FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.

Development and validation of a nomogram for predicting poor operative visibility during FESS in Chinese adult patients with CRS.

Objective: The purpose of this study is to develop and evaluate a nomogram that is capable of predicting poor operative visibility during functional endoscopic sinus surgery. Method: To identify potential risk factors, patients with chronic rhinosinusitis who underwent functional endoscopic sinus surgery (FESS) between January 2019 and December 2022 were selected from our hospital's electronic medical record system. Data on general patient information, clinical manifestations, clotting-related test indices, Lund-Machay score of sinuses CT scanning, Lund-kennedy score of nasal endoscopies, anesthesia methods, intraoperative blood pressure and heart rate, and Boezaart bleeding score were collected. Minimum absolute convergence and selection operator (LASSO) regression, as well as multivariate logistic regression, were used to determine the risk factors. A nomogram was developed in order to predict poor operating visibility during FESS, and its performance was evaluated utilizing both the training and verification datasets via various measures including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC), Hosmer-Lemeshow goodness-of-fit test, calibration curve, and decision curve analysis. Results: Of the 369 patients who met the inclusion criteria, 88 of them exhibited POV during FESS. By deploying LASSO and multivariate logistic regression analyses, six risk factors were identified and used to construct a nomogram for predicting POV during FESS. These factors include prothrombin time (PT), prothrombin activity (PTA), Lund-Mackay score (LMS), Lund-Kennedy score (LKS), anesthetic method, and intraoperative hypertension. The AUC of the training set was found to be 0.820 while that of the verification set was 0.852. The Hosmer-Lemeshow goodness-of-fit test and calibration curve analysis revealed good consistency between predicted and actual probabilities. Also, the decision curve demonstrated that the nomogram had a high degree of clinical usefulness and net benefit. Conclusion: The constructed nomogram has a strong ability to predict the poor intraoperative field in patients with chronic rhinosinusitis, which can help preoperative judgment of high-risk patients and provide evidence for perioperative management and preoperative plan formulation.

A Purposefully Designed pH/GSH-Responsive MnFe-Based Metal-Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo-Chemodynamic-Starvation Synergistic Therapy.

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

Engineered bacteria combined with doxorubicin nanoparticles suppress angiogenesis and metastasis in murine melanoma models.

Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.

dSTORM-Based Single-Cell Protein Quantitative Analysis Can Effectively Evaluate the Degradation Ability of PROTACs.

As an emerging therapeutic strategy, proteolysis-targeting chimeras (PROTACs) have been proven to be superior to traditional drugs in many aspects. However, due to their unique mechanism of action, existing methods for evaluating the degradation still have many limitations, which seriously restricts the development of PROTACs. In this methodological study, using direct stochastic optical reconstruction microscopy (dSTORM)-based single-cell protein quantitative analysis, we systematically investigated the dynamic degradation characteristics of FLT3 protein during PROTACs treatment. We found that the distribution of FLT3 varies between FLT3-ITD mutation and FLT3-WT cells. PROTACs had an obvious time-course effect on protein degradation and present two distinct phases; this provided a basis for deciding when to evaluate protein degradation. High concentrations of PROTACs were more effective than long-time administration because a higher Dmax was achieved. Two-color dSTORM-based colocalization analysis efficiently detected the proportion of ternary complexes, making it very useful in screening PROTACs. Taken together, our findings show that the dSTORM method is an ideal tool for evaluating PROTACs and will accelerate the development of new PROTACs.

Head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in the detection of biochemical recurrence of prostate cancer: summary of head-to-head comparison studies.

