Healthy lifestyles are associated with alleviating the single-nucleotide polymorphism-based genetic risks of ischaemic stroke, intracerebral haemorrhage and myocardial infarction.

BACKGROUND: Both genetic and lifestyle factors contribute to myocardial infarction (MI) and stroke, including ischaemic stroke (IS) and intracerebral haemorrhage (ICH). We explored how and the extent to which a healthy lifestyle, by considering a comprehensive list, could counteract the genetic risk of those diseases, respectively. METHODS: 315 044 participants free of stroke and MI at baseline were identified from the UK Biobank. Genetic risk scores (GRS) for those diseases were constructed separately and categorised as low, intermediate and high by tertile. Lifestyle risk scores (LRS) were constructed separately using smoking, alcohol intake, physical activity, dietary patterns and sleep patterns. Similarly, participants were categorised into low, intermediate and high LRS. The data were analysed using Cox proportional hazard models. RESULTS: Over a median follow-up of 12.8 years, 4642, 1046 and 9485 participants developed IS, ICH and MI, respectively. Compared with participants with low levels of GRS and LRS, the HRs of those with high levels of GRS and LRS were 3.45 (95% CI 2.71 to 4.41), 2.32 (95% CI 1.40 to 3.85) and 4.89 (95% CI 4.16 to 5.75) for IS, ICH and MI, respectively. Moreover, among participants with high GRS, the standardised 14-year rates of IS events were 4.40% (95% CI 3.45% to 5.36%) among those with high LRS. In contrast, it is only 1.78% (95% CI 1.63% to 1.94%) among those with low LRS. Similarly for MI, the high LRS group had standardised rates of 8.60% (95% CI 7.38% to 9.81%), compared with 3.34% (95% CI 3.12% to 3.56%) in low LRS. Among the high genetic risk group of ICH, the rate is reduced by about half compared low LRS to high LRS, although the rate was low for both (0.36% (95% CI 0.31% to 0.42%) and 0.71% (95% CI 0.36% to 1.05%), respectively). CONCLUSION: Healthy lifestyles were substantially associated with a reduction in the risk of IS, ICH and MI and attenuated the genetic risk of IS, ICH and MI by at least half, respectively.

Euphorbia helioscopia L. exhibits promising therapeutic effects on hemangioendothelioma and melanoma through angiogenesis inhibition.

BACKGROUND: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor. PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma. METHODS: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations. RESULTS: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects. CONCLUSION: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis.

Single extracellular vesicle surface protein-based blood assay identifies potential biomarkers for detection and screening of five cancers.

Extracellular vesicles (EVs) and EV proteins are promising biomarkers for cancer liquid biopsy. Herein, we designed a case-control study involving 100 controls and 100 patients with esophageal, stomach, colorectal, liver, or lung cancer to identify common and type-specific biomarkers of plasma-derived EV surface proteins for the five cancers. EV surface proteins were profiled using a sequencing-based proximity barcoding assay. In this study, five differentially expressed proteins (DEPs) and eight differentially expressed protein combinations (DEPCs) showed promising performance (area under curve, AUC > 0.900) in pan-cancer identification [e.g., TENM2 (AUC = 0.982), CD36 (AUC = 0.974), and CD36-ITGA1 (AUC = 0.971)]. Our classification model could properly discriminate between cancer patients and controls using DEPs (AUC = 0.981) or DEPCs (AUC = 0.965). When distinguishing one cancer from the other four, the accuracy of the classification model using DEPCs (85-92%) was higher than that using DEPs (78-84%). We validated the performance in an additional 14 cancer patients and 14 controls, and achieved an AUC value of 0.786 for DEPs and 0.622 for DEPCs, highlighting the necessity to recruit a larger cohort for further validation. When clustering EVs into subpopulations, we detected cluster-specific proteins highly expressed in immune-related tissues. In the context of colorectal cancer, we identified heterogeneous EV clusters enriched in cancer patients, correlating with tumor initiation and progression. These findings provide epidemiological and molecular evidence for the clinical application of EV proteins in cancer prediction, while also illuminating their functional roles in cancer physiopathology.

Long-standing overt ventriculomegaly in adulthood with primary presentation of psychiatric disturbance: A case report.

