Association of cannabis use disorder with cardiovascular diseases: A two-sample Mendelian randomization study.

Background: The use of cannabis has increased globally due to more regions decriminalizing marijuana use for therapeutic and recreational aims. Several observational studies have revealed that cannabis use is associated with an increased risk of adverse cardiovascular pathologies and diseases. Nevertheless, the causal associations between cannabis use and cardiovascular diseases remain unclear. Hence, we performed single-variable and multivariable Mendelian randomization (MR) to evaluate the association between cannabis use disorder and various cardiovascular diseases. Materials and methods: Summary statistics were collected from the largest-to-date genome-wide association studies (GWAS) of cannabis use disorder. The 12 SNPs for cannabis use disorder were used as instrumental variables in this study. MR estimates were pooled using a random-effects inverse-variance weighted (IVW) method. Simple median and weighted median methods were conducted as sensitivity analyses. Results: The genetic liability to cannabis use disorder was associated with an augmented risk of coronary artery disease, myocardial infarction, atrial fibrillation, heart failure, deep venous thrombosis, pulmonary embolism, and stroke. Except for stroke, the results were inconsistent in the sensitivity analyses. The overall patterns for the associations of cannabis use disorder with atrial fibrillation, heart failure, pulmonary embolism and stroke remained in multivariable MR analyses adjusting for potential mediators, including smoking, alcohol, body mass index, blood lipid, type 2 diabetes, hypertension, and depression. However, the association with coronary artery disease, myocardial infarction, and deep venous thrombosis did not persist in multivariable MR analyses. Mediation analysis demonstrated that smoking, body mass index, low-density lipoprotein, hypertension, and depression have more significant mediation effects, which suggests that these factors partly mediate the link from cannabis use disorder to coronary artery disease, myocardial infarction, and deep venous thrombosis. Conclusion: The genetic liability to cannabis use disorder was associated with a higher risk of atrial fibrillation, heart failure, pulmonary embolism, and stroke. The evidence for the association between cannabis use disorder, coronary artery disease, myocardial infarction, and deep venous thrombosis was weak. Hence, future use of cannabis for therapeutic and recreational aims should consider its potential impact on cardiovascular diseases.

Piceatannol alleviates glucolipotoxicity induced vascular barrier injury through inhibition of the ROS/NF-kappa B signaling pathway.

Vascular barrier dysfunction is considered as the initial and critical event in atherosclerosis progression. Recent studies have revealed that treatment with piceatannol (PIC) alleviates both acute and chronic responses to vascular injury. We investigated whether PIC treatment would have beneficial effects on glucolipotoxicity-induced endothelial barrier dysfunction. Target proteins of PIC were identified from several online databases. Then, we confirmed the effect of PIC on endothelial barrier function. PIC treatment mitigated the impairment of endothelial cell motility, adhesion and migration ability associated with high glucose/lipid stimulation. PIC stabilized cytoskeletal reorganization and expression of cell cytoskeletal associated proteins GTPase. PIC reversed changes in critical vascular junction proteins and thus preserved endothelial barrier function and permeability. Finally, we confirmed that reducing of nuclear factor kappa B (NF-κB)/p65 activation and elimination of reactive oxygen species (ROS) were involved in the protective effect of PIC against glucolipotoxicity-induced vascular barrier injury. We identify PIC as a promising therapeutic strategy for glucolipotoxicity-induced endothelial barrier injury.

Distinct origins and functions of cardiac orthotopic macrophages.

Macrophages are one cell type in the innate immune system. Recent studies involving macrophages have overturned the conventional concept that circulating bone marrow-derived blood mononuclear cells in the adult body continuously replace macrophages residing in the tissues. Investigations using refined technologies have suggested that embryonic hematopoiesis can result in the differentiation into macrophage subgroups in some tissues. In adulthood, these macrophages are self-sustaining via in situ proliferation, with little contribution of circulating bone marrow-derived blood mononuclear cells. Macrophages are integral component of the heart, accounting for 8% of the non-cardiac cells. The use of innovative molecular techniques in paradigm shifting researches has revealed the complexity of cardiac macrophages, including their heterogeneity and ontological diversity. Resident cardiac macrophages modulate the physiological and pathophysiological processes of the cardiovascular system, with distinct and crucial roles in healthy and injured hearts. Their functions include sensing of pathogens, antigen presentation, digesting cell debris, regulating inflammatory responses, generating distinct cytokines, and secreting some regulatory factors. More recent studies have revealed further functions of cardiac macrophages. This review focuses on macrophages within the cardiovascular system. We discuss evidence that has changed our collective view of cardiac macrophage subgroups, and improved our understanding of the different phenotypes, cell surface markers, heterogeneities, origins, developments, and the dynamic and separate roles of these cardiac macrophage subgroups in the steady state and injured hearts. This review may provide novel insights concerning the pathophysiology of cardiac-resident macrophages in cardiovascular diseases and innovative therapeutic strategies that could include the modulation of the role of macrophages in cardiovascular injuries.

