Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.

Forecast for peak infections in the second wave of the Omicron after the adjustment of zero-COVID policy in the mainland of China.

On December 7, 2022, the Chinese government optimized the current epidemic prevention and control policy, and no longer adopted the zero-COVID policy and mandatory quarantine measures. Based on the above policy changes, this paper establishes a compartment dynamics model considering age distribution, home isolation and vaccinations. Parameter estimation was performed using improved least squares and Nelder-Mead simplex algorithms combined with modified case data. Then, using the estimated parameter values to predict a second wave of the outbreak, the peak of severe cases will reach on 8 May 2023, the number of severe cases will reach 206,000. Next, it is proposed that with the extension of the effective time of antibodies obtained after infection, the peak of severe cases in the second wave of the epidemic will be delayed, and the final scale of the disease will be reduced. When the effectiveness of antibodies is 6 months, the severe cases of the second wave will peak on July 5, 2023, the number of severe cases is 194,000. Finally, the importance of vaccination rates is demonstrated, when the vaccination rate of susceptible people under 60 years old reaches 98%, and the vaccination rate of susceptible people over 60 years old reaches 96%, the peak of severe cases in the second wave of the epidemic will be reached on 13 July 2023, when the number of severe cases is 166,000.

Impacts of climate change on vegetation pattern: Mathematical modeling and data analysis.

Climate change has become increasingly severe, threatening ecosystem stability and, in particular, biodiversity. As a typical indicator of ecosystem evolution, vegetation growth is inevitably affected by climate change, and therefore has a great potential to provide valuable information for addressing such ecosystem problems. However, the impacts of climate change on vegetation growth, especially the spatial and temporal distribution of vegetation, are still lacking of comprehensive exposition. To this end, this review systematically reveals the influences of climate change on vegetation dynamics in both time and space by dynamical modeling the interactions of meteorological elements and vegetation growth. Moreover, we characterize the long-term evolution trend of vegetation growth under climate change in some typical regions based on data analysis. This work is expected to lay a necessary foundation for systematically revealing the coupling effect of climate change on the ecosystem.

MLK3 Is Associated With Poor Prognosis in Patients With Glioblastomas and Actin Cytoskeleton Remodeling in Glioblastoma Cells.

Mixed lineage kinase 3 (MLK3) has been implicated in human melanoma and breast cancers. However, the clinical significance of MLK3 in human gliomas and the underlying cellular and molecular mechanisms remain unclear. We found that MLK3 proteins were highly expressed in high-grade human glioma specimens and especially prevalent in primary and recurrent glioblastoma multiforme (GBM). High levels of MLK3 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) gliomas. Furthermore, genetic ablation of MLK3 significantly suppressed the migration and invasion abilities of GBM cells and disrupted actin cytoskeleton organization. Importantly, MLK3 directly bound to epidermal growth factor receptor kinase substrate 8 (EPS8) and regulated the cellular location of EPS8, which is essential for actin cytoskeleton rearrangement. Overall, these findings provide evidence that MLK3 upregulation predicts progression and poor prognosis in human IDH-wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton via MLK3-EPS8 signaling.

[Warm acupuncture on chronic obstructive pulmonary disease with phlegm-turbid obstructing of the lung: a randomized controlled trial].

