Mutations in the oncogene p53 are present in nearly all types of carcinomas and are commonly inactivated in certain tumor types, resulting in a poor prognosis for these patients. In contrast to the prevailing perspective that targeting p53 protein is not feasible, an increasing number of scholars have found that strategies such as directly or indirectly targeting P53 to enhance or restore the function of wild-type P53, or degrading mutant P53 so that the gain of function caused by it disappears, as well as modulating the immune response and cellular metabolism, can control the progression of tumor cells in different states of P53. This article aims to provide a comprehensive overview of the most recent targeted drugs for solid tumors with different P53 status. At the same time, it conducts a thorough analysis of the efficacy of relevant drugs in patients and puts forward possible reasons for the poor efficacy of some medicines.

e13006 Background: The optimal treatment for HER2-positive advanced breast cancer (ABC) in later lines remains unclear, particularly after progression on monoclonal antibodies and tyrosine kinase inhibitors (TKIs). Disitamab vedotin (RC48) is a novel HER2-targeted antibody-drug conjugate (ADC) composed of hertuzumab coupled with monomethyl auristatin E (MMAE) via a cleavable linker. This study aimed to evaluate the efficacy and safety of RC48 in real-world HER2+ ABC patients. Methods: This nationwide, observational cohort study was conducted at 22 sites in China. Patients with HER2+ ABC who received RC48 treatment were included. Demographics, treatment patterns, clinical outcomes, and safety data were analyzed. Real-world progression-free survival (PFS) and overall survival (OS) were assessed. Results: From June 2021 to October 2023, 67 patients were enrolled, with a median age of 51 (45-59) years. 98.33% of all patients were female. Among all, 59.70% had hormone receptor-positive tumors. All patients had received prior anti-HER2 TKI therapy and 96.67% were anti-HER2 monoclonal antibodies pretreated. Anti-microtubule chemotherapy was given in 82.09% of patients, 80.00% of whom achieved disease control as best overall response (BOR). The median number of RC48 treatment lines was three (2nd to 13th-line), with a median treatment duration of 4.07 months (IQR: 2.56-7.98). Median PFS was 7.85 months (95% CI: 4.60-9.59), consistent with previous studies. The overall ORR and DCR were 27.4% (95% CI: 16.9%-40.2%) and 72.6% (95% CI: 59.8%-83.2%), respectively. The median duration of response (DoR) for the 17 responders was 5.78 months. The median PFS of patients who received RC48 as > 3 lines of treatment was 5.95 months (95% CI: 4.01-8.84). No statistical differences were found across subgroups based on prior anti-microtubule chemotherapy, regardless of BOR or RC48 continuity (Table). Grade ≥3 adverse events occurred in 23.88% of patients. The most common was decreased white blood cell count (8.95%). Conclusions: RC48 showed promising antitumor activity and manageable tolerability in this heavily pretreated HER2+ ABC population, offering a reasonable option for later-line treatment in clinical practice. Prior chemotherapy with anti-microtubule agents did not seem to affect RC48 efficacy in our study, while further studies with larger sample sizes are still needed. Clinical trial information: ChiCTR2500095450 . Efficacy summary. Median PFS, mo (95% CI) Overall (n=67) 7.85(4.60-9.59) RC48 treatment lines≤3 (n=35)>3 (n=32) 8.00(4.86-16.16)5.95(4.01-8.84) Prior anti-microtubule therapyYes (n=55)No (n=12) 7.85 (4.60-14.46)7.00(2.96-8.00) BOR in prior anti-microtubule therapyDisease control (n=44)Disease progression (n=11) 8.84(4.30-14.46)6.70(1.28-16.16) Continuity between prior anti-microtubule therapy and RC48Yes (n=33)No (n=22) 9.76(4.00-16.36)7.85(4.17-13.90)

