Unilateral biportal endoscopic spine surgery for lumbar spinal stenosis: a systematic review and meta-analysis.

OBJECTIVE: Lumbar spinal stenosis is the most common spinal degenerative disease in patients over 60 years, and the unilateral biportal endoscopic (UBE) spine surgery treatment of lumbar spinal stenosis (LSS) has achieved preliminary clinical results. This systematic review and meta-analysis aimed to reveal the clinical efficacy of UBE for LSS and provide evidence for clinical practice. MATERIALS AND METHODS: PubMed, Embase, Web of Science, and Cochrane databases were searched for literature. The papers selected were those published from inception till October 2021. The selected pieces of literature were graded for evidence using the Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). Outcomes measures were operation time, blood loss, complication rate, admission period, Visual Analogue Scale (VAS)-back, VAS-leg, and Oswestry Disability Index (ODI) score, and radiological outcomes. The mean comparisons were based on VAS and ODI scores. RESULTS: A total of 823 patients with a single LSS segment were included from the selected nine studies. There were nine studies comparing UBE clinical outcomes and micro-endoscopic unilateral laminotomy for bilateral decompression (M-ULBD). The meta-analysis revealed that the UBE group had better VAS-leg and -back scores in the first week postoperatively [total: mean difference (MD) = -0.96, 95% confidence interval (CI): -1.19, -0.74, p < 0.00001; total: MD = -1.69, 95% CI: -1.93, -1.45, p < 0.00001], 1st month postoperatively (total: MD = -0.35, 95% CI: -0.61, -0.08, p = 0.01; total: MD = -0.40, 95% CI: -0.68, -0.12, p = 0.005), 6th month postoperatively (total: MD = -0.22, 95% CI: -0.35, -0.08, p = 0.002; total: MD = -0.24, 95% CI: -0.40, -0.07, p = 0.005), and UBE group also performed better in ODI score at 1st month postoperatively (total: MD = -3.36, 95% CI: -4.26, -2.46, p < 0.00001). There was no significant difference in VAS-leg and -back scores between both groups at the 3rd and 12th month postoperatively, and ODI scores did not significantly differ between both groups at 3, 6, and 12 months postoperatively (all p > 0.05). CONCLUSIONS: UBE has achieved good preliminary clinical results and may be a minimally invasive alternative surgery for patients with single segmental LSS.

[Spatiotemporal changes of COVID-19 outbreak in Shanghai].

Objective: To clarify the epidemiological characteristics and spatiotemporal clustering dynamics of COVID-19 in Shanghai in 2022. Methods: The COVID-19 data presented on the official websites of Municipal Health Commissions of Shanghai during March 1, 2022 and May 31, 2022 were collected for a spatial autocorrelation analysis by GeoDa software. A logistic growth model was used to fit the epidemic situation and make a comparison with the actual infection situation. Results: Pudong district had the highest number of symptomatic and asymptomatic infectants, accounting for 29.30% and 35.58% of the total infectants. Differences in cumulative attack rates and infection rates among 16 districts (P<0.001) were significant. The rates were significantly higher in Huangpu district than in other districts. The attack rate of COVID-19 from March 1, 2022 to May 31, 2022 had a global spatial positive correlation (P<0.05). Spatial distribution of COVID-19 attack rate was different at different periods. The global autocorrelation coefficient from March 16 to March 29, April 6 to April 12 and May 18 to May 24 had no statistical significance (P>0.05). Our local autocorrelation analysis showed that 22 high-high clustering areas were detected in eight periods.The high-risk hot-spot areas have experienced a "less-more-less" change process. The growth model fitting results were consistent with the actual infection situation. Conclusion: There was a clear spatiotemporal correlation in the distribution of COVID-19 in Shanghai. The comprehensive prevention and control measures of COVID-19 epidemic in Shanghai have effectively prohibited the growth of the epidemic, not only curbing the spatially spread of high-risk epidemic areas, but also reducing the risk of transmission to other cities.

Estimating Local Cellular Density in Glioma Using MR Imaging Data.

BACKGROUND AND PURPOSE: Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density. MATERIALS AND METHODS: We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard. RESULTS: The random forest methodology estimated cellular density with R 2 = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R2 = 0.52). Outputs were also reported as graphic maps. CONCLUSIONS: Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.