Nonvolatile Control of the Electronic Properties of In2-xCrxO3 Semiconductor Films by Ferroelectric Polarization Charge.

A series of Cr-doped In2-xCrxO3 (ICO) semiconductor thin films were epitaxially grown on (111)-oriented 0.71Pb(Mg1/3Nb2/3)O3-0.29PbTiO3 (PMN-0.29PT) single-crystal substrates by the pulsed laser deposition. Upon the application of an electric field to the PMN-0.29PT substrate along the thickness direction, we realized in situ, reversible, and nonvolatile control of the electronic properties and Fermi level of the films, which are manifested by abundant physical phenomena such as the n-type to p-type transformation, metal-semiconductor transition, metal-insulator transition, crossover of the magnetoresistance (MR) from negative to positive, and a large nonvolatile on-and-off ratio of 5.5 × 104% at room temperature. We also strictly disclose that both the sign and the magnitude of MR are determined by the electron carrier density of ICO films, which could modify the s-d exchange interaction and weak localization effect. Our results demonstrate that the ferroelectric gating approach using PMN-PT can be utilized to gain deeper insight into the carrier-density-related electronic properties of In2O3-based semiconductors and provide a simple and energy efficient way to construct multifunctional devices which can utilize the unique properties of composite materials.

Cystic and solitary nodular pulmonary metastases in a patient with low-grade endometrial stromal sarcoma: A case report and literature review.

Pulmonary metastases of endometrial stromal sarcoma (ESS) are uncommon and can be difficult to diagnose. The aims of the present study were to investigate the clinical and pathological features, and enhance the awareness of pulmonary metastases in patients with low-grade ESS. The study reports a case of low-grade ESS that resulted in cystic and nodular pulmonary metastases. Furthermore, the PubMed database was searched using 'pulmonary metastases of low-grade endometrial stromal sarcoma' as the key phrase. The literature on pulmonary metastases of low-grade ESS was reviewed and 35 cases were included in the present study. The clinical manifestations, imaging data, pathological features, treatment and prognosis of the 35 previously reported cases and the current case were retrospectively analyzed. The age range of the 36 patients diagnosed with low-grade ESS was 28-65 years. The time period from confirmation of ESS to lung metastases was 1.5-27 years. In 50% of the patients, the pulmonary metastases were asymptomatic. The most common pulmonary symptom was dyspnea, followed by chest pain, pneumothorax and coughing. The most common chest imaging presentation was multiple pulmonary nodules, followed by a solitary nodule or mass. Histology was used to identify that the pulmonary metastases had the pathological features of low-grade ESS. The immunohistochemical results demonstrated strong diffuse immunoreactivity for cluster of differentiation 10, estrogen receptor and progesterone receptor in almost all the specimens. The review of the literature revealed that pulmonary metastases from low-grade ESS are rare but not negligible. Furthermore, the detailed clinical information, imaging findings and immunohistochemical detection are important for making a diagnosis.

Prognostic significance of miR-1268a expression and its beneficial effects for post-operative adjuvant transarterial chemoembolization in hepatocellular carcinoma.

Our recent investigation has shown that the variables of microRNA-1268a may involve in hepatocellular carcinoma (HCC) tumorigenesis. Here, we attempted to identify the prognostic significance of microRNA-1268a expression in tumor tissues by a retrospective analysis in 411 patients with HCC, and analyze its effects on post-operative adjuvant transarterial chemoembolization (TACE) improving HCC prognosis. All cases received tumor resection or tumor resection plus post-operative adjuvant TACE as an initial treatment. Logistical regression analysis exhibited that microRNA-1268a expression was significantly correlated with tumor stage, tumor grade, tumor size, and microvessel density. Cox regression analysis showed that microRNA-1268a expression was an independent prognostic factor for HCC, and TACE treatment had no effects on prognosis of HCC patients with high microRNA-1268a expression. More intriguingly, TACE improved the prognosis of HCC patients with low microRNA-1268a expression. Functionally, overexpression of microRNA-1268a inhibited while its inhibitor enhanced doxorubicin-induced the death of cancer cells. These results suggest that microRNA-1268a may be an independent prognostic factor for HCC patients, and that decreasing microRNA-1268a expression may be beneficial for post-operative adjuvant TACE treatment in HCC.