Background Esophageal carcinoma is the eighth prevalent malignancy and ranks the sixth in carcinoma-related death worldwide. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has been identified as a tumor suppressor in multiple carcinomas. However, its roles and molecular mechanisms underlying esophageal carcinoma progression are still undefined till now. Methods RT-qPCR assay was employed to detect the expression of TIPE2 mRNA. TIPE2 protein expression was measured by using western blot assay. Ad-V and Ad-TIPE2 adenoviruses were constructed to overexpress TIPE2. The effects of TIPE2 overexpression on cell proliferation, invasion and apoptosis were assessed by MTT and Edu incorporation assays, transwell invasion assay and flow cytometry analysis, respectively. The effect of TIPE2 overexpression on xenograft tumor growth was determined by measuring tumor volume and weight, together with immunohistochemistry assay. The effect of TIPE2 overexpression on the Wnt/β-catenin signaling pathway was evaluated by detecting the protein levels of β-catenin, c-Myc and cyclinD1 in EC9076 cells and xenograft tumors of esophageal carcinoma. Results TIPE2 expression was downregulated in esophageal carcinoma tissues and cells. Adenovirus-mediated TIPE2 overexpression suppressed cell proliferation and invasion, and induced apoptosis in esophageal carcinoma cells. Enforced expression of TIPE2 inhibited tumor growth in vivo, as evidenced by the reduced tumor volume, tumor weight and proliferating cell nuclear antigen expression. Overexpression of TIPE2 inhibited the Wnt/β-catenin signaling pathway in esophageal carcinoma in vitro and in vivo. Conclusions These results suggest that TIPE2 suppressed progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway.

Abstract Purpose: The study aimed to evaluate the causal association between the level of total testosterone and the risk of non-small cell lung cancer (NSCLC) utilizing Mendelian randomization (MR) approach. Methods: Genetic variants extracted from genome-wide association studies (GWAS) datasets of total testosterone level and NSCLC were utilized as instrumental variables (IVs). Five methods were employed to generate overall estimates of the effect, including the inverse variance weighted (IVW), MR Egger, maximum likelihood (ML), weighted median, and IVW (multiplicative random effects). Leave-one-out validation, MR Steiger test, pleiotropy and heterogeneity testing were conducted to ensure the reliability of our results. Results: The MR analysis demonstrated a causal effect between total testosterone level and NSCLC, IVW (OR = 0.74, 95% CI = 0.60-0.92, P= 7.44E-03), MR Egger (OR = 0.53, 95% CI = 0.34-0.84, P = 6.98E-03), ML (OR = 0.74, 95% CI = 0.61-0.91, P = 3.49E-03), weighted median (OR = 0.66, 95% CI = 0.48-0.91, P = 1.25E-03), and IVW (multiplicative random effects) (OR = 0.74, 95% CI = 0.60-0.92, P = 7.44E-03). The leave-one-out test revealed that removing any IV did not significantly alter the results. The MR Steiger test confirmed the direction of causality. The absence of significant pleiotropy and negligible effect of heterogeneity supported our finding. Conclusion: According to our findings, increased levels of testosterone may potentially reduce the likelihood of developing NSCLC. These outcomes could provide valuable insights for the advancement of innovative therapeutic strategies manipulating testosterone levels to lower the risk of NSCLC.

Abstract Background: Gastric cancer represents a significant global public health burden worldwide. Although treatment strategies are continuously improving, the overall prognosis remains poor. Cuproptosis is a newly discovered form of cell death, and the relationship between cuproptosis in tumor immune microenvironment (TIME) and prognosis in STAD has hitherto not been reported.Methods: Stomach adenocarcinoma (STAD) data were downloaded from TCGA and GEO databases. Bioinformatics analysis was performed to construct a cuproptosis-related risk model and identify cancer subtypes. The association between TIME and risk score was comprehensively explored.Results: STAD samples were stratified into three subtypes according to prognostic cuproptosis gene expression. A cuproptosis risk model was constructed and validated based on the expression of 5 genes (RPL39L, PEG10, SYNPO2, MMP11, and KRT17). The model was significantly associated with the prognosis of STAD patients and TIME, including immune cell infiltration, microsatellite instability (MSI) status, tumor mutational burden (TMB) score, immune checkpoint, and human leukocyte antigen (HLA) gene expression. A prognostic nomogram based on the cuproptosis risk score was additionally constructed.Conclusion: We identified a practical prognostic model based on cuproptosis-related genes in STAD and comprehensively established the relationship between cuproptosis and tumor immunity. Further research is warranted on the predictive value of the cuproptosis risk score during immunotherapy in gastric cancer patients in clinical practice and the molecular mechanisms by which cuproptosis influences the TIME.

