Fluvastatin prevents lung metastasis in triple-negative breast cancer by triggering autophagy via the RhoB/PI3K/mTOR pathway.

Triple-negative breast cancer is more common among younger than older women and is associated with the poorest survival outcomes of all breast cancer types. Fluvastatin inhibits tumour progression and induces the autophagy of breast cancer cells; however, the role of autophagy in fluvastatin-induced inhibition of breast cancer metastasis is unknown. Therefore, this study aimed to determine this mechanism. The effect of fluvastatin on human hormone receptor-negative breast cancer cells was evaluated in vitro via migration and wound healing assays, western blotting, and morphological measurements, as well as in vivo using a mouse xenograft model. Chloroquine, a prophylactic medication used to prevent malaria in humans was used as an autophagy inhibitor. We found that fluvastatin administration effectively prevented the migration/invasion of triple-negative breast cancer cells, an effect that was largely dependent on the induction of autophagy. Administration of the autophagy inhibitor chloroquine prevented the fluvastatin-induced suppression of lung metastasis in the nude mouse model. Furthermore, fluvastatin increased Ras homolog family member B (RhoB) expression, and the autophagy and anti-metastatic activity induced by fluvastatin were predominantly dependent on the regulation of RhoB through the protein kinase B-mammalian target of rapamycin (Akt-mTOR) signaling pathway. These results suggest that fluvastatin inhibits the metastasis of triple-negative breast cancer cells by modulating autophagy via the up regulation of RhoB through the AKT-mTOR signaling pathway. Fluvastatin may be a promising therapeutic option for patients with triple-negative breast cancer.

Combined effects of lipase and Lactiplantibacillus plantarum 1-24-LJ on physicochemical property, microbial succession and volatile compounds formation in fermented fish product.

BACKGROUND: Studies have shown that either the addition of starter culture or enzyme can improve fermentation in fish or other products. However, little research has been carried out on the effects of coupling starter cultures with lipase on the microbial community and product quality. Suanzhayu is a Chinese fermented fish product that mainly relies on spontaneous fermentation, resulting in an unstable flavor and quality. The present study investigated the impact of lipase and Lactiplantibacillus plantarum 1-24-LJ on the quality of Suanzhayu. RESULTS: Inoculation decreased pH and 2-thiobarbituric acid reactive substances (TBARS) values, and also helped the dominance of the strain in the ecosystem, whereas lipase addition raised TBARS values and had little effect on pH, water activity (aw ) and microbiota. The addition of lipase and/or Lpb. plantarum increased the content of alcohols, aldehydes, ketones, esters and umami amino acids. The co-additions with the most significant effect and the total contents of volatile compounds (VCs) and free amino acids (FAAs) were 1801.92 g per 100 g and 21 357.05 mg per 100 g, respectively. Former-Lactobacillus was negatively correlated with pH, aw and Prevotella, but positively with VCs (ethyl ester of heptanoic acid, ethyl ester of octanoic acid) and FAAs (Tyr, Phe). Furthermore, adding Lpb. plantarum 1-24-LJ alone or in combination with lipase shortened the fermentation process. CONCLUSION: The present study provides a recommended Suanzhayu process approach for improving product quality and flavor, as well as shortening fermentation time, by adding Lpb. plantarum 1-24-LJ with or without lipase. © 2023 Society of Chemical Industry.

Analysis of carotenoid profile changes and carotenogenic genes transcript levels in Rhodosporidium toruloides mutants from an optimized Agrobacterium tumefaciens-mediated transformation method.

Rhodosporidium toruloides has been reported as a potential biotechnological microorganism to produce carotenoids. The most commonly used molecular and genetic manipulation methods based on Agrobacterium-mediated transformation (ATMT). However, this method was of relatively lower transformation efficiency. In this study, we optimized the ATMT method for R. toruloides on account of the promoter on T-DNA, the ratio of A. tumefaciens to R. toruloides NP11, acetosyringone concentration, cocultivation temperature and time, and a transformation efficiency of 2,369 cells per 105 recipient cells was obtained and was 24 times as that of the previous report. With this optimized method, four redder mutants and four yellower mutants were selected out with torularhodin and ß-carotene production preference, respectively. The highest torularhodin production was 1,638.15 µg/g dry cell weight in A1-13. The yellower mutants were found to divert the metabolic flux from torularhodin and torulene to γ-carotene and ß-carotene, and the proportion of γ-carotene and ß-carotene were all over 92%. TAIL-PCR was carried out to found T-DNA insertion in these mutants, and insertion hotspot was found. RT-qPCR results showed that CTA1 genes in these mutants were closely related to the synthesis of total carotenoids, especially torularhodin, and was a potenial metabolic engineering site in the future.

