Controlled siRNA Release of Nanopolyplex for Effective Targeted Anticancer Therapy in Animal Model.

Introduction: Spatiotemporally controlled release of siRNA for anti-tumor therapy poses significant challenges. Near-infrared (NIR) light, known for its exceptional tissue penetration and minimal tissue invasiveness, holds promise as a viable exogenous stimulus for inducing controlled siRNA release in vivo. However, the majority of light-responsive chemical bonds exhibit absorption wavelengths in the ultraviolet (UV) or short-wavelength visible light range. Methods: To achieve NIR-controlled siRNA release, the study synthesized a UV-sensitive triblock copolymer cRGD-poly(ethylene glycol)-b-poly(aspartic acid ester-5-(2'-(dimethylamino)ethoxy)-2-nitrobenzyl alcohol)-b-polyphenylalanine, abbreviated as cRGD-PEG-PAsp(EDONB)-PPHE. This copolymer is composed of a cRGD-capped PEG block (cRGD-PEG), a poly(aspartate) block modified with cationic moieties through UV-cleavable 2-nitrobenzyl ester bonds [PAsp(EDONB)], and a hydrophobic polyphenylalanine block (PPHE). The cationic amphiphilic polymer cRGD-PEG-PAsp(EDONB)-PPHE can assemble with hydrophobic upconversion nanoparticles (UCNPs) to form a cationic micelle designated as T-UCNP, which subsequently complexes with siRNA to create the final nanopolyplex T-si/UCNP. siRNA-PLK1 was employed to prepare T-PLK1/UCNP nanopolyplex for anti-tumor therapy. Results: T-PLK1/UCNP not only exhibited outstanding tumor cell targeting through cRGD modification but also achieved 980 nm NIR-controlled PLK1 gene silencing. This was achieved by utilizing the encapsulated UCNPs to convert NIR into UV light, facilitating the cleavage of 2-nitrobenzyl ester bonds. As a result, there was a significant suppression of tumor growth. Conclusion: The UCNPs-encapsulated nanopolyplex T-si/UCNP, capable of co-delivering siRNA and UCNPs, enables precise NIR-controlled release of siRNA at the tumor site for cancer RNAi therapy. This nanopolyplex can enhance the controllability and safety of RNAi therapy for tumors, and it also holds the potential to serve as a platform for achieving controlled release and activation of other drugs, such as mRNA and DNA.

Comparative study on wound healing and infection between open and minimally invasive surgical methods in pediatric otolaryngology surgery.

Pediatric otolaryngology surgeries are crucial interventions requiring careful consideration of surgical methods to optimize outcomes. The choice between open and minimally invasive surgical approaches in this context warrants thorough investigation. While both methods aim to address ear, nose, and throat conditions in children, a comparative study assessing their impact on crucial factors such as intraoperative parameters, wound healing, complications, and postoperative pain is essential. This study aims to compare the effects of open and minimally invasive surgical methods on wound healing and infection in pediatric otolaryngology surgery, and provide a scientific basis for the selection of surgical methods. Two groups of patients were selected, with 90 people in each group. One group received open surgery and the other received minimally invasive surgery. Recording the intraoperative time, anesthesia time, and intraoperative blood loss; the number of days required for wound healing; the occurrence of wound-related complications; the comparison of pain on postoperative Days 1, 3, and 7; and the factors influencing postoperative wound healing were analyzed. In the minimally invasive surgery group, the intraoperative time was shorter, the anesthesia time was relatively reduced, and the amount of bleeding was significantly reduced. Wounds also take fewer days to heal and have lower rates of wound-related complications. When comparing the pain on 1, 3, and 7 days after surgery, the minimally invasive surgery group had relatively mild pain. Analysis of postoperative wound healing factors showed that minimally invasive surgical methods have a positive impact on healing. In pediatric otolaryngology surgery, minimally invasive surgery performs better than open surgery in terms of intraoperative operation time, anesthesia time, blood loss, wound healing time, complication rate, and postoperative pain. Therefore, minimally invasive surgery may be a safer and more effective surgical method.

lncRNA BANCR promotes the colorectal cancer metastasis through accelerating exosomes-mediated M2 macrophage polarization via regulating RhoA/ROCK signaling.