Back cover image: Highly biocompatible and self-illuminating carbon nanogels (CNGs) with dual ability of ROS imaging and PDT have been designed with self-assembled chemiluminescent carbonized polymer dots (CPDs). Different CPDs have been derived from biomass materials and exhibit polymer-like property, enabling their ability of self-assembling into CNGs through the hydrophilic and hydrophobic interaction. With efficient deep-red/near-infrared (NIR) CL emission and distinctive PDT capacity, H2O2-driven water-soluble chemiluminescent carbon nanogels are further designed by assembling the polymeric conjugate and CL donors. Mechanistically, ROS generated in the inflammatory sites can trigger the chemically initiated electron exchange luminescence between the CPDs and intermediate, enabling in vitro and in vivo CL imaging. Meanwhile, the production of such as 1O2, •OH and •–O2 from the chemiluminescent CNGs under the self-illumination can efficiently induce the apoptosis of tumor cell thus inhibit the tumor growth, resulting in cancer therapy. (DOI: 10.1002/smm2.1099)

Abstract Carbon nanogels (CNGs) with dual ability of reactive oxygen species (ROS) imaging and photodynamic therapy have been designed with self‐assembled chemiluminescent carbonized polymer dots (CPDs). With efficient deep‐red/near‐infrared chemiluminescence (CL) emission and distinctive photodynamic capacity, the H2O2‐driven chemiluminescent CNGs are further designed by assembling the polymeric conjugate and CL donors, enabling an in vitro and in vivo ROS bioimaging capability in animal inflammation models and a high‐performance therapy for xenograft tumors. Mechanistically, ROS generated in inflammatory sites or tumor microenvironment can trigger the chemically initiated electron exchange luminescence in the chemical reaction of peroxalate and H2O2, enabling in vivo CL imaging. Meanwhile, part of the excited‐state electrons will transfer to the ambient H2O or dissolved oxygen and in turn lead to the type I and type II photochemical ROS production of hydroxyl radicals or singlet oxygen, endowing the apoptosis of tumor cells and thus enabling cancer therapy. These results open up a new avenue for the design of multifunctional nanomaterials for bioimaging and antienoplastic agents.

Heterocycle is a ring containing at least one atom that is not carbon. Nitrogen, oxygen, and sulfur are the primary elements seen in common heterocycles. Heterocycles may be aromatic or notaromatic, which play a vital role in the drug discovery [1]. In their general structure, heterocyclic compounds resemble cyclic organic compounds that incorporate only carbon atoms in the rings, for example, cyclopropane (with a three-carbon-atom ring) or benzene (with a six-carbon-atom ring)-but the presence of the heteroatoms gives heterocyclic compounds physical and chemical properties that are often quite distinct from those of their all-carbon-ring analogs. Nitrogen heterocycle, as a class of heterocycles, is among the most significant structural components of pharmaceuticals [2]. Nitrogen heterocycles contain at least one nitrogen atom in the ring which can be aromatic, saturated or unsaturated. They are also grouped on the basis of ring size including three-, four-, five-, six-, seven, eight-membered heterocycles, as well as fused, bridged bicyclic, and macrocyclic nitrogen heterocycles [3]. N-heterocycles occurs in pharmaceuticals, natural products, dyes, organic materials, and particularly in biologically active molecules [4, 5]. Over the past decades, so much attention has been devoted to the development and pharmacology of heteroaromatic organic compounds, such as benzimidazoles, benzothiazoles, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines for their diverse activities [6, 7]. These N-heterocyclic compounds produce a range of effects in different types of diseases through corresponding mechanisms, as the ring size is related to their features, reactivity and stability [8, 9].