PURPOSE: Our meta-analysis aimed to evaluate the diagnostic performance of 68Ga-PSMA-11 PET/CT vs. 68Ga-PSMA-11 PET/MRI for biochemical recurrence of prostate cancer. METHODS: We searched for relevant articles in PubMed and Embase until February 2022. Studies evaluating head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in men with prostate cancer biochemical recurrence were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 (QUADAS-2) tool. RESULTS: A total of 5 studies with 219 patients were included in the analysis. The pooled overall detection rates of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in detecting recurrent PCa after definitive treatment were 0.89 (95% CI: 0.65-1.00), 0.92 (95% CI: 0.77-1.00), while the detection rates were 0.20 (95% CI: 0.05-0.41) and 0.29 (95% CI: 0.10-0.53) in local recurrence, 0.51 (95% CI: 0.33-0.69) and 0.52 (95% CI: 0.44-0.61) in lymph node metastasis, 0.18 (95% CI: 0.07-0.33) and 0.20 (95% CI: 0.09-0.35) in bone metastasis. There was no significant difference between the two imaging modalities in the overall detection rate (P = 0.82). In addition, detection rates were also not significantly different in local recurrence, lymph node metastasis, or bone metastasis (P = 0.54, 1.00, 0.82). CONCLUSIONS: 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI seem to have equivalent performance in detecting biochemical recurrence in prostate cancer. However, the results of the meta-analysis were drawn from studies with small samples. Further larger studies in this setting are warranted.

Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.

Chemodynamic therapy (CDT) has advantages in site-specific killing tumor and avoiding systemically side effect. Although numerous nano-systems have been developed to enhance the intracellular hydrogen peroxide (H2O2) for improving CDT effect, the biocompatibility of the materials limits their further biomedical applications. Herein glycogen, as a natural biological macromolecule, was used to construct a new targeted separable GOx@GF/HC nanoparticle system to deliver glucose oxidase (GOx) for CDT/starvation tumor therapy. Amination glycogen-ferrocene (GF) as a guest core and hyaluronic acid-ß-cyclodextrin (HC) as a host shell were synthesized and self-assembled through host-guest interactions to deliver GOx. After being entered into tumor cells, GOx were released to catalyze glucose to produce gluconic acid and H2O2, which in turn cut off the nutrition of tumor cells for starvation therapy and enhanced the generation of OH with ferrous ion through Fenton reaction. Furthermore, GOx@GF/HC also exhibited remarkable tumor-targeting and tumor-suppression in vivo. Therefore, the GOx@GF/HC system can exert excellent synergistic effect of CDT and starvation therapy on cancer treatment through a cascade reaction, which have some potential application for the development of CDT tumor-treatment.

Cardiac-Related Lesions in Newly Diagnosed Patients With Acute Leukemia: A Chinese Population-Based Real-World Study.

The relationship between newly diagnosed acute leukemia (AL) and heart-related lesions remains unclear. This study aimed to investigate baseline cardiac function and risk of cardiovascular diseases (CVDs) in patients with new-onset AL, and provide data on cardiac management strategies for patients with AL. We retrospectively collected data on baseline characteristics, echocardiography, and biochemical blood indicators (e.g., myocardial enzymes) from 408 patients, 200 with newly diagnosed AL, 103 with coronary artery disease (CAD), and 105 controls from January 1, 2015 to August 31, 2019. The creatine kinase isoenzyme myocardial band, lactate dehydrogenase, highly sensitive troponin-I, and B-type natriuretic peptide levels and left ventricular internal diameter (LVID) were significantly higher in patients with newly diagnosed AL than in the control group. The degree of cardiac damage was lower in newly diagnosed AL patients than in CAD patients. The best predictor of heart damage was LVID (AUC [area under the curve] = 0.709; 95% CI [confidence interval]: 0.637-0.781; p < 0.001), and independent prognostic risk factors were age and ejection fraction (HR [hazard ratio] = 1.636; 95% CI: 1.039-2.575; p = 0.033). The ratio of leukemia blasts among patients with AL was positively correlated with cardiac damage. Our data indicated that newly diagnosed AL patients had certain myocardial damage before treatment. Clinicians need to pay attention to these manifestations, which may be related to the prognosis.

Role of STAT3 Expression in Thyroid Cancer: A Meta-Analysis and Systematic Review Based on the Chinese Population.

