Neoadjuvant chemotherapy is linked to an amended anti-tumorigenic microenvironment in gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a frequently intervention for patients with locally advanced gastric cancer (GC). Nevertheless, its impact on the tumor immune microenvironment remains unclear. METHODS: We used immunohistochemistry to identify T-cell subpopulations, tumor-associated neutrophils (TANs), and tumor-associated macrophages (TAMs) in the GC microenvironment (GCME) among paired samples (pre-chemotherapy and post-chemotherapy) from 48 NAC-treated patients. Multiplex immunofluorescence (mIF) was performed to assess immune biomarkers, including CK, CD4, CD8, FOXP3, PD1, PD-L1, CD163, CD86, myeloperoxidase and Arginase-1 in paired samples from 6 GC patients whose response to NAC were rigorously defined. RESULTS: NAC was intricately linked to enhanced CD8+:CD4+ ratio, reduced CD163+ M2-like macrophages, augmented CD86+ M1: CD163+ M2-like macrophage ratio, and diminished FOXP3+ regulatory T cells (T-regs) and TANs density. Based on mIF, PD1+CD8+T-cells, FOXP3+T-regs, PD-L1+ TANs, and CD163+ M2-like macrophages exhibited marked reduction and greater co-localization with tumor cells following NAC. The pre-NAC FOXP3+ T-regs and CD163+ M2-like macrophages content was substantially elevated in the response cohort, whereas, the post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were intricately linked to the tumor pathologic response. We observed greater CD163+ M2-like macrophages and tumor cells co-localization following NAC, which was correlated with tumor pathologic response. Lastly, multivariate analysis revealed that post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were stand-alone indicators of positive patient prognosis. CONCLUSIONS: NAC converts the GCME to an anti-tumorigenic state that is conducive to enhanced patient outcome. These finding can significantly benefit the future planning of highly efficacious and personalized GC immunotherapy.

Determination of the ED95 of intranasal sufentanil combined with intranasal dexmedetomidine for moderate sedation during endoscopic ultrasonography.

BACKGROUND: Sedation during endoscopic ultrasonography (EUS) poses many challenges and moderate-to-deep sedation are often required. The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids. However, this combination has some limitations. Intranasal medication delivery may be an alternative to this sedation regimen. AIM: To determine, by continual reassessment method (CRM), the minimal effective dose of intranasal sufentanil (SUF) when combined with intranasal dexmedetomidine (DEX) for moderate sedation of EUS in at least 95% of patients (ED95). METHODS: Thirty patients aged 18-65 and scheduled for EUS were recruited in this study. Subjects received intranasal DEX and SUF for sedation. The dose of DEX (1 µg/kg) was fixed, while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95. The sedation status was assessed by modified observer's assessment of alertness/sedation (MOAA/S) score. The adverse events and the satisfaction scores of patients and endoscopists were recorded. RESULTS: The ED95 was intranasal 0.3 µg/kg SUF when combined with intranasal 1 µg/kg DEX, with an estimated probability of successful moderate sedation for EUS of 94.9% (95% confidence interval: 88.1%-98.9%). When combined with intranasal 1 µg/kg DEX, probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows: 0 µg/kg SUF, 52.8%; 0.1 µg/kg SUF, 75.4%; 0.2 µg/kg SUF, 89.9%; 0.3 µg/kg SUF, 94.9%; 0.4 µg/kg SUF, 98.0%; 0.5 µg/kg SUF, 99.0%. CONCLUSION: The ED95 needed for moderate sedation for EUS is intranasal 0.3 µg/kg SUF when combined with intranasal 1 µg/kg DEX, based on CRM.

Prospective, randomized comparison of two supplemental oxygen methods during gastroscopy with propofol mono-sedation in obese patients.

