Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: The objective of this study is to utilize Mendelian randomization to scrutinize the mutual causality between migraine and venous thromboembolism (VTE) thereby addressing the heterogeneity and inconsistency that were observed in prior observational studies concerning the potential interrelation of the two conditions. METHODS: Employing a bidirectional Mendelian randomization approach, the study explored the link between migraine and VTE, incorporating participants of European descent from a large-scale meta-analysis. An inverse-variance weighted (IVW) regression model, with random-effects, leveraging single nucleotide polymorphisms (SNPs) as instrumental variables was utilized to endorse the mutual causality between migraine and VTE. SNP heterogeneity was evaluated using Cochran's Q-test and to account for multiple testing, correction was implemented using the intercept of the MR-Egger method, and a leave-one-out analysis. RESULTS: The IVW model unveiled a statistically considerable causal link between migraine and the development of VTE (odds ratio [OR] = 96.155, 95% confidence interval [CI]: 4.342-2129.458, p = 0.004), implying that migraine poses a strong risk factor for VTE development. Conversely, both IVW and simple model outcomes indicated that VTE poses as a weaker risk factor for migraine (IVW OR = 1.002, 95% CI: 1.000-1.004, p = 0.016). The MR-Egger regression analysis denoted absence of evidence for genetic pleiotropy among the SNPs while the durability of our Mendelian randomization results was vouched by the leave-one-out sensitivity analysis. CONCLUSION: The findings of this Mendelian randomization assessment provide substantiation for a reciprocal causative association between migraine and VTE within the European population.

Comparative Efficacy and Safety of Neoadjuvant Immunotherapy with Chemotherapy versus Chemotherapy Alone in Non-Small Cell Lung Cancer: A Propensity Score and Inverse Probability Treatment Weighting Analysis.

Purpose: This study aimed to compare the efficacy and safety of neoadjuvant chemotherapy (NCT) and neoadjuvant immunotherapy combined with chemotherapy (NICT) combined with radical lung cancer resection for the treatment of patients with resectable non-small cell lung cancer (NSCLC). To adjust for confounding factors, we innovatively adopted two matching methods: propensity score (PS) and inverse probability of treatment weighting (IPTW). Patients and Methods: We conducted a retrospective analysis of the clinicopathological features and prognosis of patients with resectable NSCLC treated with NCT or NICT combined with radical lung cancer resection using propensity score matching (PSM) at a ratio of 1:1 and IPTW to balance potential bias. Results: After PSM, 116 pairs of patients who had undergone NCT or NICT were selected for the final analysis. The pathological complete remission (pCR) and major pathological remission (MPR) rates were significantly better in the NICT group than in the NCT group (pCR rate of 44.8% vs 2.6%, P< 0.001; MPR rate of 66.4% vs 20.7%, P< 0.001). No significant difference was seen between the NICT and NCT groups in terms of postoperative complications (12.1% vs 9.5%, P=0.182). Patients in the NICT group had significantly better disease-free survival (DFS) and overall survival(OS) than those in the NCT group ([3-year DFS: 75.2% vs 43.3%, P< 0.001] and [3-year OS: 91.5% vs 58.0%, P< 0.001]). Among all patients, those with postoperative pathology of pCR had better DFS (P< 0.001) and OS (P= 0.009). Patients with postoperative pathology of MPR had better DFS (P< 0.001) and OS (P< 0.001). The IPTW method yielded similar pathologic and prognostic results. Conclusion: Patients with resectable NSCLC treated with NICT had better pathological responses and prognosis, than those treated with NCT, and the safety profiles of NICT and NCT were similar.

Y06014 is a selective BET inhibitor for the treatment of prostate cancer.

Bromodomain and extra-terminal proteins (BETs) are potential targets for the therapeutic treatment of prostate cancer (PC). Herein, we report the design, the synthesis, and a structure-activity relationship study of 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2(1H)-one derivative as novel selective BET inhibitors. One representative compound, 19 (Y06014), bound to BRD4(1) in the low micromolar range and demonstrated high selectivity for BRD4(1) over other non-BET bromodomain-containing proteins. This molecule also potently inhibited cell growth, colony formation, and mRNA expression of AR-regulated genes in PC cell lines. Y06014 also shows stronger activity than the second-generation antiandrogen enzalutamide. Y06014 may serve as a new small molecule probe for further validation of BET as a molecular target for PC drug development.

Analysis of internal spermatic vein embolization through catheter versus laparoscopic high ligation in treatment of left varicocele.

