SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1.

Selective serotonin reuptake inhibitors (SSRIs) have shown promise in cancer therapy, particularly for hepatocellular carcinoma (HCC), but their molecular targets and mechanisms remain unclear. Here, we show that SSRIs exhibit significant anti-HCC effects independent of their classical target, the serotonin reuptake transporter (SERT). Using global inverse gene expression profiling, drug affinity responsive target stability assays, and in silico molecular docking, we demonstrate that citalopram targets glucose transporter 1 (GLUT1), resulting in reduced glycolytic flux. A mutant GLUT1 variant at the citalopram binding site (E380) diminishes the drug's inhibitory effects on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis reveals that SSRI use correlates with a lower risk of metastasis among patients with HCC. Our study describes a role for SSRIs in cancer metabolism, establishing a rationale for their repurposing as potential anti-cancer drugs for HCC.

Phosphodiesterase 5 and its inhibitors with ischemic heart disease: a Mendelian randomization analysis and a real-world study.

BACKGROUND: Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits. OBJECTIVES: This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data. METHODS: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers. RESULTS: MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A = 1.22,95% CI = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49) and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84). CONCLUSION: This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.

PDE5 inhibition mitigates heart failure in hyperlipidemia.

PDE5 inhibitors was reported to play a protective role in both regulating lipid metabolism and reducing heart failure (HF). This study aimed to clarify the effectiveness of PDE5 inhibitors against hyperlipidemia-related HF by combining evidence from population-based study and animal models. The nationwide cohort study found that post-diagnostic use of PDE5 inhibitors was associated with a significantly lower risk of HF compared with patients who used alprostadil, especially among individuals with hyperlipidemia (adjusted HR = 0.56, 95% CI = 0.40-0.78). In animal models, sildenafil significantly recovered the cardiac structure and function induced by AAB surgery, as well as reversed liver dysfunction and ameliorated hyperlipidemia induced by HFD via reducing the level of ALT, AST and serum lipids. Lipidomic analysis identified four lipid metabolites involved in sildenafil administration, including FA 16:3, LPC O-18:1, DG24:0_18:0 and SE28:1/20:4. This study revealed the protective effect of PDE5 inhibitors against HF in hyperlipidemia, indicating the potential of being repurposed as an adjuvant for HF prevention in patients with hyperlipidemia if these findings can be further confirmed in clinical trials.

Association of levonorgestrel-releasing intrauterine device with gynecologic and breast cancers: a national cohort study in Sweden.

BACKGROUND: The levonorgestrel-releasing intrauterine device (LNG-IUD) is widely used for the treatment of menorrhagia, dysmenorrhea, and for contraception. However, the association between the use of LNG-IUD and the risk of site-specific gynecologic and breast cancers remains inconclusive. OBJECTIVE: We aim to address this knowledge gap by investigating whether the use of LNG-IUD is associated with a significant risk of site-specific gynecologic and breast cancers. This will be achieved by accessing the nationwide Swedish Registers, with consideration given to the influence and potential interaction of family history of cancer. STUDY DESIGN: A total of 514,719 women aged 18 to 50 years who have used LNG-IUD between July 2005 and December 2018 were identified from the Swedish Prescribed Drug Register and randomly matched with 1,544,157 comparisons who did not use LNG-IUD at a ratio of 1:3. The propensity score was calculated and matched among women who used LNG-IUD and the matched comparisons. The follow-up period started from the date of the first prescription of LNG-IUD for users as well as for their matched comparisons and ended at the date of diagnosis of gynecologic and breast cancers, date of death from any cause, and the end of the study period, whichever came first. The Cox proportional hazard model with a competing risk analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Additive interaction was calculated as the relative excess risk for interaction, while multiplicative interaction was calculated by including a product term in the regression model. RESULTS: The use of LNG-IUD was associated with a 13% higher risk of breast cancer (adjusted HR, 1.13; 95% CI, 1.10-1.17), a 33% lower risk of endometrial cancer (adjusted HR, 0.67; 95% CI, 0.56-0.80), a 14% lower risk of ovarian cancer (adjusted HR, 0.86; 95% CI, 0.75-0.99), and a 9% reduced risk of cervical cancer (adjusted HR, 0.91; 95% CI, 0.84-0.99) compared to women who did not use LNG-IUD. A significant additive interaction between LNG-IUD use and family history of cancer was observed in breast cancer, indicating a relative 19% excess risk for interaction (P<.002), and 1.63 additional cases per 10,000 person-years. CONCLUSION: The risk of gynecologic and breast cancers exhibits a site-specific effect among LNG-IUD users. It is important to note that the observed effect is small for breast cancer and the results are limited by the observational study design. Clinical recommendations regarding the use of LNG-IUD should carefully weigh its potential benefits and risks. Close monitoring is advisable for the potential development of breast cancer, particularly among women with a family history of breast cancer.