BACKGROUND: Hypoxemia is a common complication in obese patients during gastroscopy with sedation. The Wei nasal jet tube (WNJT) is a new special nasopharyngeal airway with the ability to provide supraglottic jet ventilation and oxygen insufflation via its built-in wall channels. The aim of this study was to compare the efficacy and safety of the WNJT vs a nasal cannula for supplemental oxygen during gastroscopy with propofol mono-sedation in obese patients. AIM: To compare the efficacy and safety of the WNJT vs a nasal cannula for supplemental oxygen during gastroscopy with propofol mono-sedation in obese patients. METHODS: A total of 103 obese patients with a body mass index of 30 kg/m2 or more undergoing elective gastroscopy under propofol mono-sedation were randomly assigned to receive supplemental oxygen at 5 L/min through either a WNJT (WNJT group, n = 51) or a nasal cannula (nasal cannula group, n = 52). The lowest pulse oxygen saturation (SpO2) and mild and severe hypoxemia during gastroscopy were recorded. The primary outcome was the incidence of hypoxemia. RESULTS: The lowest SpO2 during gastroscopy with propofol mono-sedation was significantly increased in the WNJT group compared with the nasal cannula group. The incidence of mild hypoxemia and total incidence of hypoxemia were significantly lower in the WNJT group than in the nasal cannula group. Other than a higher incidence of epistaxis in the WNJT group, the occurrence of adverse events was similar between the devices. While neither device demonstrated a statistically significant difference in satisfaction among patients, the WNJT did result in improved satisfaction among anesthetists and physicians. CONCLUSION: During gastroscopy with propofol mono-sedation in obese patients, the WNJT, when compared with a nasal cannula for supplemental oxygen, can significantly reduce the occurrence of hypoxemia and improve both arterial oxygenation and satisfaction among anesthetists and physicians. The use of the WNJT may, however, lead to epistaxis in a few patients. In view of this clinically acceptable risk-benefit ratio, the WNJT may be recommended as an alternative tool for supplemental oxygen for the prevention of hypoxemia during gastroscopy with propofol mono-sedation in obese patients.

ARF3 inhibits proliferation and promotes apoptosis in gastric cancer by regulating AKT and ERK pathway.

ADP-ribosylation factor 3 (ARF3) has confirmed participate in diverse biological processes in many cancers. However, the expression patterns and roles of ARF3 in gastric cancer (GC) remains largely unknown. In our study, by using qRT-PCR and western blot, we found that, in In GC tissues and cells, the expression of ARF3 was significantly down-regulated. Functional experiments demonstrated that ARF3 inhibited proliferation, induced cycle arrest and enhanced apoptosis of GC cells. Moreover, by performing western blot, we found that ARF3 could regulate the protein expression of key factors of AKT and ERK pathway. Using orthotopic xenograft mouse models, it is showed that ARF3 could inhibit GC tumorigenesis in vivo. To sum up, ARF3 may suppress proliferation, induced cycle arrest and promotes apoptosis of GC by modulating AKT and ERK pathway. It might act as a potential biomarker for GC prognosis.

Helicobacter pylori infection is associated with the co-occurrence of bacteria in the oral cavity and the gastric mucosa.

BACKGROUND: Pathogens capable of impacting gastrointestinal tract tumor development are located in the oral cavity, but whether these oral bacteria are able to colonize the gastric mucosa in gastric cancer (GC) patients and whether Helicobacter pylori infection can influence this process remains to be established. METHODS: Microbial 16S rDNA deep sequencing was conducted to characterize bacteria present in paired gastric mucosa and tongue coating samples in 27 patients with superficial gastritis (SG) and 11 GC patients. RESULTS: While the overall composition of the gastric mucosa and tongue coating microbiomes differed substantially, certain bacteria were present in both of these communities. The co-occurrence of bacteria between the tongue coating and gastric mucosa differed significantly between SG and GC patients. Of the 15 most abundant shared oral bacteria genera (the core shared oral bacteria), which were associated with differences in microbiota composition between these tongue coating and gastric mucosa, three were enriched in the gastric mucosa of GC patients relative to SG patients, whereas, 12 were depleted in GC patient samples. Furthermore, the prevalence and relative abundance of these core shared oral bacteria in the gastric mucosa were also linked to H. pylori infection status, and the core shared oral bacteria were also associated with the overall composition of the gastric mucosal microbiome. CONCLUSIONS: Helicobacter pylori infections are linked to the co-occurrence of bacteria in the oral microbiome and the gastric mucosal microbiome. Ectopic colonization of oral microbes may be a primary driver of H. pylori-induced gastric microbial dysbiosis in patients with GC.

A Comparison of Tumor-Associated and Non-Tumor-Associated Gastric Microbiota in Gastric Cancer Patients.

