Cervical cancer and risk of dementia: real-world insights from a nationwide cohort study in Taiwan.

OBJECTIVE: Cervical cancer, linked to human papillomavirus (HPV), ranks fourth among women's cancers globally. Several studies have found an association between viral infections or cancer and dementia, which is a major public health concern. This study aimed to provide real-world data on the association between cervical cancer and the risk of dementia. METHODS: This population-based cohort study, utilizing Taiwan's National Health Insurance Research Database, included 53 905 patients, with 10 781 having cervical cancer, matching with 43 124 controls in a 1:4 ratio based on age and indexed date. Incidence density rates were used to calculate the incidence rate of dementia. Adjusting for comorbidities, a multivariable Cox proportional hazards regression model was used to estimate the hazard ratios and 95% confidence intervals. Additionally, the risk of dementia was further verified using the cumulative incidence analyzed by the Kaplan-Meier method. RESULTS: This study indicated a significantly higher dementia risk in the cervical cancer cohort compared with the non-cervical cancer cohort (adjusted HR (aHR)=1.64, 95% CI 1.16 to 2.26; p<0.001), suggesting a 1.64-fold increased risk. Notably, cervical cancer posed a greater risk of dementia (aHR=1.69, 95% CI 1.21 to 2.29; p<0.001) compared with carcinoma in situ of the cervix (p=0.18) and cervical intraepithelial neoplasia (p=0.23). The cumulative incidence of dementia in the cervical cancer group was significantly higher (log-rank test, p<0.001) than the control group. CONCLUSIONS: Cervical cancer (invasive disease) was associated with a significant risk of dementia, unlike carcinoma in situ of the cervix and cervical intraepithelial neoplasia (pre-invasive diseases), suggesting HPV infections may play a role in dementia, particularly oncogenic types. This highlights the importance of further investigation into the underlying mechanisms of the association between cervical cancer and dementia.

Bayesian semiparametric joint model of multivariate longitudinal and survival data with dependent censoring.

We consider a novel class of semiparametric joint models for multivariate longitudinal and survival data with dependent censoring. In these models, unknown-fashion cumulative baseline hazard functions are fitted by a novel class of penalized-splines (P-splines) with linear constraints. The dependence between the failure time of interest and censoring time is accommodated by a normal transformation model, where both nonparametric marginal survival function and censoring function are transformed to standard normal random variables with bivariate normal joint distribution. Based on a hybrid algorithm together with the Metropolis-Hastings algorithm within the Gibbs sampler, we propose a feasible Bayesian method to simultaneously estimate unknown parameters of interest, and to fit baseline survival and censoring functions. Intensive simulation studies are conducted to assess the performance of the proposed method. The use of the proposed method is also illustrated in the analysis of a data set from the International Breast Cancer Study Group.

Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway.

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.

Effects of comorbid alcohol use disorder on bipolar disorder: Focusing on neurocognitive function and inflammatory markers.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers. METHOD: We recruited 641 BD patients, 150 patients with BD+AUD, and 185 healthy controls (HC). Neuropsychological tests [Wisconsin card sorting test (WCST), continuous performance test (CPT), and Wechsler memory scale - third edition (WMS-III)] and cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were assessed. RESULTS: BD+AUD patients had worse cognitive performance than those without AUD. There was a significant difference in the plasma levels of TNF-α, IL-8, and BDNF (P < 0.001, <0.001, and 0.01, respectively) between the patients and the HC groups. Post hoc analysis showed that BD+AUD patients had higher levels of TNF-α and IL-8 than BD-only patients (P < 0.001). Additionally, plasma IL-8 levels were negatively associated with number of completed categories in WCST (P = 0.02), and TNF-α levels were negatively associated with visual immediate index in WMS-III (P = 0.05). CONCLUSION: Our results suggest that comorbid AUD and BD might worsen cognitive impairments and inflammatory processes. Further longitudinal studies on BD+AUD may be needed.

The association between hormone therapy and the risk of lung cancer in postmenopausal women: a 16-year nationwide population-based study.