RATIONALE: Hydrocephalus is a common disease in neurosurgery. The typical symptoms of hydrocephalus include urinary incontinence, gait instability, and cognitive decline. Irritability rarely occurs in patients with hydrocephalus. Irritability rarely occurs in patients with hydrocephalus, especially in long-standing overt ventriculomegaly of adulthood (LOVA). PATIENT CONCERNS: A 30-year-old female was admitted to our hospital because of mental retardation and unstable gait for more than 15 years. She had undergone ventriculoperitoneal shunt 15 years prior due to ventriculomegaly and related symptoms. However, the shunt catheter was removed shortly after surgery because of blockage, with no further postoperative treatment. DIAGNOSIS: The patient was diagnosed with long-standing overt ventriculomegaly according to her head circumference and clinical symptoms, including adult hydrocephalus development, overt triventriculomegaly and absence of a secondary cause for aqueductal stenosis in adulthood. INTERVENTIONS: After considerable discussion, she underwent ventriculoperitoneal shunt placement and showed dramatic and sustained improvement. OUTCOMES: The patient has been followed at 3-month intervals for over 2 years since discharge, and both the patient and family have reported a significant change in their daily life. She was able to live independently and control her emotions. Slight epilepsy was noted approximately 5 months after surgery but recovered 2 months later. LESSONS: It is difficult to decide whether to treat LOVA when the in patients whose symptoms are not significant. We believe that early diagnosis and positive treatment can help improve outcomes and would recommend ventriculoperitoneal (VP) shunting in patients with LOVA.

Retraction Note to: Oridonin triggers G2/M cell cycle arrest, cellular apoptosis and autophagy in human gastric cancer cells.

Retraction of "Oridonin triggers G2/M cell cycle arrest, cellular apoptosis and autophagy in human gastric cancer cells", by Dongliang Zhu, Xiaoling Tian, Xiaoping Yin, Haidong Yan, Weihao Li. JBUON 2020;25(5):2308-2314; PMID: 33277850 Following the publication of the above article, readers drew to our attention that part of the data was unreliable: Figures of this article appeared in other articles (by totally different authors). The authors were requested to provide the raw data and were also asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. Given above, we decided to retract this article. Authors were informed of the retraction. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Life-threatening hemoptysis accompanied by internal thoracic artery aneurysms in a 28-year-old perinatal woman: a case report.

BACKGROUND: Life-threatening hemoptysis presents an immediate diagnostic and therapeutic challenge, especially during the perinatal period. CASE PRESENTATION: A 28-year-old perinatal woman with no significant past medical or surgical history presented with repeating hemoptysis and respiratory failure. Computed tomography revealed a 2.1 × 3.2  cm2 inhomogeneous tumorous lesion in the right superior mediastinum and a right main bronchus obstruction along with atelectasis of the right lung. Bronchoscopy showed a tumorous protrusion blocking the right main bronchus with active hemorrhage, and malignancy was suspected. Bronchial artery embolization (BAE) was performed to control the bleeding. The arteriogram revealed tortuosity, dilation and hypertrophy of the right bronchial arteries and aneurysms of the internal thoracic artery (ITA). The bleeding completely stopped after BAE. Bronchoscopy was performed again to remove residual blood clots. The patient recovered soon after the procedure and was discharged. CONCLUSIONS: Life-threatening hemoptysis concomitant with ITA aneurysms, which may have a misleading clinical diagnosis and treatment options, has not been reported previously in perinatal women. BAE could be used as a first-line treatment irrespective of the underlying causes.

Oridonin triggers G2/M cell cycle arrest, cellular apoptosis and autophagy in human gastric cancer cells.

PURPOSE: Gastric carcinoma is the fourth principal cause of cancer-related deaths throughout the globe. There are inadequate clinical therapies for gastric cancer due to lack of operational drugs and ambiguity in molecular mechanisms. As such there is a persistent requirement for novel and effective anticancer drugs for gastric cancer. The main purpose of the current study was to investigate the antitumor effects of a plant diterpenoid, namely Oridonin, against SGC-7901 human gastric cancer cells along with examining its effects on cellular apoptosis, cell autophagy and cell cycle phase distribution. METHODS: WST-1 cell proliferation assay was used to evaluate cell viability of SGC-7901 human gastric cancer cells. Apoptosis was evaluated by using DAPI and comet assays using fluorescence microscopy. Autophagy was evaluated by transmission electron microscopy (TEM) and western blot method. Effects on cell cycle phase distribution were studied by flow cytometry. RESULTS: Oridonin molecule led to considerable and dose-dependent antiproliferative effects on SGC-7901 human gastric cancer cells exerting only mild cytotoxic effects in normal cells thus exhibiting selective toxicity. The number of gastric cancer cell colonies decreased significantly as oridonin dose increased. DAPI and comet assays revealed that oridonin induced powerful apoptotic effects in these cells, triggering significant DNA damage and both these effects exhibited dose-dependence. TEM indicated that oridonin induced autophagy in SGC-7901 cells by creating autophagosomes and autophagic vacuoles. Oridonin also targeted G2/M phase cell cycle in these gastric cancer cells along with targeting some key cell cycle related proteins including cyclin-B1, cyclin D1 and cyclin E. CONCLUSION: In conclusion, the results show that oridonin showed strong anticancer effects in SGC-7901 human gastric cancer cells by triggering apoptosis and autophagy, and targeting cell cycle at G2/M phase.