Cancer cells-derived exosomal lncRNAs could modulate the tumorigenesis of colorectal cancer (CRC) via modulating macrophage M2 polarization. However, the clarified mechanism and function of lncRNA BANCR in CRC remains unclear. Exosomes were identified by TEM, NTA, western blot and fluorescent staining. M2 macrophages were identified by CD206 and CD163 expressions using by flow cytometry and RT-qPCR. In addition, the relation between IGF2BP2 and BANCR or RhoA were explored by RIP assay. The malignant behaviors of CRC cells were examined by CCK-8, EdU and transwell assays. Histopathological changes in mice were observed by H&E staining. Silencing of BANCR notably inhibited the proliferation, migration and invasion of CRC cells. SW620 and HCT-15 cells-derived exosomal BANCR positively regulated the macrophage M2 polarization. In addition, exosomal BANCR remarkably enhanced the promoting roles mediated by M2 macrophages on proliferation and invasion in CRC cells. Meanwhile, exosomal BANCR promoted the M2 macrophage polarization via activation of RhoA/Rock pathway by recruiting IGF2BP2. Inhibition of RhoA/Rock pathway reversed exosomal BANCR-mediated macrophages M2 polarization and CRC malignant behaviors in SW620 and HCT-15 cells. Exosomal lncRNA BANCR derived from SW620 and HCT-15 cells promoted the metastasis of CRC via inducing the polarization of M2 macrophages. Thus, BANCR might be a new target for the treatment of CRC.

LINC01836 Promotes Colorectal Cancer Progression and Functions as ceRNA to Target SLC17A9 by Sponging miR-1226-3p.

BACKGROUND: Increasing evidence proves that long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of colorectal cancer. However, the function and molecular mechanism of LINC01836 in CRC are still unknown. METHODS: The differentially expressed lncRNAs in colorectal cancer were obtained from the RNA sequencing data. The effects of LINC01836 on colorectal cancer cells were tested in in vitro experiments. The mechanism of LINC01836 action was investigated through western blot, RNA immunoprecipitation assay and luciferase reporter assay. Moreover, the xenograft mouse model was conducted to examine the effects of LINC01836 in vivo. RESULTS: In this study, we showed that LINC01836 was significantly elevated in colorectal cancer tissues and cells. Elevated LINC01836 expression significantly correlated with larger tumor size, positive lymph node metastasis, distant metastasis, advanced tumor-node-metastasis (TNM) stage, and poor prognosis. Furthermore, decreased expression of LINC01836 repressed proliferation, migration, and invasion in vitro and vivo, and high LINC01836 expression displayed the opposite effect. Further analysis revealed that LINC01836 could regulate the expression of SLC17A9 by competing with miR---1226-3p. Furthermore, down-regulation of LINC01836 or increased expression of miR-1226-3p markedly reversed the effects of SLC17A9 overexpression on colorectal cancer cells. CONCLUSION: This study showed that LINC01836 regulated the expression of SLC17A9 through sponge miR-1226-3p by acting as a competitive endogenous RNA (ceRNA), promoted the progression of colorectal cancer, and suggested a new prognostic biomarker and potential cancer treatment target for colorectal cancer.

Determinants of Meningococcal Vaccination Coverage and Adherence: A Targeted Literature Review Supporting a 16-year-old Healthcare Visit.