Composite diffuse large B-cell lymphoma and classical Hodgkin's lymphoma of the stomach: case report and literature review.

The combination of classical Hodgkin's lymphoma (cHL) and non-Hodgkin lymphoma coexisting in the same patient is not common, especially in one extranodal location. Here we present a rare case of composite diffuse large B-cell lymphoma (DLBCL) and cHL occurring simultaneously in the stomach of a 53-year-old female who presented with upper abdominal discomfort and gas pain. Surgery was performed and the disease was diagnosed pathologically as composite lymphoma of DLBCL and cHL using hematoxylin-eosin and immunohistochemical staining. Epstein-Barr virus (EBV) infection was not detected by in situ hybridization for EBV-encoded RNA or immunohistochemistry for EBV latent membrane protein-1. Polymerase chain reaction analysis from the two distinct components of the tumor demonstrated clonal immunoglobulin κ light chain gene rearrangements. The patient died approximately 11 mo after diagnosis in spite of receiving eight courses of the CHOP and two courses of the rituximab-CHOP (RCHOP) chemotherapy regimen. This case report showed that the two distinct components, DLBCL and cHL, appeared to originate from the same clonal progenitor cell, and that EBV infection was not essential for transformation during the course of tumorigenesis.

Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia.

Impaired local cellular immunity contributes to the pathogenesis of persistent high-risk human papillomavirus (HR-HPV) infection and related cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms remain unclear. Recently, the programmed death 1/programmed death 1 ligand (PD-1/PD-L1; CD279/CD274) pathway was demonstrated to play a critical role in attenuating T-cell responses and promoting T-cell tolerance during chronic viral infections. In this study, we examined the expression of PD-1 and PD-L1 on cervical T cells and dendritic cells (DCs), respectively, from 40 women who were HR-HPV-negative (-) or HR-HPV-positive (+) with CIN grades 0, I and II-III. We also measured interferon-γ, interleukin-12 (IL-12) and IL-10 in cervical exudates. The most common HPV type was HPV 16, followed by HPV 18, 33, 51 and 58. PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, was associated with HR-HPV positivity and increased in parallel with increasing CIN grade. The opposite pattern was observed for CD80 and CD86 expression on DCs, which decreased in HR-HPV+ patients in parallel with increasing CIN grade. Similarly, reduced levels of the T helper type 1 cytokines interferon-γ and IL-12 and increased levels of the T helper type 2 cytokine IL-10 in cervical exudates correlated with HR-HPV positivity and CIN grade. Our results suggest that up-regulation of the inhibitory PD-1/PD-L1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to the progression of HR-HPV-related CIN. These results may aid in the development of PD-1/PD-L1 pathway-based strategies for immunotherapy of HR-HPV-related CIN.

Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China.

In hepatocellular carcinoma (HCC), hotspot mutation in codon 249 of the p53 gene has been associated with exposure to aflatoxin B1 (AFB1). While the polymorphism of DNA repair gene X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln may be related with AFB1-DNA adducts and gene mutations. Five hundred one HCCs were included in this study to investigate the role of the XRCC1 codon 399 polymorphism on hotspot mutation in codon 249 of the p53 gene. The genotypes of XRCC1 codon 399 and p53 codon 249 were examined by PCR-RFLP. The HCC patients with XRCC1 genotypes with 399 Gln (namely: XRCC1-AG/GG) exhibited a significantly higher frequency of the p53 hotspot mutations in codon 249 than those with the wild-type homozygote of XRCC1 [namely: XRCC1-AA, adjusted odds ratio (OR) = 6.77, 95% confidence interval (CI) = 4.34-10.57]. Compared with those individuals who did express XRCC1-AA as reference (OR = 1), moreover, individuals featuring XRCC1-AG/GG and AFB1-DNA adducts did experience a significantly greater frequency of the hotspot mutation in codon 249 of the p53 gene (adjusted OR = 28.37, 95% CI = 13.19-61.02, P < 0.01). This study suggests that the XRCC1 Arg399Gln polymorphism and AFB1-DNA adducts are associated with the increased frequency of the p53 mutations in codon 249.