Objective Head and neck squamous cell carcinoma (HNSCC) is the most common type of malignancy in the head and neck region worldwide. The therapeutic strategies for HNSCC remain unsatisfying and limited. Here, we found a population of resistant Bmi1-expressing cells in the presence of cetuximab treatment and reported a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting HNSCC resistance to cetuximab. This study aimed to investigate the regulatory mechanism of Sox18 in Bmi1-positive cells and to search for better therapeutic targets.Methods We successfully obtained Bmi1(CreER), Rosa(tdTomato), and Rosa(DTA) mice and identified Bmi1-expressing cells through lineage tracing. SOX18 expression in HNSCC and normal tissues was analyzed by immunohistochemistry, colocalization of Sox18, and Bmi1-expressing cells was analyzed by immunofluorescence, and SOX18 expression in SCC9 cell lines was quantified by western blotting and quantitative real-time PCR. The investigation of the mechanism of SOX18-mediated cetuximab resistance in Bmi1-positive cells was based on the analysis of single-cell RNA-seq data obtained from the Gene Expression Omnibus (GEO) database. Western blotting was performed to verify the results obtained from the single-cell RNA-seq analysis.Results In our study, we demonstrated that Bmi1-expressing cells were resistant to cetuximab treatment and that depletion of Bmi1-expressing cells improved cetuximab efficacy in HNSCC. We then discovered that Sox18 mediated the stem cell-like properties of Bmi1-expressing cells and promoted cellular cetuximab resistance through an oxidative phosphorylation pathway. There was a significant downregulation of key genes in the oxidative phosphorylation pathway in Sox18 knockout cell lines.Conclusions Taken together, the findings of our study suggest that Sox18 mediates the resistance of Bmi1-expressing cells to cetuximab in HNSCC via the oxidative phosphorylation pathway.

ObjectiveTo investigate the prognostic value of preoperative neoadjuvant therapy (NT) compared to upfront surgery (US) in patients with resectable and borderline resectable pancreatic cancer.MethodsPubMed, Embase, Web of Science were searched to collect randomized controlled trials on preoperative neoadjuvant therapy versus upfront surgery for resectable and borderline resectable pancreatic cancer before April 7, 2023, and data were extracted after screening according to inclusion and exclusion criteria, and HRs were obtained indirectly using enguage software; Stata 12.0 software was used for data analysis.ResultsA total of 8 randomized controlled trials (RCTs) were included in this study, comprising a total of 1058 cases, including 503 cases in the NT group and 555 cases in the US group. Using an intention-to-treat population (ITT) analysis, the results showed that neoadjuvant treatment improved the R0 resection rate (RR 2.71, 95% CI 1.59-4.62; P = 0.000; I2 = 46.20%) and overall survival (HR 0.66, 95% CI 0.54-0.82; P = 0.000; I2 = 0.00%). In the subgroup of patients with resectable pancreatic cancer, the R0 resection rate in the NT group versus the US group (RR 1.14, 95% CI 0.93-1.39; P = 0.196; I2 = 0.00%) and overall survival (HR 0.89, 95% CI 0.64-1.24; P = 0.489; I2 = 0.00%) were not statistically significant.ConclusionsPreoperative neoadjuvant treatment is of prognostic value in patients with borderline resectable pancreatic cancer, as it increases the R0 resection rate and improves overall survival compared to upfront surgery.