We conducted a targeted literature review to understand the determinants of meningococcal serogroups A, C, W, and Y (MenACWY) and meningococcal serogroup B (MenB) vaccination coverage and adherence to vaccination schedules in the USA, and to identify evidence to support improvement of MenACWY and MenB vaccination coverage and adherence in older adolescents. Sources published since 2011 were considered, with sources published since 2015 given preference. Out of 2355 citations screened, 47 (46 studies) were selected for inclusion. Determinants of coverage and adherence ranging from patient-level sociodemographic factors to policy-level factors were identified. Four determinants identified were associated with improved coverage and adherence: (1) well-child, preventive, or vaccination-only appointments (particularly for older adolescents); (2) provider-initiated, provider-driven vaccine recommendations; (3) provider education about meningococcal disease and vaccine recommendations; and (4) state-level school-entry immunization policies. This robust review of the literature sheds light on the continued low MenACWY and MenB vaccination coverage and adherence among older adolescents (16-23 years of age) compared with that of younger adolescents (11-15 years of age) in the USA. The evidence supports a renewed call to action by local and national health authorities and medical organizations urging healthcare professionals to implement a healthcare visit for 16-year-olds and focus on vaccination as a key component of the visit.

Certain meningococcal vaccines are recommended for young people (ages 11­23) in the USA at specific ages. We analyzed scientific studies to understand how many young people in the USA have received meningococcal vaccines and whether they received them at the recommended ages. We found that a low proportion of young people age 16 or older have received appropriate meningococcal vaccination, compared with those under age 16. We looked at reasons why this might be the case and identified actions that could be taken to increase the proportion of young people age 16 or older who receive appropriate meningococcal vaccination. Overall, the information found confirms the importance of encouraging healthcare professionals to establish routine appointments with 16-year-olds, during which they can administer recommended, age-appropriate vaccines.

Mesenchymal stem cells-derived exosomal miR-653-5p suppresses laryngeal papilloma progression by inhibiting BZW2.

OBJECTIVES: Although miR-653-5p has been validated to participate in the progression of multiple types of cancer, the functional role of exosomal miR-653-5p derived from Mesenchymal Stem Cells (MSCs) in Laryngeal Papilloma (LP) has still remained elusive. Hence, this study aimed to investigate the role of MSCs-derived exosomal miR-653-5p in LP. METHODS: LP tissues (n = 15) and adjacent normal tissues (n = 10) were collected to examine the expression level of miR-653-5p. The expression level of miR-653-5p in LP cells and normal cells was also detected. Then, miR-653-5p was overexpressed or silenced to explore its effects on the proliferation, migration, invasion, and apoptosis of LP cells. Thereafter, the effects of exosomal miR-653-5p derived from MSCs on LP cell progression and the potential regulatory mechanism of miR-653-5p were assessed. RESULTS: It was revealed that the expression level of miR-653-5p was downregulated in LP tissues and cells. In addition, miR-653-5p suppressed the proliferation, migration, invasion, and apoptosis of LP cells. Exosomes derived from MSCs played a suppressive role in LP development and mediated the transmission of miR-653-5p to LP cells. Further exploration identified Basic leucine Zipper and W2 domains 2 (BZW2) as the target of miR-653-5p. More importantly, the rescue experiments revealed that MSCs-secreted exosomal miR-653-5p efficiently inhibited the aggressive phenotypes of LP cells, which could be significantly reversed by BZW2 overexpression in LP cells. CONCLUSION: MSCs-derived exosomal miR-653-5p exerted inhibitory effects on LP progression through targeting BZW2, which provided a novel idea for the therapy of LP. CLINICAL TRIAL REGISTRATION NUMBER: chictr-ior-17011021.