The relationship between post-diagnostic statin usage and breast cancer prognosis varies by hormone receptor phenotype: a systemic review and meta-analysis.

BACKGROUND: Preclinical studies and epidemiologic data had indicated statins had antineoplastic properties in breast cancer patients. Since breast cancer treatment is based on its phenotype, it is important to explore influence of post-diagnosis statin usage on breast cancer patients with different phenotypes. METHODS: We searched the related studies between inception and August, 2019 from MEDLINE and EMBASE. A total of 7 studies with 24,541 patients were identified. Stata/SE 15.0 and Review Manager 5.3 were used to analyze data. Inconsistency index was used to estimate heterogeneity. Begg's and Egger's regression test was used to examine publication bias. RESULTS: Overall post-diagnostic statin use was associated with improved recurrence free survival (recurrence free survival (RFS); hazard ratio (HR) 0.74; 95% confidential interval (95% CI) 0.57-0.98), overall survival (overall survival (OS); HR 0.53; 95% CI 0.31-0.91) and cancer-specific survival (cancer-specific survival (CSS); and HR 0.61; 95% CI 0.41-0.91). In hormone receptor positive patients, statin use was associated with improved CSS (HR 0.74, 95% CI 0.65-0.84). No protective effect was found in either OS or RFS. In hormone receptor negative patients, statin was associated with reduced OS (HR 2.19, 95% CI 1.34-3.59) and reduced RFS, but without statistical significance. CONCLUSIONS: Post-diagnostic statin use was associated with improved RFS, OS and CSS in breast cancer patients. Subgroup analysis indicted that the benefits of statin usage varied from hormone receptor phenotype type. Prospective randomized trial with patients of different hormone receptor types might be needed to help identify which subtype of breast cancer patients would benefit from post-diagnostic statin usage.

Mechanisms of protection against diabetes-induced impairment of endothelium-dependent vasorelaxation by Tanshinone IIA.

BACKGROUND: Impairment of endothelium-dependent vasorelaxation has been suggested to play a principle role of endothelial dysfunction in the development of cardiovascular complications of diabetes. Recent studies have demonstrated a protective effect of Tanshinone IIA (Tan) on endothelial nitric oxide synthase (eNOS)-NO pathway. However, its role in endothelium-dependent vasorelaxation in diabetes and precise mechanisms remain elusive. METHODS: Sprague-Dawley rats were injected intraperitoneally with streptozotocin (STZ) to induce diabetes and then administered orally with Tan for 2 weeks. For the in vitro study, human umbilical vein endothelial cells (HUVECs) were co-incubated with Tan and high glucose for 48 h. RESULTS: eNOS expression and NO generation were significantly decreased in diabetic rats. These decreases were accompanied by an impairment of endothelium-dependent relaxation. Administration of Tan ameliorated the aberrant changes in eNOS expression, NO generation and endothelium-dependent relaxation in diabetic rats. Expectedly, Tan also inhibited high glucose-induced decrease of eNOS expression and NO generation in a concentration-dependent manner in HUVECs. Mechanistically, high glucose attenuated eNOS transcriptional activity through inhibiting the binding activity and nuclear translocation of Sp1 and AP-1. However, Tan did not prevent these effects. At post-transcriptional level, Tan increased eNOS expression and activity through multiple mechanisms including regulation of mRNA and protein half-life, degradation, coupling and serine 1177 phosphorylation. Rather than affecting protein phosphatase 2A (PP2A) expression and activity, Tan markedly inhibited the translocation of PP2A-A from cytosol to membrane and subsequently impaired PP2A-A/eNOS interaction, leading to prevent eNOS dephosphorylation. All these alterations underlie the protective role of Tan on eNOS expression following high glucose stimulation. CONCLUSIONS: Our data demonstrate that high glucose decreases eNOS expression initiating at a transcriptional level, whereas Tan prevents such effect through multiple ways of post-transcriptional mechanism. GENERAL SIGNIFICANCE: Our work provided novel mechanisms for Tan in regulating vasorelaxation and may help to better understand the cardiovascular protective action of Tan.

Inhibition of autophagy enhances the cytotoxic effect of PA-MSHA in breast cancer.