A dominant strain of Elizabethkingia anophelis emerged from a hospital water system to cause a three-year outbreak in a respiratory care center.

BACKGROUND: Elizabethkingia species are ubiquitous bacteria but uncommonly cause human infection. An outbreak of Elizabethkingia anophelis bacteraemia was observed in a respiratory care center of a tertiary hospital in Taiwan from 2015 to 2018. METHODS: Clinical and environmental isolates were collected for the outbreak investigation. Pulsed-field gel electrophoresis (PFGE) and complete-genome sequencing were conducted to elucidate the mechanism of transmission. FINDINGS: The three-year outbreak involved 26 patients with E. anophelis bacteraemia and the incidence significantly increased during the outbreak period compared with that observed from 2010 to 2014 (P<0.05). All 26 clinical isolates during the outbreak period belonged to a cluster by PFGE analysis. In contrast, the PFGE pattern was heterogeneous among comparative historical strains. Hospital tap water was highly contaminated by Elizabethkingia species (18/34, 52.9%); among that, five E. anophelis belonged to the outbreak cluster (5/18, 27.8%). As for the inanimate surface survey, 3.4% sites (4/117) revealed positive growth of E. anophelis including two from feeding tubes/bags and two from sputum suction regulators. All four isolates belonged to the outbreak clone. The outbreak strain had no apparent relationship to currently known E. anophelis strains worldwide through complete-genome sequencing analysis. Specific infection control strategies aimed at water source control and environmental disinfection were implemented subsequently and the outbreak ended in mid-2018. CONCLUSIONS: A specific E. anophelis strain was identified from a three-year outbreak. The elucidation of the mechanism of dominance and intra-hospital transmission is crucial for development of corresponsive infection control policies and outbreak control.

Imaging-Based Algorithm for the Local Grading of Glioma.

BACKGROUND AND PURPOSE: Gliomas are highly heterogeneous tumors, and optimal treatment depends on identifying and locating the highest grade disease present. Imaging techniques for doing so are generally not validated against the histopathologic criterion standard. The purpose of this work was to estimate the local glioma grade using a machine learning model trained on preoperative image data and spatially specific tumor samples. The value of imaging in patients with brain tumor can be enhanced if pathologic data can be estimated from imaging input using predictive models. MATERIALS AND METHODS: Patients with gliomas were enrolled in a prospective clinical imaging trial between 2013 and 2016. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, followed by image-guided stereotactic biopsy before resection. An imaging description was developed for each biopsy, and multiclass machine learning models were built to predict the World Health Organization grade. Models were assessed on classification accuracy, Cohen κ, precision, and recall. RESULTS: Twenty-three patients (with 7/9/7 grade II/III/IV gliomas) had analyzable imaging-pathologic pairs, yielding 52 biopsy sites. The random forest method was the best algorithm tested. Tumor grade was predicted at 96% accuracy (κ = 0.93) using 4 inputs (T2, ADC, CBV, and transfer constant from dynamic contrast-enhanced imaging). By means of the conventional imaging only, the overall accuracy decreased (89% overall, κ = 0.79) and 43% of high-grade samples were misclassified as lower-grade disease. CONCLUSIONS: We found that local pathologic grade can be predicted with a high accuracy using clinical imaging data. Advanced imaging data improved this accuracy, adding value to conventional imaging. Confirmatory imaging trials are justified.

Virtual memory CD8 T cells expanded by helminth infection confer broad protection against bacterial infection.

Epidemiological data and animal studies suggest that helminth infection exerts potent immunomodulatory effects that dampen host immunity against unrelated pathogens. Despite this notion, we unexpectedly discovered that prior helminth infection resulted in enhanced protection against subsequent systemic and enteric bacterial infection. A population of virtual memory CD8 T (CD8 TVM) cells underwent marked expansion upon infection with the helminth Heligmosomoides polygurus by an IL-4-regulated, antigen-independent mechanism. CD8 TVM cells disseminated to secondary lymphoid organs and established a major population of the systemic CD8 T cell pool. IL-4 production elicited by protein immunization or selective activation of natural killer T cells also results in the expansion of CD8 TVM cells. Notably, CD8 TVM cells expanded by helminth infection are sufficient to transfer innate non-cognate protection against bacteria to naïve animals. This innate non-cognate "collateral protection" mediated by CD8 TVM might provide parasitized animals an advantage against subsequent unrelated infections, and represents a potential novel strategy for vaccination.