Background: Signal transduction and activator of transcription 3 (STAT3) is an oncogene with transcriptional activity. In recent years, there have been several studies concerning the clinicopathological significance of the expression of the STAT3 protein in thyroid cancer. However, the results are still inconsistent. In this study, we conducted a meta-analysis to evaluate the relationship between the expression of STAT3 protein and thyroid cancer susceptibility and its clinicopathological characteristics. Methods: We searched the China National Knowledge Infrastructure (CNKI) database, Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wanfang, PubMed, and EMBASE. The time frame of the publication search was from the establishment of each of the databases until December 2021. We performed a meta-analysis to quantitatively evaluate the relationship between the expression of the STAT3 protein in thyroid cancer and its clinicopathological characteristics. Results: A total of eight articles were included in the meta-analysis, covering 448 thyroid cancer patients and 227 controls. Results indicated that the expression of STAT3 protein in thyroid cancer tissue is highly expressed (OR = 14.41, 95% CI (6.94, 29.91), p < 0.001). Besides, we also discovered that STAT3 protein is negatively correlated with thyroid cancer tumor diameter and TNM stage (OR = 0.13, 95% CI (0.05, 0.33), p < 0.001; OR = 0.40, 95% CI (0.24, 0.67), p < 0.001) and positively correlated with lymph node metastasis (OR = 2.83, 95% CI (1.08, 7.46), p = 0.035). However, STAT3 expression is not related to gender (OR = 0.88, 95% CI (0.54, 1.44), p = 0.609), age (OR = 0.54, 95% CI (0.21, 1.36), p = 0.191), capsular invasion (OR = 2.98, 95% CI (0.23, 38.29), p = 0.403), or tumor multiplicity (OR = 0.25, 95% CI (0.003, 19.28), p = 0.533). Conclusions: This study reveals that STAT3 protein expression is significantly related to the susceptibility and clinicopathological characteristics of thyroid cancer. It also suggests that STAT3 may be a potential predictor of the clinical progression of thyroid cancer.

Fabrication of pH/Reduction Sensitive Polyethylene Glycol-Based Micelles for Enhanced Intracellular Drug Release.

At present, the drug is still difficult to release completely and quickly only with single stimulation. In order to promote the rapid release of polymeric micelles at tumor site, pH/reduction sensitive polymers (PCT) containing disulfide bonds and orthoester groups were synthesized. The PCT polymers can self-assemble in water and entrap doxorubicin to form drug-loaded micelles (DOX/PCT). In an in vitro drug release experiment, the cumulative release of DOX/PCT micelles in the simulated tumor microenvironment (pH 5.0 with GSH) reached (89.7 ± 11.7)% at 72 h, while it was only (16.7 ± 6.1)% in the normal physiological environment (pH 7.4 without GSH). In addition, pH sensitive DOX loaded micellar system (DOX/PAT) was prepared as a control. Furthermore, compared with DOX/PAT micelles, DOX/PCT micelles showed the stronger cytotoxicity against tumor cells to achieve an effective antitumor effect. After being internalized by clathrin/caveolin-mediated endocytosis and macropinocytosis, DOX/PCT micelles were depolymerized in intercellular acidic and a reductive environment to release DOX rapidly to kill tumor cells. Additionally, DOX/PCT micelles had a better inhibitory effect on tumor growth than DOX/PAT micelles in in vivo antitumor activity studies. Therefore, pH/reduction dual sensitive PCT polymers have great potential to be used as repaid release nanocarriers for intercellular delivery of antitumor drugs.

Bacteria-mediated cancer therapies: opportunities and challenges.

In recent years, cancer therapy strategies utilizing live tumor-targeting bacteria have presented unique advantages. Engineered bacteria have the particular ability to distinguish tumors from normal tissues with less toxicity. Live bacteria are naturally capable of homing to tumors, resulting in high levels of local colonization because of insufficient oxygen and low pH in the tumor microenvironment. Bacteria initiate their antitumor effects by directly killing the tumor or by activating innate and adaptive antitumor immune responses. The bacterial vectors can be reprogrammed following advanced DNA synthesis, sophisticated genetic bioengineering, and biosensors to engineer microorganisms with complex functions, and then produce and deliver anticancer agents based on clinical needs. However, because of the lack of knowledge on the mechanisms and side effects of microbial cancer therapy, developing such smart microorganisms to treat or prevent cancer remains a significant challenge. In this review, we summarized the potential, status, opportunities and challenges of this growing field. We illustrated the mechanism of tumor regression induced by engineered bacteria and discussed the recent advances in the application of bacteria-mediated cancer therapy to improve efficacy, safety and drug delivery. Finally, we shared our insights into the future directions of tumor-targeting bacteria in cancer therapy.