OBJECTIVE: To verify the effect of warm acupuncture combined with western medicine in patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD) with phlegm-turbid obstructing of the lung. METHODS: Ninety patients with AECOPD were randomly divided into a western medicine group, a warm acupuncture group and a sham acupuncture group, 30 cases in each group. Routine treatment according to the Global initiative for chronic obstructive lung disease (GOLD) guidelines was used in the western medicine group. On the basis of the routine treatment, the warm acupuncture was applied at Fenglong (ST 40), Feishu (BL 13), Zusanli (ST 36) and other acupoints in the warm acupuncture group. In the sham acupuncture group, non-acupoints were taken on the basis of conventional treatment, and superficial acupuncture was performed for 1-3 mm, once a day for 2 weeks. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, cough and sputum assessment questionnaire (CASA), COPD assessment test (CAT), and the change of TCM syndrome score were observed before and after treatment in all groups. RESULTS: After treatment, the FEV1, FVC and FEV1/FVC in each group were higher than those before treatment (P<0.05), there was no significant difference among groups after treatment (P>0.05). The CASA score, CAT score and TCM syndrome score in each group were lower than those before treatment (P<0.05). The change of the scores before and after treatment in the warm acupuncture group was higher than that in the sham acupuncture group and the western medicine group (P<0.05). There was no significant difference between the sham acupuncture group and the western medicine group (P>0.05). CONCLUSION: Warm acupuncture has a significant effect on the improvement of symptoms in patients with AECOPD with phlegm-turbid obstructing of the lung.

Therapeutic Outcomes of Kalix II in Treating Juvenile Flexible Flatfoot.

OBJECTIVES: To evaluate the therapeutic outcomes with Kalix II subtalar arthroereisis in sinus tarsi for juvenile flexible flatfoot. METHODS: A retrospective analysis of the data of 20 juveniles with symptomatic flexible flatfoot (27 feet) who underwent the Kalix II implant procedure from January 2008 to September 2012 was performed. The pain during daily activities was assessed and followed up by use of a standard 10-point visual analog scale (VAS), and function was evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot scoring system, and anteroposterior talar-first metatarsal angle, lateral talar-first metatarsal angle, calcaneal pitch angle, and talar declination angle at X-ray film were measured to assess the therapeutic outcomes. Patients were asked to grade the result of the procedure as excellent, good, fair, or poor at latest follow-up. The data was expressed as mean ± standard deviation (SD). A paired Student's t -test was used for comparisons of the preoperative and postoperative angular measurements for each foot, VAS scores, and AOFAS scores. In all tests, P < 0.05 was considered statistically significant. RESULTS: The mean age of the patients was 12.1 years (range, 7-16 years), and 16 left feet and 11 right feet were involved. All patients finished the follow-up with a mean period of 28.1 months (range, 23-60 months). Eleven feet were treated with subtalar arthroereisis combined with reconstruction of the end point of the posterior tibialis tendon after dissection of the accessory scaphoid. The subtalar arthroereisis device displaced in 1 foot due to a fall from the inversion position 3 months after surgery, and was replaced by a new device after the failure of conservative treatment. The mean VAS score decreased from 5.6 ± 0.5 preoperatively to 1.2 ± 0.2 (P < 0.001), and the mean AOFAS hindfoot and ankle score improved from 71.1 ± 6.1 preoperatively to 88.1 ± 6.3 (P < 0.001). Differences between preoperative and postoperative measurements for each radiographic variable were statistically significant (P < 0.001). Comparison of radiographic measurements showed that the anteroposterior talar-first metatarsal (Meary) angle decreased by a mean of 12.8° ± 1.5°, the lateral talar-first metatarsal (Meary) angle decreased by a mean of 15.4° ± 1.3°, the calcaneal pitch angle increased by a mean of -2.1° ± 0.7°, and the talar declination angle decreased by a mean of 17.9° ± 2.8°. Overall, 12 patients rated the result as excellent, 6 as good, and 2 as fair. CONCLUSION: The application of Kalix II in subtalar arthroereisis combined with dissection of accessory scaphoid and reconstruction of posterior tibialis tendon is an effective therapy for flexible juvenile flatfoot.

Synthetic paclitaxel-octreotide conjugate reverses the resistance of paclitaxel in A2780/Taxol ovarian cancer cell line.