The role of fibroblast growth factor receptor 4 (FGFR4) in colorectal cancer (CRC) is poorly characterized. Therefore, the objective of the current study was to investigate the expression levels of FGFR4 in colorectal cancer and its prognostic value, and clarify the role of FGFR4 in the proliferation and metastasis of colorectal cancer cells. Immunohistochemistry was used to detect the association between FGFR4 expression and clinicopathological features in colorectal cancer tissues. The effect of FGFR4 silencing on tumor cell proliferation, cell cycle, apoptosis, migration and invasion was evaluated via lentiviral transfection of the colorectal cancer cell line SW620. Western blot analysis was used to detect the changes of epithelial‑mesenchymal transition (EMT) markers, following FGFR4 silencing. FGFR4 is upregulated in CRC tissues compared with normal tissues. Patients with high FGFR4 expression exhibited a lower 5‑year survival rate compared with patients with low FGFR4 expression (64 vs. 74%). FGFR4 silencing reduced proliferation, inhibited cell invasion, arrested cells in S phase and promoted apoptosis in colorectal cancer cells. FGFR4 silencing partially reversed EMT progression and FGFR4 this effect was enhanced in the presence of XAV939 (a β‑catenin inhibitor). The current data suggest that FGFR4 may be associated with prognosis in patients with colorectal cancer. In vitro functional tests revealed that FGFR4 may represent an effective therapeutic target for colorectal cancer. FGFR4 may also regulate EMT via the Wnt/β‑catenin pathway.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes. The treatment of NKTCL requires intensive chemotherapy. Long noncoding RNAs (lncRNAs) have been implicated in many cancers, including NKTCL. The elucidation of the multidrug resistance (MDR) may greatly contribute to explore novel therapeutic strategies. Herein, we explored the roles and potential regulatory mechanism of lncRNAs small nucleolar RNA host gene 12 (SNHG12) in MDR of NKTCL. We found that SNHG12 was upregulated in NKTCL tissue sections, and its high expression was positively correlated with clinical grade of malignancy of NKTCL. c-Myc and SNHG12 expression was upregulated in NKTCL cell lines. c-Myc- and SNHG12 overexpression promoted proliferation and inhibited sensitivity to cisplatin (CDDP) in NK/T-cell lymphoma cell line YTS cells, and c-Myc and SNHG12-downregulation inhibited proliferation and enhanced sensitivity to CDDP in SNK-6 cells. Moreover, c-Myc- and SNHG12 overexpression increased Ki67 and P-gp expression in YTS cells, whereas c-Myc and SNHG12-downregulation reduced the Ki67 and P-gp expression in SNK-6 cells. Correlational analyses revealed that c-Myc expression was positively correlated with SNHG12 expression in NKTCL tissues. Mechanism research showed that SNHG12 was a direct transcriptional target of c-Myc and c-Myc promoted SNHG12 expression in NKTCL cell lines. Further research showed that SNHG12 overexpression reversed the effects of c-Myc downregulation on proliferation and sensitivity to CDDP in NKTCL cell lines. Taken together, our findings first report that c-Myc mediated upregulation of SNHG12 promotes proliferation and inhibits drug sensitivity in NKTCL, which provides new insights into the therapeutic target for NKTCL.

Background: Accumulated evidence has shown that long non-coding RNAs (lncRNAs) are emerging as key molecules in human malignancies. The lncRNA metallothionein 1D, pseudogene (MT1DP) was recently identified as a tumor suppressor in liver cancers. However, its expression pattern and clinical performance in colorectal cancer (CRC) have not been addressed. Methods: Our investigation was carried out on 78 cases of CRC tissues and matched adjacent normal tissues. The expression levels of MT1DP were determined by quantitative real-time PCR. Subsequently, its clinical values in CRC were further evaluated. Results: MT1DP expression was significantly downregulated in 55 of 78 CRC tissues (70.5%, P<0.001). The area under curve (AUC) of the ROC was 0.714; 95% confidence interval (CI) was 0.636-0.783, the sensitivity was 88.46% and the specificity was 51.28%. Moreover, low level of MT1DP expression in CRC was closely correlated with TNM stage (P=0.020) and distant metastasis (P=0.005). In addition, low MT1DP expression had a poorer overall survival (OS) and disease-free survival (DFS) rates in CRC patients (P=0.002 and 0.006, respectively). Additionally, univariate and multivariable Cox regression analyses further identified that downregulated MT1DP might act as an independent prognostic factor for OS and DFS of CRC patients. Conclusions: Low expression of MT1DP is involved in CRC progression and could be a novel biomarker of diagnostic and prognostic evaluation of CRC patients.