Purpose. With the increasing incidence of thyroid cancer (TC), associations between genetic polymorphisms and TC risk have attracted a lot of attention. Considering that the results of associations of genetic variants with TC were usually inconsistent based on publications until now, we attempted to comprehensively evaluate the real evidence of associations between single nucleotide polymorphisms (SNPs) and TC risk. Method. We performed meta-analyses on 36 SNPs in 23 genes associated with TC susceptibility based on the data from 99 articles and comprehensively valued the epidemiological evidence of significant associations through the Venice criteria and false-positive report probability (FPRP) test. OR and P value were also calculated for 19 SNPs in 13 genes based on the insufficient data from 22 articles. Results. 19 SNPs were found significantly associated with TC susceptibility. Of these, strong epidemiological evidence of associations was identified for the following seven SNPs: POU5F1B rs6983267, FOXE1 rs966423, TERT rs2736100, NKX2-1 rs944289, FOXE1 rs1867277, FOXE1 rs2439302, and RET rs1799939, in which moderate associations were found in four SNPs and weak associations were found in eight SNPs. In addition, probable significant associations with TC were found in nine SNPs. Conclusion. Our study systematically evaluated associations between SNPs and TC risk and offered reference information for further understanding of polymorphisms and TC susceptibility.

随着我国人口老龄化程度的加剧,老年人口不断增多,骨质疏松(osteoporosis,OP)将成为严峻的公共卫生问题.与此同时,男性OP的发病率逐渐上升,却一直未受到应有的关注.目前可用于男性OP 治疗的药物有维生素D与钙剂、双膦酸盐、锶盐、甲状旁腺素制剂、核因子-κB受体配体(nuclear factor-κB receptor ligand,RANKL)活化剂、骨硬化蛋白单克隆抗体、选择性雌激素调节剂(selective estrogen receptor modulator,SERMs)等.另有许多新药处于研发或临床试验阶段,有望进一步改善男性骨质疏松治疗效果,提高生活质量.笔者将简要介绍男性OP治疗药物的种类及作用机理,以提高认识.

Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.

Abnormal telomerase activity is implicated in cancer initiation and development. The rs2736100 T > G polymorphism in the telomerase reverse transcriptase (TERT) gene, which encodes the telomerase catalytic subunit, has been associated with increased cancer risk. We conducted a meta-analysis to more precisely assess this association. After a comprehensive literature search of the PubMed and EMBASE databases up to November 1, 2016, 61 articles with 72 studies comprising 108,248 cases and 161,472 controls were included in our meta-analysis. Studies were conducted on various cancer types. The TERT rs2736100 polymorphism was associated with increased overall cancer risk in five genetic models [ homozygous model (GG vs. TT): odds ratio (OR) = 1.39, 95% confidence interval (95% CI) = 1.26-1.54, P < 0.001; heterozygous model (TG vs. TT): OR = 1.16, 95% CI = 1.11-1.23, P < 0.001; dominant model (TG + GG vs. TT): OR = 1.23, 95% CI = 1.15-1.31, P < 0.001; recessive model (GG vs. TG + TT): OR = 1.25, 95% CI = 1.16-1.35, P < 0.001; and allele contrast model (G vs. T): OR = 1.17, 95% CI = 1.12-1.23, P < 0.001]. A stratified analysis based on cancer type associated the polymorphism with elevated risk of thyroid cancer, bladder cancer, lung cancer, glioma, myeloproliferative neoplasms, and acute myeloid leukemia. Our results confirm that the TERT rs2736100 polymorphism confers increased overall cancer risk.

Objective: This study aims to investigate the effect of octreotide combined with ulinastatin on the serum endotoxin and intestinal mucosal permeability in patients with severe pancreatitis.Methods: A total of 88 patients with severe pancreatitis were randomly selected in our hospital from January 2015 to June 2016. They were then randomly assigned to either the observation group (n=44) or the control group (n=44) using the random number method. The patients in the control group were treated with octreotide, whereas those in the observation group were given octreotide combined with ulinastatin. The serum endotoxin and hypersensitive C Reactive Protein (hs-CRP) levels as well as intestinal mucosal permeability of the two groups were investigated before and after treatment.Results: Before treatment, no significant difference was observed in the serum endotoxin, hs-CRP, plasma Diamine Oxidase (DAO), and Lactulose/Mannitol (L/M) levels of patients between the two groups (P>0.05). However, the endotoxin and hs-CRP levels of the patients in the two groups were significantly lower after treatment than those before treatment (P<0.05). After treatment, the plasma DAO levels of the patients in the two groups were significantly lower than those before treatment (P<0.05), and their L/M levels were significantly higher than those before treatment (P<0.05). However, the serum endotoxin, hs-CRP, plasma DAO, and L/M levels of the patients in the observation group were significantly lower than those in the control group (P<0.05).Conclusion: Octreotide combined with ulinastatin can significantly decrease the serum endotoxin level of patients with severe pancreatitis. Furthermore, this treatment can help in the restoration of intestinal mucosal function barrier in patients.

