ABSTRACT
Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. Using a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell lines, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. Selective GPER1 and ASNS inhibitors suppressed cell proliferation with increased caspase-3 activity of MT cells under glutamine depletion condition particularly in the presence of estradiol. In a clinical colon cancer cohort from The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression, along with the interaction between nutrient supply and KRAS mutations shed additional light on the mechanisms underlying sex differences in metabolism and growth in CRC, and have clinical implications in the precision management of KRAS mutant CRC.
ABSTRACT
The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/PD-L1 inhibition therapy, encouraging further investigation into this promising field.
Subject(s)
B7-H1 Antigen , Immune Checkpoint Inhibitors , Neoplasms , Programmed Cell Death 1 Receptor , RNA, Circular , RNA, Small Interfering , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen/immunology , B7-H1 Antigen/genetics , B7-H1 Antigen/antagonists & inhibitors , RNA, Small Interfering/genetics , RNA, Circular/genetics , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/genetics , Immunotherapy/methods , Animals , Piwi-Interacting RNAABSTRACT
BACKGROUND: Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS-/- and HCT 116 ASNS+/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice. RESULTS: ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS-/- xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth. CONCLUSIONS: Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.
Subject(s)
Aspartate-Ammonia Ligase , Animals , Humans , Female , Male , Mice , Aspartate-Ammonia Ligase/genetics , Aspartate-Ammonia Ligase/metabolism , HCT116 Cells , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Receptors, Estrogen/metabolism , Receptors, Estrogen/genetics , Cell Proliferation/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Gene Expression Regulation, Neoplastic/genetics , Xenograft Model Antitumor Assays , Heterografts , Sex Factors , Carbon-Nitrogen Ligases with Glutamine as Amide-N-DonorABSTRACT
BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.
Subject(s)
Endometrial Neoplasms , Hypertension , Humans , Female , Endometrial Neoplasms/epidemiology , Risk Factors , Hypertension/epidemiology , Middle Aged , Case-Control Studies , Aged , Adult , IncidenceABSTRACT
BACKGROUND: Alterations to DNA methylation have been identified in both hepatocellular carcinoma (HCC) tumor and circulating DNA from affected individuals. These markers have potential utility in HCC screening. Adherence to HCC screening is poor and acceptable HCC screening tests are needed. METHODS: A feasibility study was performed on a subset of case patients and control subjects from a prior study of risk factors for HCC. Case patients (n=12) included adults aged 47-85 years with a first diagnosis of HCC between 2011 and 2016 and without viral hepatitis. Control subjects (n=12) were matched on age, sex, and state of residence. Participants provided saliva samples for DNA genotyping. Log fold change in salivary DNA methylation at 1359 CpG sites representing 25 candidate genes previously associated with HCC was compared across case patients and control subjects. RESULTS: The quantity of DNA ranged from 9.65 to 257.79 µg. The purity of DNA isolates was good, with mean OD260/280 ratio of 1.78 (SD: 0.14). Of 25 candidate genes, 16 had at ≥1 CpG site with detectable differences in methylation across HCC case patients and control subjects. Sites differentially methylated in HCC case patients included genes encoding tumor suppressors (PRDM2, RUNX3, p15/16, and RASSF1/5), regulators of cell cycle progression (DAPK1 and TP73), and DNA repair (MGMT and GSTP1). No associations met the significance threshold 3.7 × 10-5 required for multiple comparisons. CONCLUSIONS: Salivary DNA may be a feasible alternative to blood samples in the era of novel DNA-based screening tests for HCC. The ease of saliva-based testing supports further investigation of its potential.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Adult , Humans , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , DNA Methylation/genetics , Cell Cycle Proteins/genetics , DNA/metabolismABSTRACT