Characterization of efficacy and safety of pathogen inactivated and quarantine plasma in routine use for treatment of acquired immune thrombotic thrombocytopenic purpura.

BACKGROUND: Auto-immune thrombotic thrombocytopenic purpura (TTP) is a morbid multi-organ disorder. Cardiac involvement not recognized in initial disease descriptions is a major cause of morbidity. Therapeutic plasma exchange (TPE) requires exposure to multiple plasma donors with risk of transfusion-transmitted infection (TTI). Pathogen inactivation (PI) with amotosalen-UVA, the INTERCEPT Blood System for Plasma (IBSP) is licensed to reduce TTI risk. METHODS: An open-label, retrospective study evaluated the efficacy of quarantine plasma (QP) and IBSP in TTP and defined treatment emergent cardiac abnormalities. Medical record review of sequential patient cohorts treated with QP and IBSP characterized efficacy by remission at 30 and 60 days (d) of treatment, time to remission, and volume (L/kg) of plasma required. Safety outcomes focused on cardiac adverse events (AE), relapse rates, and mortality. RESULTS: Thirty-one patients (18 IBSP and 13 QP) met study criteria for auto-immune TTP. The proportions (%) of patients in remission at 30 d (IBSP = 61·1, QP = 46·2, P = 0·570) and 60 d (IBSP = 77·8, QP = 76·9, P = 1·00) were not different. Median days to remission were less for IBSP (15·0 vs. 24·0, P = 0·003). Relapse rates (%) 60 d after remission were not different between cohorts (IBSP = 7·1, QP = 40·0, P = 0·150). ECG abnormalities before and during TPE were frequent; however, cardiac AE and mortality were not different between treatment cohorts. CONCLUSIONS: Cardiac and a spectrum of ECG findings are common in TTP. In this study, IBSP and QP had similar therapeutic profiles for TPE.

Clinicopathological and prognostic significance of preoperative serum epidermal growth factor levels in patients with oral squamous cell carcinoma.

Epidermal growth factor (EGF) promotes tumourigenesis and tissue repair of epithelial and mesenchymal cells and has a role in chemotaxis, mitogenesis, cell motility, and cytoprotection. It also enhances the growth of cancers. EGF may therefore have a role in the initiation or promotion of oral carcinogenesis. The cases of 152 patients with oral squamous cell carcinoma whose preoperative serum EGF level was determined by enzyme-linked immunosorbent assay were analyzed retrospectively, along with those of 40 age- and sex-matched controls. Patients with higher levels of EGF were more likely to have neck lymph node metastasis (P=0.026), advanced stage cancer (P=0.04), and a worse survival status (P=0.0019). Multivariate analysis using the Cox proportional hazards model indicated that the EGF level was an independent predictor of poor survival (hazard ratio 1.99, P=0.018). Patients with higher preoperative serum EGF levels had significantly poorer cancer-specific survival by Kaplan-Meier analysis (P=0.032). This study indicates that a higher preoperative serum EGF level is associated with neck lymph node metastasis, more advanced stage, and poor survival. EGF should be considered as a potential prognostic biomarker and a therapeutic target for patients with oral cancer.

[Enhancing Soft-tissue Reattachment with Artificial Mesh in Joint Endoprosthetic Reconstruction for Bone Tumors].

