New-generation advanced PROTACs as potential therapeutic agents in cancer therapy.

Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines inhibit tubulin polymerisation and act as anticancer agents.

A series of cis-restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound 9p, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that 9p potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, 9p could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that 9p conformed well to the Lipinski's rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.

Design, synthesis, and bioevaluation of 1h-pyrrolo[3,2-c]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities.

A new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 µM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 µM and 5 µM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 µM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 µM, 0.24 µM, and 0.36 µM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnß349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski's rule of five.

Exosomes from human urine-derived stem cells carry NRF1 to alleviate bladder fibrosis via regulating miR-301b-3p/TGFßR1 pathway.

Bladder outlet obstruction (BOO) is a common disease that always make the bladder develops from inflammation to fibrosis. This study was to investigate the effect of exosomes from human urine-derived stem cells (hUSCs) on bladder fibrosis after BOO and the underlying mechanism. The BOO mouse model was established by inserting a transurethral catheter, ligation of periurethral wire, and removal of the catheter. Mouse primary bladder smooth muscle cells (BSMCs) were isolated and treated with TGFß1 to mimic the bladder fibrosis model in vitro. Exosomes from hUSCs (hUSC-Exos) were injected into the bladder of BOO mice and added into the culture of TGFß1-induced BSMCs. The associated factors in mouse bladder tissues and BSMCs were detected. It was confirmed that the treatment of hUSC-Exos alleviated mouse bladder fibrosis and down-regulated fibrotic markers (a-SMA and collagen III) in bladder tissues and TGFß1-induced BSMCs. Overexpression of NRF1 in hUSC-Exos further improved the effects of hUSC-Exos on bladder fibrosis both in vivo and in vitro. TGFßR1 was a target of NRF1 and miR-301b-3p, and miR-301b-3p was a target of NRF1. It was next characterized that hUSC-Exos carried NRF1 to up-regulate miR-301B-3p, thereby reducing TGFßR1level. Our results illustrated that hUSC-Exos carried NRF1 to alleviate bladder fibrosis through regulating miR-301b-3p/TGFßR1 pathway.

Built environment and schizophrenia re-hospitalization risk in China: A cohort study.

BACKGROUND: Built environment exposure, characterized by ubiquity and changeability, has the potential to be the prospective target of public health policy. However, little research has been conducted to explore its impact on schizophrenia. This study aimed to investigate the association between built environmentand and schizophrenia rehospitalization by simultaneously considering substantial built environmental exposures. METHODS: We recruited eligible schizophrenia patients from Hefei, Anhui Province, China between 2017 and 2019. The main outcome for this study was the time interval until the first recurrent hospital admission occurred within one year after discharge. For each included subject, we estimated the built environment exposures, including population density, walkability, land use mix, green and blue space, public transportation accessibility and road traffic indicator. Lasso (Least Absolute Shrinkage and Selection Operator) analysis was used to select the key variables. Multivariable Cox regression model was applied to obtain hazard ratio (HR) and its corresponding 95% confidence intervals (CI). Further, we also evaluated the joint effects of built environment characteristics on rehospitalization for schizophrenia by Quantile g-computation model. RESULTS: A total of 1564 hospitalized schizophrenia patients were enrolled, with 347 patients (22.2%) had a rehospitalization within one-year after discharge. Multivariable Cox regression analysis indicated that the re-hospitalization rate for schizophrenia would be higher in areas with a high population density (HR: 1.10, 95%CI: 1.04-1.16). Nonetheless, compared to the reference (Q1), participants who lived in a neighborhood with the highest walkability and NDVI (Normalized Difference Vegetation Index) (Q4) had a 76% and 47% lower risk of re-hospitalization within one year (HR:0.24, 95%CI: 0.13-0.45; and 0.53, 95%CI:0.32-0.85), respectively. Moreover, quantile-based g-computation analyses revealed that increased walkability and green space significantly eliminated the adverse effects of population density increases on schizophrenia patients, with a HR ratio of 0.61 (95%CI:0.48,0.79) per one quartile change at the same time. CONCLUSION: Our study provides scientific evidence for the significant role of built environment in schizophrenia rehospitalization, suggesting that optimizing the built environment is required in designing and building a healthy city.

