Cancer causes millions of deaths globally every year. At its later stages, cancers are primarily treated with systemic therapies which do not provide an effective cure; the remaining cancer cells ultimately acquire drug resistance, relapse, and metastasize. In particular, polyploid giant cancer cells (PGCCs), which arise in response to diverse cellular stressors such as therapeutic pressure, modulate the tumor microenvironment (TME) and immunity involved in cancer development. However, without the knowledge of well-established signaling cascades targeting PGCCs, the current treatment options for these cells remain limited. This review provides a summary of the latest research associated with PGCC formation and treatment outcomes in common metastatic cancers. In addition, we highlight how some traditional Chinese medicine (TCM) and their bioactive compounds may serve as prospective agents for arresting PGCCs through cell cycle regulation, cell death induction, and TME modulation. Specifically, we identify how these processes are closely associated with the initiation, self-renewal, and termination phases of the PGCC life cycle. Based on the principle in TCM of "strengthening vital qi to eliminate pathogenic factors," the most efficacious herbs for counteracting PGCCs have been identified as Coptis chinensis, Oldenlandia diffusa, Scutellaria baicalensis, Salvia miltiorrhiza, Curcuma longa, Astragali radix, and Panax ginseng. The bioactive compounds of these herbs include berberine, oleanolic acid, wogonin, tanshinone IIA, curcumin, Astragaloside IV, and ginsenoside Rh2. Given the multi-target characteristics of TCM, network pharmacology was performed to allow for an integrative approach to elucidating underlying mechanisms. In particular, TCM administration may modulate both the p53 signaling pathway and cell cycle-related proteins. This, in turn, alleviates PGCC-induced tumor recurrence and resistance. Collectively, this review emphasizes the central role of PGCCs in advanced cancer progression while strengthening the mechanistic insights of TCM in PGCC-oriented therapy.

BACKGROUND:Anxiety disorders, major psychiatric disorders (e.g., schizophrenia and major affective disorders), and neurodevelopmental disorders (e.g., autism and attention-deficit/hyperactivity disorder [ADHD]) may cluster together within families. However, whether the first-degree relatives (FDRs) of individuals with generalized anxiety disorder (GAD) are at an elevated risk of neurodevelopmental or major psychiatric disorders remains unknown. METHODS:We identified 2,378,190 FDRs of patients with GAD and 9,512,760 birth year-matched and sex-matched controls from Taiwan's National Health Insurance Research Database. Neurodevelopmental disorders, including autism and ADHD, and major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, and GAD, were identified. RESULTS:The FDRs-parents, offspring, and siblings-of individuals with GAD were more likely to be diagnosed as having schizophrenia (relative risk: 1.22), bipolar disorder (1.36), major depressive disorder (1.29), autism (1.20), ADHD (1.52), obsessive-compulsive disorder (1.21), and GAD (1.61) than are the FDRs of individuals without GAD. CONCLUSION:Our findings support the notion of a familial coaggregation between GAD, major psychiatric disorders, and neurodevelopmental disorders. Future studies should elucidate the definitive genetic etiology of this familial coaggregation.

BACKGROUND:As the relationship between attention deficit hyperactivity disorder (ADHD) and traumatic brain injury (TBI) is gaining increasing attention, the TBI risk in patients with ADHD, unaffected siblings of ADHD probands, and non-ADHD controls remains unclear. METHODS:Overall, 18,645 patients with ADHD, 18,880 unaffected siblings of ADHD probands, and 188,800 age-/sex-matched controls were followed up from enrollment to the end of 2011. The cases of TBI and TBI requiring hospitalization were identified during follow-up. RESULTS:Patients with ADHD (hazard ratio [HR]: 1.57) and unaffected siblings (HR: 1.20) had an increased risk of any TBI compared with non-ADHD controls. Surprisingly, the likelihood of developing TBI requiring hospitalization during follow-up was higher in the unaffected siblings group (HR: 1.21) than in the control group, whereas it was lower in the ADHD probands group (HR: 0.86). CONCLUSIONS:Patients with ADHD and unaffected siblings of ADHD probands were more likely to develop any TBI during follow-up than controls. Unaffected siblings of patients with ADHD exhibited the highest risk of subsequent TBI requiring hospitalization compared with patients with ADHD and healthy controls. Therefore, TBI risk in patients with ADHD and their unaffected siblings would require further investigation. IMPACT:ADHD diagnosis and ADHD trait are associated with risk of traumatic brain injury (TBI). Both patients with ADHD and their unaffected siblings were more likely to develop TBI during the follow-up compared with the control group. TBI requiring hospitalization occurred more in the sibling group than in the proband group. TBI risk should be closely monitored among unaffected siblings of patients with ADHD.