OBJECTIVE: Although an association between hormone therapy (HT) and the risk of developing lung cancer has been reported, the results on the topic are inconsistent. Our study objective was to investigate whether postmenopausal women who undergo HT exhibit a risk of developing lung cancer. METHODS: In this matched cohort study, we obtained the data of 38,104 postmenopausal women older than 45 years who were treated using HT between 2000 and 2015 from Taiwan's National Health Insurance Research Database, and 152,416 matched participants who were not treated using HT were enrolled as controls at a 1:4 ratio. RESULTS: We used a Cox proportional hazards regression model to identify the risk of developing lung cancer during 16 years of follow-up, and the results indicate no significant difference in the proportion of postmenopausal women treated using HT ( P = 0.129) who developed lung cancer and that of those not treated using HT (0.866% [330 of 38,104] vs 0.950% [1,449 of 152,416]). After adjustment for age and other variables, the adjusted hazard ratio was 0.886 (95% CI, 0.666-1.305, P = 0.433), indicating no association between HT and lung cancer development in postmenopausal women. In a subgroup analysis, the risk of lung cancer was significantly lower in the women who were treated using HT when the HT cumulative dosage was ≥401 mg or when the therapy duration was ≥5 years compared with in those not treated using HT; the adjusted hazard ratios were 0.633 (95% CI, 0.475-0.930; P < 0.001) and 0.532 (95% CI, 0.330-0.934; P < 0.001), respectively, after adjustment. CONCLUSIONS: Our results indicate that HT is not associated with the risk of lung cancer development in postmenopausal women; furthermore, a higher cumulative dosage and the long-term effects of HT reduce the risk of developing lung cancer.

The association between abused adults and substance abuse in Taiwan, 2000-2015.

OBJECTIVE: To investigate whether adults suffering from violence were at risk of substance abuse and provides insight into the relationship between male and female abusers and substance abuse from 2000 to 2015 in Taiwan. METHODS: This study used data on outpatient, emergency, and inpatient visits for 2 million people enrolled in universal health insurance from 2000 to 2015. ICD-9 diagnosis codes 995.8 (abused adult) and E960-E969 (homicide and injury purposely inflicted by other persons) were defined in this case study, analyzing first-time violence in adults aged 18-64 (study group). Non-abused patients (control group) were matched in a 1:4 ratio, and the paired variables were gender, age (± 1 year), pre-exposure Charlson Comorbidity Index, and year of medical treatment. SAS 9.4 and Cox regression were used for data analysis. RESULTS: A total of 8,726 people suffered violence (control group: 34,904 people) over 15 years. The prevalence of substance abuse among victims of violence was 78.3/104, 61.9/104, and 51.5/104 for tobacco use disorder, alcoholism, and alcohol abuse, respectively. The risk (adults, overall) of drug abuse, drug dependence, and alcoholism after exposure to violence (average 9 years) was 7.47, 7.15, and 6.86 times (p < 0.01), respectively, compared with those without violence. The risk (adults, males) of drug abuse, drug dependence, and alcohol abuse after exposure to violence (average 9 years) was 6.85, 6.27, and 6.07 times, respectively, higher than those without violence (p < 0.01). Risks of drug dependence, alcohol abuse and alcoholism (adults, females) after exposure to violence (average 9 years) were 14.92, 12.26, and 11.55 times, respectively, higher than non-abused ones (p < 0.01). CONCLUSION: The risks of substance abuse, after adult violence, are higher than in those who have not suffered violent injuries.

Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1.

Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage in vivo. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.

Association between long-term usage of acetylcholinesterase inhibitors and lung cancer in the elderly: a nationwide cohort study.

This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval [CI] = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.

Risk of depression in patients with oral cancer: a nationwide cohort study in Taiwan.

This study investigates an association between oral cancers and the risk of developing depression. We conducted a total of 3031 patients with newly diagnosed oral cancers and 9093 age-, sex-, and index year-matched controls (1:3) from 2000 to 2013 were selected from the National Health Insurance Research Database (NHIRD) of Taiwan. After adjusting for confounding factors, multivariate Cox proportional hazards analysis was used to compare the risk of depression over a 13-year follow-up. Of the patients with oral cancer, 69 (2.28%, or 288.57 per 105 person-years) developed depression compared to 150 (1.65%, 135.64 per 105 person-years) in the control group. The Cox proportional hazards regression analysis showed that the adjustment hazard ratio (HR) for subsequent depression in patients with oral cancer diagnosed was 2.224 (95% Confidence Interval [CI] 1.641-3.013, p < 0.001). It is noteworthy that in the sensitivity analysis is the adjusted HR in the group with depression diagnosis was 3.392 and in the oral cancer subgroup of "Tongue" was 2.539. This study shows oral cancer was associated with a significantly increased risk for developing subsequent depression and early identification and treatment of depression in oral cancer patients is crucial.