Mesenchymal stem cells-derived exosomal miR-653-5p suppresses laryngeal papilloma progression by inhibiting BZW2

Abstract Objectives: Although miR-653-5p has been validated to participate in the progression of multiple types of cancer, the functional role of exosomal miR-653-5p derived from Mesenchymal Stem Cells (MSCs) in Laryngeal Papilloma (LP) has still remained elusive. Hence, this study aimed to investigate the role of MSCs-derived exosomal miR-653-5p in LP. Methods: LP tissues (n = 15) and adjacent normal tissues (n = 10) were collected to examine the expression level of miR-653-5p. The expression level of miR-653-5p in LP cells and normal cells was also detected. Then, miR-653-5p was overexpressed or silenced to explore its effects on the proliferation, migration, invasion, and apoptosis of LP cells. Thereafter, the effects of exosomal miR-653-5p derived from MSCs on LP cell progression and the potential regulatory mechanism of miR-653-5p were assessed. Results: It was revealed that the expression level of miR-653-5p was downregulated in LP tissues and cells. In addition, miR-653-5p suppressed the proliferation, migration, invasion, and apoptosis of LP cells. Exosomes derived from MSCs played a suppressive role in LP development and mediated the transmission of miR-653-5p to LP cells. Further exploration identified Basic leucine Zipper and W2 domains 2 (BZW2) as the target of miR-653-5p. More importantly, the rescue experiments revealed that MSCs-secreted exosomal miR-653-5p efficiently inhibited the aggressive phenotypes of LP cells, which could be significantly reversed by BZW2 overexpression in LP cells. Conclusion: MSCs-derived exosomal miR-653-5p exerted inhibitory effects on LP progression through targeting BZW2, which provided a novel idea for the therapy of LP. Clinical Trial registration number: chictr-ior-17011021.

Incidence of Pneumonitis Among Limited Stage Small Cell Lung Cancer Patients Exposed to Concurrent Chemoradiation: A Systematic Literature Review and Meta-Analysis.

Severe pneumonitis (≥ grade 3 by Common Terminology Criteria for Adverse Events [CTCAE]) is a toxicity associated with concurrent chemoradiation therapy (CCRT), which is the standard first-line treatment for patients with limited-stage small cell lung cancer (LS-SCLC). We summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT. A systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines. Electronic databases were searched to identify relevant randomized controlled trials (RCTs), observational studies, and non-randomized trials between 2014 to July 16, 2020. The primary outcome was incidence of pneumonitis. Thirteen studies were included in the SLR and 1539 pooled patients from 10 studies were included in the base-case meta-analysis. The pooled incidence of ≥ grade 3 pneumonitis was 3.28% (95% confidence interval [CI]: 1.52%-5.04%) in RCTs, and 6.34% (95% CI: 3.64%-9.04%) in non-RCTs. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% (95% CI: 0.00%-0.62%) in RCTs and 0.88% (95% CI: 0.02%-1.74%) in non-RCT. Results from sensitivity analyses were consistent with the base-case analysis. The results from this analysis show that the incidence of ≥ grade 3 pneumonitis in patients with LS-SCLC was 3.28% to 6.34%. The incidence of pneumonitis was higher in studies conducted in non-RCTs compared to RCTs. These results can be used to understand the safety, with regard to pneumonitis, of novel therapeutic agents when administered with CCRT to treat patients with LS-SCLC. To summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT, a systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines.

Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway.