Aims Research evidence has established an association of obsessive-compulsive disorder (OCD) with suicidal thoughts and suicide attempts. However, further investigation is required to determine whether individuals with OCD have higher risk of death by suicide compared with those without OCD.Methods Of the entire Taiwanese population, between 2003 and 2017, 56,977 individuals with OCD were identified; they were then matched at a 1:4 ratio with 227,908 non-OCD individuals on the basis of their birth year and sex. Suicide mortality was assessed between 2003 and 2017 for both groups. Time-dependent Cox regression models were used to investigate the difference in suicide risk between individuals with versus without OCD.Results After adjustment for major psychiatric comorbidities (i.e., schizophrenia, bipolar disorder and major depressive disorder), the OCD group had higher risk of suicide (hazard ratio: 1.97, 95% confidence interval: 1.57-2.48) during the follow-up compared with the comparison group. Furthermore, OCD severity, as indicated by psychiatric hospitalizations due to OCD, was positively correlated with suicide risk.Conclusions Regardless of the existence of major psychiatric comorbidities, OCD was found to be an independent risk factor for death by suicide. A suicide prevention program specific to individuals with OCD may be developed in clinical practice in the future.

Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we verified the inhibitory properties and the pivotal molecules regimented by Scutellaria baicalensis on advanced hepatocellular carcinoma. At first, the viability of SK-Hep-1 cells was significantly reduced under treatment of Scutellaria baicalensis extract in a dose-dependent manner without affecting the growth of normal hepatocyte. Scutellaria baicalensis extract application could remarkably cause apoptosis of SK-Hep-1 cells through p53/cytochrome C/poly-ADP ribose polymerase cascades and arrest the cell cycle at the G1/S phase by downregulating cyclin-dependent kinases. Meanwhile, administration of Scutellaria baicalensis extract remarkably attenuated the migration capability as well as suppressed matrix metalloproteinase activity of advanced hepatocellular carcinoma cells. The proteome profiles and network analysis particularly implied that exposure to Scutellaria baicalensis extract downregulated the expression of HSP90β, and the clinical stage of hepatocellular carcinoma is also positively correlated with the HSP90β level. Combined treatment of Scutellaria baicalensis extract and HSP90β siRNAs could markedly enhance the ubiquitination activity and the degradation of vimentin to subsequently inhibit the metastatic property of SK-Hep-1 cells. Moreover, application of Scutellaria baicalensis extract and HSP90β siRNAs depleted phosphorylation of AKT, which stimulated the expression of p53 and consecutively triggered cell apoptosis. These findings suggest that HSP90β may be a prospective target for the effective therapy of advanced hepatocellular carcinoma via accelerating apoptosis of hepatocellular carcinoma cells and eliciting mesenchymal–epithelial transition with the administration of Scutellaria baicalensis extract.

Psoriasis is a chronic and recurrent skin problem that affects 3% of the global population. Nowadays, most medicines may not promise a complete cure for patients with psoriasis because of the development of pharmacoresistance and the side effects of drugs due to the microenvironment impact in the context of skin imbalance. Herein, we attempt to explore the pharmaceutical efficacy of Scutellaria baicalensis (S. baicalensis) in modulating the microenvironment created by macrophages and keratinocytes in psoriasis. The results indicated that treatment of S. baicalensis extract significantly reduced the thickness of epidermis and attenuated psoriatic lesions. Moreover, S. baicalensis extract obviously inhibited the activation and infiltration of macrophages by alleviating inflammatory factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). The administration of S. baicalensis extract also remarkably abolished oxidative damage upon DNA and proteins, which attributed to the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1). The network analysis of redox proteomics and cytokine profiles suggested that S. baicalensis administration regulated the specific pathways associated with oxidative stress, inflammation and cytokine signaling cascades to ameliorate the macrophage-targeted responses and subsequently arrest proliferation of keratinocytes. Collectively, our findings highlighted the importance of S. baicalensis application in reprogramming microenvironment to provide an alternative and complementary intervention for long-term psoriatic therapy.

Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.

Background: Sjögren’s syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren’s syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer’s test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44–4.41 mm) and 3.45 mm (95% CI, 2.32–4.59 mm), respectively, and a significant reduction in artificial tear use, which was −1.38 times/day, 95% CI, −1.95 to −0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren’s syndrome.

Background and Purpose: Patients with obsessive-compulsive disorder (OCD) tend to be comorbid with stroke-related risk factors, including obesity, hypertension, and diabetes. However, the temporal association between OCD and subsequent stroke risk is unclear. Methods: Using data collected between 2001 and 2010 by Taiwan's National Health Insurance Research Database, 28 064 adult patients with OCD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code: 300.3) and 28 064 age-, sex-, and comorbidity-matched controls were included in this study. Patients who developed ischemic (ICD-9-CM codes: 433, 434, and 435) and hemorrhagic (ICD-9-CM codes: 430, 431, and 432) stroke during follow-up (from enrollment to end of 2011) were identified. Moreover, medications used for treating OCD were assessed. Results: Patients with OCD (hazard ratio [HR], 3.02 [95% CI, 1.91-4.77]), especially middle-aged (HR, 2.66 [95% CI, 1.34-5.29]) and elderly adults (HR, 3.46 [95% CI, 1.70-7.05]), had an elevated risk of developing ischemic stroke during the follow-up period compared with non-OCD controls. The cumulative HR of hemorrhagic stroke did not differ (HR, 0.87 [95% CI, 0.42-1.80]) between the OCD and non-OCD groups. In patients with OCD, both short- (HR, 1.69 [95% CI, 0.74-3.88]; HR, 0.31 [95% CI, 0.05-1.95]) and long-term use (HR, 1.37 [95% CI, 0.60-3.16]; HR, 0.90 [95% CI, 0.22-3.76]) of OCD medications were not correlated with ischemic and hemorrhagic stroke compared with nonuse. Conclusions: Clinicians should closely monitor cerebrovascular disease and related risks in patients with OCD. The pathomechanism of OCD with an increased risk of ischemic stroke warrants further investigation.

Hepatic fibrosis is a wound-healing process caused by prolonged liver damage and often occurs due to hepatic stellate cell activation in response to reactive oxygen species (ROS). Red raspberry has been found to attenuate oxidative stress, mainly because it is rich in bioactive components. In the current study, we investigated the inhibitory effects and associated molecular mechanisms of red raspberry extract (RBE) upon activated hepatic stellate cell (aHSC) in cellular and rat models. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in the dimethylnitrosamine (DMN)-applied samples, whereas treatment of RBE significantly suppressed the activities of these enzymes. In addition, a histopathological analysis demonstrated that RBE could substantially diminish the hepatic collagen content and alpha-smooth muscle actin (α-SMA) expression induced by DMN. Administration of 250 μg/mL RBE could also arrest the growth and enhance the apoptosis of activated HSC-T6 cells, which was accompanied with elevated levels of activated caspases and poly (ADP-ribose) polymerase (PARP) cleavage. Particularly, RBE application remarkably abolished oxidative damage within the cells and reduced the carbonylation of proteins, which was attributed to the upregulation of catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Moreover, the knockdown of Nrf2 together with the RBE treatment synergistically abrogated the expression of α-SMA and promoted the level of peroxisome proliferator-activated receptor gamma (PPAR-γ), suggesting that RBE could mitigate the transdifferentiation of HSC in a Nrf2-independent manner. These findings implied that the application of RBE could effectively remove oxidative stress and relieve the activation of HSC via modulating the caspase/PARP, Nrf2/HO-1 and PPAR-γ pathways, which may allow the development of novel therapeutic strategies against chemical-caused liver fibrogenesis.

