Signaling threshold regulating transmembrane adaptor 1 (SIT1) encodes a disulfide-linked homodimeric lymphocyte-specific glycoprotein involved in immune cell activation. However, the relationship between SIT1 and the prognosis of skin cutaneous melanoma (SKCM) and tumor-infiltrating lymphocytes remains elusive. Here, we first compared the differences in SIT1 expression levels between SKCM tissues and adjacent normal tissues. Next, we found that the immune cell infiltration levels and signature pattern of immune infiltration were positively associated with the SIT1 gene mRNA levels. TCGA_SKCM RNA-seq data unveiled that the SIT1 upregulated several immune-associated signaling pathways in GSEA analysis. The high expression of SIT1 was closely related to improved survival in patients with SKCM. A pathway enrichment analysis of SIT1-associated immunomodulators indicated the involvement of the NF-κB signaling pathways. Based on SIT1-associated immunomodulators, we built a 13-gene signature by LASSO Cox regression which served as an independent prognostic factor for the survival of melanoma patients. By using the signature risk score, we achieved a good prediction result for the immunotherapy response and survival of SKCM patients. Our findings provided evidence for SIT1’s implication in tumor immunity and survival of SKCM patients. The nominated immune signature is a promising predictive model for prognosis and immunotherapy sensitivity in SKCM patients.

Depression is the most common psychiatric disorder associated with brain and immune system abnormalities. In recent years, xanthohumol (Xn) a bioactive prenylated flavonoid has received ample attention for its polypharmacological effects, therefore, here we aimed to explore the protective effects of Xn against the LPS-induced depressive-like symptoms mediated by inflammation and oxidative stress. We tested the effect of Xn against LPS-induced behavioural changes in mice by means of forced swimming test (FST), tail suspention test (TST), sucrose preference test (SPT) and open field test (OPT). Examined the neuroinflammation and oxido-nitrosative stress (O&NS) markers and analyze Nrf2 and NF-κB signalling pathways in the hippocampus. Our results indicated that peripheral repeated administration of lipopolysaccharides (LPS) (1 mg/kg, intra peritoneally) induced depressive-like behavior, neuroinflammation and O&NS in mice. Pretreatment with Xn (10 and 20 mg/kg, intra gastrically) reverse the behavioural impairments prophylactically as obvious in the FST and TST without effecting locomotion, however only 20 mg dose improve anhedonic behavior as observed in SPT. Similarly, Xn pretreatment in dose-dependent manner prevented the LPS induced neuro-inflammation and O&NS. Immunofluorescence analysis showed that Xn reduced activated gliosis via attenuation of Iba-1 and GFAP in hippocampus. In addition, Xn considerably reduced the expression of phospho-NF-κB and cleaved caspase-3 while enhanced Nrf2 and HO-1 expression in the hippocampus. To the best of our knowledge, this is the first study to examine the underlying beneficial prophylactic effects of the Xn in neuroinflammation and O&NS mediating depressive-like behaviors.

Introduction Glioma is the most common malignant brain tumor in adults. Radiation is a key therapy in glioma. However, the radioresistance of glioma was a big challenge. HLA complex P5 (HCP5) has been reported dysregulated in several types of malignant tumor, including glioma. The role of HCP5 in the radiosensitivity of glioma is so far unknown. The present study aimed to investigate the effect of HCP5 on radiosensitivity in gliomas. Methods The levels of HCP5 and microRNA (miR)-128 were detected using qRT-PCR. The cell growth curve was used to show the cell proliferation and evaluate the radiosensitivity of glioma cells following exposure to X-ray. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to test the cellular senescence. Luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to determine the correlation between HCP5 and miR-128. Results HCP5 level of glioma cells was significantly higher than human astrocytes, whereas miR-128 level was lower in glioma cells. Besides, the HCP5 expression was increased in glioma tissues compared to normal brain tissues (NBTs). Knockdown of HCP5 inhibited cell proliferation and increased radiosensitivity in glioma cells. MiR-128 was predicted to be a target of HCP5. It was demonstrated that HCP5 directly bound to miR-128 and regulated its expression in glioma cells. Furthermore, the effects of HCP5 knockdown on radiosensitivity of glioma cells were attenuated by the inhibitor of miR-128. Conclusion These findings suggested that interaction between lncRNA HCP5 and microRNA-128 could regulate the radiosensitivity of glioma cells by intervening in cellular senescence. This might be used as the potential radio-sensitization targets for glioma therapy.