BACKGROUND: PA-MSHA, a genetically engineered Pseudomonas aeruginosa (PA) strain, is currently under investigation as a new anti-cancer drug. It can induce cell cycle arrest and apoptosis in different human cancer cells, including hormone receptor negative breast cancer cells. However, the underlying mechanism of tumor lethality mediated by PA-MSHA remains to be fully investigated. METHODS: The effect of PA-MSHA on human hormone receptor negative breast cancer cells was analyzed by morphological measurement, western blot, cell proliferation assay and mouse xenograft model. RESULTS: PA-MSHA was found to induce endoplasmic reticulum (ER) stress in breast cancer cell lines through the IRE1 signaling pathway. Inhibiting autophagy potentiated the cytotoxic effect of PA-MSHA while treating breast cancer cell lines. In mouse xenograft model, PA-MSHA produced more pronounced tumor suppression in mice inoculated with IRE1 gene knockdown. MDA-MB-231HM cells. CONCLUSIONS: These findings demonstrated inhibiting autophagy together with PA-MSHA might be a promising therapeutic strategy in treating hormone receptor negative breast cancer cells.

CircHIRA sponges miR-196b-5p to promote porcine early embryonic development.

Circular RNA (circRNA) is abundantly expressed in preimplantation embryos and embryonic stem cells in mice and humans. However, its function and mechanism in early development of mammalian embryos remain unclear. Here, we showed that circHIRA mediated miR-196b-5p to regulate porcine early embryonic development. We verified the circular feature of circHIRA by sanger sequencing, and proved the authenticity of circHIRA by enzyme digestion test. HIRA and circHIRA were expressed in porcine early embryos, and its expression levels significantly increased from 8-cell stage onwards and reached the maximum at the blastocyst stage. Functional studies revealed that circHIRA knockdown not only significantly reduced the developmental efficiency of embryos from 8-cell stage to blastocyst stage, but also impaired the blastocyst quality. Mechanistically, integrated analysis of miRNA prediction and gene expression showed that circHIRA knockdown significantly increased the expression of miR-196b-5p in porcine early embryos. Furthermore, miR-196b-5p inhibitor injection could rescue the early development of circHIRA knockdown embryos. Taken together, the findings reveal that circHIRA regulates porcine early embryonic development via inhibiting the expression of miR-196b-5p.

Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer.

Background: Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. Materials and methods: A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. Results: The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. Conclusion: A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.

Imaging diagnosis and efficacy monitoring by [89Zr]Zr-DFO-KN035 immunoPET in patients with PD-L1-positive solid malignancies.

Rationale: Although programmed death-ligand 1 (PD-L1) inhibitors have achieved efficacy in cancer therapy, their response rate is low. Differences in the prognosis of patients with cancer under anti-PD-L1 treatment are related to the PD-L1 level in tumors. Accurate PD-L1 detection can optimize the accuracy of tumor immunotherapy and avoid ineffective clinical diagnosis and treatments. Methods: We investigated the imaging efficiency and therapy monitoring capacity of [89Zr]Zr-DFO-KN035 immunoPET for tumors. We labeled the monodomain anti-PD-L1 antibody KN035 with the radionuclide zirconium-89 and used this tracer for PET imaging. [89Zr]Zr-DFO-KN035 uptakes in patients with PD-L1-positive tumors, including primary and metastatic tumors, as well as in normal tissues, were comparatively assessed by using positron emission tomography/computed tomography imaging. Results: In PD-L1-positive patients, [89Zr]Zr-DFO-KN035 was sensitive in tumor-targeting imaging and could detect multiple metastatic foci, including multiple bone metastases (tumor-to-muscle ratios of 7.102 and 6.118 at 55 and 120 h, respectively) and lymph-node metastases (tumor-to-muscle ratios of 11.346 and 6.542 at 55 and 120 h, respectively). The needed radioactive dose of [89Zr]Zr-DFO-KN035 (55.5-92.5 MBq) used in this study was considerably lower than that of [18F]FDG (370-555 MBq). [89Zr]Zr-DFO-KN035 monitored and predicted the site of adverse reactions in antitumor immunotherapy. Moreover, after antitumor treatment, [89Zr]Zr-DFO-KN035 enabled observational imaging for therapeutic efficacy evaluation, which can help predict patient prognosis. Conclusion: [89Zr]Zr-DFO-KN035 can be used for the diagnosis and therapy monitoring of PD-L1-positive tumors and provide noninvasive and comprehensive observations for tumor diagnostic imaging, prognosis prediction, and efficacy evaluation.