Background: Retrospective studies have suggested that patients with dementia have higher prevalence of atopic dermatitis (AD) than those without dementia. However, the temporal association of AD with subsequent dementia remains unknown. Objective: To assess the temporal association of AD with subsequent dementia. Methods: We included data of patients with AD aged 45 years and older (n = 1059) and 1:10 age, sex, residence, income, and dementia-related comorbidity-matched controls (n = 10,590) from the Taiwan National Health Insurance Research Database and reviewed their subsequent dementia development from the enrollment date to the end of 2013. Results: After adjustments for dementia-related comorbidities, patients with AD were found to be more likely to develop any dementia (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.24-3.29), particularly Alzheimer's disease (HR, 3.74; 95% CI, 1.17-11.97), during the follow-up period than those in the control group. Moderateto-severe AD was associated with a high subsequent dementia risk (HR, 4.64; 95% CI, 2.58-8.33). Sensitivity analyses with the exclusion of the first 3 (HR, 2.20; 95% CI, 1.28-3.80) or 5 (HR, 2.05; 95% CI, 1.08-3.89) years of observation revealed consistent findings. Conclusion: AD may be an independent risk factor for new-onset dementia. Clinicians may monitor the trajectory of neurocognitive function among elderly patients with AD. Additional studies elucidating the pathomechanisms between AD and subsequent dementia are warranted. (c) 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Background Retrospective studies have suggested that patients with dementia have higher prevalence of atopic dermatitis (AD) than those without dementia. However, the temporal association of AD with subsequent dementia remains unknown. Objective To assess the temporal association of AD with subsequent dementia. Methods We included data of patients with AD aged 45 years and older (n = 1059) and 1:10 age, sex, residence, income, and dementia-related comorbidity–matched controls (n = 10,590) from the Taiwan National Health Insurance Research Database and reviewed their subsequent dementia development from the enrollment date to the end of 2013. Results After adjustments for dementia-related comorbidities, patients with AD were found to be more likely to develop any dementia (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.24-3.29), particularly Alzheimer's disease (HR, 3.74; 95% CI, 1.17-11.97), during the follow-up period than those in the control group. Moderate-to-severe AD was associated with a high subsequent dementia risk (HR, 4.64; 95% CI, 2.58-8.33). Sensitivity analyses with the exclusion of the first 3 (HR, 2.20; 95% CI, 1.28-3.80) or 5 (HR, 2.05; 95% CI, 1.08-3.89) years of observation revealed consistent findings. Conclusion AD may be an independent risk factor for new-onset dementia. Clinicians may monitor the trajectory of neurocognitive function among elderly patients with AD. Additional studies elucidating the pathomechanisms between AD and subsequent dementia are warranted.

Objective This study explored the bidirectional relationship between fibromyalgia and migraine among probands with either of the two disorders and their unaffected siblings. Background Evidence suggests a bidirectional association between fibromyalgia and migraine in individuals and in twins. However, whether a bidirectional association between fibromyalgia and migraine also occurs among siblings remains unknown. Methods Using the Taiwan National Health Insurance Research Database, we examined the data of 2677 probands with fibromyalgia, 2780 unaffected siblings, and 11,120 matched controls to assess the risk of migraine. In contrast, 1830 probands with migraine, 1936 unaffected siblings, and 7744 matched controls to assess the risk of fibromyalgia. Results Logistic regression analyses demonstrated that patients with fibromyalgia (odds ratio [OR]: 3.69; 95% confidence interval [CI]: 2.87-4.74) and unaffected siblings (OR: 1.51; 95% CI: 1.08-2.10) were more likely to develop migraine than the controls during the follow-up period. Moreover, patients with migraine and unaffected siblings had a 4.86-fold (95% CI: 3.86-6.09) and 1.59-fold (95% CI: 1.18-2.12) increased risk of fibromyalgia than the controls. Conclusion The bidirectional association between fibromyalgia and migraine among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation.