Physical or psychological stress can cause an immunologic imbalance that disturbs the central nervous system followed by neuroinflammation. The association between inflammation and depression has been widely studied in recent years, though the molecular mechanism is still largely unknown. Thus, targeting the signaling pathways that link stress to neuroinflammation might be a useful strategy against depression. The current study investigated the protective effect of melatonin against lipopolysaccharide (LPS)-induced neuroinflammation and depression. Our results showed that LPS treatment significantly induced depressive-like behavior in mice. Moreover, LPS-treatment enhanced oxidative stress, pro-inflammatory cytokines including TNFα, IL-6, and IL-1β, NF-κB phosphorylation, and glial cell activation markers including GFAP and Iba-1 in the brain of mice. Melatonin treatment significantly abolished the effect of LPS, as indicated by improved depressive-like behaviors, reduced cytokines level, reduced oxidative stress, and normalized LPS-altered Sirt1, Nrf2, and HO-1 expression. However, the melatonin protective effects were reduced after luzindole administration. Collectively, it is concluded that melatonin receptor-dependently protects against LPS-induced depressive-like behaviors via counteracting LPS-induced neuroinflammation.

Methyltransferase-like 3 (METTL3) is identified as a methyltransferase responsible for N6-methyladenosine (m6A) modification of mRNA, miRNA and lncRNA. Emerging evidences suggest that METTL3 is involved in tumorigenesis and progression of multiple tumor types. However, the functional role of METTL3 in esophageal cancer (EC) remains unclear. We used specific shRNA to down-regulate the METTL3 expression, and used pcDNA3.1-METTL3 cDNA plasmid to up-regulate the METTL3 expression in Eca-109 and KY-SE150 cells. Biological functions of METTL3 were performed by CCK-8, colony formation, apoptosis analysis, transwell and wound healing assays. Finally, an in-depth mechanism study was performed by an AKT inhibitor. METTL3 knockdown reduced the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and induced cell apoptosis, which may be mediated by activation of the mitochondrial apoptotic pathway. Further, METTL3 overexpression promoted the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and inhibited cell apoptosis. In addition, METTL3 regulated the expression of Wnt/β-catenin and AKT signaling pathway components. A double-effect inhibitor (BEZ235) inhibited AKT and mTOR phosphorylation and hindered the effect of METTL3 overexpression on the proliferation and migration of Eca-109 and KY-SE150 cells. Our data suggest that METTL3 plays a carcinogenic role in human EC progression partially through AKT signaling pathways, suggesting that METTL3 may serve as a potential therapeutic target for EC therapy.

目的 建立放射性肺炎小鼠模型,应用槲皮素对其干预,观察槲皮素对小鼠放射性肺炎的疗效.方法 随机数字表法将80只BALB/c小鼠分为6组:健康对照组(n=8)、单纯给药组(n=8)、单纯照射组(n=16)、照射+阿米福汀组(n=16)、照射+槲皮素(4 mg/mL)组(n=16)、照射+槲皮素(2 mg/mL)组(n=16).以6 mV X射线全肺单次10 Gy照射,各槲皮素给药组尾静脉注射不同浓度槲皮素(2、4 mg/mL),单纯给药组注射槲皮素4 mg/mL,健康对照组、单纯照射组注射4 mg/mL生理盐水,照射+阿米福汀组注射4 mg/mL阿米福汀.照射后1～8周,每周取各组小鼠双侧肺组织,HE染色观察小鼠肺组织炎性病理变化;采用免疫组织化学法和Western blotting技术观察槲皮素对丝裂原活化蛋白激酶(MAPK)标志蛋白p38、SAPK/JNK和p44/p42表达的影响.结果 与单纯照射组比较,各照射+槲皮素组小鼠的肺组织炎性表现减轻(P<0.01),肺组织p38、SAPK/JNK和p44/p42染色阳性程度、蛋白表达均降低(P<0.01).结论 槲皮素通过遏抑MAPK标志蛋白p38、SAPK/JNK、p44/p42的表达,从而阻止炎性因子的释放,最终降低了组织损伤和炎症程度.