The high mortality of ovarian cancer is partly due to the frequent resistance of ovarian cancer to current chemotherapy agents such as paclitaxel and platinum. Somatostatin analogue (SSTA) has been shown to inhibit the proliferation of some tumors through binding to somatostatin receptor (SSTR) and activation of Ras-, Rapl- and B-Raf-dependent extracellular signal-regulated kinase 2 (Erk2). It was reported that paclitaxel-octreotide conjugate (POC) exhibited enhanced tumor growth inhibition with reduced toxicity. In the present study, we prepared the POC and investigated its effects and mechanism for the reversal of drug resistance in paclitaxel-resistant ovarian cancer cell line. We demonstrated that treatment with POC led to more cell apoptosis than either paclitaxel or octreotide (OCT) alone. Moreover, the expression of multidrug resistance 1 (MDR1) and vascular endothelial growth factor (VEGF) mRNA, and protein decreased in a dose-dependent manner while the expression of SSTR remained stable following treatment with POC. Although the exact action, in vivo effects and pharmacologic kinetics of POC remain to be investigated, we have demonstrated the feasibility for the synthesis of POC, and more significantly, provided a potential approach to overcome the resistance of ovarian cancer against taxol. The findings also shed some new light on the mechanisms underlying the development of resistance to taxol by ovarian cancer cells.

Signal of Acceleration and Physical Mechanism of Water Cycle in Xinjiang, China.

Global warming accelerates water cycle with features of regional difference. However, little is known about the physical mechanism behind the phenomenon. To reveal the links between water cycle and climatic environment, we analyzed the changes of water cycle elements and their relationships with climatic and environmental factors. We found that when global warming was significant during the period of 1986-2003, the precipitation in Tarim mountains as well as Xinjiang increased rapidly except for Tarim plains, which indicated that there existed a signal of acceleration for water cycle in Xinjiang. The speed of water cycle is mainly affected by altitude, latitude, longitude, slope direction, and the most fundamental element is temperature. Moreover, according to Clausius-Kela Bai Lung relation, we found that the climate change induced the increase of temperature and accelerated the local water cycle only for the wet places. Our results provide a possible physical mechanisms of water cycle and thus well link the climate change to water circulation.

Synthetic paclitaxel-octreotide conjugate reversing the resistance of A2780/Taxol to paclitaxel in xenografted tumor in nude mice.

Peptide hormone-based targeted therapy to tumors has been studied extensively. Our previous study shows that somatostatin receptor expresses high level on drug-resistant human ovarian cancer. The paclitaxel-octreotide conjugate (POC) exhibits enhanced growth inhibition, as well as reduced toxicity, in paclitaxel-resistant human ovarian cancer cells. The aim of this study was to investigate the effect of targeted cytotoxicity and potential reversal mechanism of resistance in paclitaxel-resistant human ovarian cancer cells xenografted into nude mice. The SSTR2 shows higher expression levels in tumor tissue. Moreover, fluorescein-labeled POC displays favorable targeting in tumor cells. POC presents the perfect efficacy in inhibiting tumor growth and exerts lower or no toxic effects on normal tissues. Real-time PCR and Western Blotting has demonstrated that the mRNA and protein expressions of SSTR2 in POC group were significantly higher, while MDR1, α-tubulin, ßIII-tubulin, VEGF and MMP-9 were significantly lower than in the other treatment groups and controls. Combined with the previous study in vitro, this study evaluates an effective approach on the treatment of paclitaxel-resistant ovarian cancer which expresses somatostatin receptor SSTR. Our investigation has also revealed the possible molecular mechanism of POC in treating the ovarian cancer, and therefore, provided a theoretical basis for the clinical application of this newly-invented compound.

Apelin-13 as a novel target for intervention in secondary injury after traumatic brain injury.

