Combined oral low-dose cyclophosphamide endocrine therapy may improve clinical response among patients with metastatic breast cancer via Tregs in TLSs.

Despite limited research on refractory and/or endocrine therapy failure in elderly metastatic breast cancer (MBC) patients, a prior study showed that low-dose oral cyclophosphamide (CY) can improve the overall survival rate of MBC patients, possibly through the immunoregulation of regulatory T cells (Tregs). We preliminarily investigated the combination of endocrine therapy (ET) with oral low-dose CY as salvage therapy in elderly patients via peripheral blood regulatory T-cell analyses. In addition, we evaluated the associations of tumor tertiary lymphoid structures (TLSs) with therapeutic outcomes. HR+/HER2- advanced breast cancer patients who received low-dose CY combined with ET or ET only from April 2015 to August 2021 were enrolled in this retrospective study. The primary outcome was the clinical control rate (CCR), and the secondary outcome was progression-free survival (PFS). Circulating T lymphocyte subpopulations represented by Tregs were monitored during treatment by flow cytometry methods. TLSs wereconfirmed by hematoxylin-eosin staining of pretreatment specimens, and CD3, CD4, and Foxp3 were detected using Opal multicolor immunofluorescence. A total of 85 patients who received CY + ET and 50 patients who received ET only were enrolled, the percentage of patients who received CCR was 73% (62/85) vs. 70% (45/50), and the objective response rate (ORR) was 28% (24/85) vs. 24% (12/50). No deaths occurred during the study period. The mean PFS time was 13 vs. 11 months (P = 0.03). In the CY + ET group, decreases in CD4+/CD25+/Foxp3+ T cells (P < 0.001) were favorable for both clinical control and prolonged PFS (P < 0.001). Compared with patients without TLSs, those with TLSs were more likely to have better clinical control and PFS (mean time = 6 months), and a greater number of Treg cells during TLS pretreatment correlated with longer PFS (P = 0.043). Oral low-dose CY combined with standard ET exerts immunological effects by decreasing Treg levels to achieve improved clinical responses. Moreover, patients with TLSs might benefit more from such therapy than those without TLSs, and a high Treg cell count in TLSs before treatment predicts better therapeutic efficacy.

N-acetylserotonin alleviates retinal ischemia-reperfusion injury via HMGB1/RAGE/NF-κB pathway in rats.

AIM: To observe the effects of N-acetylserotonin (NAS) administration on retinal ischemia-reperfusion (RIR) injury in rats and explore the underlying mechanisms involving the high mobility group box 1 (HMGB1)/receptor for advanced glycation end-products (RAGE)/nuclear factor-kappa B (NF-κB) signaling pathway. METHODS: A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye. Eighty male Sprague Dawley were randomly divided into five groups: sham group (n=8), RIR group (n=28), RIR+NAS group (n=28), RIR+FPS-ZM1 group (n=8) and RIR+NAS+ FPS-ZM1 group (n=8). The therapeutic effects of NAS were examined by hematoxylin-eosin (H&E) staining, and retinal ganglion cells (RGCs) counting. The expression of interleukin 1 beta (IL-1ß), HMGB1, RAGE, and nod-like receptor 3 (NLRP3) proteins and the phosphorylation of nuclear factor-kappa B (p-NF-κB) were analyzed by immunohistochemistry staining and Western blot analysis. The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats. With NAS therapy, the HMGB1 and RAGE expression decreased significantly, and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression. Additionally, NAS exhibited an anti-inflammatory effect by reducing IL-1ß expression. The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression, so as to the IL-1ß expression and retinal edema, accompanied by an increase of RGCs in RIR rats. CONCLUSION: NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway, which may be a useful therapeutic target for retinal disease.

N-Acetylserotonin Alleviates Retinal Autophagy via TrkB/AKT/Nrf2 Signaling Pathway in Retinal Ischemia-Reperfusion Injury Rats.

