This study aimed to determine the correlation between HIF-1α and miR-27a expression and to evaluate the effect of inhibition of HIF-1α expression on miR-27a expression and drug resistance in gastric cancer (GC). In the present study, real time-PCR and Western blot were performed to detect the expression of HIF-1α in GC tissues and cell lines. Then, OCUM-2MD3/L-OHP cells were transfected with HIF-1α-siRNA, a miR-27a mimic or pcDNA-HIF-1α, and cell survival was determined via the MTT assay. The expression of HIF-1α, miR-27a, and MDR-related genes was measured via real time-PCR and Western blot. ChIP and dual luciferase activity assays were performed to assess the transcriptional regulation of HIF-1α and miR-27a. The results revealed that transfection with HIF-1α-siRNA markedly decreased the levels of miR-27a, resulting in dramatically enhanced inhibition of the proliferation rate of OCUM-2MD3/L-OHP cells. Compared to non-transfected cells, the survival rate was significantly reduced in the cells transfected with HIF-1α-siRNA after treatment with L-OHP. The cell survival rate was significantly increased in OCUM-2MD3/L-OHP cells transfected with the miR-27a mimic, whereas HIF-1α overexpression did not result in any clear change in cell survival. The results of the dual luciferase activity assay demonstrated that HIF-1α enhances the transcriptional activity of the miR27a promoter in cells transfected with a reporter plasmid containing the upstream promoter region of miR27a together with pcDNA-HIF-1α. ChIP analysis suggested that HIF-1α directly binds to the promoter region of miR27a. Inhibition of HIF-1α or miR27a expression decreased MDR1/P-gp, LRP, and Bcl-2 expression in OCUM-2MD3/L-OHP cells. Thus, we found that HIF-1α is closely associated with MDR in GC and that HIF-1α may suppress MDR1/P-gp, LRP and Bcl-2 expression by inhibiting miR-27a expression.

Background Previous studies have confirmed that systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) can predict the prognosis and chemotherapy efficacy of various malignant tumors. However, to the best of our knowledge, no study investigated the SII combined with PNI score to predict the efficacy of anti-programmed death 1 (anti-PD-1) antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in the treatment of locally advanced gastric cancer. This study aims to evaluate the predictive value of pre-treatment SII-PNI score on the sensitivity of sintilimab immunotherapy combined with XELOX chemotherapy in patients with locally advanced gastric cancer. Methods We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI. Results All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003). Conclusion The pre-treatment SII-PNI score is a significant indicator for predicting chemosensitivity of locally advanced patients after sintilimab immunotherapy combined with XELOX chemotherapy, which can help to identify high-risk groups and predict prognosis. Trial registration: The registered name of the trial is “Prospective clinical study of sintilimab combined with chemotherapy for neoadjuvant therapy in locally advanced gastric cancer”. Its Current Controlled Trials number is ChiCTR2000030414. Its date of registration is 01/03/2020.

Abstract:Objective:This study was conducted to investigate the efficacy and safety of using a concurrent neoadjuvant chemoradiotherapy (a XELOX regimen) to treat adenocarcinoma of the gastroesophageal junction.Methods:Seventy-six patients having resectable adenocarcinoma at the gastroesophageal junction (T3/4, N+, M0) were recruited to participate and randomly assigned to either a chemoradiotherapy group or a surgery group. Patients in the chemoradiotherapy group were orally given capecitabine (1,000 mg/m2, twice daily for 14 days, days 1–14) and intravenous oxaliplatin (130 mg/m2 on day 1) for 2 cycles. Radiotherapy was performed with a total of 45 Gy administered in 25 sessions for 5 weeks. Patients in the surgery group received only surgical intervention.Results:In the concurrent chemoradiotherapy group, the overall response rate was 55.6% (20/36), tumor control rate was 100% and a pathological complete response was achieved in 16.7% (6/36). The entire chemoradiotherapy group had R0 resections as did 80% of the surgery group (32/40) (P < 0.05). In the concurrent chemoradiotherapy group, 6 patients developed grade 3 side effects. Treatment was either discontinued or the dose adjusted. Major hematological side effects in the chemoradiotherapy group included leukopenia, neutropenia, anemia and thrombocytopenia. Nonhematological side effects included nausea, vomiting and appetite loss. Chemoradiotherapy-related death was not observed.Conclusions:Concurrent neoadjuvant chemoradiotherapy administration increased the rate of R0 resection and demonstrated favorable safety in patients with Siewert II or III adenocarcinoma at the gastroesophageal junction. These results support the use of neoadjunctive chemoradiotherapy in the treatment of adenocarcinoma of the gastroesophageal junction.

