Real-world evidence of a novel tetravalent immunoglobulin Y effectiveness and safety in patients with the refractory Helicobacter pylori infection.

BACKGROUND: Refractory Helicobacter pylori (H. pylori) infection inevitably increase the difficulty of drug selection. Here, we described our experience with the use of a novel tetravalent IgY against H. pylori for the treatment of patients with refractory H. pylori infection. METHODS: Patients were randomly assigned to receive the standard quadruple therapy (amoxicillin, clarithromycin, omeprazole and bismuth potassium citrate ) for 2 weeks or 250 mg of avian polyclonal IgY orally twice a day for 4 weeks. The binding efficacy of IgY to H. pylori antigens was detected by western blotting13. C-urea breath test was performed to evaluate the eradication therap's efficacy. The side effects of IgY were evaluated via various routine tests. The questionnaire was used to gather clinical symptoms and adverse reactions. RESULTS: Western blot analysis showed that tetravalent IgY simultaneously bind to VacA, HpaA, CagA and UreB of H. pylori. Tetravalent IgY had an eradication rate of 50.74% in patients with refractory H. pylori and an inhibition rate of 50.04% against DOB (delta over baseline) of 13C-urea. The symptom relief rate was 61.76% in thirty-four patients with clinical symptoms, and no adverse reactions were observed during tetravalent IgY treatment period. CONCLUSIONS: Polyclonal avian tetravalent IgY reduced H. pylori infection, and showed good efficacy and safety in the treatment of refractory H. pylori infection patients, which represented an effective therapeutic option of choice for patients with refractory H. pylori infection.

Chronic low-dose deltamethrin exposure induces colon injury and aggravates DSS-induced colitis via promoting cellular senescence.

OBJECTIVE: Deltamethrin (DLM) is a commonly used insecticide, which is harmful to many organs. Here, we explored the effects of chronic low-dose DLM residues on colon tissue and its potential mechanism. METHODS: The mice were given long-term low-dose DLM by intragastric administration, and the body weights and disease activity index (DAI) scores of the mice were regularly recorded. The colon tissues were then collected for hematoxylin-eosin, immunofluorescence and immunohistochemistry staining. Besides, the RNA sequencing was performed to explore the potential mechanism. RESULTS: Our results showed that long-term exposure to low-dose DLM could cause inflammation in mice colon tissue, manifested as weight loss, increased DAI score, increased apoptosis of colonic epithelial cells, and increased infiltration of inflammatory cells. However, we observed that after long-term exposure to DLM and withdrawal for a period of time, although apoptosis was restored, the recovery of colon inflammation was not ideal. Subsequently, we performed RNA sequencing and found that long-term DLM exposure could lead to the senescence of some cells in mice colon tissue. The results of staining of cellular senescence markers in colon tissue showed that the level of cellular senescence in the DLM group was significantly increased, and the p53 signalling related to senescence was also significantly activated, indicating that cellular senescence played a key role in DLM-induced colitis. We further treated mice with quercetin (QUE) after long-term DLM exposure, and found that QUE could indeed alleviate DLM-induced colitis. In addition, we observed that long-term accumulation of DLM could aggravate DSS-induced colitis in mice, and QUE treatment could reverse this scenario. CONCLUSION: Continuous intake of DLM caused chronic colitis in mice, and the inflammation persisted even after discontinuation of DLM intake. This was attributed to the induction of cellular senescence in colon tissue. Treatment with QUE alleviated DLM-induced colitis by reducing cellular senescence. Long-term DLM exposure also aggravated DSS-induced colitis, which could be mitigated by QUE treatment.

A nomogram based on platelet-to-lymphocyte ratio for predicting pathological complete response of breast cancer after neoadjuvant chemotherapy.