Cleft lip and palate transmembrane 1-like (CLPTM1L) gene rs402710 (C > T) and rs401681 (C > T) polymorphisms have been widely studied for their potential relation to cancer risk, but studies have produced conflicting results. To systematically evaluate the association between these two polymorphisms and overall cancer risk, we conducted a comprehensive meta-analysis on all relevant articles found in the PubMed and EMBASE databases published prior to May 1, 2017. There were 26 articles with 28 studies, including 30,770 cases and 34,089 controls, for the rs402710 polymorphism and 38 articles with 48 studies, including 67,849 cases and 328,226 controls, for the rs401681 polymorphism. The pooled results indicated that both rs402710 and rs401681 polymorphisms are significantly associated with decreased overall cancer risk. In our stratification analysis, a significant association of the rs402710 polymorphism with lung and bladder cancers was identified among Asian and Caucasian populations in both hospital-based and population-based studies. The rs401681 polymorphism was significantly associated with a decreased risk of lung cancer, bladder cancer, and basal cell carcinoma in Asians and in hospital-based studies. CLPTM1L gene rs402710 and rs401681 polymorphisms thus have a protective association with various types of cancer, especially lung cancer among Asians.

The association between the TOC high mobility group box family member 3 (TOX3) gene rs3803662 C > T polymorphism and breast cancer risk have been investigated in multiple ethnic groups. However, studies conducted in the Chinese population have yielded contradictory results. Therefore, we performed the current meta-analysis to drive a more precise evaluation of the association between TOX3 rs3803662 C > T polymorphism and breast cancer risk in the Chinese population. A total of seven eligible studies with 12,800 cases and 11,550 controls were involved in this meta-analysis. Overall, the SNP was shown to significantly increase the risk of developing breast cancer in the Chinese population under all genetic models (homozygous model: OR = 1.28, 95% CI = 1.17-1.39, P < 0.001; heterozygous model: OR = 1.12, 95% CI = 1.03-1.22, P = 0.009; recessive model: OR = 1.17, 95% CI = 1.11-1.23, P < 0.001; dominant model: OR = 1.20, 95% CI = 1.10-1.30, P < 0.001; as well as allele comparison: OR = 1.13, 95% CI = 1.09-1.18, P < 0.001). Meanwhile, no between-study heterogeneity and publication bias was observed, indicating the reliability of the findings. In conclusion, our meta-analysis results suggested that TOX3 rs3803662 C > T polymorphism might confer increased susceptibility to breast cancer in the Chinese population.

The association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk has been widely investigated, but remains controversial. We therefore undertook a comprehensive meta-analysis to provide a high-quality evaluation of this association. A literature search was performed among Pubmed, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases prior to July 31, 2016, and the strength of the association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk was assessed based on odds ratio (OR) and 95% confidence interval (95% CI). In total, 12 studies with 50,525 cases and 54,302 controls were included. Pooled risk estimates indicated a significant association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk. Analysis of cases stratified based on ethnicity suggested that the association was significant in both Caucasian and Asian populations. Stratification based on source of controls revealed an association only in population-based studies. These findings indicate the LSP1 rs3817198 T > C polymorphism is associated with increased risk of breast cancer, especially in Caucasian and Asian populations. Large, well-designed studies with different ethnicities are still needed to verify our findings.