Silencing hsa_circ_PVT1 (circPVT1) suppresses the growth and metastasis of glioblastoma multiforme cells by up-regulation of miR-199a-5p.

Background: Glioblastoma multiforme (GBM) is one of the most prevailing primary brain tumours among adults and most aggressive cancers. Despite multiple developments in medical and surgical treatments, GBM is still a deadly disease with a high mortality rate. Here, this study was performed to investigate the function of circPVT1 on GBM.Methods: CCK-8 and flow cytometry were utilised to estimate viability and apoptosis in both cells. qRT-PCR was performed to determine circPVT1 and miR-199a-5p expression. Western blot was conducted to determine apoptosis, migration and EMT-related proteins levels when silencing circPVT1. Subsequently, these parameters were re-tested after up-regulating miR-199a-5p.Results: CircPVT1 was highly expressed in GBM tissues. Silencing circPVT1 raised two cells apoptosis and reduced viability and migration capacity. Moreover, EGF-induced EMT was repressed by silencing circPVT1. In addition, miR-199a-5p expression was elevated when silencing circPVT1. And silencing circPVT1 exerted above changes via up-regulating miR-199a-5p. Finally, silencing circPVT1 repressed YAP1 and PI3K/AKT pathways via up-regulating miR-199a-5p.Conclusion: Our data suggested that silencing circPVT1 inhibited viability, migration, EGF-induced EMT and promoted apoptosis as well as repressed YAP1 and PI3K/AKT pathways by up-regulating miR-199a-5p.HIGHLIGHTSCircPVT1 expression is highly expressed in GBM tissues;Si-circPVT1 represses migration and promoted apoptosis in U539 and U251 cells;Si-circPVT1 represses migration and promoted apoptosis when elevating miR-199a-5p;Si-circPVT1 represses EGF-induced EMT when increasing miR-199a-5p;Si-circPVT1 suppresses YAP1 and PI3K/AKT pathways by up-regulating miR-199-5p.

Catastrophic thoracolumbar spinal massive hematoma triggered by intraspinal anesthesia puncture: A CARE-compliant case report.

RATIONALE: Intraspinal anesthesia, the most common anesthesia type of orthopedic operation, is regarded as safe and simple. Despite of the rare incidence, puncture related complication of intraspinal anesthesia is catastrophic for spinal cord. Here we present an intradural hematoma case triggered by improper anesthesia puncture. The principal reason of this tragedy was rooted in the neglect of spine deformities diagnosis before anesthesia. To the best of our knowledge, there is no specific case report focusing on the intradural hematoma triggered by improper anesthesia puncture. PATIENT CONCERNS: Hereby a case of thoracolumbar spinal massive hematoma triggered by intraspinal anesthesia puncture was reported. The presenting complaint of the patient was little neurologic function improvement after surgery at 6-month follow-up. DIAGNOSES: Emergency MRI demonstrated that massive spindle-like intradural T2-weighted image hypointense signal masses from T12 to S2 badly compressed the dural sac ventrally, and his conus medullaris was at L3/4 intervertebral level with absence of L5 vertebral lamina. Hereby, the diagnoses were congenital spinal bifida, tethered cord syndrome, spine intradural hematoma, and paraplegia. INTERVENTIONS: Urgent surgical interventions including laminectomy, spinal canal exploration hematoma removal, and pedicle fixation were performed. The patient received both medication (mannitol, mecobalamin, and steroids) and rehabilitation (neuromuscular electric stimulation, hyperbaric oxygen). OUTCOMES: Postoperation, he had regained only hip and knee flexion at II grade strength. His neurologic function was unchanged until 3 weeks postoperation. Six-month follow-up showed just little neurologic function improvement, and the American Spinal Injury Association grade was C. LESSONS: By presenting an intradural hematoma case triggered by improper anesthesia puncture, we shared the treatment experience and discussed the potential mechanism of neurologic compromise. The principal reason for this tragedy is preanesthesia examination deficiency. Necessary radiology examinations must be performed to prevent misdiagnosis for spinal malformation.

