistance. 3ßHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3ßHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3ßHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3ßHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3ßHSD1 inhibitor even after abiraterone and enzalutamide resistance.

Aging-related markers in rat urine revealed by dynamic metabolic profiling using machine learning.

The process of aging and metabolism is intimately intertwined; thus, developing biomarkers related to metabolism is critical for delaying aging. However, few studies have identified reliable markers that reflect aging trajectories based on machine learning. We generated metabolomic profiles from rat urine using ultra-performance liquid chromatography/mass spectrometry. This was dynamically collected at four stages of the rat's age (20, 50, 75, and 100 weeks) for both the training and test groups. Partial least squares-discriminant analysis score plots revealed a perfect separation trajectory in one direction with increasing age in the training and test groups. We further screened 25 aging-related biomarkers through the combination of four algorithms (VIP, time-series, LASSO, and SVM-RFE) in the training group. They were validated in the test group with an area under the curve of 1. Finally, six metabolites, known or novel aging-related markers, were identified, including epinephrine, glutarylcarnitine, L-kynurenine, taurine, 3-hydroxydodecanedioic acid, and N-acetylcitrulline. We also found that, except for N-acetylcitrulline (p < 0.05), the identified aging-related metabolites did not differ between tumor-free and tumor-bearing rats at 100 weeks (p > 0.05). Our findings reveal the metabolic trajectories of aging and provide novel biomarkers as potential therapeutic antiaging targets.

Tracing steroidogenesis in prostate biopsy samples to unveil prostate tissue androgen metabolism characteristics and potential clinical application.

Androgens are essential for prostate cancer development. However, steroidogenesis has mainly been investigated in a limited number of prostate cancer cell lines, leading to varied conclusions and elusive clinical significance. Here, we established an ex vivo research platform with fresh biopsy samples transiently cultured with tritium- labelled androgens to trace steroidogenesis in prostate tissues and investigate its potential clinical application. DHEA was confirmed as the major precursor for androgen synthesis in the prostate. Significant amounts of oxidized DHEA and 5α-androstanedione were generated from DHEA in prostate biopsy samples. Prostatic steroidogenesis was independent of other clinical factors. Furthermore, prostatic steroidogenesis was suppressed after androgen deprivation therapy but increased upon treatment resistance, indicating that prostatic steroidogenesis was affected by clinical treatments. Overall, we provide an accessible research platform to characterize steroidogenesis in prostate tissue and indicate the correlation between prostatic steroidogenesis and disease progression.

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment.

The tumor immune microenvironment is heterogeneous, and its impact on treatment responses is not well understood. It is still a challenge to analyze the interaction between malignant cells and the tumor microenvironment to apply suitable immunotherapy in lung adenocarcinoma. We performed the nonnegative matrix factorization method to 513 messenger RNA expression profiles of lung adenocarcinomas (LUADs) from The Cancer Genome Atlas (TCGA) to obtain an immune-related expression pattern. Subsequently, we characterized the immune-related gene signatures and clinical and survival characteristics. We used 576 patients from Gene Expression Omnibus to confirm our findings. Of the patients in the training cohort, 51% had a high immune enrichment score, high expression of immune cell signaling, cytolytic activity, and interferon (IFN)-related signatures (all P < .05). We denoted these as the Immune Class. We further subdivided the Immune Class into two subclasses based on the tumor microenvironment. These were denoted the Active Immune Class and Exhausted Immune Class. The former showed significant IFN, T-cells, M1 macrophage signatures, and better prognosis (all P < .05), while the latter presented an exhausted immune response with activated stromal enrichment, M2 macrophage signatures, and immunosuppressive factors such as WNT/transforming growth factor-ß (all P < .05). Furthermore, we predicted the response of our immunophenotypes to immunological checkpoint inhibitors (P < .05). Our findings provide a novel insight into the immune-related state of LUAD and can identify the patients who will be receptive to suitable immunotherapeutic treatments.

Sites of distant metastases and overall survival in ovarian cancer: A study of 1481 patients.

OBJECTIVE: To assess the association between patterns of distant metastases and overall survival in metastatic ovarian cancer and identify prognostic factors for site-specific distant metastases. METHODS: Data was obtained from the SEER database between 2010 and 2014. Univariate and multivariate Cox proportional hazard models were used to identify variables associated with overall survival. Survival times between different groups were compared using Kaplan-Meier analysis and log-rank tests. RESULTS: We analyzed 1481 patients. The most common distant metastatic site was liver, followed by distant lymph nodes, lung, bone, and brain. The site of distant metastases was an independent prognostic factor for overall survival. Using liver metastases as reference, overall survival was lower for lung metastases (p = 0.0297) and higher for distant lymph node metastases (p = 0.0006). Using distant lymph nodes as reference, distant metastases to the liver (p = 0.0006), lung (p < 0.0001), brain (p = 0.0455), and bone (p = 0.0138) were all associated with worse overall survival. The number of metastatic sites did not affect overall survival. We also found that surgery and chemotherapy affected overall survival for patients with distant lymph node metastases only; age, histological subtype, surgery, and chemotherapy affected overall survival for patients with liver metastases only, while histological subtype and chemotherapy affected overall survival for patients with lung metastases only. CONCLUSIONS: The site of distant metastases affected overall survival in metastatic ovarian cancer. Patients with specific distant metastatic sites should receive special treatment and management. The identified prognostic factors can help clinician evaluate the prognosis for ovarian cancer patients with distant metastases.