OBJECTIVE: Varicocele is a common disease in young and middle-aged men. This study aims to compare the efficacy of internal spermatic vein embolization of left varicocele versus laparoscopic high ligation. METHODS: From January 2017 to September 2018, a total of 69 varicocele patients were admitted and given the opportunity to choose the treatment option. Among these, 26 patients were treated with sclerosing agent injection, while 43 patients underwent laparoscopic surgery. They were followed up for 12 months after surgery, and the technical success rate, recurrence rate, complication rate, cost, operative time, and hospitalization time with regard to these two methods were analyzed. RESULTS: All patients completed the medical procedures. There was no recurrence in patients in the sclerotherapy group during the follow-up period; however, the complication rate was 19.2%. Furthermore, the operative time, hospitalization time, and cost of treatment were 31.1 ± 11.1 min, 1.2 ± 0.49 days, and 9613.11 ± 895.97 Yuan, respectively. In the laparoscopic group, 9 patients underwent laparoscopic bilateral high ligation, while 34 patients received treatment on the left side alone. The recurrence rate of left varicocele was 4.7% and the complication rate was 44.2%. Furthermore, the operative time, hospitalization time, and treatment cost were 50.4 ± 14.48 min, 4.0 ± 2.02 days, and 10,948.29 ± 2547.00 Yuan, respectively. Moreover, there were statistically significant differences (P < 0.05) in operative time, hospitalization time, and treatment cost. Patients in the sclerotherapy group had an advantage with respect to the overall complication rate when compared with patients from the laparoscopic group (X2 = 4.448, P < 0.05), and there was a statistically significant difference in hydrocele (X2 = 4.555, P < 0.05). However, there was no significant difference in the recurrence rate between these two groups (X2 = 1.245, P > 0.05). CONCLUSION: Patients who underwent sclerotherapy showed a higher technical success rate, a lower recurrence rate, fewer complications, and shorter hospitalization time compared to those treated with laparoscopic ligation. Transcatheter sclerosing agent injection may be a preferable treatment option for patients with unilateral varicocele.

One-step electrodeposition of the MOF@CCQDs/NiF electrode for chiral recognition of tyrosine isomers.

Electrochemical enantiorecognition of tyrosine (Tyr) isomers using a MOF@CCQDs/NiF electrode prepared by electrodepositing a metal-organic framework (MOF) and chiral carbon quantum dots (CCQDs) on Ni foil is reported. MOF@CCQDs/NiF not only shows highly selective, sensitive and quantitative analysis towards Tyr enantiomers but also presents the ability to determine l-Tyr% in racemic mixtures. This proposed that chiral sensors could be considered for practical applications in the field of Tyr related medical recognition.

MOF-Based Supramolecule Helical Nanomaterials: Toward Highly Enantioselective Electrochemical Recognition of Penicillamine.

For the first time, we report the formation of a chiral MOF-based helical nanomaterial (h-HDGA@ZIF-67) through arranging zeolitic imidazolate framework (ZIF-67) nanocrystals on helical l-glutamic acid terminated bolaamphiphile (h-HDGA) via a facile process at room temperature. The self-assembly leads to the chiral function of the ZIF-67 from an achiral ligand. The h-HDGA@ZIF-67 served as a new type of electrochemical sensing interface for recognizing and quantifying Pen enantiomers that realize significant enantioselectivity, satisfactory stability, and reproducibility. The synergetic effect from ZIF-67 nanocrystals on h-HDGA and stereoselectivity of h-HDGA@ZIF-67 lead to the excellent enantioselectivity. The present strategy showed the first example of a chiral MOF-based supramolecule helical nanomaterial, presenting high enantioselectivity for electrochemical enantiomeric determination.

Efficacy of Endovenous Laser Treatment Combined with Sclerosing Foam in Treating Varicose Veins of the Lower Extremities.

INTRODUCTION: This study aims to investigate the efficacy of incision-free endovenous laser treatment (EVLT) combined with sclerosing foam in treating varicose veins of the lower extremities. METHODS: A total of 140 patients (186 limbs) who underwent laser closure of the great saphenous vein + injection sclerotherapy were included in the present study. Preoperative information, intraoperative conditions, duration of the operation, and length of hospital stay were recorded in detail. During the 6-month follow-up, the closure of the trunk and branches of the great saphenous vein, postoperative pain, the recovery of ulcer and dermatitis, and postoperative complications were traced. RESULTS: All patients were treated with laser closure of the great saphenous vein and lauromacrogol injection. Twenty-six stage C6 limbs (lower extremity with ulcer) healed within 6 months, and the postoperative subjective pain disappeared after 1 month. In six patients, pigmentation in the surgical site did not completely disappear at 6 months after the operation. Saphenous nerve injury was found in five patients within 3 months after the operation, and all healed at 6 months after the operation. CONCLUSION: EVLT combined with sclerosing foam is effective for treating varicose great saphenous veins. TRIAL REGISTRATION: This study was registered at http://www.chictr.org.cn (registration number: ChiCTR1900021409).

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation.

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Nanoliposome-mediated FL/TRAIL double-gene therapy for colon cancer: in vitro and in vivo evaluation.