OBJECTIVE: Based upon similarities between the urge to move and sensory discomfort of restless legs syndrome (RLS) and properties of melanocortin hormones, including their incitement of movement and hyperalgesia, we assessed plasma and cerebrospinal fluid (CSF) α-melanocyte-stimulating hormone (α-MSH) and ß-endorphin in RLS patients and controls. METHODS: Forty-two untreated moderate-to-severe RLS patients and 44 matched controls underwent venipuncture at 19:00, 20:30, and 22:00; 37 RLS and 36 controls had lumbar puncture at 21:30. CSF and plasma were analyzed for pro-opiomelanocortin (POMC), adrenocorticotropin hormone (ACTH), α-MSH, ß-MSH, and ß-endorphin by immunoassay. RLS severity was assessed by International RLS Study Group Severity Scale. RESULTS: RLS participants were 52.7 ± 12.0 years old, 61.9% were women, 21.4% had painful RLS, and RLS severity was 24.8 ± 9.0. Controls had similar age and sex. Plasma ACTH, α-MSH, and ß-endorphin were similar between groups. Plasma POMC was significantly greater in RLS than controls (17.0 ± 11.5 vs 12.7 ± 6.1fmol/ml, p = 0.048). CSF ACTH was similar between groups. CSF ß-MSH was significantly higher in painful than nonpainful RLS or controls (48.2 ± 24.8 vs 32.1 ± 14.8 vs 32.6 ± 15.2pg/ml, analysis of variance [ANOVA] p = 0.03). CSF α-MSH was higher in RLS than controls (34.2 ± 40.9 vs 20.3 ± 11.0pg/ml, p = 0.062). CSF ß-EDP was lowest in painful RLS, intermediate in nonpainful RLS, and highest in controls (8.0 ± 3.4 vs 10.8 ± 3.1 vs 12.3 ± 5.0pg/ml, ANOVA p = 0.049). The ratio of the sum of CSF α- and ß-MSH to CSF ß-endorphin was highest, intermediate, and lowest in painful RLS, nonpainful RLS, and controls (p = 0.007). INTERPRETATION: CSF ß-MSH is increased and CSF ß-endorphin decreased in RLS patients with painful symptoms. ANN NEUROL 2024;95:688-699.
Subject(s)
Endorphins , Neuropeptides , Restless Legs Syndrome , Humans , Female , Adult , Middle Aged , Male , Pro-Opiomelanocortin/analysis , alpha-MSH/analysis , beta-Endorphin/analysis , Melanocortins , beta-MSH , Adrenocorticotropic HormoneABSTRACT
COVID-19 lockdown can lead to job adaptation disorders, which are heterogeneous among individuals. The purpose of this study was to explore the association between perceived social support and job adaptation disorders among workers in China during the COVID-19 pandemic. The questionnaires of Psychological Questionnaire for Public Health Emergencies, Multidimensional Scale of Perceived Social Support, Work Attitude Scale were used for this cross-section study via an online survey. The study included 626 employees. Hierarchical regression analysis and Bootstrap method were used to investigate the mediation effect of perceived social support between the emergency and job adaptation disorders. The percentages of the 5 dimensions of depression, neurasthenia, fear, compulsion-anxiety, and hypochondria in workers were 59.7%, 56.1%, 92.3%, 42.0%, and 18.7%, respectively. Social support mediated the relationship between depression, neurasthenia, obsessive-compulsive anxiety and job adaptation disorder, accounting for 18.1%, 16.1%, and 17.5% of the total effect (ab/c), respectively. Perceived social support could alleviate COVID-19 pandemic-related depression, neurasthenia, compulsion-anxiety, and job adaptation disorder in Chinese workers. Improving their perception of social support, workers may better adapt themselves to work in the challenging of the public health emergency during COVID-19 pandemic.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , COVID-19/psychology , Cross-Sectional Studies , Pandemics , Communicable Disease Control , Anxiety/epidemiology , Social Support , Depression/epidemiologyABSTRACT
tRFtarget 1.0 (http://trftarget.net/) is a platform consolidating both computationally predicted and experimentally validated binding sites between transfer RNA-derived fragments (tRFs) and target genes (or transcripts) across multiple organisms. Here, we introduce a newly released version of tRFtarget 2.0, in which we integrated 6 additional tRF sources, resulting in a comprehensive collection of 2614 high-quality tRF sequences spanning across 9 species, including 1944 Homo sapiens tRFs and one newly incorporated species Rattus norvegicus. We also expanded target genes by including ribosomal RNAs, long non-coding RNAs, and coding genes >50 kb in length. The predicted binding sites have surged up to approximately 6 billion, a 20.5-fold increase than that in tRFtarget 1.0. The manually curated publications relevant to tRF targets have increased to 400 and the gene-level experimental evidence has risen to 232. tRFtarget 2.0 introduces several new features, including a web-based tool that identifies potential binding sites of tRFs in user's own datasets, integration of standardized tRF IDs, and inclusion of external links to contents within the database. Additionally, we enhanced website framework and user interface. With these improvements, tRFtarget 2.0 is more user-friendly, providing researchers a streamlined and comprehensive platform to accelerate their research progress.