Background: The MYBL2 gene, a highly conserved member of the Myb transcription-factor family, has been implicated in the genesis and progression of many types of tumors. Methods: We analyzed the expression of MYBL2 and Ki67 in tissue samples of esophageal squamous-cell carcinoma (ESCC) patients by immunohistochemistry. We further analyzed the effect of MYBL2 on cell proliferation and DNA replication using a CCK8 assay, 5-ethynyl-2'-deoxyuridine-retention assay, flow-cytometry analysis, real-time quantitative PCR, Western blot, and a xenograft model of ESCC cells in nude mice. Results: MYBL2 expression was significantly higher in ESCC tissue when compared to the adjacent normal tissue (P=0.007). MYBL2 was found to be positively correlated with Ki67 (gamma=0.286, P=0.003). Furthermore, Kaplan-Meier curves indicated that MYBL2 expression in ESCC tissue was associated with poor patient outcome (P<0.001), with MYBL2-positive patients who exhibited high Ki67 expression in ESCC tissue showing the worst prognosis for overall survival (P=0.003). Our in vitro results showed that downregulation of MYBL2 in ESCC cell lines inhibited cell proliferation and DNA replication (P<0.05 for both). We also found that loss of MYBL2 caused a reduction in levels of cell cycle-related G2/M proteins CDK1 and cyclin B1 in ESCC cells. In contrast, overexpression of MYBL2 caused an increase in these proteins. In vivo, we found that in nude mice that received cells knocked down for MYBL2, tumor growth was inhibited in comparison to the group that received control cells (P<0.05). Conclusion: MYBL2 overexpression induces tumor proliferation in ESCC cells by regulating cell-cycle at the S and G2/M phase. Therefore, MYBL2 may serve as a novel prognostic biomarker in ESCC patients.

Ammonium tetrathiomolybdate (TM) has been verified to be tightly implicated in antitumor efficacy in a wide range of tumor types. Here, we found TM significantly suppressed tumor proliferation in vitro in esophageal squamous cell carcinoma (ESCC) cells. Besides, TM markedly arrested cell cycle in S phase, induced cell apoptosis and reduced cell migration and invasion ability in a variety of ESCC cells, which may be tightly associated with c-Abl downregulation in ESCC cells. Importantly, TM significantly enhanced the killing efficacy of cisplatin on ESCC cell lines, and TM combined with cisplatin obviously induced cell apoptosis and reduced invasive cell numbers in different ESCC cells. Most strikingly, TM combined with cisplatin evidently inactivated Stat3 signaling pathway in ESCC cells, but IL-6 abolished the inactivation of Stat3 signaling pathway triggered by TM/cisplatin in ESCC cells. As expected, Stat3 activation evoked by IL-6 significantly reversed anti-proliferation ability mediated by TM/cisplatin in ESCC cells. Furthermore, in vivo animal experiments revealed that TM/cisplatin markedly suppressed tumor growth, and stepwise investigation demonstrated that TM, cisplatin or TM/cisplatin significantly reduced the expressions of angiogenesis related factors including VEGF, CD31 and ERG-1 proteins as well as p-Stat3 level in xenografted nude mice tumors. Our current results presented herein suggest that TM may be an underlying antitumor drug for ESCC and a promising agent for improving cisplatin resistance in clinic, which may be at least in part achieved by inactivating Stat3 signaling pathway.

This post-hoc analysis of 2 randomized trials of the once weekly glucagon-like peptide-1 receptor agonist dulaglutide (DU) assessed the proportion of Chinese patients with type 2 diabetes (T2D) achieving a composite endpoint of glycated hemoglobin (A1C) <7.0%, no weight gain (≤0 kg), and no hypoglycemia (confirmed glucose ≤3.9 mmol/L or report of severe hypoglycemia) after 26 or 52 weeks of treatment with DU 1.5 mg or 0.75 mg vs. glimepiride (GLIM) or insulin glargine (GLAR). Patients in the DU vs. GLIM study (n = 556) were treatment-naive or discontinued from oral monotherapy; those in the DU vs. GLAR study (n = 591) continued on metformin and/or sulfonylurea. Analyses in each trial were on modified intent—to-treat population; missing values were imputed using last observation carried forward. Significantly (p<.001, Fisher’s exact test) more patients achieved the composite endpoint with DU 1.5 mg or 0.75 mg vs. GLIM after 26 weeks (47.8% and 39.2% vs. 19.9%), as well as vs. GLAR after 26 weeks (39.5% and 30.1% vs. 14.9%) and after 52 weeks (26.0% and 23.0% vs. 6.7%). Similar results were observed for composite endpoints of A1C <7.0% and no weight gain, and A1C <7.0% and no hypoglycemia. Dulaglutide is an effective treatment option for Chinese patients with T2D, resulting in a large proportion of patients reaching A1C targets without weight gain or hypoglycemia. Disclosure X. Xiao: None. C. Wang: None. F. Wang: None. P. Li: Employee; Self; Eli Lilly and Company. L. Gu: Employee; Self; Eli Lilly and Company.