Allopurinol attenuates oxidative injury in rat hearts suffered ischemia/reperfusion via suppressing the xanthine oxidase/vascular peroxidase 1 pathway.

Allopurinol, a xanthine oxidase (XO) inhibitor, is reported to alleviate myocardial ischemia/reperfusion (I/R) injury by reducing the production of reactive oxygen species (ROS). As an XO-derived product, H2O2 can act as a substrate of vascular peroxidase 1 (VPO1) to induce the generation of hypochlorous acid (HOCl), a potent oxidant. This study aims to explore whether the XO/VPO1 pathway is involved in the anti-oxidative effects of allopurinol on the myocardial I/R injury. In a rat heart model of I/R, allopurinol alleviated I/R oxidative injury accompanied by decreased XO activity, XO-derived products (H2O2 and uric acid), and VPO1 expression (mRNA and protein). In a cardiac cell model of hypoxia/reoxygenation (H/R), allopurinol or XO siRNA reduced H/R injury concomitant with decreased XO activity, VPO1 expression as well as the XO and VPO1-derived products (H2O2, uric acid, and HOCl). Although knockdown of VPO1 could also exert a beneficial effect on H/R injury, it did not affect XO activity, XO expression, and XO-derived products. Based on these observations, we conclude that the novel pathway of XO/VPO1 is responsible for, at least partly, myocardial I/R-induced oxidative injury, and allopurinol exerted the cardioprotective effects on myocardial I/R injury via inhibiting the XO/VPO1 pathway.

Risk of Colorectal Cancer in Patients With Attention-Deficit Hyperactivity Disorder: A Nationwide, Population-Based Cohort Study.

Background: The association between attention-deficit hypersensitivity disorder (ADHD) and the risk of developing colorectal cancer (CRC) is, as yet, to be investigated, and thus, we have conducted this nationwide, cohort study to examine the association in patients from Taiwan. Methods: In this study, 798 individuals with newly diagnosed ADHD and 2,394 (1:3) age-, gender-, and index year- matched controls without ADHD were enrolled, between 2000 and 2013, from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database in Taiwan. The cumulative incidence of CRC was assessed in each cohort by the Kaplan-Meier method. The multivariate Cox proportional hazards model was used to estimate the crude, and the adjusted hazards ratios (HRs) with 95% confidence intervals (CIs), was conducted to estimate the association between ADHD and CRC. Results: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with ADHD than in those without it (log rank test, p < 0.001). After adjustments for age, gender, comorbidities, and other covariates, the ADHD group was associated with an increased risk of CRC in comparison to the non-ADHD group (adjusted HR = 3.458, 95% CI = 1.640-7.293, p < 0.001). In addition, the usage of methylphenidate was not associated with the risk of developing CRC in patients with ADHD. Conclusion: This retrospective cohort study depicts the evidence that ADHD was associated with the increased risk of CRC. Further studies are needed to confirm the association and the underlying mechanisms.

Effect of Long-Term Diving Exposure on Sleep of Male Occupational Divers in Southern Taiwan: A Cross-Sectional Study.

OBJECTIVE: Divers with a history of decompression sickness may be at high risk for sleep problems. However, limited studies have investigated the relationship between diving exposure and sleep problems of occupational divers. This study investigated the association between diving exposure and sleep quality and quantity among male occupational divers in southern Taiwan. METHODS: This descriptive, cross-sectional study included 52 occupational divers and 121 non-divers recruited from southern Taiwan in 2018. Survey data were collected using the Taiwanese version of the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and a self-report questionnaire that included demographic variables, diving exposure/protocols, and factors associated with sleep quality. RESULTS: Among all participants examined, occupational divers were significantly more likely to have both poor sleep quality (adjusted odds ratio [OR] = 3.00; 95% confidence interval [CI] = 1.48-6.06; P = 0.002) and excessive daytime sleepiness (adjusted OR = 4.49; 95% CI = 2.12-9.52; P < 0.001). The diving exposure time, depth, ascent rate, and decompression table use showed no significant associations between poor and good sleepers in the divers group. However, a history of decompression sickness was associated with poor sleep quality among divers (adjusted OR = 2.20; 95% CI = 1.07-4.54; P = 0.032). CONCLUSIONS: Our results showed that occupational divers had poor sleep quality and more excessive sleepiness than non-divers. Decompression sickness likely contributes to poor sleep quality. Prevention and early detection of decompression sickness-related sleep problems should be an occupational health priority.