Spectrally Combined Encoding for Profiling Heterogeneous Circulating Tumor Cells Using a Multifunctional Nanosphere-Mediated Microfluidic Platform.

Comprehensive phenotypic profiling of heterogeneous circulating tumor cells (CTCs) at single-cell resolution has great importance for cancer management. Herein, a novel spectrally combined encoding (SCE) strategy was proposed for multiplex biomarker profiling of single CTCs using a multifunctional nanosphere-mediated microfluidic platform. Different cellular biomarkers uniquely labeled by multifunctional nanosphere barcodes, possessing identical magnetic tags and distinct optical signatures, enabled isolation of heterogeneous CTCs with over 91.6 % efficiency and in situ SCE of phenotypes. By further trapping individual CTCs in ordered microstructures on chip, composite single-cell spectral signatures were conveniently and efficiently obtained, allowing reliable spectral-readout for multiplex biomarker profiling. This SCE strategy exhibited great potential in multiplex profiling of heterogeneous CTC phenotypes, offering new avenues for cancer study and precise medicine.

Associations between DNAH1 gene polymorphisms and male infertility: A retrospective study.

Genetic abnormalities could account for 10% to 15% of male infertility cases, so increasing attention is being paid to gene mutations in this context. DNAH1 gene polymorphisms are highly correlated with astheno-teratozoospermia, but limited information has been reported on pathogenic variations in DNAH1 in the Chinese population. We explored 4 novel variations of the DNAH1 gene in Chinese infertile patients. Mutation screening of the DNAH1 gene was performed on 87 cases of asthenozoospermia with targeted high-throughput sequencing technology; another 200 nonobstructive azoospermia cases were further analyzed to investigate the prevalence of DNAH1 variations. The effects of the variations on protein function were further assessed by bioinformatic prediction. For carriers of DNAH1 variations, genetic counseling should be considered. Assisted reproductive technologies should be performed for these individuals and microsurgery should be considered for patients with azoospermia. DNAH1 variations were identified in 6 of 287 patients. These included 8 heterozygous variations in exons and a splicing site. Among these, 4 variations (g.52400764G>C, g.52409336C>T, g.52430999_52431000del, g.52412624C>A) had already been registered in the 1000 Genomes and Exome Aggregation Consortium databases. The other 4 novel variations (g.52418050del, g.52404762T>G, g.52430536del, g.52412620del) were all predicted to be pathogenic by in silico analysis. The variations g.52418050del and g.52430999_52431000del were detected in 1 patient who was more severe than another patient with the variation g.52430999_52431000del. Physicians should be aware of genetic variants in male infertility patients and DNAH1 mutations should be considered in patients with asthenospermia or azoospermia.

Preparation of Monodisperse Hydrophilic Quantum Dots with Amphiphilic Polymers.

Monodisperse hydrophilic quantum dots (QDs) are promising labeling materials for biomedical applications. However, the controllable preparation of monodisperse hydrophilic QDs with amphiphilic polymers remains a challenge. Herein, the molecular structures of amphiphilic polymers assembled on different-sized QDs are investigated. Both the experimental results and the molecular dynamics (MD) calculation suggest that the grafting ratio of amphiphilic polymers assembled on QDs increases as the size of QDs increases. Thus, the controllable preparation of different-sized monodisperse hydrophilic QDs can be achieved by simply varying the grafting ratio of amphiphilic molecules and applied in the simultaneous labeling of three tumor biomarkers.

ERα propelled aberrant global DNA hypermethylation by activating the DNMT1 gene to enhance anticancer drug resistance in human breast cancer cells.