BACKGROUND: Mesenchymal stem cells (MSCs) are considered to be a potential therapeutic tool for liver fibrosis. Inhibiting the activation of hepatic stellate cells (HSCs) and protecting hepatocytes are important mechanisms for the anti-fibrotic effect of MSCs. However, how MSCs inhibit liver fibrosis by regulating the expression of microRNAs (miRNAs) has not been fully clarified. METHODS: Transforming growth factor-ß1 (TGF-ß1)-activated HSCs LX-2 were single cultured or co-cultured with human umbilical cord mesenchymal stem cells (HUC-MSCs). High-throughput sequencing was used to evaluate the differentially expressed microRNAs (DEMs) between the two groups. Quantitative real-time PCR (qRT-PCR), Western blot, and transfection experiments were used to investigate and screen the most significantly up-regulated DEM. Bioinformatics analysis was used to predict the target mRNAs and the potential functions of the DEM. The possible mechanism of HUC-MSCs against liver fibrosis was analyzed by co-culture experiment of HUC-MSCs with LX-2 cells, and HUC-MSCs treatment of Bile duct ligation (BDL)-induced liver fibrosis in mice. Finally, the mechanism of the DEM regulating liver fibrosis was confirmed in human liver fibrosis specimens. RESULTS: MicroRNA-148a-5p (miR-148a-5p) was the most significantly up-regulated DEM in activated LX-2 cells co-cultured with HUC-MSCs compared with LX-2 cells single cultured. Up-regulation of the expression of miR-148a-5p in activated LX-2 cells could significantly inhibit the expression of hepatic fibrosis markers α-SMA and Col1α1. Notch2 was one target gene of miR-148a-5p. Co-cultured with HUC-MSCs could inhibit the activation of LX-2 cells by inhibiting the expression of the Notch2 and the Notch signaling pathway. In addition, HUC-MSCs treatment could up-regulate the expression of miR-148a-5p in liver tissue and hepatocytes, promote the proliferation and avoid the apoptosis of hepatocytes, and reduce the degree of fibrosis by inhibiting expression of the Notch2 and the Notch signaling pathway in BDL-induced liver fibrosis mice. Moreover, miR-148a-5p was down-regulated and Notch2 was up-regulated in fibrotic human liver tissues compared with the normal livers. CONCLUSIONS: HUC-MSCs treatment could inhibit HSCs activation, protect hepatocytes, and alleviate BDL-induced liver fibrosis in mice by up-regulating the expression of miR-148-5p and inhibiting the Notch signaling pathway. The down-regulation of miR-148-5p and up-regulation of Notch2 could be used as biomarkers to monitor the progression of liver fibrosis.

Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: A systematic literature review and meta-analysis.

INTRODUCTION: High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients. METHODS: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis. RESULTS: Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies. CONCLUSION: These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

Phosphatidylethanolamine-binding protein 1 (PEBP1) mediates the regulatory role of microRNAs (miRNAs)-205-5p in degranulation and histamine release.

miR-205-5p plays a vital role in the inflammation of allergic rhinitis (AR). The study is designed to investigate the effects and mechanism of miR-205-5p in AR in vivo and in vitro. An OVA-induced mice model and anti-DNP IgE-induced RBL-2H3 cell model were established. The pathological alterations in the nasal mucosa were evaluated by hematoxylin-eosin (HE) staining. IgE and histamine levels were detected by corresponding kits and the expressions of PEBP1, High mobility group box-1 (HMGB1) and Toll-like receptor 4 (TLR4) were detected by western blot. The association of miR-205-5p and PEBP1 was determined by dual-luciferase reported assay. ß-hexosaminidase activity was to evaluate the degranulation of RBL-2H3 cell. The pathological injury of nasal mucosa was significantly improved by miR-205-5p inhibition compared to AR mice. Following the treatment of miR-205-5p inhibitor, the levels of helper T cell (Th1) cytokines, interleukin (IL)-2 and interferon-γ (IFN-γ) were increased, while the levels of Th2 cytokines, IL-4 and IL-13, as well as the levels of IgE and histamine were markedly decreased in AR mice. We further found that miR-205-5P inhibition induced increased expression of PEBP1 and decreased expressions of HMGB1and TLR4. In vitro, miR-205-5P was verified to bind to PEBP1. PEBP1 silencing led to the reverse of miR-205-5p effects on decreasing the levels of ß-hexosaminidase activity and histamine, as well as the expressions of HMGB1 and TLR4 on anti-DNP IgE-induced RBL-2H3 cells. Our results indicate that miR-205-5P inhibition may ameliorate pathological injury via PEBP1. MiR-205-5P/ PEBP1 could be potential drug targets in AR.

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer.

Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50 values < 1 µM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.

Prognostic Value of PTENP1 Expression in Patients with Cancer: a Systematic Review and Meta-Analysis.