The impact of hazes on schizophrenia admissions and the synergistic effect with the combined atmospheric oxidation capacity in Hefei, China.

OBJECTIVES: Currently, most epidemiological studies on haze focus on respiratory diseases, cardiovascular diseases, etc. However, the relationship between haze and mental health has not been adequately explored. The purpose of this study was to investigate the influence of hazes on schizophrenia admissions and to further explore the potential interaction effect with the combined atmospheric oxidative indices (Ox and Oxwt). METHODS: We collected 5328 cases during the cold season from 2013 to 2015 in Hefei, China. By integrating the Poisson Generalized Linear Models with the Distributed Lag Non-linear Models, the association between haze and schizophrenia admissions was evaluated. The interaction between hazes and two combined oxidation indexes was tested by stratifying hazes and Ox, and Oxwt. RESULTS: Haze was found to be significantly linked to an increased risk of hospitalization for schizophrenia, and a 9-day lag effect on schizophrenia (lag 3-lag 11), with the largest effect on lag 6 (RR = 1.080, 95% confidence interval (CI): 1.046-1.116). Males, females, and <40 y (people under 40 years old) were sensitive to hazes. Furthermore, in the stratified analysis, we found synergies between two combined oxidation indexes and hazes. The interaction relative risk (IRR) and relative excess risk due to interaction (RERI) between Ox and hazes were 1.170 (95% CI: 1.071-1.277) and 0.149 (95% CI: 0.045-0.253), respectively. For Oxwt, the IRR and RERI were 1.179 (95% CI: 1.087-1.281) and 0.159 (95% CI: 0.056-0.263), respectively. It is noteworthy that this synergistic effect was significant in males and <40 y when examining the various subgroups in the interaction analysis. CONCLUSIONS: Our findings suggest that exposure to haze significantly increases the risk of hospitalization for schizophrenia. More significant public health benefits can be obtained by prioritizing haze periods with high combined atmospheric oxidation capacity.

The global burden of schizophrenia and the impact of urbanization during 1990-2019: An analysis of the global burden of disease study 2019.

BACKGROUND AND HYPOTHESIS: The burden of schizophrenia is increasing. Assessing the global distribution of schizophrenia and understanding the association between urbanization factors and schizophrenia are crucial. STUDY DESIGN: We conducted a two-stage analysis utilizing public data from GBD (global burden of disease) 2019 and the World Bank. First, the distribution of schizophrenia burden at the global, regional, and national levels as well as temporal trends was analyzed. Then, four composite indicators of urbanization (including demographic, spatial, economic, and eco-environment urbanization) were constructed from ten basic indicators. Panel data models were used to explore the relationship between urbanization indicators and the burden of schizophrenia. RESULTS: In 2019, there were 23.6 million people with schizophrenia, an increase of 65.85% from 1990, and the country with the largest ASDR (age-standardized disability adjusted life years rate) was the United States of America, followed by Australia, and New Zealand. Globally, the ASDR of schizophrenia rose with the sociodemographic index (SDI). In addition, six basic urbanization indicators including urban population proportion, employment in industry/services proportion, urban population density, the population proportion in the largest city, GDP, and PM2.5 concentration were positively associated with ASDR of schizophrenia, with the largest coefficients being urban population density. Overall, demographic, spatial, economic, and eco-environment urbanization all had positive effects on schizophrenia, and the estimated coefficients indicated that demographic urbanization was the most significant influence. CONCLUSIONS: This study provided a comprehensive description of the global burden of schizophrenia and explored urbanization as a factor contributing to the variation in the burden of schizophrenia, and highlighted policy priorities for schizophrenia prevention in the context of urbanization.

The modification of air particulate matter on the relationship between temperature and childhood asthma hospitalization: An exploration based on different interaction strategies.