Add-on memantine may improve cognitive functions and attenuate inflammation in middle- to old-aged bipolar II disorder patients.

OBJECTIVES: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation. METHODS: We combined two 12-week randomized, double-blind, placebo-controlled studies (NCT01188148 and NCT03039842) for analysis. Each participant was allocated to the MM or placebo group. Symptom severity, neuropsychological tests, and the cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were evaluated at baseline and endpoint. A subgroup analysis of middle- to old-aged BP-II patients was also performed. RESULTS: We recruited 155 BP-II patients (23 of which were middle- to old-aged) for the MM group and 170 patients (20 of which were middle- to old-aged) for the placebo group. Add-on MM did not result in significant improvements in cognitive functions in all BP-II patients, but a group difference in TNF-α levels was found in the MM group (P=0.04). Specifically, in middle- to old-aged BP-II patients, there was a significant time and group interaction effect on omission T-scores, hit reaction time T-scores, and hit reaction time standard error T-scores on continuous performance tests (CPTs) in the MM group (P=0.007, 0.02, and 0.01, respectively), and a decrease in plasma TNF-α levels (P=0.04). LIMITATIONS: The sample size of middle- to old-aged BP-II patients were limited. CONCLUSION: Add-on MM may attenuate inflammation in BP-II and improve cognition in middle- to old-aged BP-II patients.

Acyl-CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis.

AIMS: Acyl-CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post-SAH EBI using a rat model of SAH. METHODS: The rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin-1 and Liproxstatin-1) to investigate the role of ferroptosis in EBI. RESULTS: We found that ACSL4 levels in brain tissue increased significantly in post-SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood-brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis. CONCLUSIONS: ACSL4 exacerbated SAH-induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post-SAH EBI.

Specific determination of hepatitis B e antigen by antibodies targeting precore unique epitope facilitates clinical diagnosis and drug evaluation against hepatitis B virus infection.

Hepatitis B e antigen (HBeAg) is a widely used marker both for chronic hepatitis B (CHB) clinical management and HBV-related basic research. However, due to its high amino acid sequence homology to hepatitis B core antigen (HBcAg), most of available anti-HBe antibodies are cross-reactive with HBcAg resulting in high interference against accurate measurement of the status and level of HBeAg. In the study, we generated several monoclonal antibodies (mAbs) targeting various epitopes on HBeAg and HBcAg. Among these mAbs, a novel mAb 16D9, which recognizes the SKLCLG (aa -10 to -5) motif on the N-terminal residues of HBeAg that is absent on HBcAg, exhibited excellent detection sensitivity and specificity in pairing with another 14A7 mAb targeting the HBeAg C-terminus (STLPETTVVRRRGR, aa141 to 154). Based on these two mAbs, we developed a novel chemiluminescent HBeAg immunoassay (NTR-HBeAg) which could detect HBeAg derived from various HBV genotypes. In contrast to widely used commercial assays, the NTR-HBeAg completely eliminated the cross-reactivity with secreted HBcAg from precore mutant (G1896A) virus in either cell culture or patient sera. The improved specificity of the NTR-HBeAg assay enables its applicability in cccDNA-targeting drug screening in cell culture systems and also provides an accurate tool for clinical HBeAg detection.

Ubiquitin-specific protease 7 promotes ferroptosis via activation of the p53/TfR1 pathway in the rat hearts after ischemia/reperfusion.