OBJECTIVE: To investigate the role of platelet-to-lymphocyte ratio (PLR) in complete pathological response (pCR) of breast cancer (BC) patients after neoadjuvant chemotherapy (NAC), as well as to establish and validate a nomogram for predicting pCR. METHODS: BC patients diagnosed and treated in the First Affiliated Hospital of Xi'an Jiaotong University from January 2019 to June 2022 were included. The correlation between pCR and clinicopathological characteristics was analyzed by Chi-square test. Logistic regression analysis was performed to evaluate the factors that might affect pCR. Based on the results of regression analysis, a nomogram for predicting pCR was established and validated. RESULTS: A total of 112 BC patients were included in this study. 50.89% of the patients acquired pCR after NAC. Chi-square test showed that PLR was significantly correlated with pCR (X2 = 18.878, P < 0.001). And the PLR before NAC in pCR group was lower than that in Non-pCR group (t = 3.290, P = 0.001). Logistic regression analysis suggested that white blood cell (WBC) [odds ratio (OR): 0.19, 95% confidence interval (CI): 0.04-0.85, P = 0.030)], platelet (PLT) (OR: 0.19, 95%CI: 0.04-0.85, P = 0.030), PLR (OR: 0.18, 95%CI: 0.04-0.90, P = 0.036) and tumor grade (OR: 9.24, 95%CI: 1.89-45.07, P = 0.006) were independent predictors of pCR after NAC. A nomogram prediction model based on WBC, PLR, PLR and tumor grade showed a good predictive ability. CONCLUSION: PLR, PLT, WBC and tumor grade were independent predictors of pCR in BC patients after NAC. The nomogram based on the above positive factors showed a good predictive ability.

The comparison of long-term oncological outcomes and complications after proximal gastrectomy with double tract reconstruction versus total gastrectomy for proximal gastric cancer.

BACKGROUND: Conventional methods for treating patients with proximal gastric cancer (PGC) include proximal gastrectomy (PG) and total gastrectomy (TG) and such methods have become challenging due to double tract reconstruction (DTR). However, the clinical outcomes remain unclear. This study was performed with the aim of verifying that PG-DTR was beneficial in terms of reducing the incidence of postoperative complications and improving the prognosis. METHODS: The PGC patient cohort was retrospectively grouped into the PG-DTR and TG groups. Clinicopathological features, complications, and survival data were compared between the two groups. RESULTS: A total of 388 patients were included in the analyses. Patients who were subjected to TG tended to have more severe gastroesophageal reflux (GR) (P = 0.041), anemia (P = 0.007), and hypoalbuminemia (P < 0.001). Overall survival rates, regardless of clinical stage, were significantly different between the PG-DTR and TG groups (all P < 0.05). The multivariate Cox regression analysis confirmed that surgical procedure, tumor size, infiltration depth, lymph node metastasis, differentiation, and age were independent risk factors. The patients were likely to benefit from PG-DTR (all HR > 1 and P < 0.05). However, no significant differences were observed in the risks of GR, anemia, and hypoalbuminemia (all P > 0.05). Moreover, the nomogram derived from significant parameters showed great calibration and discrimination ability and significant clinical benefit. CONCLUSIONS: The patients who underwent PG-DTR had a favorable prognosis. The risk of postoperative complications, such as severe GR, anemia, and hypoalbuminemia, was lower in PG-DTR than in TG. Thus, PG-DTR is more beneficial for patients with PGC and may be a valuable and promising surgical procedure.

Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.

OBJECTIVE: To date, it is unclear whether deltamethrin (DLM) intake causes damage to colon tissue. Hence, in this study, we aimed to clarify the effect of long-term exposure to low-dose DLM on colon tissues, and its potential mechanisms. METHODS: Mice were treated with DLM (0.2 mg/kg/day) or DLM combined with N-acetyl-l-cysteine (NAC) (50 mg/kg/day) for 8 weeks. Human colon cancer cells (HCT-116) were treated with DLM (0, 25, 50, or 100 µM), NAC (2 mM), or overexpression plasmids targeting peroxiredoxin 1 (PRDX1) for 48 h. DLM was detected using a DLM rapid detection card. Colon injury was evaluated using haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was determined using immunofluorescence staining (IF), western blotting (WB) and flow cytometry (FC) assays. MitoTracker, JC-1, and glutathione (GSH) detection were used to detect mitochondrial oxidative stress. Intestinal flora were identified by 16 S rDNA sequencing. RESULTS: DLM accumulation was detected in the colon tissue and faeces of mice following long-term intragastric administration. Interestingly, our results showed that, even at a low dose, long-term intake of DLM resulted in severe weight loss and decreased the disease activity index scores and colon length. The results of IF, WB, and FC showed that DLM induced apoptosis in the colon tissue and cells. MitoTracker, JC-1, and GSH assays showed that DLM increased mitochondrial stress in colonic epithelial cells. Mechanistic studies have shown that increased mitochondrial stress and apoptosis are mediated by PRDX1 inhibition. Further experiments showed that PRDX1 overexpression significantly reduced DLM-induced oxidative stress injury and apoptosis. In addition, we observed that chronic exposure to DLM altered the composition of the intestinal flora in mice, including an increase in Odoribacter and Bacteroides and a decrease in Lactobacillus. The gut microbial richness decreased after DLM exposure in mice. Supplementation with NAC both in vivo and in vitro alleviated DLM-induced oxidative stress injury, colonic epithelial cell apoptosis, and gut microbial dysbiosis. CONCLUSION: Chronic exposure to DLM, even at small doses, can cause damage to the colon tissue, which cannot be ignored. The production and use of pesticides such as DLM should be strictly regulated during agricultural production.