Objective: To investigate the operative method and clinical application of the BARD(®) Mesh in enhancing joint stability and function of endoprosthetic reconstruction for bone tumors. Methods: From Jan 2013 to Jun 2015, the clinical data of 51 patients aged (44.75±23.18) years underwent wide resection of tumor and endoprosthetic reconstruction using the BARD(®) Mesh were collected. Among them, 27 were male and 24 were female. The surgical treatments received by these patients included 5 shoulder arthroplasties, 12 elbow replacements, 12 hip replacements and 32 knee replacements (including 24 femoral tumors and 8 tibial tumors). According to the pathologic type, there were 12 metastatic tumors, 20 osteosarcomas, 7 chondrosarcomas, 5 malignant fibrous histiocytomas, 4 giant cell tumors of bone, 1 Ewing sarcoma, 1 leiomyosarcoma and 1 pigmented villonodular synovitis (pvns). These patients received extensive tumor resection, tumorous prosthesis replacement, preserved articular capsule and muscles repair with artificial mesh and endoprosthesis wrapping. The curative effect including joints range of motion and Musculoskeletal Tumour Society Scores (MSTS) were evaluated. Results: The median follow-up time was (19.75±8.17) months. The drainages were removed out on an average of 4 days after operation. The postoperative complications included 2 superficial incision infection, 1 deep incision infection and 1 osteofascial compartment syndrome, infection or dislocation of prosthesis wasn't observed. The mean active flexion of shoulder joint after replacement was (34.00±10.84)°, mean active abduction was (20.00±9.35)° and the mean MSTS was 19.80±9.54. The superior rate of shoulder flexion function was 0. The mean active flexion of elbow joint after replacement was (75.00±7.07)°, mean active abduction was (-5.00±7.07)° and the mean MSTS was 25.00±2.83. The superior rate of elbow flexion function was 50.0% (1/2). The mean active flexion of hip joint after replacement was (86.67±20.60)°, mean active abduction was (2.08±4.98)° and the mean MSTS was 25.42±1.78. The superior rate of hip flexion function was 83.3% (10/12). The mean active flexion of knee joint after replacement was (89.69±22.39)°, mean active abduction was (-0.63±1.68)° and the mean MSTS was 23.31±2.09. The superior rate of knee flexion function was 50.0%(16/32). Among them, the superior rate of femoral flexion function was 66.7% (16/24), the superior rate of tibial flexion function was 0. All of patients were satisfied with the curative effect of operation at the end of follow-up time. Conclusions: The BARD(®) Mesh may enhance the attachment of soft-tissue to endoprosthesis, improve the joint stability, decrease the endoprosthetic infection and dislocation, facilitate the attachment of tendon to endoprosthesis and recover the muscular motivation after endoprosthetic reconstruction. This plays an important role in joint stability and motivation reconstruction of soft-tissue impairment, effectively prevents surgical complications.

Performance Assessment for Brain MR Imaging Registration Methods.

BACKGROUND AND PURPOSE: Clinical brain MR imaging registration algorithms are often made available by commercial vendors without figures of merit. The purpose of this study was to suggest a rational performance comparison methodology for these products. MATERIALS AND METHODS: Twenty patients were imaged on clinical 3T scanners by using 4 sequences: T2-weighted, FLAIR, susceptibility-weighted angiography, and T1 postcontrast. Fiducial landmark sites (n = 1175) were specified throughout these image volumes to define identical anatomic locations across sequences. Multiple registration algorithms were applied by using the T2 sequence as a fixed reference. Euclidean error was calculated before and after each registration and compared with a criterion standard landmark registration. The Euclidean effectiveness ratio is the fraction of Euclidean error remaining after registration, and the statistical effectiveness ratio is similar, but accounts for dispersion and noise. RESULTS: Before registration, error values for FLAIR, susceptibility-weighted angiography, and T1 postcontrast were 2.07 ± 0.55 mm, 2.63 ± 0.62 mm, and 3.65 ± 2.00 mm, respectively. Postregistration, the best error values for FLAIR, susceptibility-weighted angiography, and T1 postcontrast were 1.55 ± 0.46 mm, 1.34 ± 0.23 mm, and 1.06 ± 0.16 mm, with Euclidean effectiveness ratio values of 0.493, 0.181, and 0.096 and statistical effectiveness ratio values of 0.573, 0.352, and 0.929 for rigid mutual information, affine mutual information, and a commercial GE registration, respectively. CONCLUSIONS: We demonstrate a method for comparing the performance of registration algorithms and suggest the Euclidean error, Euclidean effectiveness ratio, and statistical effectiveness ratio as performance metrics for clinical registration algorithms. These figures of merit allow registration algorithms to be rationally compared.

Patient outcomes and amotosalen/UVA-treated platelet utilization in massively transfused patients.