Iron overload triggers the ferroptosis in the heart following ischemia/reperfusion (I/R) and transferrin receptor 1 (TfR1) charges the cellular iron uptake. Bioinformatics analysis shows that the three molecules of ubiquitin-specific protease 7 (USP7), p53 and TfR1 form a unique pathway of USP7/p53/TfR1. This study aims to explore whether USP7/p53/TfR1 pathway promotes ferroptosis in rat hearts suffered I/R and the underlying mechanisms. The SD rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion, showing myocardial injury (increase in creatine kinase release, infarct size, myocardial fiber loss and disarray) and up-regulation of USP7, p53 and TfR1 concomitant with an increase of ferroptosis (reflecting by accumulation of iron and lipid peroxidation while decrease of glutathione peroxidase activity). Inhibition of USP7 activated p53 via suppressing deubiquitination, which led to down-regulation of TfR1, accompanied by the decreased ferroptosis and myocardial I/R injury. Next, H9c2 cells underwent hypoxia/reoxygenation (H/R) in vitro to mimic the myocardial I/R model in vivo. Consistent with the results in vivo, inhibition or knockdown of USP7 reduced the H/R injury (decrease of LDH release and necrosis) and enhanced the ubiquitination of p53 along with the decreased levels of p53 and TfR1 as well as the attenuated ferroptosis (manifesting as the decreased iron content and lipid peroxidation while the increased GPX activity). Knockdown of TfR1 inhibited H/R-induced ferroptosis without p53 deubiquitination. Based on these observations, we conclude that a novel pathway of USP7/p53/TfR1 has been identified in the I/R-treated rat hearts, where up-regulation of USP7promotes ferrptosis via activation of the p53/TfR1 pathway.

Eating disorders and the risk of esophageal and stomach cancers-A nationwide, population-based cohort study in Taiwan.

BACKGROUND: Previous studies have shown elevated cancer risk in anorexia nervosa but the literature on other eating disorders (EDs) is scarce. This study aimed to investigate the association between all EDs and esophageal, stomach, and other cancers. METHODS: We used a retrospective cohort design, based on a two-million randomized longitudinal health insurance dataset, a sub-dataset of Taiwan's National Health Insurance Research Database. From all the potential participants aged 20 years or more, a total of 6,628 participants were enrolled, including 1,657 patients with EDs, with sex-, age-, and indexed date-matched (1:3) 4,971 controls. Each participant was individually tracked from 2000 to 2015 to identify incident cases of cancers, including esophageal cancer (EC), stomach cancer (SC), and all other cancers (AOC). The multivariate Cox proportional hazards model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between EDs and cancer. RESULTS: Of the total 6,628 enrollees, 222 in 1,657 individuals with EDs and 810 in the 4,971 non-ED control individuals developed cancer (1,262.40 vs. 1,472.15 per 100,000 person-years), and the Kaplan-Meier survival analysis was not statistically significant (log-rank, p = .324). However, after adjusting for covariates, the risk of EC and SC among the individuals with an ED was significantly higher, with adjusted HRs of 5.32 (95% CI: 1.07-26.49, p < .001) and 4.61 (95% CI: 1.91-11.14, p < .001), respectively. EDs were not associated with other cancers. CONCLUSIONS: This study provides evidence for the association between EDs and the risk for EC and SC. Further research on mechanisms and prevention is therefore needed.

Risk of colorectal cancer in patients with alcoholism: A nationwide, population-based nested case-control study.

BACKGROUND: Colorectal cancer (CRC) is regarded as a multifactorial disease and shares many risk factors with alcoholism. However, the association between alcoholism and CRC remains controversial. OBJECTIVES: In this study, we aimed to evaluate the association between alcoholism and risk of CRC. METHODS: We performed a large-scale, population-based nested case-control study using the Longitudinal Health Insurance Database 2013, derived from Taiwan's National Health Insurance Research Database, and collected data from 2000 to 2013. There were 49,095 diagnosed cases of CRC defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Each case was matched with three controls by sex, age, index date of CRC, and annual medical visits; a total of 147,285 controls were identified. Multiple risk factors of CRC in alcoholism cases were investigated using unconditional multiple logistic regression analysis. RESULTS: Among 49,095 cases of CRC, alcoholism was associated with a significantly higher risk of CRC (adjusted odds ratio (OR), 1.631; 95% CI, 1.565-1.699) in multivariate logistic regression, after adjusting other CRC risk factors, and in stratified analysis with multivariate logistic regression. In addition, there was a time-dependent relationship between alcoholism duration and CRC risk in >1 year, > 2 years, >5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788-1.967, 1.948-2.158, 2.498-2.835, and 2.511-2.989 respectively). CONCLUSION: An association between alcoholism and risk of CRC was found in this study. Furthermore, patients with longer alcoholism history showed higher likelihood of developing CRC, which indicates a time-dependent relationship between alcoholism exposure and CRC. Further research on colorectal tumorigenesis is needed.