Knockdown of RSPH14 inhibits proliferation, migration, and invasion and promotes apoptosis of hepatocellular carcinoma via RelA.

BACKGROUND: High RSPH14 expression appears to be related to poor prognosis of hepatocellular carcinoma (HCC). This study aimed to investigate the possible roles of RSPH14 in the proliferation, apoptosis, and invasion of HCC cells. METHODS: The UALCAN database and Kaplan-Meier Plotter were used to evaluate the expression level and prognostic role of RSPH14 in HCC. Lentiviral vectors containing shRNA against RSPH14 were constructed to transfect the BEL-7404 and SMMC-7721 HCC cell lines. Cell proliferation was investigated by BrdU, MTT, and colony-formation assays. Apoptosis was detected using flow cytometry. Cell migration and invasion were evaluated using the scratch wound-healing and Transwell assays. Immunohistochemistry and western blot were used to determine the expression levels of the proteins. The function of RSPH14 in vivo was evaluated using a xenograft mouse model. RESULTS: The expression of RSPH14 was higher in HCC tumor tissues than in adjacent normal tissues and was closely related to unfavorable prognostic factors and poorer survival (all P < 0.05). Knockdown of RSPH14 inhibited the cell proliferation, migration, and invasion of HCC cells and promoted apoptosis (all P < 0.05). Knockdown of RSPH14 inhibited tumor growth in vivo (P < 0.05). RSPH14 knockdown led to decreased expression of RelA (NF-κBp65), CDH2, and AKT1, thereby affecting the functions of the HCC cells (all P < 0.05). RelA overexpression could abate the inhibitory effect of BEL-7404 cell proliferation caused by RSPH14 depletion. CONCLUSION: Knockdown of RSPH14 could decrease cell proliferation, migration, and invasion and increase apoptosis of HCC cells by inhibiting RelA expression. RSPH14 could be a new treatment target for HCC.

Advanced lung cancer inflammation index (ALI) predicts prognosis of patients with gastric cancer after surgical resection.

INTRODUCTION: Advanced lung cancer inflammation index (ALI) has been implicated in the prognosis of many types of tumors. But few studies elucidate its role in gastric cancer (GC). MATERIALS AND METHODS: We consecutively recruited 615 GC patients who underwent radical gastrectomy. Patients were grouped according to ALI status. Risk factors for overall survival (OS) and disease-free survival (DFS) in overall and sex-stratified cohorts were determined using multivariate cox regression analysis. We also compared survival differences between the two groups after one-to-one propensity score matching (PSM). RESULTS: Patients with low ALI showed larger tumor size, more advanced TNM staging, shorter OS (median: 37 vs 42 months) and DFS (median: 37 vs 42 months) (all P < 0.001). Multivariate analysis showed that elevated ALI was independently associated with longer OS and DFS. After stratification by sex, low ALI was an independent risk factor for OS and DFS in male patients but not in female patients. But our further PSM analysis showed prognostic value of ALI in both male and female subgroups. CONCLUSION: Preoperative ALI is an independent prognostic factor for GC patients undergoing curative gastrectomy.

The global, regional and national burden of peptic ulcer disease from 1990 to 2019: a population-based study.