OBJECTIVE:To explore the role of SIRT1 in the occurrence of epithelial-mesenchymal transition (EMT) in EC-9706 and Eca-109 cells and the possible mechanism.METHODS:Three chemically synthesized siRNA targeting SIRT1 were transfected into EC-9706 and Eca-109 cells with the non-transfected cells and cells transfected with the negative siRNAs as controls. Real-time PCR and Western blotting were used to detect the expressions of SIRT1, E-cadherin, vimentin, Snail, Twist1 and ZEB in the cells. Transwell invasion assay and wounding healing assay were used to examine the changes in the invasion and metastasis abilities of the cells after transfection.RESULTS:EC-9706 and Eca-109 cells transfected with SIRT1 siRNA1 and SIRT1 siRNA3 showed significantly decreased mRNA and protein expressions of SIRT1 (P &lt; 0.05). Transwell invasion assay and wounding healing assay showed that transfection with SIRT1 siRNA1 and SIRT1 siRNA3 caused significantly lowered invasion and metastasis abilities in EC-9706 and Eca-109 cells (P &lt; 0.05). In EC-9706 and Eca-109 cells transfected with SIRT1 siRNA1 and SIRT1 siRNA3, the expression level of E-cadherin was significantly increased while the expressions of vimentin, Snail and Twist were significantly lowered (P &lt; 0.05).CONCLUSIONS:SIRT1 participates in the invasion and metastasis of EC-9706 and Eca- 109 cells probably by inducing EMT via regulating the expression of Snail.

Objective: The main purpose of this study was to analyze the serum cathepsin B (CTSB) and cystatin C (CysC) levels in patients with esophageal carcinoma and their correlation with the clinical indices and prognosis.Methods: The serum levels of CTSB and CysC from 56 patients with esophageal carcinoma and 30 healthy donors were determined preoperatively by using enzyme-linked immunosorbent assay. The correlation between CTSB and CysC was evaluated by Spearman correlation coefficient test. Kaplan-Meier survival curves were plotted, while the survival rates were compared using the log-rank test. Univariate and multivariate analyses of prognostic factors for survival were performed using the Cox proportional hazard regression model with a 95% confidence interval.Results: CTSB (38.35 +/- 4.3 ng/mL) and CysC (703.96 +/- 23.6 ng/mL) levels were significantly higher in the sera of the patients than in controls. A significant correlation was observed between CTSB and CysC (r=0.754, P < 0.001). The levels of CTSB and CysC/CTSB in the patient serum significantly correlated with the T status. CysC/CTSB ratio was also found to be significantly correlated with lymph node metastasis. None of the parameters were observed to be related to CysC, including age, gender, pathologic type, tumor differentiation and tumor invasion depth. Kaplan-Meier analysis showed that patients with higher levels of CysC/CTSB and negative lymph node metastasis experienced significantly longer overall survival time, whereas patients with higher CSTB levels tended to live shorter, although the difference was not statistically significant (P=0.081).Conclusion: Serum CTSB and CysC levels are of diagnostic significance in esophageal cancer. The ratio of serum CysC/CTSB is prognostic for the survival of esophageal carcinoma patients.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in a numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What’s more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC.

