Growth Inhibition and Induction of Apoptosis in SHG-44 Glioma Cells by Chinese Medicine Formula “Pingliu Keli”

The present study was carried out to evaluate the effects of the water extract of Chinese medicine “Pingliu Keli” (PK) on human glioma cell viability and apoptosis and to investigate its mechanisms of action in SHG-44 cells. MTT assay showed that PK had a strong cytotoxic effect on SHG-44 cells. The number of live cells was less than 20% after exposure to 90 μg/mL PK for 24 h. PK increased cytotoxicity of SHG-44 cells in a dose-dependent manner. PK caused arrest of SHG-44 cells in G1 phase at low concentration and in G2 phase at high concentration. The percentage of apoptotic cells by flow cytometric analysis of the DNA-stained cells increased to 38% and 52% after treatment with 72 and 108 μg/mL PK, respectively. In addition, PK increased the expression of proapoptotic protein (Bax) and decreased antiapoptotic protein (Bcl-2), with a concomitant increase in the levels of cleaved caspase-3, cleaved caspase-9 and cleaved poly-ADP-ribose polymerase (PARP). These results suggest that PK has a significant apoptosis inducing effect on SHG-44 glioma cells in vitro and caspase-3 may act as a potential mediator in the process

Exosomes: A Novel Strategy for Treatment and Prevention of Diseases

An “exosome” is a nanoscale membrane vesicle derived from cell endocytosis that functions as an important intercellular communication mediator regulating the exchange of proteins and genetic materials between donor and surrounding cells. Exosomes secreted by normal and cancer cells participate in tumor initiation, progression, invasion, and metastasis. Furthermore, immune cells and cancer cells exert a two-way bidirectional regulatory effect on tumor immunity by exchanging exosomes. Current studies on exosomes have further expanded their known functions in physiological and pathological processes. The purpose of this review is to describe their discovery and biological functions in the context of their enormous potential in the clinical diagnosis, prevention, and treatment of cancer as well as bacterial and viral infectious diseases

Methodological quality of radiomic-based prognostic studies in gastric cancer: a cross-sectional study

BackgroundMachine learning radiomics models are increasingly being used to predict gastric cancer prognoses. However, the methodological quality of these models has not been evaluated. Therefore, this study aimed to evaluate the methodological quality of radiomics studies in predicting the prognosis of gastric cancer, summarize their methodological characteristics and performance.MethodsThe PubMed and Embase databases were searched for radiomics studies used to predict the prognosis of gastric cancer published in last 5 years. The characteristics of the studies and the performance of the models were extracted from the eligible full texts. The methodological quality, reporting completeness and risk of bias of the included studies were evaluated using the RQS, TRIPOD and PROBAST. The discrimination ability scores of the models were also compared.ResultsOut of 283 identified records, 22 studies met the inclusion criteria. The study endpoints included survival time, treatment response, and recurrence, with reported discriminations ranging between 0.610 and 0.878 in the validation dataset. The mean overall RQS value was 15.32 ± 3.20 (range: 9 to 21). The mean adhered items of the 35 item of TRIPOD checklist was 20.45 ± 1.83. The PROBAST showed all included studies were at high risk of bias.ConclusionThe current methodological quality of gastric cancer radiomics studies is insufficient. Large and reasonable sample, prospective, multicenter and rigorously designed studies are required to improve the quality of radiomics models for gastric cancer prediction.Study registrationThis protocol was prospectively registered in the Open Science Framework Registry (https://osf.io/ja52b)

Targeting PKC iota-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Introduction: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKC iota) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKC iota-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. Methods: The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKC iota inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. Results: The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKC iota, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. Conclusions: Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKC iota-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients

Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis.

Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing

Yupingfeng Pulvis Regulates the Balance of T Cell Subsets in Asthma Mice

Background. Yupingfeng Pulvis (HFBP) had played an active role in many diseases, especially respiratory tract infections. Exploring the possible prevention mechanism of HFBP may provide new ideas in clinical applications for this well-known herbal formula. Purpose. To study the possible mechanisms of therapy effect of HFBP on asthma mice via regulating the balance of Tregs and Th17 cells. Method. The female BALB/c mice were divided into five groups: control group, model group, prednisone (5.5 mg/kg) group, and 22 g/kg HFBP and 44 g/kg HFBP groups. Ovalbumin was used to make the asthma model of mice; the drug was ig administered daily after atomization for consecutive 15 d. The mice were killed after the last administration. The paraffin-embedded tissue sections of the lungs were stained by H&E. Tregs and Th17 cells in bronchoalveolar lavage fluid were detected by flow cytometry. IL-4, TGF-β, and TNF-α in the serum were detected by ELISA assay. Results. HFBP could alleviate the inflammation in the lung tissue of mice, decrease the proportion of Th17 cells, and increase the proportion of Treg cells in bronchoalveolar lavage fluid. HFBP could decrease IL-4 and TNF-α level and increase TGF-β level in blood. Conclusion. HFBP could treat the asthma through impacting the balance of Th17 cells and Treg cells as well as the levels of related inflammatory cytokines in asthma mice

The comparison of manual and mechanical anastomosis after total pharyngolaryngoesophagectomy

BackgroundTotal pharyngolaryngoesophagectomy (TPLE) is considered as a curative treatment for hypopharynx cancer and cervical esophageal carcinomas (HPCECs). Traditional pharyngo-gastric anastomosis is usually performed manually, and postoperative complications are common. The aim of this study was to introduce a new technique for mechanical anastomosis and to evaluate perioperative outcomes and prognosis.MethodsFrom May 1995 to Nov 2021, a series of 75 consecutive patients who received TPLE for a pathological diagnosis of HPCECs at Sun Yat-sen Memorial Hospital were evaluated. Mechanical anastomosis was performed in 28 cases and manual anastomosis was performed in 47 cases. The data from these patients were retrospectively analyzed.ResultsThe mean age was 57.6 years, and 20% of the patients were female. The rate of anastomotic fistula and wound infection in the mechanical group were significantly lower than that in the manual group. The operation time, intraoperative blood loss and postoperative hospital stays were significantly higher in the manual group than that in the mechanical group. The R0 resection rate and the tumor characteristics were not significantly different between groups. There was no significant difference in overall survival and disease-free survival between the two groups.ConclusionThe mechanical anastomosis technology adopted by this study was shown to be a safer and more effective procedure with similar survival comparable to that of manual anastomosis for the HPCECs patients

Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy

Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and αvβ3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non–small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes

Economic analysis of border control policies during COVID-19 pandemic : a modelling study to inform cross-border travel policy between Singapore and Thailand

With countries progressing towards high COVID-19 vaccination rates, strategies for border reopening are required. This study focuses on Thailand and Singapore, two countries that share significant tourism visitation, to illustrate a framework for optimizing COVID-19 testing and quarantine policies for bilateral travel with a focus on economic recovery. The timeframe is the month of October 2021, when Thailand and Singapore were preparing to reopen borders for bilateral travel. This study was conducted to provide evidence for the border reopening policy decisions. Incremental net benefit (INB) compared to the pre-opening period was quantified through a willingness-to-travel model, a micro-simulation COVID-19 transmission model and an economic model accounting for medical and non-medical costs/benefits. Multiple testing and quarantine policies were examined, and Pareto optimal (PO) policies and the most influential components were identified. The highest possible INB for Thailand is US $125.94 million, under a PO policy with no quarantine but with antigen rapid tests (ARTs) pre-departure and upon arrival to enter both countries. The highest possible INB for Singapore is US$29.78 million, under another PO policy with no quarantine on both sides, no testing to enter Thailand, and ARTs pre-departure and upon arrival to enter Singapore. Tourism receipts and costs/profits of testing and quarantine have greater economic impacts than that from COVID-19 transmission. Provided healthcare systems have sufficient capacity, great economic benefits can be gained for both countries by relaxing border control measures