BACKGROUND: Peptic ulcer disease (PUD) is a common digestive disorder, of which the prevalence decreased in the past few decades. However, the decreasing tendency has plateaued in recent years due to changes in risk factors associated with the etiology of PUD, such as non-steroidal anti-inflammatory drug use. In this study, we investigated the epidemiological and the sociodemographic characteristics of PUD in 204 countries and territories from 1990 to 2019 based on data from the Global Burden of Disease, Injuries and Risk Factors (GBD) Study. METHODS: Demographic characteristics and annual prevalence, incidence, mortality, disability-adjusted life years (DALYs) and age-standardized death rate (ASR) data associated with PUD were obtained and analyzed. According to the sociodemographic index (SDI), the numbers of patients, ASRs, estimated annual percentage changes and geographical distributions were assessed with a generalized linear model and presented in world maps. All evaluations of numbers and rates were calculated per 100,000 population with 95% uncertainty intervals (UIs). RESULTS: In 2019, the global prevalence of PUD was approximately 8.09 [95% UI 6.79-9.58] million, representing a 25.82% increase from 1990. The age-standardized prevalence rate was 99.40 (83.86-117.55) per 100,000 population in 2019, representing a decrease of 143.37 (120.54-170.25) per 100,000 population from 1990. The age-standardized DALY rate in 2019 was decreased by 60.64% [74.40 (68.96-81.95) per 100,000 population] compared to that in 1990. In both sexes, the numbers and ASRs of the prevalence, incidence, deaths and DALYs were higher in males than in females over 29 years. Regionally, South Asia had the highest age-standardized prevalence rate [156.62 (130.58-187.05) per 100,000 population] in 2019. A low age-standardized death rate was found in the high-income super-region. Among nations, Kiribati had the highest age-standardized prevalence rate [330.32 (286.98-379.81) per 100,000 population]. Regarding socioeconomic status, positive associations between the age-standardized prevalence, incidence, death rate, DALYs and SDI were observed globally in 2019. CONCLUSIONS: Morbidity and mortality due to PUD decreased significantly from 1990 to 2019, while a gradual upward inclination has been observed in recent 15 years, which might be associated with changes in risk factors for PUD. Attention and efforts by healthcare administrators and society are needed for PUD prevention and control.

The Early Diagnostic and Prognostic Value of BIRC5 in Clear-Cell Renal Cell Carcinoma Based on the Cancer Genome Atlas Data.

PURPOSE: The aim of this study was to investigate the role of BIRC5 for early diagnosis and prognosis in clear-cell renal cell carcinoma (ccRCC) by studying the expression of BIRC5 and the correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC. METHODS: The BIRC5 expression in ccRCC tissues and normal kidney tissues was measured using the Cancer Genome Atlas database and the Human Protein Atlas database. The correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC was analyzed using UALCAN, the Kaplan-Meier plotter, GEPIA, and SurvExpress. Thirteen-paired ccRCC plasma samples were used to verify the BIRC5 early diagnosis value of ccRCC. RESULTS: The BIRC5 expression is significantly higher in ccRCC than in normal kidney tissues, and is correlated with the clinical stage and pathological grade of ccRCC (p < 0.05). The result of analyzing the relationship between BIRC5 expression and outcomes in ccRCC indicates that a high BIRC5 expression is an independent prognostic factor affecting the overall survival and disease-free survival of ccRCC (p < 0.05). Compared with normal kidney tissues, the immunohistochemical test shows that BIRC5 is significantly upregulated in ccRCC tissues. mRNA expression levels of BIRC5 were significantly higher in the ccRCC plasma than normal (p < 0.05). CONCLUSIONS: The high expression of BIRC5 is an important indicator for the prognosis of ccRCC, which makes BIRC5 an effective biomarker for predicting the prognosis of patients in ccRCC. BIRC5 may be a great potential biomarker for early diagnosis of ccRCC.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703).

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

Postoperative oxaliplatin-based hyperthermic intraperitoneal chemotherapy: an effective and safe palliative treatment option for colorectal cancer with peritoneal metastasis.