Background: The association between postpartum depression and postpartum psychosis and subsequent maternal and offspring mental disorders in Western countries has been established; however, whether the relationship can be generalized to the Asian population is unknown.Methods: Using the Taiwan National Health Insurance Research Database, this study enrolled 933,745 mother-infant pairs who delivered their first child and had no history of severe mental illness before childbirth from 2001 to 2010. Postpartum depression and postpartum psychosis were assessed in 3 periods between childbirth and 3, 6, or 12 months after childbirth. Subsequent maternal schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM code: 296 except 296.2x, 296.3x, 296.9x, and 296.82), and depressive disorder (ICD-9-CM codes: 296.2x, 296.3x, 300.4, and 311) and offspring autism spectrum disorder (ASD; ICD-9-CM code: 299) and attention-deficit/hyperactivity disorder (ADHD; ICD-9-CM code: 314) were identified during the follow-up period to the end of 2011.Results: Both postpartum depression and postpartum psychosis were found to be related to increased risks of schizophrenia, bipolar disorder, and depressive disorder in mothers, with hazard ratios (HRs) ranging between 8.80 (95% CI, 7.95-9.74) and 63.96 (95% CI, 50.39-81.18). Children exposed to maternal postpartum depression and psychosis were more likely to develop ADHD. Only postpartum depression was related to the likelihood of offspring ASD.Conclusions: Per these findings, we clinicians and health care providers should closely monitor the mental health condition of postpartum women and their children.

BACKGROUND:Studies have indicated that parental depression was slightly related to the increased risk of offspring attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the association between exposure to parental depression at different neurodevelopmental stages (i.e., perinatal or postnatal period) and subsequent ADHD and ASD development remained uncertain. METHOD:708,515 children born between 2001 and 2008 were screened for ADHD and ASD based on ICD-9-CM codes of 314 and 299 given by psychiatrists from their birth to the end of 2011. Paternal and maternal depression was separately assessed during five periods, namely those before pregnancy (pre-pregnancy), during pregnancy (perinatal), and <1, 1-3, and >3 years after childbirth (postnatal). Cox regression analyses were performed. RESULTS:Both paternal and maternal depression occurring in the pre-pregnancy, perinatal and postnatal periods were significantly associated with subsequent ADHD and ASD in the offspring, with hazard ratios between 1.42 (95% confidence interval [CI]: 1.35-1.49) and 2.25 (2.09-2.41). The chronicity and additive effect of paternal and maternal depression were related to increased risks of offspring ADHD and ASD. The effects of maternal depression were stronger than the effects of paternal depression for offspring ADHD (HR: 1.35, 95% CI: 1.27-1.45) and ASD (HR: 1.23, 95% CI: 1.05-1.46) risks. CONCLUSION:Both paternal depression and maternal depression in the pre-pregnancy, perinatal and postnatal periods increases offspring ADHD and ASD risks, and these risks increase further with increases in the duration of parental depression and with the additive effect of parental and maternal depression.

Poor prognosis due to the high relapse and metastasis rates of breast cancer has been particularly linked to the luminal B subtype. The current study utilized MCF-7 and ZR-75-1 to investigate various luminal subtypes of breast cancers that have discrepant expressions in the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Understanding of the differential protein profiles and the associated pathways could help alleviate the malignance and promote the long-term survival rate of breast cancer patients. Functional proteome tools were applied to comprehensively delineate the global protein alterations that reflect the varieties of biological features between the two subtypes. In this study, a total of 11 proteins with significant and meaningful changes were identified. These protein targets including PRX2, CK19, nucleophosmin and cathepsin D were mostly involved in cell differentiation or proliferation. Particularly, cathepsin D was highly expressed in the luminal B subtype. Moreover, the level of cathepsin-D was also upregulated in the clinical metastatic tissues. Accordingly, the RNA interference-mediated silencing of cathepsin D stimulated ER expression but suppressed the level of HER2. The knockdown of cathepsin D enhanced the level of ZO-1 and a remarkable decrease in N-cadherin was also detected. Again, the matrix metalloproteinases (MMP) activity was impaired under the cathepsin D abolishment. Collectively, this study represented a modality to explore novel relationships in a proteome complex and highlighted the functional roles of cathepsin D in treatment options for different subtypes of breast cancer.