INTRODUCTION: The objective of this study was to investigate the impact of N-acetylserotonin (NAS) on the autophagy of retinal cells in rats with retinal ischemia-reperfusion injury (RIRI) and to explore the mechanisms by which NAS administration can alleviate RIRI through the tropomyosin-related kinase receptor B (TrkB)/protein kinase B (Akt)/nuclear factor erythroid-derived factor 2-related factor (Nrf2) signaling pathway. METHODS: Healthy adult male rats were randomly assigned to four groups: sham, RIRI, RIRI+NAS, and RIRI+NAS+ANA-12. The RIRI group was induced by elevating intraocular pressure, and changes in retinal structure and edema were assessed using H&E staining. The RIRI+NAS and RIRI+NAS+ANA-12 groups received intraperitoneal injections of NAS before and after modeling. The RIRI+NAS+ANA-12 group was also administered ANA-12, a TrkB antagonist. Immunohistochemical staining and Western blot analysis were used to evaluate phosphorylated TrkB (p-TrkB), phosphorylated Akt (p-Akt), Nrf2, sequestosome 1 (P62), and microtubule-associated protein 1 light chain 3 (LC3-II) levels in the retinas of each group. Electroretinogram was recorded to detect retinal function in each group of rats 24 h after modeling. RESULTS: The RIRI+NAS group had a thinner retina and more retinal ganglion cells (RGCs) than RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Immunohistochemical staining and Western blot results showed that p-TrkB, p-Akt, n-Nrf2, and P62 levels in the RIRI+NAS group were higher compared with those in RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Also, lower LC3-II levels were observed in the RIRI+NAS group compared with that in RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Electroretinogram recording results showed that 24 h after retinal ischemia-reperfusion, the magnitude of b-wave changes was attenuated in the RIRI+NAS group compared with the RIRI group (p < 0.05). CONCLUSION: The administration of NAS activates the TrkB/Akt/Nrf2 signaling pathway, reduces autophagy, alleviates retinal edema, promotes the survival of retinal ganglion cells (RGCs), and provides neuroprotection against retinal injury.

A shape-memory poly(ε-caprolactone) hybridized TiO2/poly(l-lactide) composite with antibacterial properties.

Organic-inorganic composites as an efficient strategy to upgrade the structural and functional properties of synthetic polymers are attracting extensive attentions. However, there are few studies on the shape memory (SM) behavior of organic-inorganic composites. In the work, poly(ε-caprolactone) hybridized TiO2 nanomaterial (PCL-TiO2) is made as the switching phase and integrated into poly (l-lactide) (PLLA) to construct an SM composite. PCL-TiO2/PLLA shows "sea-island" structure and better interfacial adhesion than PCL/PLLA, which facilitates the transmission of elastic power between the switching phase and the fixing phase. PCL-TiO2 as switching phase exhibits lower enthalpy at 57 °C than PCL, and PCL-TiO2 also acts as "heat dispersion pump station", which builds a dynamically responsive system and initiates shape change. The shape fixing and recovery ratio of PCL-TiO2/PLLA are 93.9 % and 94.4 %, respectively, and go back to the original shape within 15 s at 57 °C. At the same time, PCL-TiO2 endows SMP with good antibacterial properties. Then this work provides a well-placed way for developing SM materials with structure-function integration.

Hydroxyapatite cross-linked in situ polyvinyl alcohol hydrogel for bionic calcified cartilage layer.

Many tissue engineering constructs have been investigated for repairing the calcified cartilage layer in the recent years, but engineering a consistent and stable interface to facilitate a graft-to-bone fixation remains a concern. In the work, hydroxyapatite (HA) is modified by diisocyanate (HDI) and integrated with polyvinyl alcohol (PVA) to prepare the hydrogel. The IR shows that HDI is grafted onto HA and helps HA to cross-link in situ in the PVA gel network. When the mass ratio of HA/PVA is 3.5 wt%, the swelling rate in the PBS of different pH reduced with time prolong, and the hydrogel takes on good swelling resistance. The tensile strength and toughness are 1890 KPa and 264 KJ/m-3, respectively, while the compression strength reaches 1125 KPa at compressive strain of 60%. The hydrogel not only is well durable via continuous 100 rounds of compression-recovery, but also has excellent bioactivity. The work will provide a platform for developing multifunctional soft tissue scaffold.

[Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis]. / 基于HMGB1/NF-κB/NLRP3è½´æŽ¢è®¨è¤ªé»‘ç´ å¯¹æ°§è¯±å¯¼è§†ç½‘è†œç— å˜çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis. METHODS: Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase. RESULTS: The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05). CONCLUSIONS: Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.

Self-Powered Multifunctional Organic Hydrogel Based on Poly(acrylic acid-N-isopropylacrylamide) for Flexible Sensing Devices.