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This paper presents a tunable comb resonator by mechanically altering the suspension configuration to change its spring constant. The change of the stiffness of the resonator is achieved using electrostatic MEMS actuators. The MEMS actuators mechanically change the length of the beams to increase their spring constant and therefore the resonant frequency. The resonant frequency changed from the original value of 10.8 kHz to 17.6 kHz and 21.4 kHz depending on the spring configuration. The tunable mechanical resonator has been designed numerically using Coventorware and validated with experimental characterization. The device is built using a silicon-on-insulator (SOI) process.

BackgroundGastric cancer with only peritoneal lavage cytology (GC-CY1) is a special type of gastric cancer, which is defined as stage IV. The pre-treatment systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) are representative blood indexes of systemic inflammatory response and nutritional status. However, the clinical significance of combined detection of these two indexes is still unclear. This study aims to evaluate the clinical value of the new score system by combining SII and PNI (SII-PNI score) as a predictor of efficacy and prognosis after neoadjuvant intraperitoneal and systemic (NIPS) paclitaxel combined with Apatinib conversion therapy for GC-CY1 patients.MethodsWe registered a prospective clinical study involving 36 GC-CY1 patients from April 2018 to August 2019 (NCT03718624). All patients underwent re-laparoscopic exploration after treatment. According to free cancer cells (FCCs) status, these patients were divided into FCCs group and non-FCCs group. The SII-PNI score ranged from 0 to 2 as follows: score of 2, high SII (≥512.1) and low PNI (≤52.9); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI.ResultsAll patients underwent re-laparoscopic exploration after 3 cycles of NIPS paclitaxel and Apatinib conversion therapy. Among them, 28 cases (77.78%) were in non-FCCs group, and 8 cases (22.22%) were in FCCs group. The SII-PNI score of non-FCCs patients was significantly lower than that of FCCs patients (p=0.041). The prognosis of patients with high SII-PNI score was significantly worse than that of patients with low SII-PNI score (p&lt;0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting overall survival and progression-free survival (p=0.001, 0.002).ConclusionPretreatment SII-PNI score is an important predictor for the efficacy of GC-CY1 patients after NIPS paclitaxel combined with Apatinib conversion therapy, which can help to identify high-risk groups and predict prognosis.

In this study, the effects of hypoxia-inducible factor-1α (HIF-1α) on gastric carcinoma (GC) drug resistance through apoptosis-related genes are investigated. First, HIF-1α-specific siRNA was synthetized and transfected into drug-resistant GC cell line OCUM-2MD3/L-OHP. Then MTT assay was applied to test the inhibition rate of GC cells by 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). After that, flow cytometry (FCM) was applied to measure apoptosis rate. qPCR and Western blot assay were employed to detect HIF-1α and apoptosis-related genes. Results showed that HIF-1α in OCUM-2MD3/L-OHP cells was higher than that in OCUM-2MD3 and gastric epithelial cells. After HIF-1α-siRNA transfection, inhibition rates of 5-FU and L-OHP to tumor cells increased significantly. FCM results showed that apoptosis rate of OCUM-2MD3/L-OHP cells increased significantly. After HIF-1α-siRNA transfection, survivin and Bcl-2 decreased, whereas Bax, caspase 3, and caspase 8 increased significantly. Results from this study seem to confirm that HIF-1α getting involved in GC drug resistance is possibly due to its regulation of some apoptosis-related genes. HIF-1α may be a potential target to reverse drug resistance of GC.