OBJECTIVES:The roles and related mechanisms of six2 in regulating non-small cell lung cancer (NSCLC) cells progression are unclear. This work aimed to explore the roles of six2 in NSCLC cell stemness.MATERIALS AND METHODS:Kaplan-Meier plotter analysis was used to examine the correlation between six2 expression and the survival of NSCLC patients. Quantitative reverse transcription PCR and Western blot were performed to detect six2 expression in clinical samples. Moreover, transwell migration, tumour spheroid formation and in vivo tumour formation assays were used to examine the effects of six2 on NSCLC cell progression. Additionally, methylation analysis was carried out to measure E-cadherin methylation level in different cells. Finally, cell viability assay was performed to explore the effects of six2 on chemotherapeutic sensitivity of NSCLC cells.RESULTS:Lung cancer patients with a higher six2 expression level displayed a shorter overall survival. Six2 expression was higher in lung cancer tissues than in normal adjacent tissues. Additionally, six2 knockdown suppressed NSCLC cell stemness. Mechanistically, six2 overexpression inhibited epithelial marker E-cadherin expression via stimulating its promoter methylation. And E-cadherin knockdown rescued six2 knockdown-induced decrease of NSCLC cancer cell stemness. Notably, six2 knockdown enhanced cisplatin sensitivity in parental NSCLC cells and attenuated cisplatin resistance in cisplatin-resistant NSCLC cells.CONCLUSIONS:Our results suggest that six2 facilitates NSCLC cell stemness and attenuates chemotherapeutic sensitivity via suppressing E-cadherin expression.

Objective To obtain a better understanding of the prevalence and management of pain in patients undergoing radiotherapy for cancer in Shandong Province, China. Methods This cross-sectional study used a questionnaire during face-to-face interviews to collect data from physicians and patients regarding the recognition, prevalence and treatment of pain during the waiting period before commencement of radiotherapy and during the radiotherapy period. Physicians and patients were recruited from 10 tertiary Class A hospitals across Shandong Province, China. Results A total of 184 patients and 87 physicians were recruited to the study. During the waiting period, pain was reported by the physicians according to their experience to affect 26.0% of patients, which almost agreed with the patients' data (36.5%; 160 of 438). During the radiotherapy period, there was a significant difference in the reported prevalence of pain during the radiotherapy period between the physicians' data (23.0%) based on their experience and the patients' data (84.1%; 169 of 201 patients). The majority of physicians (98.9%; 86 of 87) agreed to the use opioids for pain management and 90.8% (79 of 87) were satisfied with the analgesic effect, but more than half of the patients who received pain treatment reported inadequate analgesia. Conclusion There was a high incidence of cancer pain, but insufficient assessment, inadequate treatment and inadequate education about pain in both the waiting and radiotherapy periods.

The desmosome is a member of intercellular junctions that named 'anchoring junction', which contributes to the integrity and homeostasis of tissue structure and function of multicellular living organisms. As an important component of the desmosome and the most widely distributed isoform of desmocollins (DSCs), desmocollin2 (DSC2) has been demonstrated to be essential for the unity of epithelial cells, and served as a vital regulator in signaling processes such as epithelial morphogenesis, differentiation, wound healing, cell apoptosis, migration, and proliferation. Recent studies suggested that the aberrant expression or disruption of DSC2 might lead to some disorders, including heart disorders, certain cancers, and some other human diseases. The distinctions in expression and regulation mechanisms of DSC2 in different human diseases provided a potential target for diagnosis and individualized treatment. Further research is required to certify the signaling capacity of DSC2 and to shed light on the down-stream consequences of the signaling for us to understand the new area of DSC2 biology and the development of certain diseases. This review summarizes the molecular structure and dynamics of desmosome and DSC2, the relationship between the disruption or aberrant expression of DSC2 and human diseases and related molecular mechanisms, as well as the possible prospects.