BACKGROUND: Amotosalen/UVA-treated platelet concentrates (PCs) have demonstrated efficacy for treating and preventing bleeding in clinical trials and in routine use; however, most studies were performed in haematology/oncology patients. We investigated efficacy during massive transfusion (MT) in general hospitalized patients. METHODS: Universal amotosalen/UVA treatment (INTERCEPT Blood System) of platelets was introduced at a large Austrian medical centre. We performed a retrospective cohort analysis comparing component use, in-hospital mortality and length of stay after MT that included platelet transfusion, for two periods (21 months each) before and after implementation. RESULTS: A total of 306 patients had MT. Patients were mostly male (74%) and ≥18 years old (99%), including 93 liver transplant, 97 cardiac or vascular surgery and 51 trauma patients. There were no differences in demographics between the periods. Component use on the day and within 7 days of the MT event was unchanged post-IBS implementation, except trauma patients received fewer RBCs on the day. The mean ratio of RBC:platelets:plasma on the day of the MT was close to 1:1:1 in both periods, except for liver transplants with MT who received more plasma components. Overall, in-hospital mortality (preimplementation = 27·6% vs. postimplementation = 24·0%; P = 0·51) and median time to discharge (preimplementation = 27 vs. postimplementation = 23 days; P = 0·37) did not change, except for cardiac and vascular surgery patients who were discharged earlier. CONCLUSION: The introduction of amotosalen/UVA-treated, pathogen-reduced PC did not adversely affect clinical outcomes in massively transfused patients in terms of blood product usage, in-hospital mortality and length of stay for a range of clinical indications for platelet transfusion support.

Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian Regional Medical Centre.

BACKGROUND: In clinical studies, pathogen inactivation (PI) of platelet concentrates (PC) with amotosalen and UVA light did not impact patient risk for haemorrhage but may affect transfusion frequency and component utilization. We evaluated the influence of platelet PI on PC, red cell concentrate (RCC) and plasma use and safety in routine practice in a large regional hospital. STUDY DESIGN AND METHODS: Comparative effectiveness of conventional vs. PI-treated PC was analysed during two 21-month periods, before and after PI implementation. RESULTS: Similar numbers of patients were transfused in the pre-PI (control, 1797) and post-PI (test, 1694) periods with comparable numbers of PC (8611 and 7705, respectively). The mean numbers of PC per patient transfused (4·8 vs. 4·5, P = 0·43) were not different but days of PC support (5·9 vs. 5·0, P < 0·01) decreased. Most patients received RCC (86·8% control vs. 84·8% test, P = 0·90) with similar mean numbers transfused (10·8 vs. 10·2 RCC, P = 0·22), and fewer patients (55·4% control vs. 44·7% test, P < 0·01) received less plasma units (mean 9·9 vs. 7·8, respectively, P < 0·01) in the test period. The frequencies of transfusion-related adverse events (AE) were comparable (1·3% vs. 1·4%, P = 0·95). Analysis of haematology-oncology (522 control, 452 test), cardiac surgery (739 control, 711 test), paediatric (157 control, 130 test) and neonate (23 control, 20 test) patients revealed no increase in PC, plasma and RCC utilization, or AE. CONCLUSION: Component utilization and patient safety were not impacted by adoption of PI for PC. RCC use per patient was comparable, suggestive of no increase in significant bleeding.

Temperature-Dependent Development and Reproductive Traits of Tyrophagus putrescentiae (Sarcoptiformes: Acaridae) Reared on Different Edible Mushrooms.

China is the largest producer, consumer, and exporter of mushrooms in the world. The storage mite, Tyrophagus putrescentiae Schrank, is one of the most important arthropod pests in mushroom cultivation. This study investigated the development and reproductive traits of this mite reared on four mushroom species: Agaricus bisporus Lange, Pleurotus ostreatus Kumm, Auricularia polytricha (Mont.) Sacc., and Flammulina velutipes (Fr.) Sing., at seven constant temperatures ranging from 16 to 34 °C at 80% relative humidity. Development time for the immature stages decreased with increasing temperature, and was also significantly affected by mushroom species. The shortest immature developmental period (7.0 ± 0.2 d) was observed at 31 °C when reared on F. velutipes, while the longest development was at 16 °C (36.0 ± 0.3 d) reared on P. ostreatus. The effects of temperature and mushroom hosts on the development, female longevity, and reproduction were also significant. The lower threshold temperatures from egg-to-adult for the four mushroom species were 11.97, 12.02, 10.80, and 11.57 °C, for A. bisporus, P. ostreatus, Au. polytricha, and F. velutipes, and the thermal constants were 133.3, 136.8, 165.2, and 135.9 degree days (°C d), for the same mushroom species, respectively. Life table parameters at 25 °C were estimated as follows: net reproductive rates (R0), 59.16, 28.94, 42.62, and 62.93, and intrinsic rate of natural increase (rm), 0.24, 0.13, 0.17, and 0.24, respectively. These results suggest that these mushrooms are suitable hosts for T. putrescentiae, and the storage mite may be able to adapt to higher temperatures.