BACKGROUND: Downregulation of PTENP1 was reported in different malignant tumors. However, the function and significance of PTENP1 in the clinical pathology and prognosis of tumors are not very clear. Therefore, we performed this research to analyze and elucidate the correlations between the PTENP1 expression and clinical pathological parameters and outcome of patients in different types of cancer. METHODS: Literature on PTENP1 was retrieved from PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, Wan Fang, Springer, Ovid, and Medline databases. Pooled ORs (odds ratios) or HRs (hazard ratios) with 95% CIs were utilized to examine the relationship between the PTENP1 and clinical pathological traits and outcome of patients with different tumor types. RESULTS: Eight studies comprising 1,047 patients were enrolled and analyzed in this research. Down-regulation of PTENP1 was correlated with differentiation (OR: 2.57; 95% CI: 1.14 - 5.80), TNM stage (OR: 0.24; 95% CI: 0.13 - 0.43), and LNM (OR: 0.27; 95% CI: 0.14 - 0.52). Moreover, PTENP1 expression level was correlated with OS in the eight types of tumors (pooled HR: 0.49; 95% CI: 0.39, 0.61). CONCLUSIONS: Low expression of PTENP1 might predict poor prognosis in patients with various carcinomas. PTENP1 may play an important role as a new prognostic indicator in patients with different malignant tumors.

LncRNA FEZF1-AS1 Promotes Multi-Drug Resistance of Gastric Cancer Cells via Upregulating ATG5.

Long non-coding RNAs (lncRNAs) play important roles in human cancers including gastric cancer (GC). Dysregulation of lncRNAs is involved in a variety of pathological activities associated with gastric cancer progression and chemo-resistance. However, the role and molecular mechanisms of FEZF1-AS1 in chemoresistance of GC remain unknown. In this study, we aimed to determine the role of FEZF1-AS1 in chemoresistance of GC. The level of FEZF1-AS1 in GC tissues and GC cell lines was assessed by qRT-PCR. Our results showed that the expression of FEZF1-AS1 was higher in gastric cancer tissues than in adjacent normal tissues. Multivariate analysis identified that high level of FEZF1-AS1 is an independent predictor for poor overall survival. Increased FEZF1-AS1 expression promoted gastric cancer cell proliferation in vitro. Additionally, FEZF1-AS1 was upregulated in chemo-resistant GC tissues. The regulatory effect of FEZF1-AS1 on multi-drug resistance (MDR) in GC cells and the underlying mechanism was investigated. It was found that increased FEZF1-AS1 expression promoted chemo-resistance of GC cells. Molecular interactions were determined by RNA immunoprecipitation (RIP) and the results showed that FEZF1-AS1 regulated chemo-resistance of GC cells through modulating autophagy by directly targeting ATG5. The proliferation and autophagy of GC cells promoted by overexpression of LncFEZF1-AS1 was suppressed when ATG5 was knocked down. Moreover, knockdown of FEZF1-AS1 inhibited tumor growth and increased 5-FU sensitivity in GC cells in vivo. Taken together, this study revealed that the FEZF1-AS1/ATG5 axis regulates MDR of GC cells via modulating autophagy.

TSHZ3 functions as a tumor suppressor by DNA methylation in colorectal cancer.