BACKGROUND: How gastric cancer (GC) incidence is associated with changes in the gastric microbiome has not been firmly established. The present study therefore aims to investigate the microbial communities present within the gastric mucosa of patients with superficial gastritis (SG) or GC. METHODS: Paired tumor and paracancerous samples of the gastric mucosa were collected from 18 patients being surgically treated for GC and from 32 patients with SG being treated via gastroscopy. The gastric microbiome in these samples was then profiled via 16S rRNA sequencing, with a linear discriminant analysis effect size (LEfSe) approach used to identify and compare different bacteria, and with PICRUSt used for predictive functional analyses. RESULTS: GC patients exhibited a distinct gastric microbiota profile from that observed in SG patients. These changes were evident in both tumor and paracancerous tissues from GC patients. Specifically, we found that 6 bacterial genera were specifically enriched in GC tissue samples relative to SG samples, while 18 genera were depleted in these same samples. Based on the differential abundance of these bacteria, we were able to calculate microbial dysbiosis index (MDI) values, which were significantly higher in GC patients than in SG patients. In addition, MDI values were negatively correlated with gastric Shannon index and were positively correlated with relative Helicobacter spp. abundance. Importantly, these MDI values were readily able to discriminate between GC and SG patient samples. Functional analysis suggested that GC patients were more likely to harbor a nitrosating microbial community. CONCLUSIONS: GC patients exhibited a gastric microbiome profile distinct from that observed in SG patients, with these differences being evident in both tumor and paracancerous tissues. Differences in the relative abundance of Helicobacter spp. may be the primary driver of gastric dysbiosis in GC patients.

Comparison of two supplemental oxygen methods during gastroscopy with propofol mono-sedation in patients with a normal body mass index.

BACKGROUND: Hypoxemia due to respiratory depression and airway obstruction during upper gastrointestinal endoscopy with sedation is a common concern. The Wei nasal jet tube (WNJT) is a new nasopharyngeal airway with the ability to provide supraglottic jet ventilation and oxygen insufflation via its built-in wall channel. The available evidence indicates that with a low oxygen flow, compared with nasal cannula, the WNJT does not decrease the occurrence of hypoxemia during upper gastrointestinal endoscopy with propofol sedation. To date, there has been no study assessing the performance of WNJT for supplemental oxygen during upper gastrointestinal endoscopy with sedation when a moderate oxygen flow is used. AIM: To determine whether the WNJT performs better than the nasal prongs for the prevention of hypoxemia during gastroscopy with propofol mono-sedation when a moderate oxygen flow is provided in patients with a normal body mass index. METHODS: This study was performed in 291 patients undergoing elective gastroscopy with propofol mono-sedation. Patients were randomized into one of two groups to receive either the WNJT (WNJT group, n = 147) or the nasal cannula (nasal cannula group, n = 144) for supplemental oxygen at a 5-L/min flow during gastroscopy. The lowest SpO2 during gastroscopy was recorded. The primary endpoint was the incidence of hypoxemia or severe hypoxemia during gastroscopy. RESULTS: The total incidence of hypoxemia and severe hypoxemia during gastroscopy was significantly decreased in the WNJT group compared with the nasal cannula group (P = 0.000). The lowest median SpO2 during gastroscopy was significantly higher (98%; interquartile range, 97-99) in the WNJT group than in the nasal cannula group (96%; interquartile range, 93-98). Epistaxis by device insertion in the WNJT group occurred in 7 patients but stopped naturally without any treatment. The two groups were comparable in terms of the satisfaction of physicians, anesthetists and patients. CONCLUSION: With a moderate oxygen flow, the WNJT is more effective for the prevention of hypoxemia during gastroscopy with propofol mono-sedation compared with nasal prongs, but causing slight epistaxis in a few patients.

X-ray flares from the stellar tidal disruption by a candidate supermassive black hole binary.

Optical transient surveys have led to the discovery of dozens of stellar tidal disruption events (TDEs) by massive black hole in the centers of galaxies. Despite extensive searches, X-ray follow-up observations have produced no or only weak X-ray detections in most of them. Here we report the discovery of delayed X-ray brightening around 140 days after the optical outburst in the TDE OGLE16aaa, followed by several flux dips during the decay phase. These properties are unusual for standard TDEs and could be explained by the presence of supermassive black hole binary or patchy obscuration. In either scenario, the X-rays can be produced promptly after the disruption but are blocked in the early phase, possibly by a radiation-dominated ejecta which leads to the bulk of optical and ultraviolet emission. Our findings imply that the reprocessing is important in the TDE early evolution, and X-ray observations are promising in revealing supermassive black hole binaries.

Control of the gyrotron filament power supplies for the experimental advanced superconducting tokamak.

The electron cyclotron heating system including four gyrotrons is being developed in the Institute of Plasma Physics, Chinese Academy of Sciences. The filament is an important part of the gyrotron, which is used to heat the cathode. The gyrotron output power can be controlled by adjusting the filament power. We have developed the filament power control and measurement system using Labview. The filament characteristics were tested using this power control system. The test results show that the filament current can be fitted with the e-exponential function of the filament voltage. It can be seen that as the voltage increases, the filament resistance gradually increases. We have developed a new "burst" function to prevent the beam current from dropping too fast, which is conducive to long pulse stable operation of the gyrotrons.