A prospective, active haemovigilance study with combined cohort analysis of 19,175 transfusions of platelet components prepared with amotosalen-UVA photochemical treatment.

BACKGROUND AND OBJECTIVES: A photochemical treatment process (PCT) utilizing amotosalen and UVA light (INTERCEPT(™) Blood System) has been developed for inactivation of viruses, bacteria, parasites and leucocytes that can contaminate blood components intended for transfusion. The objective of this study was to further characterize the safety profile of INTERCEPT-treated platelet components (PCT-PLT) administered across a broad patient population. MATERIALS AND METHODS: This open-label, observational haemovigilance programme of PCT-PLT transfusions was conducted in 21 centres in 11 countries. All transfusions were monitored for adverse events within 24 h post-transfusion and for serious adverse events (SAEs) up to 7 days post-transfusion. All adverse events were assessed for severity (Grade 0-4), and causal relationship to PCT-PLT transfusion. RESULTS: Over the course of 7 years in the study centres, 4067 patients received 19,175 PCT-PLT transfusions. Adverse events were infrequent, and most were of Grade 1 severity. On a per-transfusion basis, 123 (0.6%) were classified an acute transfusion reaction (ATR) defined as an adverse event related to the transfusion. Among these ATRs, the most common were chills (77, 0.4%) and urticaria (41, 0.2%). Fourteen SAEs were reported, of which 2 were attributed to platelet transfusion (<0.1%). No case of transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, transfusion-transmitted infection or death was attributed to the transfusion of PCT-PLT. CONCLUSION: This longitudinal haemovigilance safety programme to monitor PCT-PLT transfusions demonstrated a low rate of ATRs, and a safety profile consistent with that previously reported for conventional platelet components.

Kallistatin, a novel anti-angiogenesis agent, inhibits angiogenesis via inhibition of the NF-κB signaling pathway.

Development of a novel angiogenesis inhibitor will be essential for the improvement of therapeutics against cancer. Kallistatin had been recognized as an endogenous angiogenesis inhibitor. Here, we demonstrated kallistatin's strong anti-angiogenesis and anti-metastasis activity stimulated by breast cancer cells (MCF-7) and its mechanism of action in vitro. The anti-angiogenesis effect in vivo was evaluated by chicken chorioallantoic membrane (CAM) neovascularisation. Because of the underlying molecular mechanism of its anti-angiogenesis activity remains poorly understood. In this study, we examined whether the NF-κB signaling pathway was involved in the anti-angiogenesis and anti-metastasis activity of kallistatin. Kallistatin significantly inhibited TNF-α-induced nuclear factor-κB activation in a dose-dependent manner. Addition of kallistatin inhibited TNF-α induced IκBα degradation; phosphorylation of IκBα kinase (IKK), nuclear factor-κB-p65 protein; and nuclear translocation of p65/50. Meanwhile, we investigated the effects of kallistatin on the expression of vascular endothelial growth factor (VEGF) and other angiogenesis-related gene in human umbilical vein endothelial cells (HUVECs). We found that kallistatin decreased the expression of VEGF and some angiogenesis-related genes, which promoted angiogenesis in cancer. Taken together, we suggested that kallistatin would inhibit tumor angiogenesis via inhibition of the NF-κB signaling pathway and finally abrogate NF-κB-dependent gene expression. All the results revealed that kallistatin would have potential as a novel.

Recombinant human kallistatin inhibits angiogenesis by blocking VEGF signaling pathway.

Kallistatin has been recognized as an endogenous angiogenic inhibitor. However, the underlying molecular mechanism remains poorly understood. Taking it into account that vascular endothelial growth factor (VEGF) has been implicated in all aspects of normal and pathological vasculogenesis and angiogenesis. In this study, we investigated whether VEGF signaling pathway was impacted by the anti-angiogenic effect of recombinant human kallistatin (rhKal). We found that the rhKal inhibited proliferation as well as induced apoptosis of cultured human umbilical vein endothelial cells (HUVECs) in both concentration- and time-dependent manners. The rhKal also suppressed the VEGF-induced migration and tube formation of HUVECs. Furthermore, our data revealed that the rhKal suppressed the VEGF165-stimulated tyrosine phosphorylation of VEGFR-2 as well as its downstream signal molecular activation. The inhibition of receptor phosphorylation was correlated with a decrease in VEGF-triggered phosphorylation of angiogenesis signal molecules AKT and ERK, but not stress-related JNK. Taken together, these findings added the knowledge for us to understand the anti-angiogenic mechanism of kallistatin, which suggested that the rhKal could be worth as a candidate compound for further development for the purpose of anti-angiogenic therapies.