The adipocytokine, apelin-13, is an abundantly expressed peptide in the nervous system. Apelin-13 protects the brain against ischemia/reperfusion injury and attenuates traumatic brain injury by suppressing autophagy. However, secondary apelin-13 effects on traumatic brain injury-induced neural cell death and blood-brain barrier integrity are still not clear. Here, we found that apelin-13 significantly decreases cerebral water content, mitigates blood-brain barrier destruction, reduces aquaporin-4 expression, diminishes caspase-3 and Bax expression in the cerebral cortex and hippocampus, and reduces apoptosis. These results show that apelin-13 attenuates secondary injury after traumatic brain injury and exerts a neuroprotective effect.

Interactions of Multiple Atmospheric Circulation Drive the Drought in Tarim River Basin.

Global warming is likely to cause overall drying of land surfaces and aridity increasing leading to expansion of dry climate zones. There is an increased risk of extremely arid environment and large deserts developed progressively in the central Asia. However, the key factors causing the drying in mid-Asia remain inconclusive. Here, we analyzed the relationship among precipitation, water vapor transportation in Tarim River Basin (TRB) and Multiple Atmospheric Circulation (MAC) to explore the mechanism of MAC driving the drying in TRB, through comparing MAC between abundant and scarce precipitation years. We found that Westerly Circulation (WC) and Asian Summer Monsoon (ASM) are likely to promote the precipitation respectively. Whereas, they not only have their own influence but also restrict each other and facilitate the forming of peculiar water vapor transport channel for TRB, which is probably to restrain the precipitation and its distribution pattern and accelerate the drying in this region. Our results enrich the findings on mechanisms of wet places becoming wetter while dry areas getting drier under the global warming.

Treatment of Calcified Insertional Achilles Tendinopathy by the Posterior Midline Approach.

The present study investigated the clinical outcomes of the posterior midline approach in the treatment of 34 patients with significantly calcified insertional Achilles tendinopathy. The posterior midline approach was applied for the surgical treatment of 34 patients with chronic significantly calcified insertional Achilles tendinopathy after failed conservative treatment. Gastrocnemius recession was performed simultaneously for patients with gastrocnemius contracture. The Fowler-Philip angle and parallel pitch lines were measured before surgery, and the visual analog scale, Tegner score, and Victorian Institute of Sport tendon study group score were recorded before and after surgery. The mean follow-up period was 45.2 ± 17.7 (range 24 to 84) months. After surgery, the visual analog scale score had decreased notably, and the Tegner score and Victorian Institute of Sport tendon study group score had increased significantly. The posterior midline approach can achieve satisfactory outcomes in the treatment of significantly calcified insertional Achilles tendinopathy, and gastrocnemius recession (Strayer procedure) should be performed for patients with gastrocnemius contracture to improve the surgical outcome.

Effects of time delay and space on herbivore dynamics: linking inducible defenses of plants to herbivore outbreak.

Empirical results indicate that inducible defenses of plants have effects on herbivore populations. However, little is known about how inducible defenses of plants have influences on herbivore outbreak when space effect is considered. To reveal the relationship between inducible defenses and herbivore outbreak, we present a mathematical model to describe the interaction of them. It was found that time delay plays dual effects in the persistence of herbivore populations: (i) large value of time delay may be associated with small density of herbivore populations, and thus causes the populations to run a higher risk of extinction; (ii) moderate value of time delay is beneficial for maintaining herbivore density in a determined range which may promote the persistence of herbivore populations. Additionally, we revealed that interaction of time delay and space promotes the growth of average density of herbivore populations during their outbreak period which implied that time delay may drive the resilience of herbivore populations. Our findings highlight the close relationship between inducible defenses of plants and herbivore outbreak.

A new selaginellin derivative from Selaginella pulvinata.

Abstract: A new selaginellin derivative named as selaginellin S (1) was isolated from the whole plants of Selaginella pulvinata (Hook. et Grev.) Maxim. (Selaginellaceae), together with a known one (selaginellin M, 2). Compounds 1 and 2 were separated and purified by silica gel and Sephadex LH-20 column chromatography. Their structures were determined on the basis of extensive spectroscopic analysis including IR, MS, 1D and 2D NMR experiments, as well as ECD calculations. Compound 1 is a key intermidiant in the biosynthesis pathway of selaginellins. Compound 2 is first reported in this plant.