Assessment of the impact of climate change on endangered conifer tree species by considering climate and soil dual suitability and interspecific competition.

Climate change results in the habitat loss of many conifer tree species and jeopardizes species biodiversity and forest ecological functions. Delineating suitable habitats for tree species via climate niche model (CNM) is widely used to predict the impact of climate change and develop conservation and management strategies. However, the robustness of CNM is broadly debated as it usually does not consider soil and competition factors. Here we developed a new approach to combine soil variables with CNM and evaluate interspecific competition potential in the niche overlapping areas. We used an endangered conifer species - Chamaecyparis formosensis (red cypress) - as a case study to predict the impact of climate change. We developed a novel approach to integrate the climate niche model and soil niche model predictions and considered interspecific competition to predict the impacts of climate change on tree species. Our results show that the suitable habitat for red cypress would decrease significantly in the future with an additional threat from the competition of an oak tree species. Our approach and results may represent significant implications in making conservation strategies and evaluating the impacts of climate change, and providing the direction of the refinement of the ecological niche model.

Current evidence on the relationship between CYP1B1 polymorphisms and lung cancer risk: a meta-analysis.

The association between single-nucleotide polymorphisms (SNPs) of the CYP1B1 gene and lung cancer risk is still ambiguous. In this meta analysis, we assessed 10 case-control studies included 7,067 cases and 9,374 controls of the association between CYP1B1 SNPs of Leu432Val (rs1056836, 432C>G), Asn453Ser (rs1800440, 453A>G), Ala119Ser (rs1056827, 119G>T), Arg48Gly (rs10012, 48C>G) and the risk of lung cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of association between the polymorphism and lung cancer risk under codominant model, dominant model and additive model respectively. Although there were limitations, this meta analysis indicated that individuals with 432GG genotype had a 39.7% higher risk of having lung cancer than those with the 432CC genotype, and individuals with the 432G allele had a 26.3% increased risk as well. An increased risk of lung cancer of 2.13 fold was observed in individuals with 119TT genotype. For Arg48Gly, individuals with 48GG genotype had a significantly increased risk of lung cancer compared with individuals with 48CC (OR 3.859; 95% CI 2.536-5.87). Elevated risk of lung cancer were observed in dominant model (OR 2.115; 95% CI 1.653-2.705) as well. The risk of lung cancer was elevated as the frequency of G allele increased in additive model (P = 0.000). For individuals with the polymorphism at codon 453, no evidence of such association was observed. Furthermore, a possible association between the CYP1B1 polymorphism at codon 432 and the lung cancer could be detected in individuals of Caucasian origin, while a negative association was suggested in Asians and African-Americans. An increased lung cancer risk was also found in women with polymorphism at codon 453. These results are supportive for the hypothesis that the CYP1B1 432GG, 119TT and 48GG genotypes are low-penetrance risk factors for developing lung cancer, and further studies are needed to validate these associations.

Current evidence on the relationship between polymorphisms in the COX-2 gene and breast cancer risk: a meta-analysis.

The association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene and breast cancer risk is still ambiguous. We here try to derive a more precise estimation of the relationship by performing a meta-analysis based on currently available evidence from literature. More than 15 SNPs have been studied, and the most studied genetic variants were rs5275, rs5277, and rs20417. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between each polymorphism and breast cancer risk under the codominant model, dominant model, and recessive model, respectively (nine studies with 6,968 cases and 9,126 controls for rs5275; three studies with 2,901 cases and 3,463 controls for rs20417; two studies with 5,551 cases and 6,208 controls for rs5277). No overall significant associations were observed in single-locus analysis between the three polymorphisms of COX-2 and breast cancer risk, though a borderline significant increased risk of breast cancer was detected with rs5277 in a recessive model (OR: 1.217, 95% CI: 0.958-1.547, P = 0.107). The results were not changed when studies were stratified by ethnicity. In conclusion, the present meta-analysis suggests that none of the most studied three SNPs (rs5275, rs20417, and rs5277) in the COX-2 gene is a conspicuous low-penetrant risk factor for developing breast cancer. There is a need for further large studies into the role of these polymorphisms (especially rs5277) and other potentially functional polymorphisms/haplotypes in the COX-2 gene as breast cancer risk modifiers.