Human-machine interactions, medical monitoring, and flexible robots stimulate interest in hydrogel sensing devices. However, developing hydrogel sensors with multifunctions such as good mechanics, electroconductivity, resistance to solvent volatility as well as freezing, self-adhesion, and independence on external power supply remains a challenge. In the work, a poly(acrylic acid-N-isopropylacrylamide) P(AA-NIPAm) organic hydrogel loading LiCl is prepared by ultraviolet cross-linking in ethylene glycol/H2O. The organic hydrogel exhibits favorable mechanical properties such as an elongation of break at 700% and a breaking strength of 20 KPa, can adhere to various substrates, and resists frost and solvent volatility. Especially, it possesses an excellent conductivity of 8.51 S/m. The organic hydrogel shows wide strain sensitivity based on resistance change, and the gauge factor reaches 5.84 in the range of 300-700%. It has short responsive and recuperative time and is still stable within 1000 rounds. Moreover, the organic hydrogel is also assembled into a self-powered device in which the open-circuit voltage is 0.74 V. The device can transform external stimuli such as stretching or compressing into the output current change, so it detects human motion effectively in real time. The work provides a perspective for electrical sensing engineering.

Expansion of CD3+CD8+PD1+ T lymphocytes and TCR repertoire diversity predict clinical responses to adoptive cell therapy in advanced gastric cancer.

The adoptive cell therapy (ACT) and delivery of ex vivo activated cellular products, such as dendritic cells (DCs), NK cells, and T cells, have shown promise for the treatment of gastric cancer (GC). However, it is unknown which cells can improve patient survival. This study was focused on the antitumour activity of a subset of these cellular products and their relationships with clinical outcomes. Nineteen patients were enrolled at the Capital Medical University Cancer Center, Beijing Shijitan Hospital, from June 1, 2013, to May 30, 2016. CD8+PD1+ T-cell sorting was carried out using flow cytometry, and the T-cell receptor (TCR) repertoire during ex vivo expansion for 15 days was analyzed by next-generation sequencing. After 15 days of culture, the number of CD8+ T cells had increased significantly, and the number of CD4+ T cells had increased correspondingly. After ex vivo expansion, CD8+ T cells exhibited significantly enhanced expression of PD-1, LAG-3, and TIM-3 but not 4-1BB. Survival analysis showed that patients with a pro/pre value of CD8+PD-1+ T cells >2.4 had significantly favorable overall survival (OS) (median OS time, 248 days versus 96 days, P=0.02) and progression-free survival (PFS) (median PFS time, 183 days vs. 77 days, P=0.002). The sorted CD8+PD-1+ T cells displayed enhanced antitumor activity and increased IFN-γ secretion after coculture with autologous tumor cell lines. TCR repertoire diversity was decreased after ex vivo expansion, which decreased the Shannon index and increased the clonality value. The prognosis of patients was significantly improved and was associated with the extent of CD8+PD-1+ T-cell expansion. In summary, this study showed that after ex vivo expansion for 15 days, CD8+PD-1+ T cells could be identified as tumor-reactive cells in patients treated for GC. Changing TCR species can predict the extent of CD3+CD8+PD1+ T-cell growth and the effect of ACT treatment.

ERBB2D16 Expression in HER2 Positive Gastric Cancer Is Associated With Resistance to Trastuzumab.

The human epidermal growth factor receptor-2 (ERBB2; formerly HER2)isoform ERBB2ΔEx16 (ERBB2d16) was oncogenic by mediating epithelial-mesenchymal transition (EMT), immune evasion, and resistance cell death to the anti-HER2 (trastuzumab) therapy. However, its physiological implications in gastric cancer were unclear. In this study, we examined a total of 110 patients with either locally advanced or metastatic HER2+ gastric cancer for the expression of ERBB2d16 and EMT markers, and the infiltration of CD3+ T cells in tumor tissues, and evaluated their relevance with the responses to the standard chemotherapy plus trastuzumab according to the RECIST criteria. We found that the ERBB2d16 isoform was present at a relatively high level in about half of the tumor samples examined (53/110) and an elevated ERBB2d16/ERBB2 ratio was positively associated with the expression of high E-cadherin and low vimentin indicating EMT, and with poor CD3+ T cell infiltration and strong intratumoral expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) as well as reduced diversity of T cell receptor clones. Moreover, the progression-free survival and overall survival of patients treated with trastuzumab were substantially shorter in those with a high ERBB2d16/ERBB2 ratio. In agreement, analysis by Cox proportional hazards models confirmed that high ERBB2d16 expression was a risk factor associated with an adverse prognosis. Thus, our data fit well with an oncogenic role of ERBB2d16 in gastric cancer by promoting EMT and immunosuppression. We also found that ERBB2d16 expression resists gastric cell death in patients treated with trustuzumab, and the ERBB2d16/ERBB2 ratio may serve as a novel prognostic maker for patients with gastric cancer that receive trastuzumab therapy.