Drug-induced aberrant DNA methylation is the first identified epigenetic marker involved in chemotherapy resistance. Understanding how the aberrant DNA methylation is acquired would impact cancer treatment in theory and practice. In this study we systematically investigated whether and how ERα propelled aberrant global DNA hypermethylation in the context of breast cancer drug resistance. Our data demonstrated that anticancer drug paclitaxel (PTX) augmented ERα binding to the DNMT1 and DNMT3b promoters to activate DNMT1 and DNMT3b genes, enhancing the PTX resistance of breast cancer cells. In support of these observations, estrogen enhanced multi-drug resistance of breast cancer cells by up-regulation of DNMT1 and DNMT3b genes. Nevertheless, the aberrant global DNA hypermethylation was dominantly induced by ERα-activated-DNMT1, since DNMT1 over-expression significantly increased global DNA methylation and DNMT1 knockdown reversed the ERα-induced global DNA methylation. Altering DNMT3b expression had no detectable effect on global DNA methylation. Consistently, the expression level of DNMT1 was positively correlated with ERα in 78 breast cancer tissue samples shown by our immunohistochemistry (IHC) analysis and negatively correlated with relapse-free survival (RFS) and distance metastasis-free survival (DMFS) of ERα-positive breast cancer patients. This study provides a new perspective for understanding the mechanism underlying drug-resistance-facilitating aberrant DNA methylation in breast cancer and other estrogen dependent tumors.

The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.

Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evan's blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil's neuroprotective activities in MS.

Minocycline reduces oxygen-glucose deprivation-induced PC12 cell cytotoxicity via matrix metalloproteinase-9, integrin ß1 and phosphorylated Akt modulation.

Minocycline has shown anti-inflammatory, anti-apoptotic, and antioxidative activities in many models of cerebral ischemia and human acute ischemic stroke. However, the cellular and molecular bases for its neuroprotective effects have not been fully elucidated. In this study, we investigated whether pre-treatment with minocycline could attenuate oxygen-glucose deprivation-induced PC12 cytotoxicity. The activity of matrix metalloproteinase-9 was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. And the expressions of integrin ß1, Akt and phosphorylated Akt were analyzed by Western blot. Our results showed that minocycline could ameliorate oxygen-glucose deprivation-induced PC12 cell cytotoxicity at concentrations of 20 nM-20 µM, down-regulate the production and activity of matrix metalloproteinase-9, inhibit the degradation of integrin ß1, and up-regulate Akt phosphorylation at optimal concentration of 200 nM. The results may provide a new area for minocycline's therapeutic intervention for improving the outcomes of cerebral ischemia.

High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy.

For breast cancer patients with lymph node metastasis, paclitaxel is the first-line chemotherapy drug. Clinical studies showed that some patients with breast cancer were insensitive to paclitaxel, which led to chemotherapy failure. Today, no validated markers exist for the prediction of chemotherapy sensitivity in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis. Epidemiological studies have also associated elevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy. Additionally, our previous study proved that TIMP-1 significantly decreased the sensitivity of breast cancer cells to paclitaxel-induced apoptosis by enhancing degradation of cyclin B1. These data imply that TIMP-1 may be a useful predictive biomarker for chemotherapy resistance. In this retrospective study, we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel-based chemotherapy in 99 patients with breast cancer. With Kaplan-Meier survival analysis, the patients with high TIMP-1 levels were found to have significantly worse 5-year DFS (71.1 %) than the patients with low levels (88.5 %; P = 0.020). Similarly, the patients with high TIMP-1 levels had significantly worse 5-year OS (78.9 %) than patients with low levels (96.7 %; P = 0.004). In Cox's univariate and multivariate analyses, TIMP-1 was prognostic for both DFS and OS. Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel-based chemotherapy, and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel-based chemotherapy.

[Artemin and GFRalpha3 expressions and their relevance to perineural invasiveness and metastasis of pancreatic carcinoma].

OBJECTIVE: To investigate the association of artemin and GFRalpha3 expressions with perineural invasion and metastasis of pancreatic carcinoma. METHODS: Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to detect the expression of artemin and GFRalpha3 in pancreatic carcinoma tissues, adjacent tissues and normal pancreas tissues, and the relevance of artemin and GFRalpha3 expressions to the perineural invasion and metastasis of pancreatic carcinoma were analyzed. RESULTS: The positivity rates of artemin and GFRalpha3 expressions were 72.09% and 67.44% in pancreatic carcinoma, respectively, significantly higher than those in the adjacent tissue (18.19% and 22.73%). The positivity rates of artemin and GFRalpha3 expressions were significantly higher in patients with perineural invasion than in those without perineural invasion (chi(2)=11.11 and 11.78, respectively, P<0.01). Significantly higher expression of artemin mRNA was noted in pancreatic carcinoma (0.741-/+0.014) than in the normal pancreas tissue (0.101-/+0.031, P<0.05), and patients with perineural invasion showed significantly higher positivity rates of artemin mRNA expression (0.843-/+0.012) than those without perineural invasion (0.512-/+0.017, P<0.05). CONCLUSION: Artemin and GFRalpha3 expressions may play an important role in perineural invasion of pancreatic carcinoma and can be used a useful indicators for evaluating the biological behavior of pancreatic carcinomas.