Studies have suggested an association between metabolic and cerebrocardiovascular diseases and major depressive disorder (MDD). However, the risk of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD remains uncertain. Using the Taiwan National Health Insurance Research Database, 22,438 unaffected siblings of patients with MDD and 89,752 age-/sex-matched controls were selected and followed up from 1996 to the end of 2011. Individuals who developed metabolic and cerebrocardiovascular diseases during the follow-up period were identified. Compared with the controls, the unaffected siblings of patients with MDD had a higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), and obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic stroke (0.6% vs. 0.4%, p < 0.005) and ischemic heart disease (2.1% vs. 1.7%, p < 0.001). Logistic regression analyses revealed that the unaffected siblings of patients with MDD were more likely to develop hypertension, dyslipidemia, ischemic stroke, and ischemic heart diseases during the follow-up period than the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases. Additional studies are required to investigate the shared pathophysiology of MDD and metabolic and cerebrocardiovascular diseases.

The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.

Although men carry a higher risk of hepatocellular carcinoma (HCC) than women, it is still controversial whether men also have a poorer postoperative prognosis. A retrospective study was conducted to evaluate the postoperative prognostic predictors of HCC focusing on sex differences. We enrolled 516 consecutive adult patients with HCC (118 women, 398 men), who received surgical resection between January 2000 and December 2007, and were followed-up for >10 years. Clinical and laboratory data together with postoperative outcomes were reviewed. At baseline, female patients had a higher anti-hepatitis C virus antibody prevalence (P = 0.002); lower hepatitis B virus surface antigen prevalence (P = 0.006); less microvascular invasion (P = 0.019); and lower alpha-fetoprotein (P = 0.023), bilirubin (P = 0.002), and alanine transaminase (P = 0.001) levels. Overall, there were no significant sex differences in terms of intrahepatic recurrence-free survival (RFS), distant metastasis-free survival (MFS), and overall survival (OS). However, subgroup analysis showed that women had favorable RFS (P = 0.019) and MFS (P = 0.034) in patients with alpha-fetoprotein ≤ 35 ng/mL, independent of other clinical variables (adjusted P = 0.008 and 0.043, respectively). Additionally, men had favorable OS in patients with prothrombin time (international normalized ratio [INR]) <1.1 (P = 0.033), independent of other clinical variables (adjusted P = 0.042). Female sex is independently associated with favorable postoperative RFS and MFS in patients with alpha-fetoprotein ≤35 ng/mL, while male sex is independently associated with favorable OS in patients with prothrombin time INR <1.1.

BACKGROUND:Studies have suggested that a significant association exists between prenatal exposure to acetaminophen and the offspring's attention-deficit/hyperactivity disorder (ADHD) risk. However, this association has largely been unexplored among the Asian population, generally, and the Taiwanese population, specifically.METHODS:In our study, 950 study pairs (children with ADHD [ICD-9-CM code: 314] and their mothers) and 3,800 control pairs (children without ADHD and their mothers) matched by demographic characteristics were identified between 1998 and 2008 from the Taiwan Longitudinal Health Insurance Database. Maternal use of acetaminophen was assessed in the first trimester, second trimester, and third trimester of pregnancy and over the period from 3 months before pregnancy to the date of last menstrual cycle.RESULTS:Logistic regression analysis with adjustments for demographic data, gestational infections, comorbid perinatal conditions, and maternal mental health disorders indicated that exposure to acetaminophen in the second trimester (odds ratio [OR] = 1.19; 95% CI, 1.00-1.40), both the first and second trimesters (OR = 1.28; 95% CI, 1.00-1.64), or in any trimester (OR = 1.20; 95% CI, 1.01-1.42) was associated with an increased risk of ADHD in offspring. Sensitivity analysis excluding gestational infections and maternal mental health disorders confirmed this association (OR = 1.33; 95% CI, 1.04-1.69).CONCLUSION:Prenatal exposure to acetaminophen was associated with an increased risk of ADHD in offspring, regardless of gestational infections and maternal mental health disorders. Additional studies are necessary to clarify the underlying mechanisms by which prenatal exposure to acetaminophen leads to neurodevelopmental risks.