Clinical characteristics of glioblastoma with metastatic spinal dissemination.

BACKGROUND: Metastatic spinal dissemination (MSD) is a rare phenomenon in glioblastoma (GBM). The study aimed to analyze the clinical characteristics of GBM patients with MSD. METHODS: Fifteen GBM patients with MSD, who were treated and followed up with at the Department of Oncology, Beijing Shijitan Hospital, Capital Medical University from September 2012 to February 2021, were selected for this study. Clinical data, such as demographic characteristics, clinical manifestation, imaging, cerebrospinal fluid (CSF), treatment and prognosis data, were retrospectively analyzed. The time to MSD and overall survival (OS) were estimated using Kaplan-Meier plotting. A univariate analysis was performed using a logarithmic-rank test, and a multivariate analysis was performed using Cox proportional hazards models. RESULTS: Of the 15 GBM patients with MSD (9 males and 6 females), the primary lesions were located supratentorial region in 12 cases, and subtentorial region in 3 cases. After surgery, the ventricles were open and closed in 7 and 8 cases, respectively. There were 10 cases, 2 cases, 2 cases, and 1 case of MSD in the full spinal cord (FSC), FSC with spinal cord intramedullary infiltration, cervical spinal cord intramedullary infiltration, and cervical/thoracic MSD, respectively. Whole spinal cord magnetic resonance imaging (MRI) showed dotted-line, nodules, and mixed patterns in 3, 2, and 10 cases, respectively. The average CSF protein level during MSD was 2.49 (range, 0.42-6.68) g/L, and the average CSF d-dimer level was 23,718 (range, 4,056-69,000) ng/L. By the end of the follow-up period, all the patients had died. The median OS of all patients, the median time from surgery to diagnosis of MSD, and the median time after MSD to death was 15.0 (range, 8-52), 10.0 (range, 1-49), and 4.0 (range, 1-14) months, respectively. CONCLUSIONS: MSD is a rare, metastasized type of GBM. The OS after MSD in GBM patients is very short. Whole spinal cord-enhanced MRI may be the best way to determine the range of MSD.

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy.

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is an attractive research field in tumor immunotherapy. While CAR is genetically engineered to express certain molecules, it retains the intrinsic ability to recognize tumor cells through its own receptors. Additionally, NK cells do not depend on T cell receptors for cytotoxic killing. CAR-NK cells exhibit some differences to CAR-T cells in terms of more precise killing, numerous cell sources, and increased effectiveness in solid tumors. However, some problems still exist with CAR-NK cell therapy, such as cytotoxicity, low transfection efficiency, and storage issues. Immune checkpoints inhibit immune cells from performing their normal killing function, and the clinical application of immune checkpoint inhibitors for cancer treatment has become a key therapeutic strategy. The application of CAR-T cells and immune checkpoint inhibitors is being evaluated in numerous ongoing basic research and clinical studies. Immune checkpoints may affect the function of CAR-NK cell therapy. In this review, we describe the combination of existing CAR-NK cell technology with immune checkpoint therapy and discuss the research of CAR-NK cell technology and future clinical treatments. We also summarize the progress of clinical trials of CAR-NK cells and immune checkpoint therapy.

Multi-omics analyses on Kandelia obovata reveal its response to transplanting and genetic differentiation among populations.