OBJECTIVE: To investigate the therapeutic effects of cationic nanoliposome-mediated gene therapy combined with immunotherapy for colon cancer treatment. METHODS: Recombinant plasmids containing green and red fluorescent protein reporter genes were constructed using gene cloning methods. Gene-carrying cationic nanoliposomes were prepared based on the electrostatic adherence principle and then transfected into dendritic cells (DC), which were transplanted into colon cancer cells. RESULTS: Recombinant plasmids containing green or red fluorescent protein reporter genes were successfully constructed by gene cloning and confirmed by restriction enzyme digestion and sequencing. Gene-carrying cationic nanoliposomes were transfected into colon cancer cells, and good gene expression was detected. A better level of apoptosis was observed in the combined group of tyrosine kinase receptor 3 ligand (FL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), while the lowest level was detected in the control group. The parameters in the FL and TRAIL groups were between the above-mentioned combined group. CONCLUSION: Cationic nanoliposomes have the advantage of being gene carriers. The joint therapeutic effects of the two genes are superior to those of a single gene. Gene therapy combined with immunotherapy has significant implications for cancer treatment.

Endovascular treatment of Budd-Chiari syndrome.

BACKGROUND: Budd-Chiari syndrome (BCS) is a posthepatic portal hypertension caused by the obstruction of the lumen of the hepatic veins or the proximal inferior vena cava (IVC). This study aimed to evaluate the clinical experience of interventional therapy for Budd-Chiari syndrome. METHODS: IVC venography was carried out first, the obliteration or stenosis in the IVC was opened or dilated with the hard guided wire or Rups100 puncture needle and balloon, then a stent was routinely implanted for the type of obliteration or stenosis. RESULTS: The procedure was successful in 821 out of 903 cases including IVC intervention in 760 cases, and hepatic vein intervention in 61 cases. An IVC stent was used in 517 cases and hepatic vein stent in 19 cases. There were no pulmonary embolisms, but acute renal failure occurred in eight cases, hepatic coma in two cases and acute heart failure in 43 cases. Two patients died in this group and five cases were complicated with acute IVC thrombosis. Follow up of 7 to 124 months was made in 679 cases with recurrence found in 59 cases. CONCLUSIONS: Interventional therapy is safe and effective with a fast recovery for most types of BCS. It is gradually becoming the first therapeutic choice.

Correlation between the expression of the BAG-1 gene and clinicopathologic factors in colorectal cancer.

OBJECTIVE: The present study aims to investigate the expression and significance of the anti-apoptotic gene Bag-1 in colorectal cancer and to evaluate the relationship between the gene and the disease. METHODS: Bag-1 expression was examined in 320 colorectal cancer and 30 normal colorectal tissue samples using reverse transcriptase polymerase chain reaction (RT-PCR) and the immunohistochemical staining (streptavidin-biotin-peroxidase complex method. RESULTS: Using RT-PCR, Bag-1 was observed to be expressed in colorectal cancer tissues, but not in normal colorectal tissues. The expression of Bag-1 in colorectal cancer was closely correlated with pathologic grade, distant metastasis, Dukes stage, and prognosis, but it was not correlated with the pathologic type, tumor diameter, depth of invasion, and lymph node metastasis. CONCLUSION: Bag-1 protein was found to be overexpressed in colorectal cancer. They might be regarded as a biomarker for the diagnosis of the early stages of colorectal cancer. In addition, they have particular significance for the prognosis of colorectal cancer.

[Induced differentiation of mouse embryonic stem cell into endothelial cell in vitro].

OBJECTIVE: To explore an optional condition to induce mouse embryonic stem cell (ESC) to differentiate into endothelial cells so as to provide seed cells for tissue engineered vascular. METHODS: The embryos from one pregnant 12.5-days mouse was harvested to culture the mouse embryonic fibroblasts (MEF). The ESC was reanimated by common method, and used to cultured into embryoid body (EB) in vitro. The EB which was used to induce into endothelial cells was divided into two groups. The EB was cultured in the EB medium with 3 ng/ml transforming growth factor beta1, 50 ng/ml vascular endothelial cell growth factor and 1 micromol/L potent and selective inhibitor of activin receptor-like kinase receptors in experimental group. The EB was cultured in the EB medium in the control group. After 14 days, RT-PCR and immunohistochemistry were used to detect vWF and CD34, to analyze the morphology and type of the differentiated cells from ESC. RESULTS: The primary MEF had a high proliferation activity. At the 3rd day, the fusion rate of MEF was about 90% with a fusiform shape. The cells was fusiform shape and arranged compactly with fullness of nucleus and 2-3 entoblasts. The 3rd-5th generations EB was polygonal with fullness of cytoplasm and 3-4 entoblasts. ESC could maintain undifferentiated state, and the cells unit looked like bird nest with smooth margin; the cells was small at size and strong refractivity with high rate of nuclein and rapid proliferation. At 3 days of drop-culture, EB can seen grossly and at 3 days of suspension, large and transparent EB formed. EB was spread radiately with an intensive adhesion at the 2nd day. In experimental group, many round cells was differentiated around EB from the 4th day to the 7th day, and form tubular structures from the 10th day to the 14th day. The vWF and CD34 were expressed. In control group, EB could not form tubular structures, and the vWF and CD34 were not expressed. CONCLUSION: ESC can differentiate into endothelial cells under some conditions, and form vessel-like structure under condition culture, which can provide sources of seed cells for tissue engineered vessel.