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BACKGROUND: Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori-induced HIF-1α expression and carcinogenesis remain unclear. AIM: To explore the underlying mechanism of H. pylori-induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1). METHODS: The study was conducted with human GES-1 cells in vitro. Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively. RESULTS: H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect. CONCLUSION: H. pylori-induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.
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LESSONS LEARNED: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. BACKGROUND: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. METHODS: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. RESULTS: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. CONCLUSION: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.
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Neoplasias de Cabeza y Cuello , Linfoma Folicular , Heparina de Bajo-Peso-Molecular , Humanos , Dosis Máxima Tolerada , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
OBJECTIVE: Demoralization and depression are common in cancer patients and closely related to suicide. But the association and difference between them are not clear. The aim of this study is to investigate demoralization and depression in Chinese cancer patients. METHODS: This study is a cross-sectional study. Two hundred ninety-six cancer patients completed the questionnaire. First is using the DS-II to evaluate demoralization in advanced cancer patients and using the PHQ-9 to evaluate their depression. Then determine the association between demoralization and depression by Pearson rank correlation test. Finally, an ANOVA was conducted using DS-II as the categorical variable and PHQ-9 as the continuous variable and using PHQ-9 as the categorical variable and DS-II as the continuous variable. RESULTS: There is a positive association between demoralization and depression. A special case that patients with high demoralization but low depression was discovered, which accounted for a large proportion. CONCLUSION: Demoralization and depression are two different psychological states, which require medical staff to identify and take corresponding intervention measures in time. Patients with high demoralization but low depression require further attention.
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Desmoralización , Neoplasias , China/epidemiología , Estudios Transversales , Depresión/epidemiología , Depresión/etiología , Humanos , Neoplasias/complicaciones , Estrés PsicológicoRESUMEN
Objective:To explore the safety, feasibility and clinical value of the "posterior colon approach, uncinate process first" of total laparoscopic pancreaticoduodenectomy in low volume hospitals.Methods:The clinical data of 3 patients who underwent complete laparoscopic pancreaticoduodenectomy were analyzed from January 2020 to August 2020.Results:All the 3 patients successfully underwent total laparoscopic pancreaticoduodenectomy. For the 3 patients, the operative time was 430, 385 and 425 min, and the blood loss was 550, 420 and 400 ml. After the operation, no pancreatic fistula, bile leakage, intestinal fistula and astric emptying disorder were found in the patients. The exhaust time of the 3 patients was 4, 5 and 5 days after the operation, respectively. On the 6th day after the operation, the gastric tube was removed. The extraction time of the abdominal drainage tube of the 3 patients was the 7th, 7th and the 9th day, and the postoperative hospital stay was 18, 15 and 16 days, respectively. Postoperative pathological diagnosis results showed that the 3 patients included 1 case of pancreatic head high-moderately differentiated ductal adenocarcinoma, 1 case of duodenal ampullary high-moderately differentiated adenocarcinoma, and 1 case of duodenal papillary well-differentiated adenocarcinoma.Conclusions:"Posterior approach of uncinate process" is safe and feasible in laparoscopic pancreaticoduodenectomy. It can be popularized in low volume hospitals.
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An adjustable mounting structure is proposed to compensate for surface deformation of a mirror caused by the assembly process. The mount adopts a six-point support based on the kinematic mount principle. Three of the support points are adjustable, and they are moved along the axial direction by actuators. Surface deformation is expressed by Zernike coefficients in this paper, and a sensitivity matrix of the surface deformation is established by varying the unit displacement of each adjustment support point and getting the corresponding Zernike coefficient changes. The surface deformation is measured, and the compensation adjustment of each adjustable support point is then obtained by anti-sensitivity calculation. Finally, the feasibility of present support structure design and surface figure compensating method are verified by experiments. The experimental results show that the present structure and method could significantly reduce the surface deformation caused by the assembly process. The surface deformation is 4.6 nm RMS after assembly and it is decreased to 1.3 nm RMS after four iterations of compensation, which is close to the 1.1 nm RMS after optical polishing.
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OBJECTIVES: Identify predictors of outcome in patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) treated with weekly cetuximab and paclitaxel (CP). STUDY DESIGN: Retrospective analysis. METHODS: Patients with RMHNSCC treated with CP were identified and patient data was recorded. The Kaplan-Meier method was used to estimate outcomes, and Cox regression analysis was used to examine outcome predictors. RESULTS: Fifty-nine patients initiated CP between January 2007 and June 2014. Median age was 56 (range: 39-80) years. The most common primary sites were the oropharynx in 22 (37%) patients, oral cavity in 19 (32%), and larynx in 11 (19%). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 in seven (12%), 1 in 32 (54%), and 2 in 16 (28%) patients. In 44 (75%) patients, CP was used as a first-line R/M regimen. Median number of cycles was five (range: 1-29). Dose modifications were necessary in 27 (46%) patients. The objective response rate was 47.5%, with 27 (45.8%) partial responses and one (2%) complete response. With a median follow-up of 13.4 months, median progression-free (PFS) and overall survival (OS) were 7.7 and 13.2 months, respectively. On multivariable analysis, an ECOG of 2 of 3 was associated with inferior OS (hazard ratio [HR]: 3.94; P = 0.01; 95% confidence interval [CI]: 1.1-14.04) and PFS (HR: 7.29; P < 0.01; 95% CI: 2.1-26.0) compared to an ECOG 0 of 1. First-line CP administration was associated with superior PFS compared to second line (HR: 2.6; P = 0.02; 95% CI:1.2-5.5). CONCLUSIONS: CP is well tolerated in this population of patients, with favorable tumor efficacy. First-line use and an ECOG 0 of 1 points appears to confer superior outcomes. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1583-1588, 2017.