BACKGROUND: Restoration through planting is the dominant strategy to conserve mangrove ecosystems. However, many of the plantations fail to survive. Site and seeding selection matters for planting. The process of afforestation, where individuals were planted in a novel environment, is essentially human-controlled transplanting events. Trying to deepen and expand the understanding of the effects of transplanting on plants, we have performed a seven-year-long reciprocal transplant experiment on Kandelia obovata along a latitudinal gradient. RESULTS: Combined phenotypic analyses and next-generation sequencing, we found phenotypic discrepancies among individuals from different populations in the common garden and genetic differentiation among populations. The central population with abundant genetic diversity and high phenotypic plasticity had a wide plantable range. But its biomass was reduced after being transferred to other latitudes. The suppressed expression of lignin biosynthesis genes revealed by RNA-seq was responsible for the biomass reduction. Moreover, using whole-genome bisulfite sequencing, we observed modification of DNA methylation in MADS-box genes that involved in the regulation of flowering time, which might contribute to the adaptation to new environments. CONCLUSIONS: Taking advantage of classical ecological experiments as well as multi-omics analyses, our work observed morphology differences and genetic differentiation among different populations of K. obovata, offering scientific advice for the development of restoration strategy with long-term efficacy, also explored phenotypic, transcript, and epigenetic responses of plants to transplanting events between latitudes.

A Retrospective Study on Spinal Dissemination of Supratentorial Glioma.

OBJECTIVE: Metastatic spinal dissemination (MSD) of supratentorial glioma is very rare and there is no established standard of care. The current study investigates the clinical characteristics and course of spinal dissemination of supratentorial glioma. METHODS: A retrospective analysis of adult patients with MSD of supratentorial glioma treated in the Department of Oncology in Beijing Shijitan Hospital, Capital Medical University from June 2012 until August 2021 was performed. The time to event was estimated using Kaplan-Meier analysis. Univariate analyses were performed using log-rank test and multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Thirty-four adult patients with MSD of supratentorial glioma were enrolled in this retrospective study. The median time to MSD (TTMSD) and overall survival (OS) were 5 months (range: 0-78 months) and 15 months (range: 0.7-85 months), respectively, in the entire cohort. Univariate analysis demonstrated that the patients who had received TMZ therapy had a longer TTMSD than those who did not (mTTMSD: 15 vs. 3 months, log-rank P = 0.0004). Furthermore, a protracted duration of salvage chemotherapy of >6 months after MSD was associated with longer OS of the patients with MSD of supratentorial glioma (mOS: 13 vs. 5 months, log-rank P = 0.0163) and reduced the death risk by 64.3% (hazard ratio: 0.357, 95% CI: 0.141-0.901, P = 0.029) compared with a duration ≤6 months. CONCLUSION: Patients with MSD of supratentorial glioma experienced poor prognosis and adjuvant chemotherapy may delay the occurrence of MSD. The protracted duration of systemic salvage chemotherapy may favor survival after spinal dissemination.

Combined carboplatin and etoposide chemotherapy for patients with recurrent glioma.

BACKGROUND: Currently, there is no consensus on the standard of care for patients with recurrent glioma. This study investigated the efficacy of combined carboplatin and etoposide (CE) treatment in recurrent glioma. METHODS: A retrospective analysis was performed on adult patients with recurrent glioma who received combination chemotherapy consisting of CE from September 2017 to November 2020 at the Beijing Shijitan Hospital, Capital Medical University, Beijing. The response rate (RR), defined as the complete response (CR) + partial response (PR), and the disease control rate (DCR), defined as CR + PR + stable disease (SD), were analyzed by Chi-square or Fisher's exact test according to different clinical characteristics. Time to progression (TTP) was estimated using Kaplan-Meier plots and the log-rank test was used to compare differences. RESULTS: A total of 55 patients were assessed and 47 patients were eligible to be enrolled in this study. There was 1 case of CR (2.1%), 3 patients with PR (6.4%), and 18 patients with SD (38.3%). The RR was 8.5% and the DCR was 46.8%. When the patients were stratified by World Health Organization (WHO) grade, the DCR was significantly higher in patients with grade 2 and 3 tumors (83.3% and 50%, respectively) compared to patients with grade 4 tumors (29.6%; P=0.039). For patients with grade 4 gliomas, the median TTP and median overall survival (OS) were 2 [95% confidence interval (CI): 0.988 to 3.012] and 7 (95% CI: 3.626 to 10.374) months, respectively. By comparison, the TTP and OS for patients with grade 2-3 gliomas were 4 (95% CI: 1.947 to 6.053) and 13 (95% CI: 0.000 to 26.47) months, respectively. The 6-month progression free survival (PFS) and 12-month OS were 11.1% and 16.3%, respectively, in patients with grade 4 glioma, compared to 37.9% and 48%, respectively, in patients with grade 2-3 gliomas. CONCLUSIONS: CE regimen may be effective as a salvage treatment for recurrent glioma. Patients with anaplastic or low-grade glioma may benefit more from such therapy compared to patients with grade 4 tumors.