OBJECTIVE: Teashirt zinc finger homeobox 3 (TSHZ3) is currently reported to be aberrantly expressed in several tumors, but the detailed functions and epigenetic mechanisms of TSHZ3 in colorectal cancer (CRC) remain unclear. MATERIALS AND METHODS: In this study, the TSHZ3 expression in 118 CRC and normal adjacent tissues (NATs) was evaluated, and the methylation status of the TSZH3 promoter region in CRC tissues and cell lines was also analyzed. RESULTS: The results of PCR analysis showed that TSHZ3 was significantly down-regulated in CRC tissues, and patients with low TSHZ3 levels had a poorer 5-year overall survival (OS) rate. Analyzing the promoter sequence (-1000∼0) by MethPrimer, TSHZ3 promoter was found to harbor abundant of CpG islands. The methylation specific PCR (MSP) analysis presented a relatively hypermethylated status of THSZ3 promoter in CRC samples. The data of MSP and bisulfite sequencing PCR (BSP) also confirmed that CpG sites of TSHZ3 promoter were methylated in CRC cells, and the DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-Aza) could effectively restored the TSHZ3 expression in vitro. Functionally, the proliferation, apoptosis and metastasis of CRC cells were regulated by TSZH3 over-expression, and the suppressing effects of TSHZ3 in CRC were also confirmed in a xenograft mouse model. CONLUSIONS: Our results indicated that promoter methylation was one of the mechanisms contributing to the down-regulation of TSHZ3 in CRC, and TSZH3 might served as a potential tumor suppressor gene in the development and progression of CRC.

Comparative Efficacy (DAS28 Remission) of Targeted Immune Modulators for Rheumatoid Arthritis: A Network Meta-Analysis.

INTRODUCTION: The objective of this study was to evaluate the relative efficacy of targeted immune modulators (TIMs) in TIM-naïve/mixed populations (≤ 20% TIM-experienced) and TIM-experienced (> 20% TIM-experienced) adults with moderate-to-severe rheumatoid arthritis with an inadequate response to or intolerance of conventional disease-modifying antirheumatic drugs (cDMARDs). METHODS: A fixed-effects Bayesian network meta-analysis (NMA) was performed using published study-level data from 41 randomized controlled trials (RCTs) identified from two recent systematic literature reviews conducted by the Institute for Clinical and Economic Review, and two additional phase III trials for filgotinib (FINCH-1, FINCH-2). RCTs that compared TIMs with each other, cDMARD therapy, or placebo were included. Treatments included Janus kinase (JAK) inhibitors, tumor necrosis factor α inhibitors (TNFi), and other non-TNFi therapies. Efficacy was defined as achieving remission with a DAS28 score < 2.6 at 12 and 24 weeks. RESULTS: In the 12-week analysis for the TIM-naïve/mixed population, all TIMs combined with cDMARD therapy were significantly more likely to achieve remission compared with a cDMARD alone, with intravenous tocilizumab showing a substantially greater magnitude of effect (odds ratio 19.36; 95% credible interval 11.01-38.16). Similarly, in the 24-week analysis, intravenous and subcutaneous tocilizumab showed the highest odds ratio of achieving DAS28 remission compared with cDMARD therapy. Similar trends were observed for the analyses on monotherapy or TIM-experienced population. CONCLUSIONS: This NMA demonstrated that tocilizumab is associated with a greater likelihood of remission (DAS28 < 2.6) at 12 and 24 weeks compared with most other TIMs, including new JAK inhibitors, when used in combination with a cDMARD or as monotherapy among TIM-naïve/mixed or TIM-experienced populations.

Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Hepatic Stellate Cell Activation and Liver Fibrosis by Upregulating MicroRNA-455-3p through Suppression of p21-Activated Kinase-2.

Mesenchymal stem cells (MSCs) were shown to have potential therapeutic effects for treatment of liver fibrosis, and dysregulated expression of microRNAs (miRNAs) played a pivotal role in the pathogenesis of liver fibrosis by regulating their downstream target genes. However, the mechanism by which MSCs affect the progression of liver fibrosis by regulating miRNA expression remains unclear. Here, we investigated whether human umbilical cord MSCs (HUC-MSCs) attenuated hepatic fibrosis by regulating miR-455-3p and its target gene. Significantly upregulated miRNA (miR-455-3p) was screened out by GEO datasets analysis and coculture HUC-MSCs with hepatic stellate cell (HSC) LX-2 cells. p21-activated kinase-2 (PAK2) was forecasted to be the target gene of miR-455-3p by bioinformatics analyses and confirmed by luciferase reporter assay. HUC-MSCs were transplanted into mice with carbon tetrachloride- (CCl4-) induced liver fibrosis, the result showed that HUC-MSC transplantation significantly ameliorated the severity of CCl4-induced liver fibrosis, attenuated collagen deposition, improved liver function by reducing the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, upregulated miR-455-3p, and suppressed PAK2 expression of liver tissue in mice. Taken together, our study suggests that HUC-MSCs inhibit the activation of HSCs and mouse CCl4-induced liver fibrosis by upregulation of miR-455-3p through targeting PAK2.