4.6 GHz lower hybrid wave power control system for EAST.

In order to achieve steady state operation in experimental advanced superconducting tokamak (EAST), a 6 MW/4.6 GHz lower hybrid current drive system with twenty-four 250 kW/4.6 GHz high power klystron amplifiers (model VKC7849A) has been developed. A 4.6 GHz lower hybrid wave (LHW) power control system (4.6 GHz LPCS) with continuous wave mode has been set up, which was used to control the LHW power as needed. This paper introduces the architecture and software design of LPCS system, including microwave preamplifier subsystem, power measurement subsystem, power control computers, and so on. Proportional integral differential (PID) closed-loop control time is less than 100 µs due to the use of high-speed acquisition cards and user-programmable Field Programmable Gate Arrays. So far, high power CW operation and power control experiments with PID feedback mode by plasma parameters (beta, loop voltage, and so on) were performed in detail. Results show that 4.6 GHz LPCS is stable and reliable, suggesting that it meets the needs of EAST.

Clinicopathological and prognostic significance of CDH1 hypermethylation in hepatocellular carcinoma: a meta-analysis.

BACKGROUND: The patients with hepatocellular carcinoma (HCC) have poor prognosis due to being diagnosed at late stage or recurrence following surgery. It's critical to identify effective biomarkers that can improve overall diagnosis and treatment of HCC. METHODS: We performed a meta-analysis of all relative studies reporting the clinicopathological significance of CDH1 hypermethylation in HCC by using Review Manager 5.2. A comprehensive literature search was performed in EMBASE, PubMed, Web of Science and Google Scholar databases. Kaplan Meier Plotter online database was used for the determination of correlation between CDH1 mRNA expression and overall survival in patients with HCC. Odds Ratios (OR) with 95% corresponding confidence intervals (CIs) were calculated. A total of 12 relevant studies were included in the meta-analysis with 981 patients. RESULTS: The positive rate of CDH1 hypermethylation was significantly higher in HCC than in normal liver tissue; and the pooled OR was 4.34 with 95% CI 2.50-7.56, P<0.00001. CDH1 promoter in HCC was more frequently hypermethylated compared to the group of chronic liver disease (CLD); OR was 4.83 with 95% CI 2.67-8.72, P<0.00001. However, the rate of CDH1 promoter hypermethylation was not correlated with different grades as well as stages. High CDH1 mRNA expression was significantly correlated to better overall survival in all 231 HCC patients compared to 133 HCC patients with low level CDH1 mRNA expression; HR was 0.6 with 95% CI 0.42-0.85, P=0.0034. CONCLUSION: In summary, CDH1 promoter hypermethylation is a risk factor and promising biomarker for HCC carcinogenesis and diagnosis, as well as a predictor of poor prognosis.

Comparison of two supplement oxygen methods during gastroscopy with intravenous propofol anesthesia in obese patients: study protocol for a randomized controlled trial.

BACKGROUND: Hypoxemia is a major complication in obese patients undergoing gastrointestinal endoscopy under intravenous anesthesia or sedation due to altered airway anatomy. We design this randomized controlled trial (RCT) to compare efficacy and safety of the Wei nasal jet tube (WNJT) and nasal prongs for supplement oxygen during gastroscopy with intravenous propofol anesthesia in obese patients. METHODS: The study will be a single-center, prospective RCT. A total of 308 obese patients will be recruited and randomly assigned to receive either the WNJT (group A) or nasal prongs (group B). During gastroscopy with intravenous propofol anesthesia, 5 L/min of oxygen will be delivered through the jet port of the WNJT in the group A and via the nasal prongs in the group B. The primary outcome is the incidence of hypoxemia and severe hypoxemia. The secondary outcomes are adverse events during the gastroscopy, postoperative complications, and satisfaction of the anesthetist, physician, and patient. DISCUSSION: This RCT aims to clarify whether the WNJT can result in reduced incidences of hypoxemia and complications and provide improved satisfaction to the anesthetist, physician, and patient. Thus, it can be determined if the WNJT is a useful tool for supplement oxygen in obese patients undergoing gastroscopy with intravenous propofol anesthesia. The results will provide the evidence for anesthesiologists to make a decision regarding the choice of supplementary oxygen methods in this condition. TRIAL REGISTRATION: Chinese Clinical Trial, ChiCTR-IOR-17013089 . Registered on 23 October 2017.

Efficacy and safety of using premedication with simethicone/Pronase during upper gastrointestinal endoscopy examination with sedation: A single center, prospective, single blinded, randomized controlled trial.