Characteristics of spinal dissemination in adult low-grade glioma: a retrospective cohort study at a single institute.

BACKGROUND: In adults, metastatic spinal dissemination (MSD) in low-grade glioma (LGG) is an unusual phenomenon of the central nervous system. This study sought to investigate the clinical characteristics of adult MSD in LGG and its course. METHODS: A retrospective analysis was performed from June 2011 to July 2021 in adult LGG patients with MSD treated at the Oncology Department of the Beijing Shijitan Hospital, Capital Medical University. The time to MSD and overall survival (OS) were estimated using Kaplan-Meier plotting. A univariate analysis was performed using a logarithmic-rank test, and a multivariate analysis was performed using Cox proportional hazards models. RESULTS: Thirteen adult LGG patients with MSD were enrolled in this retrospective study. Most of the primary tumors were grade II (92.3%) or astrocyte derived (7.7%). The median total OS time from the initial surgery, the time to MSD and the OS time after MSD of the 13 adult LGG patients was 45.0, 15, and 16 months, respectively. CONCLUSIONS: Adult LGG patients with MSD had a poor prognosis. Enhanced magnetic resonance imaging was highly recommended in adult LGG patients. Maybe parts of patients appeared to experience prolonged clinical benefits from systemic salvage chemotherapy and intrathecal injection after MSD. Novel modalities need to be explored to improve the outcomes of patients with MSD.

PD-L1 Expression in Glioblastoma, the Clinical and Prognostic Significance: A Systematic Literature Review and Meta-Analysis.

Background: The clinical and prognostic value of programmed death-ligand 1, PD-L1, in glioblastoma remains controversial. The present study aimed to identify the expression of PD-L1 for its prognostic value in glioblastoma. Methods: A comprehensive literature search was performed using the PubMed and CNKI databases. The overall survival (OS) and disease-free survival (DFS) of GBM was analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for clinicopathological parameters. The statistical analysis was using RevMan 5.3 software. Results: The meta-analysis was performed by using total nine studies including 806 patients who had glioblastoma. The pooled results indicated that PD-L1 expression in tumor tissues was significantly related to a poor OS (HR = 1.63, 95%CI: 1.19-2.24, P = 0.003, random effects model) with heterogeneity (I 2 = 51%). In subgroup analyses, PD-L1 positivity was significantly associated with a worse OS for patients of American and Asian regions, but not for those of European regions. Moreover, PD-L1 expression implied a trend toward the mutation status of the IDH1 gene [coding the Isocitrate Dehydrogenase (NADP(+))-1 protein] (HR = 9.92, 95%CI: 1.85-53.08, P = 0.007, fixed effects model). However, the prediction overall survival (OS) of the patients showed that PD-L1 expression was independent from other clinicopathological features, such as gender and age. Conclusions: Our analyses indicated that high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma.

econvRBP: Improved ensemble convolutional neural networks for RNA binding protein prediction directly from sequence.

RNA binding proteins (RBPs) determine RNA process from synthesis to decay, which play a key role in RNA transport, translation and degradation. Therefore, exploring RBPs' function from the amino acid sequence using computational methods has become one of the momentous topics in genome annotation. However, there still have some challenges: (1) shallow feature: Although the sequence determines structure is self-evident, it is difficult to analyze the essential features from simple sequence. (2) Poorly understand: feature-based prediction methods mainly emphasize feature extraction, while in-depth understanding of protein mysteries limits the application of feature engineering. (3) Feature fusion: multi-feature fusion is often used, but the features are not well integrated. In view of these challenges, we propose a novel ensemble convolutional neural network (econvRBP) to predict RBPs. In order to capture the local and global features of RNA binding proteins simultaneously, first of all, One Hot and Conjoint Triad encoding methods are used to transform amino acid sequence into local and global features, respectively. After that the local and global features are combined for further high-level feature extraction using convolutional neural networks. Some experiments are constructed to evaluate our method with 10-fold cross validation and the results show that it has achieved the best performance among all the predictors so far. We correctly predicted 99% of 2875 RBPs and 99% of 6782 non-RBPs with accuracy of 0.99. In addition, the datasets provided by RBPPred are also used to validate our models with an accuracy of 0.87. These results indicate that the econvRBP is the most excellent method at present, and will provide reliable guidance for the detection of RBPs. econvRBP is available at http://47.100.203.218:3389/home.html/.