Circular RNA hsa_circ_0072309 inhibits the proliferation, invasion and migration of gastric cancer cells via inhibition of PI3K/AKT signaling by activating PPARγ/PTEN signaling.

Gastric cancer (GC) is a common malignant tumor in the digestive system, which presents without specific symptoms. Circular RNAs (circRNAs) play important roles in tumor progression and cellular functions; however, the relationship between GC and hsa_circ_0072309 remains unclear. The aim of the present study was to investigate the molecular mechanisms of hsa_circ_0072309 and the role that hsa_circ_0072309 plays in proliferation, invasion and migration of GC cells. The expression of hsa_circ_0072309 was evaluated using reverse transcription­quantitative PCR. A series of functional experiments were performed to study the role that hsa_circ_0072309 has in survival and metastasis of GC cells. In the present study, hsa_circ_0072309 was downregulated in GC cell lines and its overexpression inhibited the proliferation, migration and invasion of GC cells. In addition, hsa_circ_0072309 overexpression induced activation of the peroxisome proliferator­activated receptor γ (PPARγ)/PTEN pathway and inhibition of PI3K/AKT signaling. Moreover, pioglitazone, a PPARγ agonist, strengthened the effects of abundant hsa_circ_0072309 on the proliferative, migratory and invasive capabilities of GC cells, while GW9662, a PPARγ antagonist, abolished the effects of hsa_circ_0072309 overexpression on cell proliferation, migration and invasion. The present findings suggested that hsa_circ_0072309 inhibited proliferation, invasion and migration of gastric cancer cells via the inhibition of PI3K/AKT signaling by activating the PPARγ/PTEN signaling pathway. Targeting hsa_circ_0072309 may be an innovative therapeutic strategy for the treatment of GC.

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.

GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analogue conjugated with BODIPY showed colocalization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (proteolysis targeting chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress, with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. SIGNIFICANCE: This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.

Evidence of nigericin as a potential therapeutic candidate for cancers: A review.

Emerging studies have shown that nigericin, an H+, K+ and Pb2+ ionophore, has exhibited a promising anti-cancer activity in various cancers. However, its anti-cancer mechanisms have not been fully elucidated. In this review, the recent progresses on the use of nigericin in human cancers have been summarized. By exchanging H+ and K+ across cell membranes, nigericin shows promising anti-cancer activities in in vitro and in vivo as a single agent or in combination with other anti-cancer drugs through decreasing intracellular pH (pHi). The underlying mechanisms of nigericin also include the inactivation of Wnt/ß-catenin signals, blockade of Androgen Receptor (AR) signaling, and activation of Stress-Activated Protein Kinase/c-Jun N-terminal Kinase (SAPK/JNK) signaling pathways. In many cancers, nigericin is proved to specifically target putative Cancer Stem Cells (CSCs), and its synergistic effects on photodynamic therapy are also reported. Other mechanisms of nigericin including influencing the mitochondrial membrane potentials, inducing an increase in drug accumulation and autophagy, controlling insulin accumulation in nuclei, and increasing the cytotoxic activity of liposome-entrapped drugs, are also discussed. Notably, the potential adverse effects such as teratogenic effects, insulin resistance and eryptosis shall not be ignored. Taken together, these reports suggest that treatment of cancer cells with nigericin may offer a novel therapeutic strategy and future potential of translation to clinics.