Oxidative stress-related genetic variation and antioxidant vitamin intake in intact and ruptured abdominal aortic aneurysm: a Swedish population-based retrospective cohort study.

AIMS: The aim of this study is to investigate how genetic variations in genes related to oxidative stress, intake of antioxidant vitamins, and any potential interactions between these factors affect the incidence of intact abdominal aortic aneurysm (AAA) and its rupture (rAAA), accounting for sex differences where possible. METHODS AND RESULTS: The present retrospective cohort study (n = 25 252) uses baseline single-nucleotide polymorphisms (SNPs) and total antioxidant vitamin intake data from the large population-based, Malmö Diet and Cancer Study. Cumulative incidence of intact AAA was 1.6% and of rAAA 0.3% after a median follow-up of 24.3 years. A variant in NOX3 (rs3749930) was associated with higher rAAA risk in males [adjusted hazard ratio (aHR): 2.49; 95% confidence interval (CI): 1.36-4.35] and the overall population (aHR: 1.88; 95% CI: 1.05-3.37). Higher intakes of antioxidant vitamins, riboflavin, and folate were associated with 20% and 19% reduced intact AAA incidence, respectively. Interestingly, the inverse associations between riboflavin and vitamin D intake with intact AAA incidence were stronger in the individuals carrying the NOX3 variant as compared with the wild-type recessive genotype, i.e. by 60% and 66%, respectively (P for interaction < 0.05). Higher riboflavin intake was associated with a 33% male-specific intact AAA risk reduction, while higher intake of vitamin B12 intake was associated with 55% female-specific intact AAA risk increase; both these associations were significantly modified by sex (P for interaction < 0.05). CONCLUSIONS: Our findings highlight the role of oxidative stress genetic variations and antioxidant vitamin intake in AAA. Although a low AAA/rAAA sample size limited some analyses, especially in females, our findings highlight the need for future randomized controlled trials and mechanistic studies, to explore the potential benefits of antioxidant vitamins while accounting for genetic and sex differences.

Abdominal aortic aneurysm (AAA) is an old age-related disease with lethal complication in the form of rupture (rAAA). Present study aimed to understand how genetic variations in oxidative stress­related genes and the intake of antioxidant vitamins influence the risk of AAA and rAAA. The study identified specific genetic differences associated with an increased risk of rAAA. Interestingly, higher intakes of riboflavin and folate were linked to a reduced risk of AAA. Interestingly, we observe that both genetics and sex modify the effect of vitamin intake on intact AAA risk, providing new insight into the individual differences in the benefits of vitamins. Although the low sample for rAAA and females limits some conclusions, the findings emphasize the need for future randomized controlled trials to explore the potential benefits of antioxidant vitamins while accounting for genetic and sex differences.

Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner.

PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.

Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types.

BACKGROUND: Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences. METHODS: Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers. FINDINGS: We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P = 9.77 × 10-7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P = 5.24 × 10-6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P = 1.01 × 10-5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk. INTERPRETATIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention. FUNDING: This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).

Association of genetically predicted lipid traits and lipid-modifying targets with heart failure.

AIMS: To assess the association of genetically predicted lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF). METHODS AND RESULTS: Two-sample Mendelian randomization (MR) study was conducted using summary-level genome-wide association studies (GWASs) from UK Biobank and HERMES Consortium. Genetic variants obtained from UK Biobank GWAS data were selected as instrumental variables to predict the level of lipid traits [LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB), and apolipoprotein AI (ApoAI)] and lipid-modifying effect of eight drug targets [HMGCR, PCSK9, NPC1L1, PPARA, lipoprotein lipase (LPL), ANGPTL3, APOC3, and cholesteryl ester transfer protein (CETP)]. In this study, we observed that genetically predicted LDL-C, TG, HDL-C or ApoB were significantly related to HF, which were mainly mediated by coronary heart disease (CHD). Drug target MR analyses identified PCSK9, CETP, and LPL as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C = 1.27*10-4; PApoB = 1.94*10-4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P = 5.87*10-6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P = 3.73*10-12). CONCLUSION: This two-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition, and LPL activation were effective in HF reduction.