Ischemic strokes are categorized by permanent or transient obstruction of blood flow, which impedes delivery of oxygen and essential nutrients to brain. In the last decade, the therapeutic window for tPA has increased from 3 to 5-6 h, and a new technique, involving the mechanical removal of the clot (endovascular thrombectomy) to allow reperfusion of the injured area, is being used more often. This last therapeutic approach can be done until 24 h after stroke onset. Due to this fact, more acute ischemic stroke patients are now being recanalized, and so tMCAO is probably the "best" model to address these patients that have a potential good outcome in terms of survival and functional recovery. However, permanent occlusion patients are also important, not only to increase survival rate but also to improve functional outcomes, although these are more difficult to achieve. So, both models are important, and which target different stroke patients in the clinical scenario. Hippocampus has a vital role in memory and cognition, is prone to ischemic induced neurodegeneration. This study was designed to delineate the molecular, pathological, and neurological changes in rat models of t-MCAO, permanent MCAO (pMCAO), and pMCAO with diabetic conditions in hippocampal tissue. Our results showed that these three models showed distinct discrepancies at numerous pathological process, including key signaling molecules involved in neuronal apoptosis, glutamate induced excitotoxicity, neuroinflammation, oxidative stress, and neurotrophic changes. Our result suggests that the two commonly used MCAO models exhibited tremendous differences in terms of neuronal cell loss, glutamate excitotoxic related signaling, synaptic transmission markers, neuron inflammatory and oxidative stress molecules. These differences may reflect the variations in different models, which may provide valuable information for mechanistic and therapeutic inconsistences as experienced in both preclinical models and clinical trials.

Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss and ionic imbalance to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. These initial events are followed by neuroinflammation and oxidative stress, eventually causing neuronal neurosis and apoptosis. Complicated interplays exist between these steps happening across various stages, which not only represent the complicated nature of ischemic pathology but also warrant a detailed delineation of the underlying molecular mechanisms to develop better therapeutic options. In the present study, we examined the neuroprotective effects of polydatin against ischemic brain injury using a rat model of permanent middle cerebral artery occlusion (MCAO). Our results demonstrated that polydatin treatment reduced the infarction volume and mitigated the neurobehavioral deficits, sequentially rescued neuronal apoptosis. Ischemic stroke induced an elevation of neuroinflammation and reactive oxygen species, which could be attenuated by polydatin via the reduced activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In addition, polydatin upregulated the endogenous antioxidant nuclear factor erythroid 2-related factor 2, heme oxygenase-1, the thioredoxin pathway, and eventually reversed ischemic-stroke-induced elevation of ROS and inflammation in ischemic cortical tissue. The diverse and broad actions of polydatin suggested that it could be a multiple targeting neuroprotective agent in ameliorating the detrimental effects of MCAO, such as neuroinflammation, oxidative stress, and neuronal apoptosis. As repetitive clinical trials of neuroprotectants targeting a single step of stroke pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles in MCAO.

Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke.

Objective To observe the efficacy of compound e-jiao slurry on chemotherapy-resulted marrow suppression of small-cell lung cancer.Methods A total of 135 patients with small-cell lung cancer were divided into the control group (n=70) and treatment group (n=65).The control group was treated with EP chemotherapy program,while the treatment group took the compound e-jiao slurry (20 mL every time and three times every day) companying with EP chemotherapy program.The chemotherapy completion rates of patients were calculated.The marrow suppression,especially the change of hemoglobin,platelet,white blood cell (WBC) and neutrophil (NEUT) counts were observed.Results The chemotherapy completion rate of the treatment group is higher than that of the control group.The decreasing values of WBC and NEUT counts in these two groups were statistically significant (P＜0.05).Conclusion Compound e-jiao slurry decreases the incidence rate of the chemotherapy-resulted marrow suppression (WBC,NEUT) and relieves the decrease of WBC and NEUT counts.