Nest survival rate of Reeves's pheasant (Syrmaticus reevesii) based on artificial nest experiments.

To explore the nest survival rate of Reeves's pheasant(Syrmaticus reevesii) and the nest-site factors that affect it, we conducted artificial nest experiments with reference to natural nests at Dongzhai National Nature Reserve(DNNR), Henan Province and Pingjingguan, Hubei Province from April to June 2014 simulating the situation in its early and later breeding season. We also determined distance characteristics of the nest sites by ArcGIS 10.0. Nest survival models were constructed in Program MARK for data analysis. Results indicated that in the early breeding season, the apparent survival rate(ASR) in DNNR(52.4%) was significantly greater than that in Pingjingguan(13.5%), and the ASR in the later breeding season in DNNR(26.7%) was not indistinctively correlated with Pingjingguan(3.2%). The daily survival rate(DSR) in the later breeding season was 93.8% in DNNR and 92.0% in Pingjingguan, respectively. The DSRs were both negatively correlated with nest distance to forest edges and settlements. The DSR in Pingjingguan was positively correlated with nest distance to paths and negatively correlated with nest distance to water sources. However, the DSR in DNNR was negatively correlated with nest distance to paths but positively correlated with nest distance to water sources.

MicroRNA-588 suppresses tumor cell migration and invasion by targeting GRN in lung squamous cell carcinoma.

MicroRNAs (miRNAs) have been demonstrated to be critical in regulating tumor development and progression. The present study investigated the expression of miR­588 using reverse transcription­quantitative polymerase chain reaction analysis in 85 cases of lung squamous cell carcinoma (SCC), and observed the correlation between the expression of miR­588 with clinical pathologic features. The results indicated that the expression of miR­588 was predominantly lower in the tumor samples, compared with non­tumorous samples, and was negatively associated with tumor stages and lymph node invasion. The present study also examined the significance of the expression of miR­588 in SCC using gain­ and loss­of­function analyses. It was found that miR­588 inhibited tumor cell migration and invasion. In addition, it was revealed that the overexpression of miR­588 in SCC cells reduced the mRNA and protein levels of progranulin (GRN), whereas miR­588 silencing increased the expression of GRN. A luciferase activity assay showed that miR­588 was able to directly bind to the 3'untranslated region of GRN and regulate its expression. Furthermore, it was found that the expression of GRN was inversely correlated with the expression of miR­588 in 85 paired SCC samples. These results indicated that GRN was involved in the miR-588-mediated suppressive functions in the progression of SCC.

[Therapeutic effect of in vitro 5-aza-2'-deoxycytidine combined with imatinib on gastrointestinal stromal tumor].

OBJECTIVE: To investigate the impact of 5-aza-2'-deoxycytidine(5-aza-CdR) combined with imatinib on the proliferation, motility, invasion, and apoptosis of gastrointestinal stromal tumors(GIST) cells in vitro. METHODS: MTT assay was used to investigate the effect of the two agents on proliferation of GIST882. Plate colony forming assay was used to determine the number of colony-forming. Motility and invasion abilities were tested to evaluate the inhibitory effect of each agent. Flow cytometry was used to observe apoptosis and cell cycle. RESULTS: 5-aza-CdR or imatinib effectively inhibited the growth of GIST882 cells in concentration- and time-dependent manner. The inhibitory rate of combined treatment using 5-aza-CdR and imatinib was significantly higher than that of 5-aza-CdR or imatinib alone(P<0.05). After treatment for 48 h, the apoptosis rates of 5-aza-CdR group (1000 µg/L) and imatinib group (100 µmol/L) were (11.7±1.2)% and (14.6±0.8)%, respectively. Compared with the control group (2.8±0.3)%, the difference was statistically significant(P=0.000). Furthermore, the difference in apoptosis rate was significant between combined treatment group (19.4±1.1)% and single drug treatment group(vs. 5-aza-CdR group, P=0.000, vs. imatinib group, P=0.013). 5-aza-CdR raised G0/G1 ratio and reduced S ratio of GIST882. Imatinib and combined group had no apparent influence on the cell cycle of GIST882 cells. CONCLUSION: 5-aza-CdR may be a potential agent of GIST treatment in the near future.