Snail expression contributes to temozolomide resistance in glioblastoma.

Glioblastoma (GBM) is one of most malignancy tumors worldwide. Temozolomide (TMZ) is an important chemotherapy drug in GBM therapy. However, acquired TMZ-resistance frequently happens in GBM therapy and leads to high percentage of GBM recurrence. In our study, we demonstrated that Snail is upregulated in recurrent GBM tumors, and promotes the GBM cells resistant to TMZ induced apoptosis. Enhanced expression of Snail compromises the apoptosis induced by TMZ, and increases the cell migration and invasion. Reversely, depletion of Snail by siRNA has the opposite effects. In addition, we confirmed that the expression of Snail is modulated by STAT3 activation, since phospho-STAT3 level is relatively higher in recurrent GBM tumors and TMZ resistant cells. Knockdown of STAT3 turns down the expression of Snail in protein and mRNA level, and thereby sensitized the resistant GBM cells to TMZ treatment. Interestingly, the activation of STAT3 in GBM resistant cells is modulated by IL-6 secretion. Suppression of IL-6 abandons the STAT3 activation, and reduces its binding with Snail promoter. Inhibition of IL-6 by its antibody enhanced the killing effects of TMZ both in vivo and in vitro. Overall, our results provided a rational to overcome the TMZ resistant in GBM treatment by targeting IL-6-STAT3-Snail pathway.

Matrine induces apoptosis and autophagy of glioma cell line U251 by regulation of circRNA-104075/BCL-9.

BACKGROUND: Matrine, a traditional Chinese medicine, has been reported to exert anti-tumor effects in several types of cancers. Here, we explored the anti-tumor effects of matrine on the glioma cells. METHODS: Glioma cell line U251 cells were treated with matrine to assess viability and proliferation using CCK8 and EdU assays. PI/FITC staining was performed for apoptosis assay. Transfections were performed for circRNA-104075 or Bcl-9 overexpression. Western blot analysis was performed to evaluate changes of protein levels and changes of gene level were detected by qRT-PCR in U251 cells. RESULTS: Matrine suppressed cell viability while induced apoptosis and autophagy in U251 cells. Matrine also decreased circRNA-104075 expression significantly. Overexpression of circRNA-104075 was found to counteract the inhibitory effects of matrine on cell proliferation and promoting effects on apoptosis and autophagy in U251 cells. Moreover, the suppressed Wnt/ß-catenin and PI3K/AKT signaling pathways by matrine were activated by circRNA-104075 overexpression. Furthermore, Bcl-9 expression was also down-regulated by matrine treatment. Bcl-9 overexpression elevated the decreased cell proliferation while suppressed the increased apoptosis and autophagy induced by matrine in U251 cells. CONCLUSION: Taken together, the present findings suggested that matrine induced apoptosis and autophagy through down-regulating circ-104075 and Bcl-9 expression via inhibition of PI3K/AKT and Wnt-ß-catenin pathways in glioma cells. The present study provides a foundation for further preclinical and clinical evaluations of matrine as a glioma therapy.

Metabolic syndrome and liver-related events: a systematic review and meta-analysis.