Objective To investigate the radiobiological effects of VPA-BSANPs on C6 and U87 glioma cells in vitro.Methods C6 and U87 glioma cells were treated with different concentrations of VPA and VPA-BSANPs for 12 h and 24 h,and MTT assay was used to determine cell viability.C6 and U87 cells were treated with different concentrations of VPA and VPA-BSANPs conbined with X-ray irradiation (0,2,4,6,and 8 Gy),and colony formation assay was used to determine plating efficiency (PE).C6 and U87 glioma cells were treated with different concentrations of VPA and VPA-BSANPs for 12 h,followed by X-ray irradiation (0,4,and 8 Gy),and flow cytometry using Annexin V-FITC/PI staining was used to examine cell apoptosis.Western blot was used to evaluate the effects of VPA and VPA-BSANPs on radiation-induced apoptosis protein expression.One-way ANOVA was used for comparison of means with homogeneity of variance between multiple groups,and the t-test was used for comparison of means between two groups.Results Without irradiation,VPA and VPA-BSANPs had no significant inhibitory effects on the proliferation of C6 and U87 cells (P=0.328,0.920).The PE of cells treated with VPA-BSANPs combined with irradiation was significantly lower than that of cells treated with VPA combined with irradiation (P=0.000).In C6 and U87 cells,VPA-BSANPs combined with irradiation increased the expression of p53 and Bax (P =0.000,0.000 and P =0.010,0.002),but reduced the expression of Bcl-2 (P =0.008,0.000).Active caspase-3 fragments were only found in the cells treated with VPA-BSANPs combined with irradiation and VPA combined with irradiation,but were less in the former cells than in the latter cells (P=0.004).The active fragments of peroxisome proliferator-activated receptor were only found in the cells treated with VPA-BSANPs combined with irradiation.Conclusions VPA-BSANPs can increase the radiosensitivity of C6 and U87 glioma cells in vitro,possibly by promoting the apoptosis of tumor cells induced by radiation.

Objective To compare the gross tumor volume (GTV) and dose distributions for organs at risk (OAR) between external beam radiation therapy (EBRT) and low-dose rate (LDR) brachytherapy in the treatment of cervical vertebral metastases,in order to provide the basis for clinical treatment.Methods A total of 10 patients were randomly selected.Three-dimensional conformal radiotherapy (3D-CRT) planning was a single forth one with two oblique radiation fields.Intensity modulated radiotherapy (IMRT) planning included five equal radiation fields,and 2-arc volumetric-modulated arc radiotherapy (VMAT) was adopted.The images from Oncentra treatment planning system (TPS) were delivered to Prowess TPS to formulate LDR brachytherapy pre-operative simulation plan.Results For the same dose of spinal cord,the biologically effective dose (BED) of D90 and D95 of LDR were (184.15 ±25.84) Gy and (161.45 ±26.35) Gy.When the fraction scheme was 2 Gy/f,the D95 BED of VMAT,IMRT and 3D-CRT were (120.52 ±10.66) Gy,(119.19 ± 10.91) Gy and (96.24 ±28.65) Gy.When the fraction scheme was 3 Gy/f,the D95 BED 3 Gy/f of VMAT,IMRT and 3D-CRT were (122.19 ± 7.54) Gy,(122.37 ± 8.19) Gy and (95.94 ± 24.70) Gy.All parameters complied with the normal distribution,P =0.00 after paired t test.There was no statistical difference in V5 of the mucosa among VMAT,IMRT and LDR (P =0.16,0.34),and V5 of the mucosa of 3D-CRT was higher than that in LDR (P =0.00).The V30 and D of LDR were less than those of 3D-CRT,VMAT and IMRT,statistically (P =0.00).Other parameters of the thyroid gland,parotid gland and mandible were significantly different between LDR and 3D-CRT,VMAT and IMRT (P =0.00).Conclusion When the fraction schemes were 2 Gy/f and 3 Gy/f,3D-CRT,IMRT and VMAT had lower GTV doses than LDR,which could protect the OARs at the same time.Therefore,as to the cervical vertebral metastases after EBRT,LDR is a good choice for salvage treatment.

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid-overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.

目的 观察鼻咽癌(NPC)患者调强放疗(IMRT)后前庭功能障碍的发生情况.方法 检测38例共76侧接受过NPC根治性IMRT患者的前庭诱发肌源性电位(VEMPs),包括同侧胸锁乳突肌前庭诱发肌源性电位(cVEMP)和对侧眼外肌前庭诱发肌源性电位(oVEMP),并统计其前庭功能障碍(眩晕、异常位置觉和振动幻视等)发生情况.结果 本组放疗结束时oVEMP和cVEMP异常发生率分别为65.79%(50/76)和80.26%(61/76),放疗后3个月时分别为61.84%(47/76)和61.84%(54/76).本组放疗结束时及结束后3个月前庭功能障碍发生率分别为18.42%(7/38)和23.68%(9/38),P<0.05.本组放疗结束及结束后3个月前庭功能障碍发生率均低于同时点oVEMP和cVEMP异常发生率,P均<0.05.结论 NPC患者IMRT后普遍存在前庭功能受损,但只有少数患者有临床症状,应引起临床重视.