Subject(s)
Databases, Nucleic Acid , RNA, Transfer , Animals , Humans , Rats , RNA, Transfer/metabolismABSTRACT
Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are persistent environmental contaminants that are of increasing public concern worldwide. However, their relationship with colorectal cancer (CRC) is poorly understood. This study aims to comprehensively investigate the effect of PFOS and PFOA on the development and progression of CRC in vitro using a series of biological techniques and metabolic profiling. Herein, the migration of three-dimensional (3D) spheroids of two CRC cell lines, SW48 KRAS wide-type (WT) and SW48 KRAS G12A, were observed after exposure to PFOS and PFOA at 2 µM and 10 µM for 7 days. The time and dose-dependent migration phenotype induced by 10 µM PFOS and PFOA was further confirmed by wound healing and trans-well migration assays. To investigate the mechanism of action, derivatization-mass spectrometry-based metabolic profiles were examined from 3D spheroids of SW48 cell lines exposed to PFOS and PFOA (2 µM and 10 µM). Our findings revealed this exposure altered epithelial-mesenchymal transition related metabolic pathways, including fatty acid ß-oxidation and synthesis of proteins, nucleotides, and lipids. Furthermore, this phenotype was confirmed by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. These findings show novel insight into the relationship between PFOS, PFOA, and CRC.
Subject(s)
Alkanesulfonic Acids , Colorectal Neoplasms , Fluorocarbons , Humans , Proto-Oncogene Proteins p21(ras) , Fluorocarbons/toxicity , Alkanesulfonic Acids/toxicity , Caprylates/toxicityABSTRACT
Host immunity involves various immune cells working in concert to achieve balanced immune response. Host immunity interacts with tumorigenic process impacting disease outcome. Clusters of different immune cells may reveal unique host immunity in relation to breast cancer progression. CIBERSORT algorithm was used to estimate relative abundances of 22 immune cell types in 3 datasets, METABRIC, TCGA, and our study. The cell type data in METABRIC were analyzed for cluster using unsupervised hierarchical clustering (UHC). The UHC results were employed to train machine learning models. Kaplan-Meier and Cox regression survival analyses were performed to assess cell clusters in association with relapse-free and overall survival. Differentially expressed genes by clusters were interrogated with IPA for molecular signatures. UHC analysis identified two distinct immune cell clusters, clusters A (83.2%) and B (16.8%). Memory B cells, plasma cells, CD8 positive T cells, resting memory CD4 T cells, activated NK cells, monocytes, M1 macrophages, and resting mast cells were more abundant in clusters A than B, whereas regulatory T cells and M0 and M2 macrophages were more in clusters B than A. Patients in cluster A had favorable survival. Similar survival associations were also observed in other independent studies. IPA analysis showed that pathogen-induced cytokine storm signaling pathway, phagosome formation, and T cell receptor signaling were related to the cell type clusters. Our finding suggests that different immune cell clusters may indicate distinct immune responses to tumor growth, suggesting their potential for disease management.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Neoplasm Recurrence, Local , Survival Analysis , Cluster Analysis , Machine LearningABSTRACT
Breast cancer (BC) is a lethal malignancy with high morbidity and mortality but lacks effective treatments thus far. Despite the introduction of immune checkpoint inhibitors (ICIs) (including PD-1/PD-L1 inhibitors), durable and optimal clinical benefits still remain elusive for a considerable number of BC patients. To break through such a dilemma, novel ICI-based combination therapy has been explored for enhancing the therapeutic effect. Recent evidence has just pointed out that the HDAC2 inhibitor (HDAC2i), which has been proven to exhibit an anti-cancer effect, can act as a sensitizer for ICIs therapy. Simultaneously, dietary intervention, as a crucial supportive therapy, has been reported to provide ingredients containing HDAC2 inhibitory activity. Thus, the novel integration of dietary intervention with ICIs therapy may offer promising possibilities for improving treatment outcomes. In this study, we first conducted the differential expression and prognostic analyses of HDAC2 and BC patients using the GENT2 and Kaplan-Meier plotter platform. Then, we summarized the potential diet candidates for such an integrated therapeutic strategy. This article not only provides a whole new therapeutic strategy for an HDAC2i-containing diet combined with PD-1/PD-L1 inhibitors for BC treatment, but also aims to ignite enthusiasm for exploring this field.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Receptor , Diet , Combined Modality TherapyABSTRACT