The influence of temperature on childhood asthma was self-evident, yet the issue of whether the relationship will be synergized by air pollution remains unclear. The study aimed to investigate whether the relationship between short-term temperature exposure and childhood asthma hospitalization was modified by particulate matter (PM). Data on childhood asthma hospitalization, meteorological factors, and air pollutants during 2013-2016 in Hefei, China, were collected. First, a basic Poisson regression model combined with a distributed lag nonlinear model was used to assess the temperature-childhood asthma hospitalization relationship. Then, two interactive strategies were applied to explore the modification effect of PM on the temperature-childhood asthma hospitalization association. We found a greater effect of cold (5th percentile of temperature) on asthma during days with higher PM2.5 (RR: 2.16, 95% CI: 1.38, 3.38) or PM10 (RR: 1.87, 95% CI:1.20, 2.91) than that during days with lower PM2.5 (RR: 1.64, 95% CI: 1.06, 2.54) or PM10 (RR: 1.52, 95% CI: 0.98, 2.36). In addition, we observed a greater modification effect of PM2.5 on the cold-asthma association than did PM10, with a per 10 µg/m3 increase in PM2.5 and PM10 associated with increases of 0.065 and 0.025 for the RR corresponding to the 5th temperature percentile, respectively. For the temperature-related AF, moderate cold showed the largest change magnitude with the PM levels rising compared with other temperature ranges. For the subgroup, Females and those aged 6-18 years were more sensitive to the modification effect of PM2.5 or PM10 on the cold-asthma association. Our findings demonstrated that particulate matter could modify the associations between temperature and childhood asthma hospitalization.

Association between exposure to a mixture of metals, parabens, and phthalates and fractional exhaled nitric oxide: A population-based study in US adults.

The effects of environmental endocrine-disrupting chemicals (EDCs) (e.g., phthalates) on fractional exhaled nitric oxide (FeNO) in children have received much attention. However, few studies evaluated this relationship in adults, and the previous studies have considered only a unitary exposure or a set of similar exposures instead of mixed exposures, which contain complicated interactions. We aimed to evaluate simultaneously the relationship between three types of EDCs (six phthalate metabolites and two parabens in urine, two heavy metals in blood) and FeNO (as a continuous variable) in adults. Data of adults aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES, 2007-2012) were collected and analyzed. The generalized linear (GLM) regression model was used to explore the association of chemicals with FeNO. The combined effect of 10 chemicals on the overall association with FeNO was evaluated by the weighted quantile sum regression (WQS) model. In addition, The Bayesian kernel machine regression (BKMR) model was explored to investigate the interaction and joint effects of multiple chemicals with FeNO. Of the 3296 study participants ultimately included, among the GLMs, we found that mercury (Hg) (ß = 0.84, 95%CI:0.32-1.36, FDR = 0.01) and methyl paraben (MPB) (ß = 0.47, 95%CI:0.16-0.78, FDR = 0.015) were positively correlated with FeNO. In the WQS model, the combined effect of chemicals almost had a significantly positive association with FeNO and the top three contributors to the WQS index were Hg (40.2%), MECPP (22.1%), and MPB (19.3%). BKMR analysis showed that there may be interactions between MPB and Hg, Mono (carboxyoctyl) phthalate (MCOP) and Hg and the overall effect of the mixture showed a positive correlation with FeNO. In conclusion, our study strengthens the credibility of the view that EDCs can affect respiratory health. In the future, we should be particularly careful with products containing Hg, MECPP, MPB, and MEHP for the prevention of respiratory diseases.

Seasonal characteristics of temperature variability impacts on childhood asthma hospitalization in Hefei, China: Does PM2.5 modify the association?