BACKGROUND: Previous studies have suggested that metabolic syndrome (MetS) and its component conditions are linked to the development of many benign or malignant diseases. Some studies have described relationships among metabolic syndrome or diabetes and liver cancer, but not many articles described the relationships between MetS and cirrhosis, acute hepatic failure, end-stage liver disease, and even death. However, liver cancers, cirrhosis, acute hepatic failure, end-stage liver disease, and liver-related mortality-collectively described as liver-related events (LREs)-may have different relationships with MetS. We undertook this meta-analysis to examine the association between MetS and LREs, and to determine whether geographic region or hepatitis B virus (HBV) positivity might influence the association. METHODS: Relevant studies were identified from PubMed, EMBASE, and the Cochrane database. Two reviewers independently searched records from January 1980 to December 2017. The search terms included 'metabolic syndrome', 'diabetes mellitus', 'insulin resistance syndrome', and 'metabolic abnormalities', combined with 'cirrhosis', 'hepatic fibrosis ', 'hepatocellular carcinoma', 'complication', 'LRE', 'HCC', 'liver-related events', and 'liver cancer'. No language restriction was applied to the search. We chose the studies reporting an association between MetS and LREs. We used Begg's and Egger's tests and visually examined a funnel plot to assess publication bias. All analyses were conducted in Stata 14.0 software. RESULTS: There were 19 studies (18 cohort and 1 case-control) included in the analysis, with a total of 1,561,457 participants. The subjects' ages ranged from 18 to 84 years. The combined analysis showed an overall 86% increase risk of LREs in cases with MetS (RR: 1.86,95% CI: 1.56-2.23). The funnel plot was asymmetrical, and the Egger's test p values showed a publication bias in this meta analysis. However, through the trim and fill method, we obtained a new RR value for LREs with MetS of 1.49 (95% CI: 1.40-1.58, p = 0.000). There was no obvious difference with the two answers, so we concluded that the results were robust. For hepatitis B positive patients, the RR for MetS and LREs was 2.15 (95% CI:1.02-4.53, p = 0.038), but for the hepatitis B negative patients, the RR was 1.85 (95% CI:1.53-2.24, p = 0.000). And for non-Asians, the RR for MetS and LREs was 2.21 (95% CI: 1.66-2.69, p = 0.000), while for Asians, the RR was 1.73 (95% CI: 1.35-2.22, p = 0.000). CONCLUSIONS: This meta-analysis showed that MetS is associated with a moderately increased risk of LREs prevalence. Patients with MetS together with hepatitis B are more likely to develop hepatic events. For non-Asians, MetS is more likely to increase the incidence of LREs.

Shikonin kills glioma cells through necroptosis mediated by RIP-1.

BACKGROUND AND PURPOSE: Shikonin was reported to induce necroptosis in leukemia cells, but apoptosis in glioma cell lines. Thus, it is needed to clarify whether shikonin could cause necroptosis in glioma cells and investigate its underlying mechanisms. METHODS: Shikonin and rat C6 glioma cell line and Human U87 glioma cell line were used in this study. The cellular viability was assayed by MTT. Flow cytometry with annexin V-FITC and PI double staining was used to analyze cellular death modes. Morphological alterations in C6 glioma cells treated with shikoinin were evaluated by electronic transmission microscopy and fluorescence microscopy with Hoechst 33342 and PI double staining. The level of reactive oxygen species was assessed by using redox-sensitive dye DCFH-DA. The expressional level of necroptosis associated protein RIP-1 was analyzed by western blotting. RESULTS: Shikonin induced cell death in C6 and U87 glioma cells in a dose and time dependent manner. The cell death in C6 and U87 glioma cells could be inhibited by necroptosis inhibitor necrotatin-1, not by pan-caspase inhibitor z-VAD-fmk. Shikonin treated C6 glioma cells presented electron-lucent cytoplasm, loss of plasma membrane integrity and intact nuclear membrane in morphology. The increased ROS level caused by shikonin was attenuated by necrostatin-1 and blocking ROS by anti-oxidant NAC rescued shikonin-induced cell death in both C6 and U87 glioma cells. Moreover, the expressional level of RIP-1 was up-regulated by shikonin in a dose and time dependent manner as well, but NAC suppressed RIP-1 expression. CONCLUSIONS: We demonstrated that the cell death caused by shikonin in C6 and U87 glioma cells was mainly via necroptosis. Moreover, not only RIP-1 pathway, but also oxidative stress participated in the activation of shikonin induced necroptosis.

Ischemic postconditioning decreases cerebral edema and brain blood barrier disruption caused by relief of carotid stenosis in a rat model of cerebral hypoperfusion.