Dyslipidaemia is a well-established cause of CHD, but the relationship between lipids and heart failure (HF) is unclear, and it is still unknown if lipid-modifying treatment could prevent HF. This study provided genetic evidence that dyslipidaemia is related to a higher risk of HF, mainly through the increased risk of CHD. This study identified three drug targets that may reduce the risk of HF via modifying lipids, including PCSK9 inhibition, CETP inhibition, and LPL activation.

Identifying actionable druggable targets for breast cancer: Mendelian randomization and population-based analyses.

BACKGROUND: Drug repurposing provides a cost-effective approach to address the need for breast cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR) and then validate the candidate drugs using population-based analyses. METHODS: We identified genetic instruments for 1406 actionable targets of approved non-oncological drugs based on gene expression, DNA methylation, and protein expression quantitative trait loci (eQTL, mQTL, and pQTL, respectively). Genome-wide association study (GWAS) summary statistics were obtained from the Breast Cancer Association Consortium (122,977 cases, 105,974 controls). We further conducted a nested case-control study using data retrieved from Swedish registers to validate the candidate drugs that were identified from MR analyses. FINDINGS: We identified six significant MR associations with gene expression levels (TUBB, MDM2, CSK, ULK3, MC1R and KCNN4) and two significant associations with gene methylation levels across 21 CpG islands (RPS23 and MAPT). Results from the nested case-control study showed that the use of raloxifene (targeting MAPT) was associated with 35% reduced breast cancer risk (odds ratio, OR, 0.65; 95% confidence interval, CI, 0.51-0.83). However, usage of estradiol, tolterodine, and nitrofurantoin (also targeting MAPT) was associated with increased breast cancer risk, with adjusted ORs and 95% CI of 1.10 (1.07-1.13), 1.16 (1.09-1.24), and 1.09 (1.05-1.13), respectively. The effect of raloxifene and nitrofurantoin lost significance in further validation analyses using active-comparator and new-user design. INTERPRETATION: This large-scale MR analysis, combined with population-based validation, identified eight druggable target genes for breast cancer and suggested that raloxifene is an effective chemoprevention against breast cancer. FUNDING: Swedish Research Council, Cancerfonden, Crafoordska Stiftelsen, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, 111 Project and MAS cancer.

Use of Selective Serotonin Reuptake Inhibitors Is Associated with a Lower Risk of Colorectal Cancer among People with Family History.

Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical and population-based evidence suggests that selective serotonin reuptake inhibitors (SSRIs) might play a role in preventing CRC. We performed a nationwide cohort study to explore whether the use of SSRIs could reduce CRC risk among individuals with family history. We identified individuals aged 50 and above who had one or more first-degree relatives diagnosed with CRC. A total of 38,617 incident SSRI users were identified and matched with 115,851 non-users, on a ratio of 1:3. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). We found a significant negative association between SSRI use and the risk of CRC (adjusted HR, 0.77; 95% CI, 0.70-0.85). Restricted cubic spline regression showed a non-linear dose-responded relationship between SSRI use and CRC risk. The association was stronger in rectal cancer than colon cancer (adjusted HR, 0.73 vs. 0.79), and more pronounced in advanced-stage CRC than early-stage CRC (adjusted HR, 0.73 vs. 0.80). This population-based cohort study suggests that the use of SSRIs is associated with a reduced risk of CRC among individuals with a family history of CRC.

Proguanil and atovaquone use is associated with lower colorectal cancer risk: a nationwide cohort study.

BACKGROUND: Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking. METHODS: By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62-0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81). CONCLUSIONS: This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.

Effect of Sirolimus on the Level of Peripheral Blood Lymphocyte Autophagy in Children With Systemic Lupus Erythematosus.

Background: To observe the changes of autophagy-related protein levels in peripheral blood lymphocytes before and after sirolimus treatment in children with systemic lupus erythematosus (SLE). Methods: Children with SLE were randomly divided into two groups, 28 in the traditional treatment group and 28 in the sirolimus group. Fifteen healthy children who were in the same period were collected as the normal control group. Clinical laboratory indexes, the percentage of routine lymphocytes, complement C3, complement C4, serum Anti-dsDNA and SLEDAI were detected. Results: At 3 and 6 months after treatment, compared with the traditional treatment group, the percentage of routine lymphocytes in the sirolimus group increased (P = 0.03), SLEDAI score and positive rate of Anti-dsDNA decreased (P = 0.01). Compared with normal children, the expression of microtubule-associated protein 1 light chain 3 (LC3) protein in peripheral blood lymphocytes was significantly higher (P = 0.006); peripheral blood expression of P62/SQSTM1 (sequestosome 1) protein in lymphocytes decreased (P = 0.02). Conclusion: Sirolimus can play a role in the treatment of systemic lupus erythematosus by regulating the level of autophagy.