Hyperoside, a flavonoid compound, inhibits proliferation and stimulates osteogenic differentiation of human osteosarcoma cells.

Osteosarcoma, one of the most common malignant bone tumours, is generally considered a differentiation disease caused by genetic and epigenetic disruptions in the terminal differentiation of osteoblasts. Novel therapies based on the non-cytotoxic induction of cell differentiation-responsive pathways could represent a significant advance in treating osteosarcoma; however, effective pharmaceuticals to induce differentiation are lacking. In the present study, we investigated the effect of hyperoside, a flavonoid compound, on the osteoblastic differentiation of U2OS and MG63 osteosarcoma cells in vitro. Our results demonstrated that hyperoside inhibits the proliferation of osteosarcoma cells by inducing G0/G1 arrest in the cell cycle, without causing obvious cell death. Cell migration assay further suggested that hyperoside could inhibit the invasion potential of osteosarcoma cells. Additionally, osteopontin and runt-related transcription factor 2 protein levels and osteocalcin activation were upregulated dramatically in hyperoside-treated osteosarcoma cells, suggesting that hyperoside may stimulates osteoblastic differentiation in osteosarcoma cells. This differentiation was accompanied by the activation of transforming growth factor (TGF)-ß and bone morphogenetic protein-2, suggesting that the hyperoside-induced differentiation involves the TGF-ß signalling pathway. To our knowledge, this study is the first to evaluate the differentiation effect of hyperoside in osteosarcoma cells and assess the possible potential for hyperoside treatment as a future therapeutic approach for osteosarcoma differentiation therapy.

Research progress in the mechanism of effect of PRP in bone deficiency healing.

Platelet-rich plasma (PRP) therapy is a recently developed technique that uses a concentrated portion of autologous blood to try to improve and accelerate the healing of various tissues. There is a considerable interest in using these PRP products for the treatment used in bone deficiency healing. Because PRP products are safe and easy to prepare and administer, there has been increased attention toward using PRP in numerous clinical settings. The benefits of PRP therapy appear to be promising, and many investigators are exploring the ways in which this therapy can be used in the clinical setting. At present, the molecular mechanisms of bone defect repair studies have focused on three aspects of the inflammatory cytokines, growth factors and angiogenic factors. The role of PRP works mainly through these three aspects of bone repair. The purpose of this paper is to review the current evidence on the mechanism of the effect of PRP in bone deficiency healing.

Expression, purification, and characterization of RGD-mda-7, a His-tagged mda-7/IL-24 mutant protein.

RGD peptide (Arg-Gly-Asp tripeptide) binds to integrin αVß(3) and αVß(5), which is selectively expressed in tumor neovasculature and on the surface of some tumor cells. Some studies showed that coupling the RGD peptides to anticancer drugs yielded compounds with increased efficiency against tumors and lowered toxicity to normal tissues. The melanoma differentiation-associated gene-7/interleukin-24 gene (mda-7/IL-24) is a novel tumor-suppressor/cytokine gene that exhibits potent tumor-suppressive activity without damaging normal cells. To enhance the antitumor effect, we inserted a glycine residue into the wild type (mda-7/IL-24) between (164)Arg and (165)Asp to form a RGD peptide, named RGD-mda-7, then expressed RGD-mda-7 in Escherichia coli. Herein, we describe the expression and purification of RGD-mda-7. We detected the characterizations of immunostimulatory activity, tumor targeting, potent cytopathic effect, and apoptosis inducing exploited by RGD-mda-7 in tumor cells, and also compared these characterizations with wtmda-7/IL-24. The data showed that RGD-mda-7 had more potent tumor targeting and apoptosis-inducing effects than wtmda-7/IL-24.