Background: The systematic comparison of cancer survival between China and the USA is rare. Here we aimed to assess the magnitude of survival disparities and disentangle the impact of the stage at diagnosis between a Chinese metropolitan city and the USA on cancer survival. Methods: We included 11,046 newly diagnosed cancer patients in Dalian Cancer Registry, China, 2015, with the follow-up data for vital status until December 2020. We estimated age-standardised 5-year relative survival and quantified the excess hazard ratio (EHR) of death using generalised linear models for all cancers and 20 individual cancers. We compared these estimates with 17 cancer registries' data from the USA, using the Surveillance, Epidemiology, and End Results database. We further estimated the stage-specific survival for five major cancers by region. Findings: Age-standardised 5-year relative survival for all patients in Dalian was lower than that in the USA (49.9% vs 67.9%). By cancer types, twelve cancers with poorer prognosis were observed in Dalian compared to the USA, with the largest gap seen in prostate cancer (Dalian: 55.8% vs USA: 96.0%). However, Dalian had a better survival for lung cancer, cervical cancer, and bladder cancer. Dalian patients had a lower percentage of stage â colorectal cancer (Dalian: 17.9% vs USA: 24.2%) and female breast cancer (Dalian: 40.9% vs USA: 48.9%). However, we observed better stage-specific survival among stage â -â ¡ lung cancer patients in Dalian than in the USA. Interpretation: This study suggests that although the overall prognosis for patients was better in the USA than in Dalian, China, survival deficits existed in both countries. Improvement in cancer early detection and cancer care are needed in both countries. Funding: National Key R&D Program (2021YFC2501900, 2022YFC3600805), Major State Basic Innovation Program of the Chinese Academy of Medical Sciences (2021-I2M-1-010, 2021-I2M-1-046), and Talent Incentive Program of Cancer Hospital of Chinese Academy of Medical Sciences.
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Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.
Subject(s)
Endometrial Neoplasms , Shift Work Schedule , Female , Humans , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/etiology , Risk Factors , Shift Work Schedule/adverse effects , Sleep , Sleep Duration , Work Schedule ToleranceABSTRACT
Hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality but lacks effective treatments thus far. Although the emergence of immune checkpoint inhibitors in recent years has shed light on the treatment of HCC, a considerable number of patients are still unable to achieve durable and ideal clinical benefits. Therefore, refining the combination of immune checkpoint inhibitors (ICIs) to enhance the therapeutic effect has become a global research hotspot. Several histone deacetylase 2 inhibitors have shown advantages in ICIs in many solid cancers, except for HCC. Additionally, the latest evidence has shown that histone deacetylase 2 inhibition can regulate PD-L1 acetylation, thereby blocking the nuclear translocation of PD-L1 and consequently enhancing the efficacy of PD-1/PD-L1 inhibitors and improving anti-cancer immunity. Moreover, our team has recently discovered a novel HDAC2 inhibitor (HDAC2i), valetric acid (VA), that possesses great potential in HCC treatment as a monotherapy. Thus, a new combination strategy, combining HDAC2 inhibitors with ICIs, has emerged with significant development value. This perspective aims to ignite enthusiasm for exploring the application of ideal HDAC2 inhibitors with solid anti-tumor efficacy in combination with immunotherapy for HCC.
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Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years. Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries' data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models. Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40-1.58) and 1.40 (1.38-1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17-1.49) in 1995-1999 and 1.95 (1.53-2.49) in 2015-2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer. Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China.
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BACKGROUND: To explore the association between the self-reported health status, depressive tendency, psychological capital, and self-acceptance of college students in China during the COVID-19 pandemic. METHODS: Using the online survey platform "questionnaire star", a two-phase cross-sectional study was conducted on a total number of 1438 undergraduates with informed consents. The questionnaires of Self-Rated Health Measurement Scale (SRHMS), the Center for Epidemiological Studies-Depression Scale (CES-D), Psychological Capital Questionnaire (PCQ-24), and self-acceptance questionnaire were administered to each participant. RESULTS: Male college students had significantly higher depressive tendency scores than female (17.59 vs. 15.82) (p < 0.01). College students having no siblings had significantly higher psychological capital scores than those having siblings (108.63 vs. 105.60) (p < 0.05). Exercise had significantly positive associations with self-rated health, psychological capital, and self-acceptance scores, while online time per day had significantly negative associations. Multivariate analysis showed that the interaction between depressive tendency, psychological capital, and self-acceptance was statistically significant (ß = 0.004, p = 0.013 for phase 1 and ß = 0.002, p = 0.025 for phase 2) in health status with depressive tendency ranking the top (ß = -0.54 for phase 1 and -0.41 for phase 2, p < 0.001). Mediation analysis showed that psychological capital and self-acceptance modified the association of depressive tendency with health status. CONCLUSION: Physical exercise is beneficial to both physical and psychological health. Depressive tendency is the main risk factor that associates with self-rated health. Regardless of depressive tendency level, high psychological capital and self-acceptance could improve college students' health.