OBJECTIVES: Evidence of childhood asthma hospitalizations associated with temperature variability (TV) and the attributable risk are limited in China. We aim to use a comprehensive index that reflected both intra- and inter-day TV to assess the TV-childhood asthma relationship and disease burden, further to identify seasonality vulnerable populations, and to explore the effect modification of PM2.5. METHODS: A quasi-distributed lagged nonlinear model (DLNM) combined with a linear threshold function was applied to estimate the association between TV and childhood asthma hospitalizations during 2013-2016 in Hefei, China. Subgroup analysis was conducted by age and sex. Disease burden is reflected by the attributable fraction and attributable number. Besides, modifications of PM2.5 were tested by introducing the cross-basis of TV and binary PM2.5 as an interaction term. RESULTS: The risk estimates peaked at TV0-3 and TV0-4 in the cool and the warm season separately, with RR of 1.051 (95%CI: 1.021-1.081) and 1.072 (95%CI: 1.008-1.125), and the effects lasted longer in the cool season. The school-age children in the warm season and all subgroups except pre-school children in the cool season were vulnerable to TV. It is estimated that the disease burden related to TV account for 6.2% (95% CI: 2.7%-9.4%) and 4% (95% CI: 0.6%-7.1%) during the cool and warm seasons in TV0-3. In addition, the risks of TV were higher under the high PM2.5 level compared with the low PM2.5 level in the cool season, although no significant differences between them. CONCLUSIONS: TV exposure significantly increases the risk and disease burden of childhood asthma hospitalizations, especially in the cool season. More medical resources should be allocated to school-age children. Giving priority to pay attention to TV in the cool season in practice could obtain the greatest public health benefits and those days with high TV and high PM2.5 need more attention.

Association between sequential extreme precipitation-heatwaves events and hospitalizations for schizophrenia: The damage amplification effects of sequential extremes.

OBJECTIVES: In the context of frequent global extreme weather events, there are few studies on the effects of sequential extreme precipitation (EP) and heatwaves (HW) events on schizophrenia. We aimed to quantify the effects of the events on hospitalizations for schizophrenia and compare them with EP and HW alone to explore the amplification effect of successive extremes on health loss. METHODS: A time-series Poisson regression model combined with a distributed lag non-linear model was applied to estimate the association between sequential EP and HW events (EP-HW) and schizophrenia hospitalizations. The effects of EP-HW with different intervals and intensities on the admission of schizophrenia were compared. In addition, we calculated the mean attributable fraction (AF) and attributable numbers (AN) per exposure of extreme events to reflect the amplification effect of sequential extreme events on health hazards compared with individual extreme events. RESULTS: EP-HW increased the risk of hospitalization for schizophrenia, with significant effects lasting from lag0 (RR and 95% CI: 1.150 (1.041-1.271)) to lag11 (1.046 (1.000-1.094)). Significant associations were found in the subgroups of male, female, married people, and those aged≥ 40 years old. Shorter-interval (0-3days) or higher-intensity EP-HW (both precipitation ≥ P97.5 and mean temperature ≥ P97.5) had a longer lag effect compared to EP-HW with longer intervals or lower intensity. We found that the mean AF and AN caused by each exposure to EP-HW (AF: 0.074% (0.015%-0.123%); AN: 4.284 (0.862-7.118)) were higher than those induced by each exposure to HW occurring alone (AF:0.032% (0.004%-0.058%); AN:1.845 (0.220-3.329)). CONCLUSIONS: Sequential extreme precipitation-heatwaves events significantly increase the risk of hospitalizations for schizophrenia, with greater impact and disease burden than independently occurring extremes. The impact of consecutive extremes is supposed to be considered in local sector early warning systems for comprehensive public health decision-making.

Is higher ambient temperature associated with acute appendicitis hospitalizations? A case-crossover study in Tongling, China.

Existing studies suggested that ambient temperature may affect the attack of acute appendicitis. However, the identification of the quantitative effect and vulnerable populations are still unknown. The purposes of this study were to quantify the impact of daily mean temperature on the hospitalization of acute appendicitis and clarify vulnerable groups, further guide targeted prevention of acute appendicitis in Tongling. Daily data of cases and meteorological factors were collected in Tongling, China, during 2015-2019. Time stratified case-crossover design and conditional logistic regression model were used to evaluate the odds ratio (OR) of ambient temperature on hospitalizations for acute appendicitis. Stratified analyses were performed by sex, age, and marital status. The odds ratio (OR) of hospitalizations for acute appendicitis increased by 1.6% for per 1 ℃ rise in mean temperature at lag3[OR = 1.016, 95% confidence interval (CI): 1.004-1.028]. In addition, our results suggest it is in the women that increased ambient temperature is more likely to contribute to acute appendicitis hospitalizations; we also found that the married are more susceptible to acute appendicitis hospitalizations due to increased ambient temperature than the unmarried; people in the 21-40 years old are more sensitive to ambient temperature than other age groups. The significant results of the differences between the subgroups indicate that the differences between the groups are all statistically significant. The elevated ambient temperatures increased the risk of hospitalizations for acute appendicitis. The females, married people, and patients aged 21-40 years old were more susceptible to ambient temperature. These findings suggest that more attention should be paid to the impact of high ambient temperature on acute appendicitis in the future.