The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA(A) receptors.

The bile steroids (BS) cholic acid and chenodeoxycholic acid are produced in hepatocytes and in the brain. Nothing is known about neuronal actions of BS. Deficiency in a 27-hydroxylase enzyme coincides with reduced production of chenodeoxycholic acid (CDCA) and a relative increase in cholic acid in an inherited lipid storage disease, cerebrotendinous xanthomatosis, characterized by neurological dysfunctions, which can be treated by dietary CDCA. We have examined the modulation of hypothalamic network activity by nine common BS. Cholate and CDCA significantly reduced the firing of hypothalamic neurons and synchronized network activity with CDCA being nearly 10 times more potent. The synthetic BS dehydrocholate synchronized the activity without affecting the firing rate. Gabazine, a GABA(A) receptor antagonist, occluded synchronization by BS. Whole-cell patch clamp recordings revealed a block of NMDA- and GABA(A)-receptors by BS. Potencies of nine common BS differed between NMDA and GABA(A) receptors, however in both cases they correlated with BS affinities for albumin but not with their lipophilicity, supporting a direct action at ligand gated ion channels. GABAergic synaptic currents displayed a faster decay under BS. Our data provide new insight into extrahepatic functions of BS revealing their neuroactive potential.

MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo.

MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular carcinogenesis are still not fully elucidated. We investigated the aberrantly expressed miRNAs involved in hepatoma by comparison of miRNA expression profiles in cancerous hepatocytes with normal primary human hepatocytes, and 37 dysregulated miRNAs were screened out by twofold change with a significant difference (P<0.05). Clustering analysis based on 13 miRNAs with changes over 15-folds showed that the miRNA expression patterns between the cancerous and normal hepatocytes were clearly different. Among the 13 miRNAs, we found that miR-375 was significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Overexpression of miR-375 in liver cancer cells decreased cell proliferation, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis. To unveil the molecular mechanism of miR-375-mediated phenotype in hepatoma cells described above, we examined the putative targets using bioinformatics tools and found that astrocyte elevated gene-1 (AEG-1) was a potential target of miR-375. Then we demonstrated that miR-375 bound directly to the 3'-untranslated region of AEG-1 and inhibited the expression of AEG-1. TaqMan quantitative reverse transcriptase-PCR and western blot analysis showed that miR-375 expression was inversely correlated with AEG-1 expression in HCC tissues. Knockdown of AEG-1 by RNAi in HCC cells, similar to miR-375 overexpression, suppressed tumor properties. Ectopic expression of AEG-1, conversely, could partially reverse the antitumor effects of miR-375. In a mouse model, therapeutic administration of cholesterol-conjugated 2'-O-methyl-modified miR-375 mimics (Chol-miR-375) could significantly suppress the growth of hepatoma xenografts in nude mice. In conclusion, our findings indicate that miR-375 targets AEG-1 in HCC and suppresses liver cancer cell growth in vitro and in vivo, and highlight the therapeutic potential of miR-375 in HCC treatment.

Human infection with novel G3P[25] rotavirus strain in Taiwan.

Genotype P[25] rotaviruses are rare and to date have been reported to occur only in a few countries of mainland Asia. Here we report the molecular characterization of a novel human rotavirus genotype combination, G3P[25], detected in a 17-month-old child hospitalized due to severe gastroenteritis during 2009 in central Taiwan. Sequencing and phylogenetic analysis of the VP4 gene demonstrated a distinct origin from other strains bearing the P[25] VP4 gene, whereas the VP7, VP6 and NSP4 gene phylogenies identified common origins with cognate genes of other, presumed human-porcine reassortment Taiwanese strains. These results suggest that interactions between human and animal strains appear to contribute to the generation of genetic and antigenic diversity of rotavirus strains, with potential public health importance in Taiwan.