Use of Melatonin Is Associated With Lower Risk of Colorectal Cancer in Older Adults.

INTRODUCTION: Preclinical evidence suggests that melatonin may affect cellular pathways involved in colorectal cancer (CRC). We sought to test whether melatonin use was associated with decreased risk of CRC using population-based data. METHODS: We performed a nationwide cohort study using a new-user study design. We identified a total of 58,657 incident melatonin users aged 50 years and older from the Prescribed Drug Register, and matched them with 175,971 comparisons who did not use melatonin, on the ratio of 1:3. The Cox regression model was used to calculate hazard ratios and 95% confidence intervals. RESULTS: The incidence rate of CRC was 10.40 per 10,000 person-years for melatonin users, whereas the rate was 12.82 per 10,000 person-years in the nonusers. We found a significant negative association between melatonin use and risk of CRC (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72-0.92). A test for trend showed a significant dose-response correlation (P < 0.001). The decrease of CRC risk was independent of tumor location and stage at diagnosis. When stratified by age groups, the inverse association was significant only among individuals aged 60 years and older. DISCUSSION: This population-based cohort study suggests that the use of melatonin was associated with a reduced risk of CRC. Further studies are needed to confirm the observed association and to explore the underlying mechanisms.

Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women: A Prospective Swedish Population-Based Study.

Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.

Combined Use of Aspirin and Selective Serotonin Reuptake Inhibitors Is Associated With Lower Risk of Colorectal Cancer: A Nested Case-Control Study.

INTRODUCTION: Chemoprevention against colorectal cancer (CRC) is greatly needed. As the development of CRC involves multiple dysfunctional pathways, it is thus reasonable to combine some agents that address several pathways to achieve better chemoprotection. We aimed to explore whether the use of aspirin and selective serotonin reuptake inhibitors (SSRIs)-either as monotherapy or combined-can have a clinical benefit against CRC. METHODS: We performed a nested case-control study using nationwide Swedish registers. We recruited 24,786 CRC cases and randomly matched to 74,358 controls conditional on birth year and sex using incidence-density sampling. The conditional logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Additive interaction was calculated as the relative excess risk for interaction, and multiplicative interaction was calculated by including a product term in the regression model. RESULTS: Both aspirin and SSRIs monotherapy were negatively associated with CRC risk, but the combined use of aspirin and SSRIs was associated with an even lower CRC risk (adjusted OR, 0.77, 95% CI, 0.67-0.89) than aspirin monotherapy (adjusted OR, 0.91, 95% CI, 0.87-0.97) or SSRI monotherapy (adjusted OR, 0.93, 95% CI, 0.86-1.00). A significant interaction was observed at the additive scale with a relative excess risk for interaction of -0.07 (P < 0.001), whereas no interaction was noted on the interactive scale. The inverse associations of CRC with aspirin and SSRIs showed a dose-dependent pattern. DISCUSSION: This study suggests that the use of aspirin and SSRIs-either as monotherapy or combined-was associated with a reduced risk of CRC. The stronger chemoprevention of combined use of aspirin and SSRIs is innovative and calls for further studies to confirm the underlying mechanisms and the plausibility of clinical recommendation.

Association between Dietary Zinc and Selenium Intake, Oxidative Stress-Related Gene Polymorphism, and Colorectal Cancer Risk in Chinese Population - A Case-Control Study.

Zinc and selenium may protect against colorectal cancer (CRC) progression through their anti-oxidative effects. This study examined the independent and combined effect of dietary zinc and selenium intake, and polymorphisms of the oxidative stress-related genes (superoxide dismutase 1, superoxide dismutase 2, glutathione peroxidase, and catalase) on CRC risk in a Chinese case-control study. A total of 493 cases and 498 sex and age-matched controls were randomly selected from an ongoing case-control study. Dietary information was assessed through face-to-face interviews using a validated food frequency questionnaire. Multiplex PCR-ligase detection reaction was used for genotyping the target SNPs. Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI). Intake of selenium was found to be inversely associated with CRC risk, while zinc was not associated with CRC risk. The ORs (95% CI) for the highest vs. the lowest quartile were 0.42 (95% CI 0.28, 0.64, Ptrend < 0.001) for selenium and 0.96 (95% CI 0.63, 1.47, Ptrend = 0.505) for zinc. Combined effect was observed between zinc and SOD1 rs4998557 on CRC risk (Pinteraction < 0.05). This study identified a novel diet-gene interaction in the oxidative stress pathway on CRC risk in Chinese population.

Intake of total cruciferous vegetable and its contents of glucosinolates and isothiocyanates, glutathione S-transferases polymorphisms and breast cancer risk: a case-control study in China.