The phosphorylated epidermal growth factor receptor (P-EGFR) and phosphorylated Akt (P-Akt) protein in esophageal squamous cell carcinoma (ESCC) were studied, and its significance in clinical prognosis of patients was assessed. The expression of P-EGFR and P-Akt protein in 83 cases of ESCC and 83 normal esophageal tissues was determined by immunohistochemical staining. Log-rank test and correlation analysis were used to analyze the prognosis of ESCC. The positive expression of P-EGFR in ESCC was 88% (73/83 cases) compared with 41% in normal esophageal mucosa (34/83 cases) (P<0.05). The rate of P-Akt protein expression in ESCC was 90.4% (75/83 cases), compared with 27.7% seen in normal esophageal mucosa (23/83 cases) (P<0.05). The expression of P-EGFR and P-Akt protein was positively correlated with lymph node metastasis and degree of differentiation (P<0.05) irrespective of sex, age, tumor diameter and TNM stage (P>0.05). The expression of P-EGFR was positively correlated with that of P-Akt protein (r=0.674, P<0.01). P-EGFR expression was negatively correlated with survival time of patients with ESCC (r=-0.526, P<0.01). The Kaplan-Meier survival curves showed that the cumulative survival rate of P-EGFR-positive cases was significantly lower than that of the P-EGFR-negative cases (P<0.01). The expression of P-Akt was negatively correlated with survival in patients with ESCC (r=-0.473, P<0.01). The Kaplan-Meier survival curves showed that the cumulative survival rate of the P-Akt-positive cases was significantly lower than that of the P-Akt-negative cases (P<0.01). In conclusion, P-EGFR and P-Akt protein expression is closely related to the incidence of ESCC and mediates the development of invasive cancer and metastasis. It is used to determine the prognosis of ESCC, and may represent a new therapeutic target for the disease.

Objective Phosphorylated mammalian target of rapamycin (p-mTOR) is a promising prognostic marker in many types of cancer. However, its survival benefit in patients with breast carcinoma remains unknown. The aim of the present study was to assess the relationship between p-mTOR expression and prognosis in breast carcinoma based on a systematic review and meta-analysis. Materials and Methods Electronic databases (including Pubmed, Embase, ISI web of science, and Cochrane Library) were searched up to November 24, 2015. The outcome measures were hazard ratios (HRs) with 95% confidence interval (CI) for the association between the prognosis of breast carcinoma patients and p-mTOR expression. Primary end points were disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS). Statistical analysis was performed with STATA 12.0. Results Nine cohort studies including 3051 patients met full eligibility criteria. The pooled HRs (95% CI) for OS, DFS, and RFS were 0.84 (0.27–2.63), 0.71 (0.40–1.23), and 0.48 (0.20–1.18), respectively. Conclusions Our findings suggested that p-mTOR overexpression was not significantly related to prognosis in breast carcinoma regarding OS and disease recurrence. Prospective studies are warranted to examine the association between p-mTOR expression and survival outcomes in breast carcinoma.

Objective: To evaluate the association of the metformin therapy with the risk of bladder cancer and treatment efficacy in patients with type 2 diabetes mellitus.Methods: A computer-based online search was performed by using PubMed, Embase, Cochrane Library, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases. According to the inclusion and exclusion criteria, the literatures about metformin and the risk, and treatment efficacy of bladder cancer in patients with type 2 diabetes mellitus were selected. The primary end points included the incidence, cancer-specific mortality and recurrence-free survival. The outcome measures were hazard ratio (HR) with 95% confidence interval (95% CI) for the association between the metformin and the survival of bladder cancer patients. The Meta-analysis was performed using STATA 12.0 software.Results: A total of eight cohort studies involving 942 055 patients were included in this Meta-analysis. The present analysis showed that metformin therapy reduced the incidence of bladder cancer in patients with type 2 diabetes mellitus by 24% (HR = 0.76, 95% CI: 0.59-0.98, P = 0.032), and reduced the bladder cancer-specific mortality in patients by 22% (HR = 0.78, 95% CI: 0.61-1.00, P = 0.049), but didn’t increase the risk of recurrence survival in type 2 diabetes patients with bladder cancer (HR = 0.70, 95% CI: 0.44-1.10, P = 0.120), as compared with other hypoglycemic drugs including sulfonylurea, thiazolidine diketone and insulin.Conclusion: Metformin can significantly decrease the incidence of bladder cancer and bladder cancer-specific mortality in patients with type 2 diabetes mellitus. DOI:10.3781/j.issn.1000-7431.2016.33.130