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.

Immunogenic cell death: A link between gut microbiota and anticancer effects.

For years, intratumor injection of bacteria have been purported to be capable of an anticancer effect. However, these bacteria are mostly pathogenic including attenuated and genetically engineered bacteria. The gut microbiota has been discovered to play a key role in immunotherapy. Many remarkable advances have been made in characterizing the immune responses to gut microbiota. Interestingly, accumulating evidence has demonstrated that immunogenic cell death (ICD) plays a key role in the anticancer effect of chemotherapy, radiotherapy, photodynamic therapy and oncolytic virotherapy. Most interestingly, the gut microbiota may impact the ICD process. Given the importance of the gut microbiota in immune responses, cancer progression and the anticancer efficacy of drugs with immune effects. We propose a mechanism in which ICD may be the possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects. However, the study of the relationship between the gut microbiota and ICD is limited, and it is still not clear how gut microbiota affect the ICD pathway. In this review, we discuss the mechanism by which the gut microbiota affects ICD, and suggest that ICD may be a possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects.

lncRNA ROR Promotes Gastric Cancer Drug Resistance.

OBJECTIVE: Gastric cancer is one of the most common malignant tumors worldwide, and for resectable tumors, the most effective treatment is surgery with chemotherapy in neoadjuvant or adjuvant setting. However, the majority of patients fail to achieve the ideal initial response and/or develop resistance to chemotherapy. It was reported that long noncoding RNA regulator of reprogramming (ROR) is highly associated with the progression of gastric cancer. However, the role ROR in multidrug resistance (MDR) remains unclear. METHODS: The messenger RNA levels of 63 specimens of patients with gastric cancer were determined by real-time polymerase chain reaction analysis and were correlated with drug resistance and survival of patients. To determine the cellular functions of ROR, we generated gastric cancer MDR cells. The effect of ROR depletion on multidrug resistance-associated protein 1 (MRP1) expression and cell apoptosis were examined by immunoblotting analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry. RESULTS: We found that ROR expression levels are positively associated with increased MDR and poor prognosis of patients with gastric cancer. Regulator of reprogramming expression is increased in gastric cancer cells resistant to adriamycin (ADR) and vincristine (VCR). Depletion of ROR reduced MRP1 expression and increased apoptosis of drug-resistant gastric cancer cells in response to ADR and VCR treatment. CONCLUSIONS: We demonstrated that ROR expression promotes MRP1 expression and MDR of gastric cancer cells and is correlated with increased MDR and poor prognosis of patients with gastric cancer. Our finding highlighted the potential of targeting ROR to improve the efficacy of chemotherapy.

Up-regulation of microRNA-200c-3p inhibits invasion and migration of renal cell carcinoma cells via the SOX2-dependent Wnt/ß-catenin signaling pathway.

BACKGROUND: MicroRNA-200c-3p (miR-200c-3p) has been revealed to be related to renal cell carcinoma (RCC) progression, while the inner mechanisms remain unknown. In our study, we intend to unearth the capability of miR-200c-3p in RCC development via the Wnt/ß-catenin signaling pathway through binding to SOX2. METHODS: miR-200c-3p, SOX2, ß-catenin and GSK3ß expression in both tissues and cells of RCC were detected by RT-qPCR or western blot analysis. miR-200c-3p was restored or silenced to determine their biological functions of RCC cells. Expression of SOX2 and related proteins in the Wnt/ß-catenin signaling pathway were evaluated by RT-qPCR and western blot analysis. The effect of the combination of downregulated miR-200c-3p and downregulated SOX2 on cell biological behavior change was also determined. RESULTS: Initially, we found that miR-200c-3p was declined while SOX2, ß-catenin and GSK3ß was elevated in RCC tissues and cells. A498 cells with the largest difference in miR-200c-3p expression and OS-RC-2 cells with the smallest difference were selected for subsequent experiments. Additionally, upregulated miR-200c-3p and downregulated SOX2 was determined to suppress proliferation, migration, invasion and induce apoptosis of RCC cells. Furthermore, miR-200c-3p inhibited SOX2 to inactivate the Wnt/ß-catenin signaling pathway. CONCLUSION: Collectively, this study highlights that upregulated miR-200c-3p inhibits expression of SOX2, thereby inhibiting development of RCC cells via modulating the Wnt/ß-catenin signaling pathway activation.