Cruciferous vegetables contain high levels of glucosinolates (GSL) and isothiocyanates (ITC). ITC are known to induce glutathione S-transferases (GST) and thus exert their anticarcinogenic effects. This study explored the combined effects of cruciferous vegetable, GSL and ITC intake and GST polymorphisms on breast cancer risk. A total of 737 breast cancer cases and 756 controls were recruited into this case-control study. OR and 95 % CI were assessed by multivariable logistic regression. Higher cruciferous vegetable, GSL and ITC intakes were inversely associated with breast cancer risk, with adjusted OR of 0·48 (95 % CI 0·35, 0·65), 0·54 (95 % CI 0·40, 0·74) and 0·62 (95 % CI 0·45, 0·84), respectively. Compared with women carrying the GSTP1 rs1695 wild AA genotype and high cruciferous vegetable, GSL or ITC intake, carriers of the AA genotype with low cruciferous vegetable, GSL and ITC intake had greater risk of breast cancer, with adjusted OR of 1·43 (95 % CI 1·01, 1·87), 1·34 (95 % CI 1·02, 1·75) and 1·37 (95 % CI 1·05, 1·80), respectively. Persons with the GSTM1-null genotype and lower intake of cruciferous vegetables, GSL and ITC had higher risk of breast cancer than those with the GSTM1-present genotype and higher intake, with OR of 1·42 (95 % CI 1·04, 1·95), 1·43 (95 % CI 1·05, 1·96) and 1·45 (95 % CI 1·06, 1·98), respectively. Among women possessing the GSTT1-present genotype, low intake of cruciferous vegetables, GSL or ITC was associated with higher risk of breast cancer. But these interactions were non-significant. This study indicated that there were no significant interactions between cruciferous vegetable, GSL or ITC intake and GST polymorphisms on breast cancer risk.

An Increasing Trend in the Prevalence of Polypharmacy in Sweden: A Nationwide Register-Based Study.

AIM: Polypharmacy is becoming a global health problem. The aims of this study were to evaluate the temporal trends in the prevalence of polypharmacy in Sweden and to explore polypharmacy disparities by age, gender, education, and immigration status. METHODS: Polypharmacy and excessive polypharmacy were evaluated using data extracted from the Swedish Prescribed Drug Register between 2006 and 2014. Polypharmacy was defined as being exposed to five or more drugs and excessive polypharmacy was defined as being exposed to 10 or more drugs during 1 month respectively. Average annual percent change (AAPC) was calculated using Joinpoint Statistical Software. RESULTS: The prevalence of polypharmacy increased from 16.9% in 2006 to 19.0% in 2014 with an AAPC of 1.3; the prevalence of excess polypharmacy increased from 3.8% in 2006 to 5.1% in 2014 with an AAPC of 3.4. The prevalence of polypharmacy and excessive polypharmacy increased dramatically with age and peaked up to 79.6% and 36.4% in individuals aged 90 and above respectively. Females and individuals with lower education level were associated with a higher rate of polypharmacy and excessive polypharmacy. Immigrants from Middle-Eastern countries had the highest rate of polypharmacy and excessive polypharmacy, whereas individuals from Western Europe countries had the lowest rate. CONCLUSION: The prevalence of polypharmacy has increased gradually in Sweden during the past decade. Individuals with older age, female sex, or lower education have a higher rate of polypharmacy and excessive polypharmacy. Immigrants from Middle-Eastern countries showed a higher rate of polypharmacy.

Purification, characterization and antitumor activity of an exopolysaccharide produced by Bacillus velezensis SN-1.

A capsular polysaccharides (CPS) producer Bacillus velezensis SN-1 (B. velezensis SN-1) was isolated in Da-jiang, China. We used ultrasonic extraction to obtain CPS from a culture of B. velezensis SN-1 at a yield of 755 mg/L. Using gel permeation chromatography (GPC), CPS was separated into a single peak with a molecular weight of 1.46 × 105 Da. Its structures were characterized by gas chromatography (GC), methylation, Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR). The CPS was identified as a polysaccharide with a highly branched main chain of mannose with (1 â†’ 3) connections. Moreover, our results revealed that CPS has the capacity to scavenge DPPH radical, hydroxyl radical, ABTS radical and oxygen radical in a manner that relied on concentration. Anti-neoplastic analysis showed that CPS displayed significant anti-tumor activity towards HepG-2 tumor cells. Above findings indicate that CPS generated by B. velezensis SN-1 may be adapted for use as a natural antioxidant in foodstuffs and as an anti-tumor drug.