BACKGROUND AND PURPOSE: Complications due to brain edema and breakdown of blood brain barrier are an important factor affecting the treatment effects of patients with severe carotid stenosis. In this study, we investigated the protective effects of ischemic postconditioning on brain edema and disruption of blood brain barrier via establishing rat model of hypoperfusion due to severe carotid stenosis. METHODS: Wistar rat model of hypoperfusion due to severe carotid stenosis was established by binding a stainless microtube to both carotid arteries. Ischemic postconditioning procedure consisted of three cycles of 30 seconds ischemia and 30 seconds reperfusion. Brain edema was evaluated by measuring cerebral water content, and blood brain barrier permeability was assayed by examining cerebral concentration of Evans' Blue (EB) and fluorescein sodium (NaF). ELISA was used to analyze the expression of MMP-9, claudin-5 and occludin. The activity and location of MMP-9 was analyzed by gelatin zymography and in situ zymography, respectively. The distribution of tight junction proteins claudin-5 and occludin was observed by immunohistochemistry. RESULTS: The increased brain water content and cerebral concentration of EB and NaF were suppressed by administration of ischemic postconditioning prior to relief of carotid stenosis. Zymographic studies showed that MMP-9 was mainly located in the cortex and its activity was significantly improved by relief of carotid stenosis and, but the elevated MMP-9 activity was inhibited markedly by ischemic postconditioning. Immunohistochemistry revealed that ischemic postconditioning improved the discontinuous distribution of claudin-5 and occludin. ELISA detected that the expression of up-regulated MMP-9 and down-regulated claudin-5 and occludin caused by carotid relief were all attenuated by ischemic postconditioning. CONCLUSIONS: Ischemic postconditioning is an effective method to prevent brain edema and improve BBB permeability and could be used during relief of severe carotid stenosis.

Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress.

OBJECTIVE: To investigate the effects of inhalation of hydrogen gas on cognitive impairment induced by transient cerebral ischemia and its potential mechanism. METHODS: Two-vessel occlusion rat model was used to produce 10-minute transient global cerebral ischemia. One hundred and twenty male Wistar rats were randomly divided into sham, sham+H(2), ischemia, and ischemia+H(2) groups (n = 30 each group). Inhalation of 2% hydrogen gas was performed immediately at the end of operation and lasted for 3 hours. Cognitive function of rats was evaluated via Morris water maze. Neuronal damage in the CA1 region was quantified according to their morphological changes revealed by hematoxylin-eosin staining. The levels of oxidative stress products malondialdehyde (MDA) and 8-iso-prostaglandin F2alpha, and the activities of anti-oxidative enzymes catalase and superoxide dismutase were measured to investigate the effects of inhalation of hydrogen gas on oxidative stress. RESULTS: Inhalation of hydrogen gas decreased significantly the average latency of the ischemic rats in finding hidden platform and elongated markedly their retention in the target quadrant. The neuronal density 3·3±2·1 cells/mm in CA1 region of the ischemic rats increased to 21·7±2·6 cells/mm after they were treated with hydrogen gas. Moreover, hydrogen gas made higher levels of MDA and 8-iso-PGF2α in the ischemic rats attenuate to 3·2±0·2, 3·5±0·5, 3·4±0·3 and 26·4±2·3, 28·2±2·6, 26·8±2·1 at reperfusion 4, 24, and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time). By contrast, the activities of superoxide dismutase and catalase damaged by ischemia/reperfusion recovered to 129·7±14·8, 100·5±12·2 and 11·4±0·8, 9·6±1·1 at reperfusion 24 and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time). CONCLUSION: Inhalation of hydrogen gas could attenuate cognitive impairment in the ischemic rats. This protection is associated with decreased neuronal death in CA1 region and inhibition of oxidative stress.

[The clinical analysis of severe complications induced by esophageal foreign bodies].

OBJECTIVE: To explore and analyze the clinical characteristics and treatment strategy of severe complications caused by esophageal foreign bodies. METHOD: A retrospective study was carried out on 49 cases with foreign bodies in esophagus through careful analysis of their clinical data to explore the associated problems with etiology and therapy. Among this complications, there were cases of 13 periesophageal abscess, 20 cases of abscess in the neck, 11 cases of mediastinal abscess, 3 tracheoesophageal fistula, 1 case of aorta injury and 1 septicemia. RESULT: Forty-eight (97.96%) of the patients recovered while one died. CONCLUSION: Hard esophagoscopy under general anesthesia is the main therapeutic strategy to take out the esophageal foreign bodies. When it failed or severe complications such as perforation or others emerged, open surgery like lateral neck incision or thoracotomy supplemented with positive and timely supporting therapy are vital and essential.