ERß modulates genistein's cisplatin-enhancing activities in breast cancer MDA-MB-231 cells via P53-independent pathway.

As one of the typical food-derived phytoestrogens, genistein (GEN) could bind to estrogen receptor (ER) and was reported to be closely related to breast cancer. Our former research showed that GEN interfered with the anti-tumor effects of cisplatin (CIS) in breast cancer MCF-7 (ERα+/ERß-) cells. However, it is not clear whether ER expression pattern affects GEN's modulation on CIS's activity. In the present study, breast cancer ERß knockdown (ERßKD) MDA-MB-231 (ERα-/ERß+) cell model was established via ERß RNAi lentivirus infection. The role of ERß expression in GEN's bioeffects on cells' response to CIS was investigated and was further double-checked by pathway-specific inhibitor PHTPP. Consistent results were harvested through cell viability analysis, cell cycle distribution flow cytometry, TUNEL staining, and expression detection of key biomarkers, Bax, Bcl-2, P21, P53, and cleaved caspase-3. Compared with the control group, PHTPP-treated or ERßKD cells exhibited higher sensitivity to both GEN and CIS treatment. GEN and CIS showed synergistic effects only in ERß-deficient cells. This effect mainly resulted in G2 phase arresting and apoptosis induction with the upregulation of P21 and Bax/Bcl-2 protein level. Besides, P53 expression was strikingly suppressed in ERß-deficient cells. This indicated ERß pathway deficiency might enhance GEN-CIS bioactivity via the downregulation of P53. In summary, our data imply that daily intake of GEN-rich diet could collaborate with CIS anti-tumor treatment in ERα-/ERß- breast cancer cases. ERß pathway might be one of the potential targets which elicit GEN's positive effects in ERα- breast cancer patients.

Association of VDR-FokI and VDBP-Thr420Lys polymorphisms with cervical spondylotic myelopathy: A case-control study in the population of China.

BACKGROUND: Cervical spondylotic myelopathy (CSM), a common degenerative disorder, is characterized by chronic progressive compression of the cervical spinal cord. The present case-control study aimed to explore the potential role of VDR-FokI and VDBP-Thr420Lys polymorphisms in the susceptibility to CSM in the Chinese population. METHODS: The study enrolled 318 CSM patients and 282 healthy individuals whose clinical data were retrospectively analyzed. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to genotype VDR-FokI and VDBP-Thr420Lys polymorphisms. The severity of CSM was assessed using the Japanese Orthopaedic Association (JOA) score with magnetic resonance imaging (MRI) of cervical vertebra. A nonconditional binary logistic regression model was conducted for assessing the risk factors of CSM. RESULTS: Patients in the CSM group had longer time duration to bend over desk working than the control group. The ff genotype and f allele frequency of VDR-FokI were elevated in CSM patients. Elevated Ff + ff genotype and f allele frequency of VDR-FokI might increase the risk of CSM. The VDR-FokI polymorphism was associated with nucleus pulposus capillary invasion, necrosis, hyaline degeneration and fibrosis, genesis and hyperplasia of cartilage-like cells, and fibrocyst in the fibrous ring. The VDR-FokI and VDBP-Thr420Lys genotypes conformed to Hardy-Weinberg equilibrium which showed that VDR-FokI and VDBP-Thr420Lys had group representation characteristics. CONCLUSION: Binary logistic regression analysis confirmed that VDR-FokI polymorphism and the time to bend over desk working were risk factors of CSM. Our results indicate that VDR-FokI polymorphism may be closely associated with the risk of CSM.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.