The study aims to investigate the possible mechanisms of microRNA-133a (miR-133a) targeting CD47 on cell proliferation, apoptosis, migration, and invasion in laryngeal carcinoma. Forty-two laryngeal carcinoma tissue specimens confirmed by pathological examination from laryngeal carcinoma patients as the case group were collected, and 20 chronic laryngitis tissues were gathered as the control group. The human laryngeal carcinoma cell line Hep-2 was marked as the miR-133a mimic, negative control (NC), miR-133a inhibitor, CD47-siRNA, miR-133a inhibitor + CD47-siRNA, and Mock groups. The expression of CD47 protein and miR-133a was detected by immunohistochemistry (IHC) and qRT-PCR. Dual luciferase assay system was used to determine the relationship between CD47 and miR-133a. Western blotting was used to measure the protein expression of CD47 and miR-133a. 5-Ethynyl-2′-deoxyuridine (EDU) method was used to detect the cell proliferation, and flow cytometry and Transwell were used to measure the cell apoptosis and migration and invasion, respectively. The miR-133a expression in laryngeal carcinoma tissues was significantly lower, while the CD47 expression was higher than that in chronic laryngitis tissues (both P < 0.01). The expression of miR-133a in the miR-133a mimic group was significantly higher than that in other groups (P < 0.05), and the messenger RNA (mRNA) and protein expression of CD47 in the CD47-siRNA and miR-133a mimic groups were significantly lower than those in the Mock and NC group (all P < 0.05), while the mRNA and protein expression of CD47 in the miR-133a inhibitor group were higher than in other groups (all P < 0.05). After transfection, the CD47-siRNA group had the strongest inhibitory activity, while the number of living cells in the miR-133a inhibitor group was significantly higher than that in other groups (all P < 0.05). The apoptosis rates in the miR-133a mimic and CD47-siRNA groups were significantly higher than that in the Mock and NC groups (all P < 0.05). The cell numbers that penetrated membrane in the miR-133a mimic and CD47-siRNA groups were less than in the Mock and NC groups (all P < 0.05). Upregulated miR-133a could inhibit proliferation, invasion, and migration and promote cell apoptosis in laryngeal carcinoma by targeting CD47. miR-133a targeting CD47 could be a new direction in the diagnosis and treatment of laryngeal carcinoma.

BACKGROUND:Resistance to temozolomide (TMZ) in glioma is modulated by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). This study aimed to examine the effects of fluoxetine (FLT) on MGMT expression in glioma cells and to investigate its underlying mechanisms.MATERIALS AND METHODS:Expression of MGMT, GluR1, or IκB kinase β (IKKβ) was attenuated using short hairpin RNA-mediated gene knockdown. The 3-(4,5-dimethylthiazol -2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the growth inhibition induced by FLT or TMZ. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) was conducted to detect apoptotic cells. Western blotting was conducted to analyze the protein expression of MGMT, IKKβ, and NF-κB/p65 following FLT treatment. The murine subcutaneous xenograft model was used to evaluate the combinational effect of TMZ and FLT.RESULTS:FLT markedly reduced MGMT expression in glioma cells, which was independent of GluR1 receptor function. Further, FLT disrupted NF-κB/p65 signaling in glioma cells and consequently attenuated NF-κB/p65 activity in regulating MGMT expression. Importantly, FLT sensitized MGMT-expressing glioma cells to TMZ, as FLT enhanced TMZ's ability to impair the in vitro tumorigenic potential and to induce apoptosis in glioma cells. Knockdown of MGMT or IKKβ expression abolished the synergistic effect of FLT with TMZ in glioma cells, which suggested that FLT might sensitize glioma cells to TMZ through down-regulation of MGMT expression. Consistently, TMZ combined with FLT markedly attenuated NF-κB/p65 activity, reduced MGMT expression, and suppressed in vivo tumor growth in the murine subcutaneous xenograft model.CONCLUSION:Our findings demonstrated that FLT attenuated MGMT expression by disrupting NF-κB signaling and sensitized glioma cells to TMZ, which may warrant further investigation toward possible clinical application in MGMT-expressing glioma.