BACKGROUND: The prognosis of patients with colorectal cancer and peritoneal metastasis (CRC-PM) after incomplete cytoreductive surgery (CRS) or palliative surgery is poor. Novel and effective therapies are urgently needed. This study aimed to assess the effects of palliative postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with CRC-PM. METHODS: This retrospective study included patients with CRC-PM at the First Affiliated Hospital of Xi'an Jiaotong University in 05/2014-05/2019. Observation indicators included overall survival (OS), ascites-free survival, peritoneal cancer index (PCI), and completeness of cytoreduction (CC). Kaplan-Meier survival curves and multivariable Cox regression models were used to determine the factors associated with OS and ascites-free survival. The ascites-specific quality of life (QoL) was measured using the Functional Assessment of Chronic Illness Therapy-Ascites Index (FACIT-AI). RESULTS: Eighty-two patients were included, including 37 and 45 in the HIPEC and non-HIPEC groups, respectively. Mean OS was 10.3±3.7 (95% CI 9.5-11.2) months. Multivariable Cox proportional hazard regression suggested that PCI (HR=6.086, 95% CI 3.187-11.620, P < 0.0001) was independently associated with OS. The degree of ascites (HR=2.059, 95% CI 1.412-3.005, P < 0.0001), PCI (HR=6.504, 95% CI 2.844-14.875, P < 0.0001), and HIPEC (HR=0.328, 95% CI 0.191-0.562, P < 0.0001) were independently associated with ascites-free survival. In patients with survival >6 months, postoperative ascites-specific QoL was significantly improved after HIPEC compared with the non-HIPEC group (P < 0.001). Oxaliplatin-based HIPEC significantly increased the rates of neutropenia and peripheral neurotoxicity (both P < 0.05). CONCLUSION: These data indicate that postoperative oxaliplatin-based HIPEC might help increase ascites-free survival in CRC-PM patients after incomplete CRS or palliative surgery, with improved QoL after 6 months of follow-up.

RP11-81H3.2 Acts as an Oncogene via microRNA-490-3p Inhibition and Consequential Tankyrase 2 Up-Regulation in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a serious threat to human lives and is usually diagnosed at the late stages. Recently, there has been a rapid advancement in the treatment options for HCC, but novel therapeutic targets are still needed, especially for precision medicine. AIMS: We aimed to investigate the involvement of non-coding RNA RP11-81H3.2 in HCC. METHODS: The expression of RP11-81H3.2 was examined in the blood samples of HCC patients, and in the human HCC cell lines, including HepG2, Smmc-7721, and Huh7. Cell proliferation was determined using the CCK-8 and EdU assay, and cell invasion and migration were determined using the transwell/wound healing assay. The effects of RP11-81H3.2 knockdown on in vivo tumor growth were evaluated utilizing the nude mice HepG2 tumor xenograft model. RESULTS: Here, we have identified a long non-coding RNA, RP11-81H3.2, which is enriched in HCC and can promote its proliferation, migration, and invasion both in vitro and in vivo. In addition, our results showed that RP11-81H3.2 binds to and regulate miR-490-3p expression in the HCC cells. Moreover, we found that RP11-81H3.2 regulates the expression of TNKS2 via miR-490-3p. Further, we found that RP11-81H3.2 and miR-490-3p form a regulatory loop; the release of RP11-81H3.2 leads to the suppression of miR-490-3p expression, thus, further enhancing the expression of RP11-81H3.2. CONCLUSIONS: Our data have provided a novel target for the diagnosis and treatment of HCC, and sheds light on the lncRNA-miRNA regulatory nexus that can control the HCC related pathogenesis.

Downregulation of APE1 potentiates breast cancer cells to olaparib by inhibiting PARP-1 expression.

PURPOSE: Targeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanism of olaparib treatment in breast cancer cell lines. METHODS: We investigated the cytotoxic effect of various doses of olaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and protein levels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study. RESULTS: 2 µM or higher concentrations of olaparib lead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showed that reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment. CONCLUSION: To acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.

Young age increases the risk for lymph node metastasis in patients with early Colon Cancer.

BACKGROUND: The risk of lymph node positivity in early-stage colon cancer is a parameter that impacts therapeutic recommendations. However, little is known about the effect of age on lymph node positivity in colon cancer with mucosal invasion. In this study, we aimed to quantify the effect of younger age on lymph node positivity in colon cancer with mucosal invasion. METHODS: All patients were identified between 2004 and 2014 in the Surveillance, Epidemiology, and End Results database. Patients were stage T1-T2, did not undergo preoperative radiotherapy, had at least one lymph node examined, and underwent a standard colon cancer operation. Demographics and pathological data were compared between different age ranges. A nomogram model was built to estimate the probability of nodal involvement according to different characteristics. Decision curve analysis was performed by calculating the net benefits for a range of threshold probabilities. RESULTS: This study identified 41,490 patients who met the eligibility criteria for our study. 1.4% (n = 620) of patients were under 40 years old; 5.9% (n = 2571) were between 40 and 49 years old. Within each T stage, positive lymph node rates decreased with increasing age. In univariate analyses, the positive lymph node rates for patients 20 to 39 years of age were significantly higher than in patients in the reference group for stages T1 and T2. After dividing the colon into the left and right parts, these trends remained. The lymph node metastatic rate was higher in the right colon than in the left colon in terms of different age ranges. The nomogram prediction system represents a novel model with which to estimate lymph node metastasis in early T stage colon adenocarcinomas based on four risk factors with a C-index of 0.657 (95% CI: 0.658-0666). CONCLUSIONS: Our study demonstrates that the risk of lymph node metastasis was higher in young (< 40 years) patients with early-stage colon adenocarcinomas. Therefore, more aggressive screening and therapeutic strategies should be considered for young patients with colon adenocarcinoma.

Discovery of Glabridin as Potent Inhibitor of Epidermal Growth Factor Receptor in SK-BR-3 Cell.

The breast cancer is the leading cause of death in women. Therefore, objective of the present study was to examine the antibreast cancer effect of glabridin (GBN) and to evaluate its mechanism of action. In this study, we have demonstrated that GBN causes reduction of cellular viability of human breast cancer SK-BR-3 in MTT assay. Results from Hoechst 33342 and propidium iodide staining assay suggested that GBN causes significant enhancement in the apoptosis. At the molecular level, in western blot analysis, GBN causes significant increase in c-PARP and c-caspases 3, 8, and 9 concentrations in a dose-dependent manner in breast cancer cells. The GBN further showed reduced level of p-epidermal growth factor receptor, p-AKT, p-ERK1/2, and cyclin D1 as the concentration rose in treated cells. Subsequent to this, GBN showed beneficial effect in 7,12-dimethylbenz[a]anthracene-induced breast cancer in experimental mice as confirmed by increase in body weight, reduction in tumor volume, oxidative stress, and dose-dependent restoration of all tested enzymes (phase I and II) in the treated group. GBN may, thus, play a protective role as an antibreast cancer drug for the prevention of breast cancer.

Overexpression of Contactin 1 promotes growth, migration and invasion in Hs578T breast cancer cells.

BACKGROUND: Contactin1 (CNTN1) has been shown to play an important role in the invasion and metastasis of several tumors; however, the role of CNTN1 in breast cancer has not been fully studied. The purpose of this study is to investigate the role of CNTN1 in regulating tumor growth, migration and invasion in breast cancer. RESULTS: To investigate its function, CNTN1 was expressed in Hs578T cells. CNTN1 expression was confirmed by western blot, immunohistochemistry and real-time RT-PCR. The effect of CNTN1 overexpression on proliferation, migration and invasion of Hs578T breast cancer cells was assessed in vitro and in vivo. Our results showed that CNTN1 overexpression promoted Hs578T cell proliferation, cell cycle progression, colony formation, invasion and migration. Notably, overexpression of CNTN1 in Hs578T cells enhanced the growth of mouse xenograft tumors. CONCLUSIONS: CNTN1 promotes growth, metastasis and invasion of Hs578T breast cancer cell line. Thus, therapies targeting CNTN1 may prove efficacious for breast cancer. However, further investigation is required to understand the mechanism by which CNTN1 influences proliferation, metastasis and invasion in breast cancer.

ABCA1 inhibits PDGF-induced proliferation and migration of rat airway smooth muscle cell through blocking TLR2/NF-κB/NFATc1 signaling.