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BACKGROUND: In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. METHODS: This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided. RESULTS: Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). CONCLUSIONS: Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , Humans , Female , Biomarkers, Tumor , Insulin-Like Growth Factor I , Leptin , Biomarkers , C-Reactive Protein/analysis , Ovarian Neoplasms/therapy , Insulin/metabolismABSTRACT
The nutrient status of the tumor microenvironment has major impacts on cell growth. Under nutrient depletion, asparagine synthetase (ASNS)-mediated asparagine production increases to sustain cell survival. G protein-coupled estrogen receptor-1 (GPER1) signaling converges via cAMP/PI3K/AKT with KRAS signaling to regulate ASNS expression. However, the role of GPER1 in CRC progression is still debated, and the effect of nutrient supply on both ASNS and GPER1 relative to KRAS genotype is not well understood. Here, we modeled a restricted nutrient supply by eliminating glutamine from growing cancer cells in a 3D spheroid model of human female SW48 KRAS wild-type (WT) and KRAS G12A mutant (MT) CRC cells, to examine effects on ASNS and GPER1 expression. Glutamine depletion significantly inhibited cell growth in both KRAS MT and WT cells; however, ASNS and GPER1 were upregulated in KRAS MT compared to WT cells. When nutrient supply was adequate, ASNS and GPER1 were not altered between cell lines. The impact of estradiol, a ligand for GPER1, was examined for any additional effects on cell growth. Under glutamine deplete conditions, estradiol decreased the growth of KRAS WT cells but had no effect on KRAS MT cells; estradiol had no additive or diminutive effect on the upregulation of ASNS or GPER1 between the cell lines. We further examined the association of GPER1 and ASNS levels with overall survival in a clinical colon cancer cohort of The Cancer Genome Atlas. Both high GPER1 and ASNS expression associated with poorer overall survival for females only in advanced stage tumors. These findings suggest that KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. ASNS and GPER1 may therefore be potential therapeutic targets that can be exploited to manage and control KRAS MT CRC.
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Hepatocellular carcinoma (HCC) is a lethal malignancy with a lack of effective treatments particularly for the disease at an advanced stage. Even though immune checkpoint inhibitors (ICIs) have made great progress in the treatment of HCC, durable and ideal clinical benefits still cannot be achieved in plenty of patients with HCC. Therefore, novel and refined ICI-based combination therapies are still needed to enhance the therapeutic effect. The latest study has reported that the carbonic anhydrase XII inhibitor (CAXIIi), a novel type of anticancer drug, can modify the tumor immunosuppression microenvironment by affecting hypoxic/acidic metabolism and alter the functions of monocytes and macrophages by regulating the expression of C-C motif chemokine ligand 8 (CCL8). These observations shine a light on improving programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapy in combination with CAXIIis. This mini-review aims to ignite enthusiasm to explore the potential application of CAXIIis in combination with immunotherapy for HCC.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Ligands , Antineoplastic Agents/therapeutic use , Tumor MicroenvironmentABSTRACT
Immune checkpoint PD-1 and its ligand PD-L1 lead to T cell exhaustion, and a high level of circulating soluble PD-L1 at baseline indicates a poor prognosis in melanoma and other solid tumor types. Here we show that the dynamic changes of circulating soluble PD-1 and PD-L1 across the course of immune checkpoint blockades (ICBs) and their changes associate with patient survival in melanoma in a retrospective study. A high change of soluble PD-L1 level at a time-point but not PD-1 significantly increased the mortality, whereas a high change of soluble PD-1/PD-L1 ratio significantly reduced the mortality. After the initial immunotherapy, both soluble PD-1 and PD-L1 increased. However, the change pattern of soluble PD-L1 level was particularly dependent on patients' survival status. These findings indicate that the magnitudes of circulating soluble PD-L1 and PD-1/PD-L1 ratio changes over the time may reflect the patients' response to ICBs or the progression of the disease and predict the survival in melanoma patients treated with ICBs.