Effects of flavourzyme addition on physicochemical properties, volatile compound components and microbial community succession of Suanzhayu.

Flavourzyme is known to promote protein decomposition, resulting in more peptides and amino acids which can improve the quality of fermented foods. In this study, the effects of flavourzyme addition on the fermentation of Suanzhayu fish were investigated. The results showed that the addition of 50 U/g flavourzyme reduced the water activity (aw) of products and promoted the release of trichloroacetic acid (TCA)-soluble peptides and free amino acids (FAAs). Thus, the stability of the product was improved and its nutritional value was increased. In addition, with the addition of flavourzyme, Lactobacillus and Saccharomyces more quickly became the dominant genera in the fermentation. Furthermore, the formation of alcohols, aldehydes, and esters was promoted in flavourzyme addition group. Redundant analysis (RDA) indicated that Lactobacillus and Lactococcus play important roles in the formation of flavors, especially for the characteristic flavors of Suanzhayu. Flavourzyme addition may be a novel method to greatly improve the properties of Suanzhayu and shorten the fermentation time.

Relationships between bacterial community and metabolites of sour meat at different temperature during the fermentation.

This study was designed to explore the temperature effects on bacterial communities and metabolites, as well as their relationships during the fermentation of sour meat, a traditional fermented meat product in the ethnic minority regions of China. Results showed that reduction of pH and increase of lactic acid and free amino acid contents occurred (p < 0.05) as the fermentation temperature and time increased, and the tendency was more apparent at higher temperature. During the fermentation, Lactobacillus gradually replaced other genera, and higher the temperature, more rapid was the process. Both the number and amount of volatile organic compounds increased at higher temperatures. Hexanal, benzaldehyde, nonanal, (E,E)-2,4-decadienal, 1-octen-3-ol and octanal were identified as the key volatile organic compounds produced by Lactobacillus in sour meat as main contributors to odor as confirmed by variable importance in the projection analysis. Redundancy analysis and Pearson correlation showed positive correlation between Lactobacillus and desired product characteristics, such as higher content of lactic acid, free amino acids, volatile organic compounds, and lower pH and water activity values, which may represent a better quality and longer shelf life after fermentation at higher temperature. Therefore fermentation at 20 °C and 25 °C are proposed as optimum temperatures for sour meat production.

MicroRNA-142-3p Promotes Cellular Invasion of Colorectal Cancer Cells by Activation of RAC1.

BACKGROUND: Colorectal cancer has been proved more difficult to treat owing to potently malignant metastasis. The present study was aimed to explore the functional role of miR-142-3p in cell migration and invasion of colorectal cancer cells, as well as its underlying mechanism. MATERIALS AND METHODS: Expressions of miR-142-3p were analyzed in colorectal cancer tissues and cell lines. Ras-related C3 botulinum toxin substrate 1 (RAC1) was predicted as a target of miR-142-3p using software and network resources. SW480 cells were transfected with miR-142-3p expression plasmid and miR-142-3p silencer plasmid, and the expression of RAC1 and the cellular invasion were measured. RESULTS: In colorectal cancer cells transfected with miR-142-3p expression plasmid, RAC1 was specifically upregulated and invasiveness of cells was downregulated. Moreover, RAC1 was significantly associated with tumor stage ( P = .029) and tumor metastasis ( P = .012). CONCLUSION: miR-142-3p promotes cellular invasion in colorectal cancer cells by activating RAC1. Thereby, miR-142-3p is a potential candidate for molecular targeted therapy of colorectal cancer.

Combination of Multifunctional Nanoparticles and Interventional Techniques Makes Each Other Going Further in the Field of Cancer Treatment.

BACKGROUND: Nano-oncology and interventional oncology are both rapidly emerging fields in cancer therapies. Synergistic combination of the both fields offers drastic improvements in performance and efficacy of cancer killing agents. OBJECTIVE: This review is to overview the studies focusing on these two crossing fields and to give an overlook of their future development. Interventional techniques such as selective arterial catheterization, irreversible electroporation (IRE) and radiofrequency ablation (RFA) dramatically enhanced cancer targetability and anticancer efficacy of nanoparticles (NPs). Furthermore, synergistic effects were observed when using different interventional techniques together on NPs directed cancer treatments. On the other hand, NPs improved thermal ablation as well by fundamentally improving heating efficiency, facilitating heat triggered local drug delivery, and increasing cancer control in marginal peri-ablated zones and distant regions. CONCLUSION: Crossing applications of the both techniques such as percutaneous delivery of near infrared (NIR) into deep tumors by needle insertion and conformal thermal ablation are highly anticipated.