Airway remodeling is a key feature of asthma, characterized by abnormal proliferation and migration of airway smooth muscle cells (ASMCs). ABCA1, a member of the ATP-binding cassette family of active transporters, plays an essential role in the progression of lung diseases. However, the contributions of ABCA1 in ASMCs remain to be explored. The purpose of the present study was to investigate the functional role and potential molecular mechanism of ABCA1 in platelet derived growth factor (PDGF)-induced primary rat ASMC proliferation and migration. We observed that PDGF- led to a significant decrease in the expression of ABCA1. Overexpression of ABCA1 strikingly suppressed PDGF-induced ASMC proliferation accompanied by a decrease in the expression of PCAN stimulated by PDGF. Additionally, augmentation of ABCA1 dramatically restrained PDGF-induced migration concomitant with attenuate the accumulation of MMP-2 and MMP-9 in response to PDGF. Furthermore, forced expression of ABCA1 enhanced contractile phenotype markers proteins including α-SMA along with sm-MHC, sm-α-actin, and calponin reduced by PDGF. Meanwhile, introduction of ABCA1 depressed ECM over-deposition induced by PDGF as reflected by a decrease in the expression of ECM protein collagen I and fibronectin. More importantly, addition of ABCA1 effectively suppressed the activity of TLR2/NF-κB signaling as well as diminished the expression of NFATc1 in rat ASMCs after PDGF stimulation. Interestingly, blockage of TLR2/NF-κB signaling effectively inhibited PDGF-induced proliferation and migration, these effects were similar to ABCA1. Taken together, these data implicated that ABCA1 suppressed PDGF-induced proliferation, migration, and contraction in rat ASMCs at least partly through TLR2/NF-κB/NFATc1 signaling, which might offer hope for the future treatment of airway remodeling in asthma.

Methylation-induced silencing of SPG20 facilitates gastric cancer cell proliferation by activating the EGFR/MAPK pathway.

Spastic paraplegia 20 methylation was characterized in gastric cancer in our previous study. However, its mechanism remains unknown. Cell proliferation, colony formation, flow cytometry, wound healing, in vitro Transwell assays and in vivo xenografts were performed. A nomogram model was established to make a more accurate prognostic prediction for gastric cancer patients. Knockout of Spastic paraplegia 20 promoted gastric cancer cell proliferation, G2/M arrest in vitro and tumor growth in vivo. The EGFR/MAPK pathway was activated as a consequence of Spastic paraplegia 20 deletion. EGFR kinase or ERK1/2 inhibitors impaired Spastic paraplegia 20 knockout-induced cancer cell growth. Gastric cancer patients with poor spartin expression (72/161, 44.7%) exhibited a worse prognosis compared with the high expression group with median survival times of 16 and 54 months, respectively. The nomogram model stratified gastric cancer patients into 3 distinct prognostic groups with 3-year survival rates of 100%, 77%, and 35%. Furthermore, it had a better discrimination than the TNM staging system (C index: 0.785, AIC: 752.8708 VS. C index: 0.712; AIC: 775.1223). Methylation-induced Spastic paraplegia 20 silencing facilitates gastric cancer cell proliferation by activating the EGFR/MAPK signaling pathway. The nomogram based on spartin expression provided significantly better discrimination compared with the traditional AJCC TNM staging system and provided an individualized prediction of the survival for gastric cancer patient survival.

Clinicopathology and Survival in Patients with Gastroesophageal Reflux After Radical Surgery of Proximal Gastric Cancer.

BACKGROUND: Gastroesophageal reflux (GR) after radical resection of proximal gastric cancer (PGC) may influence survival; however, few studies have investigated survival in PGC patients who develop GR following radical resection. This study aimed to correlate the occurrence of GR after proximal gastrectomy (PG) and total gastrectomy (TG) with clinicopathological factors and long-term survival. METHODS: The PGC patient cohort was retrospectively grouped as follows: postoperative patients with and without GR (NGR). Clinicopathological characteristics and survival data were compared between the two groups. RESULTS: A total of 88 patients who underwent PG (53%) experienced postoperative GR; however, only 30 patients who underwent TG (14%) experienced GR (P = 0.000). The incidence of GR was significantly associated with surgical procedure (P < 0.01), tumor size (P < 0.01), infiltration depth (P < 0.01), lymph node metastasis (P = 0.018), postoperative distant metastasis (P < 0.01) and recurrence (P = 0.001). The 5-year overall survival of the GR group was significantly worse than that of the NGR group (39.3 vs. 46.5%, respectively; P = 0.046). The PG and TG groups had significantly different 5-year overall survival (45.2 vs. 50.9%, respectively; P = 0.047), and multivariate analysis revealed GR as an independent risk factor associated with poor overall survival. CONCLUSIONS: Patients who experienced GR after radical resection for PGC were more likely to develop recurrence and metastasis, leading to shorter survival. TG for PGC was associated with a more favorable 5-year overall survival than was PG. Thus, TG should be performed for PGC patients with tumors larger than 5 cm, T3/T4 disease or lymph node metastasis to improve their long-term survival.