BACKGROUND AND AIM: To investigate the efficacy and safety of premedication with simethicone/Pronase during esophagogastroduodenoscopy (EGD) with sedation. METHODS: Six hundred and ten patients were randomly allocated to two groups based on type of premedication given. Premedication used in the control group was 10 mL lidocaine hydrochloride mucilage (LHM, N = 314) and premedication used in the intervention group was 80 mL simethicone/Pronase solution plus 10 mL lidocaine hydrochloride mucilage (SP/LHM, N = 296). EGD was done under sedation. Visibility scores, number of mucosal areas that needed cleansing, water consumption for cleansing, time taken for examination, diminutive lesions, pathological diagnosis, patients' gag reflex and oxygenation (pulse oximetry) were recorded. RESULTS: SP/LHM has significantly lower total visibility score than LHM (7.978 ± 1.526 vs 6.348 ± 1.097, P < 0.01). During the procedure, number of intragastric areas that needed cleansing and amount of water consumed were significantly less in the SP/LHM than in the LHM group (P < 0.01). In SP/LHM (P = 0.01), endoscopy procedure duration was significantly longer. Although there was no significant difference in rate of detection of diminutive lesions between LHM and SP/LHM, the endoscopist carried out more biopsies in SP/LHM. This led to a higher rate of diagnosis of atrophic gastritis (P = 0.014) and intestinal metaplasia (P = 0.024). There was no significant difference in gag reflex (P = 0.604) and oxygenation during the endoscopy procedure for either group of patients. CONCLUSION: Routine use of premedication with simethicone/Pronase should be recommended during EGD with sedation.

Identification of RING-box 2 as a potential target for combating colorectal cancer growth and metastasis.

Development of cancer metastasis is a key contributor to mortality in patients with colorectal cancer. High expression of RING-box 2 (RBX2) in cancer cells is known to play a key role in tumor progression. However, the role of RBX2 in colorectal cancer progression is not well elucidated. In this study, we silenced RBX2 via CRISPR/Cas9 in two colorectal cancer cell lines, HCT116 and SW480. RBX2 knockout attenuated proliferation, colony formation and enhanced sensitivity of colorectal cancer cells to paclitaxel treatment. Invasive property of HCT116 and SW480 cells was also attenuated by RBX2 silencing. We confirmed that increased RBX2 correlated with higher tumor cells growth and metastasis abilities by ectopic expression of RBX2 in HCT116 and SW480 cells. In vivo studies suggested that knockout of RBX2 inhibited xenografts growth and metastasis to lung tissue, whereas ectopic expression of RBX2 promoted these cellular functions. Mechanically, RBX2 induced gastric cancer cell growth and metastasis by activating mammalian target of rapamycin/S6 kinase 1 (mTOR/S6K1). Treatment of everolimus, the specific mTOR inhibitor, significantly attenuated RBX2-mediated cell proliferation and mobility in vitro. Taken together, these results revealed a novel role of RBX2 in colorectal cancer cell growth and metastasis via the mTOR pathway and suggested RBX2 may serve as a therapeutic target in colorectal cancer.

FOXQ1 promotes cancer metastasis by PI3K/AKT signaling regulation in colorectal carcinoma.

Colorectal cancer is one of the major health problems, with invade surrounding tissues, and migrate to distant organs being the most critical concern, thus identified metastasis associated hallmarks and more efficacious treatment are urgently needed. It found that forkhead box q1 (FOXQ1) is aberrant expression in variety of human cancers and FOXQ1 is involved in oncogenic pathways. However, the role of FOXQ1 has been unexplored in colorectal cancer metastasis to date. Here, expression of FOXQ1 was higher in colorectal cancer tissue samples and cancer cell lines than in normal colorectal tissue and cell lines. Further research suggested that FOXQ1 positively regulated cell proliferation in colorectal cancer and down-regulation of CDK6, extracellular regulated protein kinases 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR). In corresponding to this result, over-expression of FOXQ1 significantly promoted colorectal cancer growth in vivo. Moreover, down regulation of FOXQ1 expression in colorectal carcinoma cell HCT116 and LOVO strikingly inhibits tumor growth in vivo. Finally, FOXQ1-dependent inhibition of colorectal cancer cell migration and invasion and down-regulation of focal adhesion kinase (FAK), phosphatidyl inositol 3-kinase (PI3K) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation and matrix metalloproteinase-2/9 (MMP-2/9) expression. These integrated efforts have identified FOXQ1 as a tumor promoter and might provide promising approaches for colorectal cancer metastasis treatment.