ACOT1 expression is associated with poor prognosis in gastric adenocarcinoma.

Acyl-CoA thioesterase 1 (ACOT1) is an important isoform of the ACOT family that catalyzes the reaction of fatty acyl-CoAs to CoA-SH and free fatty acids. Recent studies of gastrointestinal tumor metabolism suggest that there is abnormal metabolism of lipids and fatty acids during tumor progression. However, the function and contribution of ACOT1 in gastric cancer development are still poorly understood. In addition, GLI3 is a major transcription factor in the regulation of hedgehog signaling. GLI3 mutations induce glandular expansion and intestinal metaplasia in gastric cancer, which indicates a role for GLI3 in the preneoplastic process. Thus, we investigated the relationship between ACOT1 expression and GLI3 in gastric adenocarcinoma. A tissue microarray was constructed from 280 cases of gastric adenocarcinoma. The immunohistochemistry method was performed on tissue sections of 4 µm from each tissue microarray block. We found a significant correlation between ACOT1 expression and poor histologic grade, a lower T category, TNM stage, and increased GLI3 expression. In addition, the survival analysis revealed that the ACOT1-positive group had significantly decreased overall survival rates compared with the ACOT1-negative group. Furthermore, GLI3 expression had a significant positive correlation with ACOT1 expression in gastric adenocarcinoma cells. In summary, these findings demonstrate that increased expression of ACOT1 is correlated with pivotal clinicopathological parameters and poor prognosis in gastric adenocarcinoma through increased expression of the potential tumor-promoting protein GLI3.

DRR1 promotes glioblastoma cell invasion and epithelial-mesenchymal transition via regulating AKT activation.

Metastatic invasion is the primary cause of treatment failure for GBM. EMT is one of the most important events in the invasion of GBM; therefore, understanding the molecular mechanisms of EMT is crucial for the treatment of GBM. In this study, high expression of DRR1 was identified to correlate with a shorter median overall and relapse-free survival. Loss-of-function assays using shDRR1 weakened the invasive potential of the GBM cell lines through regulation of EMT-markers. The expressions of p-AKT were significantly decreased after DRR-depletion in SHG44 and U373 cells. Moreover, the invasion was inhibited by the AKT inhibitor, MK-2206. The expression of Vimentin, N-cadherin, MMP-7, snail and slug was significantly inhibited by MK-2206, while the expression of E-cadherin was upregulated. Our results provide the first evidence that DRR1 is involved in GBM invasion and progression possibly through the induction of EMT activation by phosphorylation of AKT.

Computed tomography-guided implantation of 125I seeds brachytherapy for recurrent multiple pulmonary oligometastases: initial experience and results.

PURPOSE: To retrospectively evaluate the efficacy and safety of computed tomography (CT)-guided percutaneous interstitial brachytherapy using 125I radioactive seeds for multiple pulmonary metastatic tumors. MATERIAL AND METHODS: Between September 2013 and December 2015, 22 patients with multiple pulmonary metastases, who after conventional chemotherapy and trans-arterial chemoembolization (TACE) therapy were considered unable to withstand stereotactic body radiation therapy (SBRT), received CT-guided 125I brachytherapy. Clinical data were studied retrospectively. A planning target volume of 90% (D90) was 120-160 Gy for 125I seeds with an activity of 25.9 MBq. A CT-based evaluation performed 1, 2, and 6 months' post-implantation enabled review of local control of tumors. RESULTS: Twenty-two patients with 65 pulmonary metastases successfully completed treatment. The mean value for D90 for implantation for 125I seeds was 132 Gy. Complete response (CR) + partial response (PR) was documented in 81.54%, 78.46%, and 78.46% of patients at 1, 2, and 6 months after implantation, respectively. Fourteen out of 22 patients had CR, 3 had PR, 2 had stable disease (SD), and 3 had progressive disease (PD). Most of the metastases (CR + PR + SD; 87.69% after 6 months) were controlled by implantation. CONCLUSIONS: CT-guided 125I brachytherapy is a safe and effective treatment for multiple pulmonary metastatic tumors, and can achieve good short-term local control, so long as the radiation dose is sufficient.

Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway.

In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE-/- mice by high fat and cholesterol diet (HFD) for 16 weeks. Rapamycin and 3-Methyladenine (MA) were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-ß-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression.