Attenuated Salmonella-delivered PD-1 siRNA enhances the antitumor effects of EZH2 inhibitors in colorectal cancer.

Immunotherapy has made significant progress in the treatment of malignant tumors. However, strategies to combine immunotherapy with anticancer drugs have attracted great attention due to the low response rate and unique toxicity profile of immunotherapies and the subsequent development of acquired resistance in some initial responders. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex,is highly expressed in a variety of tumors, and targeting EZH2 has become a new strategy for tumor therapy and drug combination. Here，we studied the effect of EZH2 inhibitors on colorectal cancer cells and their combination with immunotherapy. Our results demonstrated that EZH2 inhibitors can not only significantly inhibit the survival of colorectal cancer (CRC) cells and induce apoptosis, effectively inhibit cell invasion and migration, but also cause an increase in the expression of PD-L1 receptors on the cell surface. To determine the effect of EZH2 in combination with immunotherapy, we combine EZH2 inhibitors with PD-1 siRNA delivered by attenuated Salmonella. The vivo experiments have shown that the combination of EZH2 inhibitors and Salmonella-delivered PD-1 siRNA can further inhibit the development of CRC, trigger effective anti-tumor immunity, and improve therapeutic efficacy. Its underlying mechanisms mainly involve synergistic immunomodulation and apoptosis. This study suggests an emerging strategy based on a combination of EZH2 inhibitor and immunotherapy based on PD-1 inhibition.

MACC1 as a Potential Target for the Treatment and Prevention of Breast Cancer.

Metastasis associated in colon cancer 1 (MACC1) is an oncogene first identified in colon cancer. MACC1 has been identified in more than 20 different types of solid cancers. It is a key prognostic biomarker in clinical practice and is involved in recurrence, metastasis, and survival in many types of human cancers. MACC1 is significantly associated with the primary tumor, lymph node metastasis, distant metastasis classification, and clinical staging in patients with breast cancer (BC), and MACC1 overexpression is associated with reduced recurrence-free survival (RFS) and worse overall survival (OS) in patients. In addition, MACC1 is involved in BC progression in multiple ways. MACC1 promotes the immune escape of BC cells by affecting the infiltration of immune cells in the tumor microenvironment. Since the FGD5AS1/miR-497/MACC1 axis inhibits the apoptotic pathway in radiation-resistant BC tissues and cell lines, the MACC1 gene may play an important role in BC resistance to radiation. Since MACC1 is involved in numerous biological processes inside and outside BC cells, it is a key player in the tumor microenvironment. Focusing on MACC1, this article briefly discusses its biological effects, emphasizes its molecular mechanisms and pathways of action, and describes its use in the treatment and prevention of breast cancer.

Proximity ligation-transcription circuit-powered exponential amplifications for single-molecule monitoring of telomerase in human cells.

We develop a new strategy for single-molecule monitoring of telomerase based on proximity ligation-transcription circuit-powered exponential amplifications. This strategy exhibits high sensitivity with a detection limit of 0.1 aM for the synthetic telomerase product TPC4 in vitro and 1 HeLa cell in vivo. Moreover, it can screen potential inhibitors, discriminate telomerase from interferents, and distinguish cancer cells from normal cells.

Dimeric G-Quadruplex: An Efficient Probe for Ultrasensitive Fluorescence Detection of Mustard Compounds.

Some mustard compounds (mustards) are highly toxic chemical warfare agents. Some are explored as new anticancer drugs. Therefore, the fast, selective, and sensitive detection of mustards is extremely important for public security and cancer therapy. Mustards mostly target the N7 position on the guanine bases of DNA. The guanine-rich G-quadruplex DNA (G4) has been widely studied in the sensing area, and it was found that dimeric G4 (D-G4) could dramatically light up the fluorescence intensity of thioflavin T (ThT). Based on this, we used for the first time the D-G4 DNA as a selective probe for ultrasensitive fluorescence detection of nitrogen mustard (NM). When NM occupies the N7 on guanine, it can block the formation of the D-G4 structure due to the steric hindrance, and hence, it inhibits the combination of D-G4 with ThT, leading to a sharp decrease of fluorescence intensity. The proposed reaction mechanism is proved using ultraviolet-visible (UV-Vis) spectra, circular dichroism (CD) spectra, and polyacrylamide gel electrophoresis. Herein, the concentration of D-G4/ThT used is as low as 50 nM due to its highly fluorescent performance, enabling both high sensitivity and low cost. NM can be detected with a wide linear range from 10 to 2000 nM. The detection limit of NM reaches a surprisingly low concentration of 6 nM, which is 2 or 3 orders of magnitude lower than that of previously developed fluorescence methods for mustards and simulants.

Facile one-step synthesis of NIR-Responsive siRNA-Inorganic hybrid nanoplatform for imaging-guided photothermal and gene synergistic therapy.

Diagnosis-guided synergistic treatment based on innovative nanomaterials is of great significance for the development of anti-cancer therapies. However, the low delivery efficiency of therapeutic gene and the inability to trigger release on demand are still major obstacles impeding its wide application. Herein, we report an ultra-fast one-step method within 2 min to prepare a smart carrier, liposome-coated Prussian blue @ gold nano-flower, which is named LPAR after linking with tumor-targeting peptide. The versatile LPAR not only can respond to near-infrared (NIR) light, achieve the selective delivery and the controlled release of siRNA targeting the mutant gene of Kras at its codon-12 from Glycine (G) to Aspartic acid (D) (named as G12D mutant gene) in the malignant pancreatic tumors, but also efficiently convert the absorbed NIR light into the heat to realize gene-photothermal synergistic therapy both in vitro and in vivo. Theoretical simulation results reveal that the outstanding photothermal conversion efficiency of LPAR is mainly due to its higher electric field intensity and power density distributions. Furthermore, the LPAR possesses the capabilities for triple-modal imaging. Therefore, the developed NIR light-responsive LPAR has the potential to be served as a tumor-targeted nano-delivery system for imaging-guided synergistic therapy of cancers.

LncRNA MNX1-AS1 promotes ovarian cancer process via targeting the miR-744-5p/SOX12 axis.

PURPOSE: Ovarian cancer (OC) is the most common malignancy in women with high mortality. Increasing studies have revealed that long non-coding RNA (lncRNA) MNX1-AS1 has a promoting effect on various cancers. However, the mechanisms of MNX1-AS1 in OC are still unclear. Therefore, this study focused on exploring the mechanisms of MNX1-AS1 in OC. MATERIALS AND METHODS: The expression of SOX12 at the protein level was detected by western blot. Cell proliferation was detected by CCK8 assay and colony formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. Wound-healing assay, transwell assay and western blot were used to detect the ability of cell migration and invasion. The target binding was confirmed through the luciferase reporter assay. RESULTS: The expression of MNX1-AS1 was increased in OC tumor tissues and cells. Elevated MNX1-AS1 expression is associated with advanced stage and lower overall survival rate. Knockdown of MNX1-AS1 inhibited cell proliferation, migration and invasion, blocked cell cycle, and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. MNX1-AS1 was competitively binding with miR-744-5p, and its downstream target gene was SOX12. miR-544-5p expression was decreased, while SOX12 expression was increased in OC tumor tissues and cells. Overexpression of miR-744-5p inhibited cell proliferation, migration, invasion and promoted cell apoptosis in SKOV-3 and OVCAR-3 cells. CONCLUSION: MNX1-AS1 promoted the development of OC through miR-744-5p/SOX12 axis. This study revealed a novel mechanism of MNX1-AS1 in OC, which may provide a new treatment or scanning target for OC.

Correlation analysis of Ki67 and CK7 expression with clinical characteristics and prognosis of postoperative cervical adenocarcinoma patients.

BACKGROUND: The purpose of this study is to investigate the correlation between cytokeratin 7 (CK7) and marker of proliferation Ki67 protein expression and clinical characteristics and prognosis of patients with cervical adenocarcinoma after surgery. METHODS: A total of 126 patients with cervical adenocarcinoma treated by surgery in our hospital from June 2011 to September 2015 were enrolled in this study. Immunohistochemistry (IHC) was used to detect the expression of CK7 and Ki67 in 126 cases of cervical adenocarcinoma tissues. The chi-square (χ2) test was used to compare the relationship between the positive expression rate of CK7 or Ki67 and clinicopathological features. Kaplan-Meier method was used to analyze the survival of different protein expression groups and Cox proportional hazards regression model was used to analyze the risk factors affecting the prognosis. RESULTS: The positive rate of CK7 was correlated with muscle invasion, vascular invasion, differentiation, and lymph node metastasis (all P<0.05). The positive expression rate of Ki67 was related to the degree of myometrial invasion and International Federation of Gynecology and Obstetrics (FIGO) stage (both P<0.05). Both CK7 and Ki67 may be independent risk factors for the prognosis of patients with cervical adenocarcinoma after surgery (both P<0.05), and their high expression heralds worse prognosis. CONCLUSIONS: The CK7 and Ki67 proteins may be key regulatory factors in the development of cervical adenocarcinoma after surgery, and their overexpression may lead to worse prognosis. Both CK7 and Ki67 may provide new markers for prognosis evaluation of cervical adenocarcinoma.

In Situ Fluorogenic Reaction Generated via Ascorbic Acid for the Construction of Universal Sensing Platform.

A highly fluorescent emission reaction between terephthalic acid (PTA) and ascorbic acid (AA) via simple control of the reaction temperature was first revealed with the detailed formation mechanism and various characterizations including electron paramagnetic resonance and mass spectrometry. Based on the AA-responsive emission, the alkaline phosphatase (ALP) triggered the transformation of l-ascorbic acid 2-phosphate trisodium salt to AA was integrated with the present system for developing a sensitive, selective, and universal platform. The monitoring of the activity of ALP and the fabrication of ALP-based enzyme-linked immunoassay (ELISA) with carcinoembryonic antigen (CEA) as the model target was performed. The fluorescence intensity correlated well to the CEA concentration in the ranges of 0.25-30 ng/mL, with a detection limit of 0.08 ng/mL. Such a facile protocol based on the fluorescent reaction between PTA and AA without the assistance of catalysis of nanomaterials avoided the laborious synthesis procedure and provided a direct strategy for the early clinical diagnosis coupled with ALP-related catalysis.

MicroRNA-370-3p shuttled by breast cancer cell-derived extracellular vesicles induces fibroblast activation through the CYLD/Nf-κB axis to promote breast cancer progression.

Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell-to-cell communication. The present study focused on investigating whether EV-delivered miR-370-3p affects breast cancer. Initially, the miR-370-3p expression pattern was examined in the cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells-derived EVs. The relation of miR-370-3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF-7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro-inflammatory factors and nuclear factor-kappa B (NF-κB) signaling-related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell-derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR-370-3p from breast cancer cells to NFs, and EV-encapsulated miR-370-3p was also found to facilitate fibroblast activation. Mechanistically, EV-encapsulated miR-370-3p downregulated the expression of CYLD through binding to its 3'UTR and activated the NF-κB signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR-370-3p to aggravate breast cancer through downregulating CYLD expression and activating the NF-κB signaling pathway.

Effect of Rho GTPase activating protein 9 combined with preoperative ratio of platelet distribution width to platelet count on prognosis of patients with serous ovarian cancer.

BACKGROUND: This study aimed to investigate the relationship between Rho GTPase activating protein 9 (ARHGAP9) combined with preoperative ratio of platelet distribution width to platelet count (PDW/PLT) and patients prognosis with serous ovarian cancer. METHODS: The clinical data of 80 patients with serous ovarian cancer treated in Jiangsu Cancer Hospital from May 2011 to May 2016 were analyzed retrospectively. We verified ARHGAP9 expression in The Cancer Genome Atlas (TCGA) database, then detected messenger RNA (mRNA) expression encoding ARHGAP9 in ovarian cancer tissue samples using reverse transcription quantitative polymerase chain reaction (RT-qPCR). These patients were divided into an ARHGAP9 low-expression group and an ARHGAP9 high-expression group. The optimal critical value of PDW/PLT was determined by receiver operating characteristic (ROC) curve. The patients were divided into low PDW/PLT group and high PDW/PLT group. Kaplan-Meier method and log-rank test were used for univariate survival analysis, Cox regression method was used for multivariate analysis, and then a nomogram was constructed for internal verification. RESULTS: The ARHGAP9 protein was highly expressed both in TCGA serous ovarian cancer database and the serous ovarian cancer tumor tissues. There were significant differences in menstrual status, the International Federation of Gynecology and Obstetrics (FIGO) stage and grade between the ARHGAP9 low expression group and ARHGAP9 high expression group (all P<0.05). There were significant differences in FIGO stage, lymph node metastasis, and ascites between the low PDW/PLT group and high PDW/PLT group (all P<0.05). Finally, 80 patients were included, with a mortality rate of 45.0% and a survival rate of 55.0%; the median progression-free survival (PFS) was 19 months, and the median overall survival (OS) was 62.5 months. Cox multivariate analysis showed that PDW/PLT and ARHGAP9 were independent risk factors for tumor progression (P=0.026 and P=0.028, respectively). In the internal validation, the C-index of the nomogram was 0.6518 [95% confidence interval (CI): 0.5685 to 0.7352], and the prediction model had certain accuracy. CONCLUSIONS: ARHGAP9 and PDW/PLT Decrease can significantly prolong OS and PFS in serous ovarian cancer patients. Therefore, ARHGAP9 can be used as a new predictive biomarker and may be related to the immune infiltration of serous ovarian cancer.

LINC00641 inhibits the proliferation and invasion of ovarian cancer cells by targeting miR-320a.

BACKGROUND: Ovarian cancer is a common malignancy of the female reproductive system, with one of the highest mortality rates among all malignant tumors. However, the pathogenesis of ovarian cancer has not been fully elucidated. This study investigated the role and molecular mechanism of LINC00641 in the development and progression of ovarian cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of LINC00641 in ovarian cancer tissue and adjacent normal tissue. Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays were used to detect the effects of LINC00641 overexpression on the proliferation and migration of ovarian cancer cells. Bioinformatics analysis and luciferase reporter gene assay were employed to detect the binding of LINC00641 to the downstream target molecule, microRNA-320a (miR-320a). Western blotting was used to determine the effect of miR-320a overexpression on the expression of proliferation-related proteins [Ki-67 and proliferating cell nuclear antigen (PCNA)] and invasion-related proteins (E-cadherin, N-cadherin, and vimentin) in overexpressed LINC00641 cells. RESULTS: qRT-PCR results showed that LINC00641 was under-expressed in ovarian cancer tissue compared to adjacent tissue. Cell function experiments showed that the overexpression of LINC00641 could significantly inhibit the proliferation and migration of ovarian cancer cells. The luciferase reporter gene assay showed that LINC00641 could bind to miR-320a, and the overexpression of LINC00641 could markedly inhibit the expression of miR-320a in ovarian cancer cells. Overexpression of miR-320a could significantly block the inhibitory effect of LINC00641 on the proliferation and migration of ovarian cancer cells. CONCLUSIONS: As a tumor suppressor gene, LINC00641 can inhibit the proliferation and invasion of ovarian cancer cells by targeting miR-320a. The LINC00641/miR-320a axis may be a new target for the early diagnosis, treatment, or prognosis of ovarian cancer patients.

Aspergoterpenins A⁻D: Four New Antimicrobial Bisabolane Sesquiterpenoid Derivatives from an Endophytic Fungus Aspergillus versicolor.

Aspergoterpenins A⁻D (1⁻4), four new bisabolane sesquiterpenoid derivatives, were obtained from the endophytic fungus, Aspergillus versicolor, together with eight known compounds (5⁻12), and their structures were elucidated by a comprehensive analysis of their NMR (Nuclear Magnetic Resonance), MS (Mass Spectrum) and CD (Circular Dichroism) spectra. Aspergoterpenin A (1) was the first example with a characteristic ketal bridged-ring part in the degraded natural bisabolane-type sesquiterpene structures. The compounds 1⁻12 displayed no significant activities against four cancer cell lines (A549, Caski, HepG2 and MCF-7). Further, the antimicrobial activities to Erwinia carotovora sub sp. Carotovora were evaluated, and the results showed that compounds 1⁻12 displayed antimicrobial activities with MIC values ranging from 15.2 to 85.2 µg/mL.

Age is associated with prognosis in serous ovarian carcinoma.

PURPOSE: The survival duration of elderly patients with epithelial ovarian carcinoma is shorter than that of their younger counterparts. This variation in survival duration is likely attributed to differences in the distribution of histological type or grade, International Federation of Gynecology and Obstetrics (FIGO) staging, and undertreatment, but this observation remains controversial. This study aimed to investigate the biological factors other than selection bias associated with the decreased survival of elderly patients with ovarian carcinoma. METHODS: A total of 314 serous ovarian cancer (SOC) patients from Jiangsu Institute of Cancer Research (JICR, PRC) between 2002 and 2012 were retrospectively analyzed, and 774 cases from MD Anderson Cancer Center (MDACC, USA) between 1992 and 2012 were used for validation. The 8-hydroxy-2'-deoxyguanine (8-OHdG) concentration in leukocyte DNA was evaluated by using commercially available enzyme-linked immunosorbent assay kits, and tissue expression was assayed through immunohistochemistry. The associations between survival durations and covariates were assessed by using a Cox proportional hazards model and by conducting a log-rank test. RESULTS: Advanced age ≥ 65 years was correlated with high histological grade (p = 0.02), performance status (p = 0.03), primary treatment (p = 0.00), and suboptimal surgery outcome (p = 0.04) in SOC patients from JICR. Age, FIGO stage, histological grade, and optimal surgery were independently associated with the progression-free survival (PFS; p = 0.03, p = 0.03, p = 0.02, and p = 0.04, respectively) and overall survival (OS; p = 0.02, p = 0.04, p = 0.02, and p = 0.02, respectively) of the SOC patients from JICR. The 8-OHdG concentration in the leukocyte DNA was higher in the elderly patients than in the younger cases. The high 8-OHdG concentration in the leukocyte DNA indicated poorer median OS (30.0 months, confidence interval [CI]: 23.5-36.5 vs. 42.8 months, [CI] 38.3-47.2) and PFS (14.6 months, [CI] 11.9-17.2 vs. 18.9 months, [CI] 14.4-23.4) than those of their corresponding counterparts in the SOC patients who achieved a clinical complete response from primary treatment. CONCLUSIONS: Compared with younger cases, elderly patients with SOC were commonly characterized by high tumor grade, poor performance status, and undertreatment. High 8-OHdG concentration in leukocyte DNA was associated with advanced age and poor prognosis in SOC patients.

The number of cycles of neoadjuvant chemotherapy is associated with prognosis of stage IIIc-IV high-grade serous ovarian cancer.

OBJECTIVE: No consensus exists on the number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced stage epithelial ovarian cancer. The present study aims to explore the optimal number of cycles of neoadjuvant chemotherapy (NAC) and post-operation chemotherapy to treat the International Federation of Gynecology and Obstetrics stage IIIc-IV high-grade serous ovarian cancer (HG-SOC). MATERIALS AND METHODS: A total of 129 IIIc-IV stage HG-SOC cases were retrospectively analyzed. Cases were comprised of patients who underwent NAC followed by IDS and who achieved clinical complete response (CCR) at the end of primary therapy. Patients were recruited from the Jiangsu Institute of Cancer Research between 1993 and 2013. Optimal IDS-associated factors were explored with logistic regression. The association between progression-free survival (PFS), overall survival (OS) duration, and covariates was assessed by Cox proportional hazards model and log-rank test. RESULTS: The median number of NAC cycle was 3 (range 1-8). CA-125 decreasing kinetics (p = 0.01) was independently associated with optimal IDS. CA-125 decreasing kinetics, optimal IDS, and NAC cycles was independently associated with OS (p < 0.01, p < 0.01, p = 0.03, respectively) and PFS (p < 0.01, p < 0.01, p = 0.04, respectively). The PFS of patients who underwent ≥5 NAC cycles was shorter than those of patients who underwent <5 NAC cycles (12.3 versus 17.2 months). The PFS and OS of patients who underwent <5 cycles of adjuvant chemotherapy post-IDS were shorter than those of patients who underwent ≥5 cycles (14.2 and 20.3 versus 21.2 and 28.8 months). CONCLUSION: NAC cycles, CA-125 decreasing kinetics, and optimal debulking are independently associated with the prognosis of patients with advanced stage HG-SOC who underwent NAC/IDS and achieved CCR. The number of administered NAC cycles should not exceed 4.

Ascites regression following neoadjuvant chemotherapy in prediction of treatment outcome among stage IIIc to IV high-grade serous ovarian cancer.

BACKGROUND: No consensus exists on the outcome-related factors of interval debulking surgery (IDS) in patients with advanced high-grade serous ovarian cancer (HG-SOC) who underwent neoadjuvant chemotherapy (NAC). This study aimed to explore the optimal timing for IDS and the prognosis-associated factors of International Federation of Gynecology and Obstetrics stage IIIc to IV HG-SOC patients. METHODS: A total of 160 IIIc to IV stage HG-SOC patients were retrospectively analyzed. Patients with large volume ascites underwent NAC and subsequent IDS from the Jiangsu Institute of Cancer Research between 1993 and 2013. The outcome of IDS-associated factors was explored by logistic regression. To predict IDS outcome, the potential values of serum CA-125 levels and CA-125 decreasing kinetics were determined by the receiver operating characteristic curve. The associations between survival durations and covariates were assessed by Cox proportional hazards model and log-rank test. RESULTS: Optimal IDS was achieved in 80.6% of HG-SOC patients who underwent NAC. Multivariate analyses revealed that ascites regression (p = 0.01), serum CA-125 level (p = 0.02), and CA-125 decreasing kinetics (p = 0.01) were independent optimal IDS predictors. CA-125 decreasing kinetics, IDS outcome, and ascites volume were independently associated with overall survival (OS) (p = 0.04, p < 0.01, p = 0.03, respectively) and progression-free survival (PFS) (p < 0.01, p < 0.01, p = 0.02, respectively). Patients who exhibited disappearance of ascites (<500 ml) had longer PFS (19.7 months vs.14.9 months) and OS (32.1 months vs. 26.0 months) than patients who exhibited residual ascites (≥500 ml). Subsets with higher CA-125 decreasing kinetics (≥2.2) had longer PFS (21.4 months vs.13.1 months) and OS (29.6 months vs.26.8 months) than counterparts (kinetics < 2.2). CONCLUSIONS: Ascites regression and CA-125 decreasing kinetics were independently associated with surgical outcome and prognosis in advanced HG-SOC patients who underwent NAC.

Penicitroamide, an Antimicrobial Metabolite with High Carbonylization from the Endophytic Fungus Penicillium sp. (NO. 24).

Penicitroamide (1), a new metabolite with a new framework, was isolated from the ethyl acetate extract of the PDB (Potato Dextrose Broth) medium of Penicillium sp. (NO. 24). The endophytic fungus Penicillium sp. (NO. 24) was obtained from the healthy leaves of Tapiscia sinensis Oliv. The structure of penicitroamide (1) features a bicyclo[3.2.1]octane core unit with a high degree of carbonylization (four carbonyl groups and one enol group). The chemical structure of penicitroamide (1) was elucidated by analysis of 1D-, 2D-NMR and MS data. In bioassays, penicitroamide (1) displayed antibacterial potency against two plant pathogens, Erwinia carotovora subsp. Carotovora (Jones) Bersey, et al. and Sclerotium rolfsii Sacc. with MIC50 at 45 and 50 µg/mL. Compound 1 also showed 60% lethality against brine shrimp at 10 µg/mL. Penicitroamide (1) exhibited no significant activity against A549, Caski, HepG2 and MCF-7 cells with IC50 > 50 µg/mL. Finally, the possible biosynthetic pathway of penicitroamide (1) was discussed.

MicroRNA expression profiles of drug-resistance breast cancer cells and their exosomes.

Exosomes have been shown to transmit drug resistance through delivering miRNAs. We aimed to explore their roles in breast cancer. Three resistant sublines were established by exposing parental MDA-MB-231 cell line to docetaxel, epirubicin and vinorelbine, respectively. Preneoadjuvant chemotherapy biopsies and paired surgically-resected specimens embedded in paraffin from 23 breast cancer patients were collected. MiRNA expression profiles of the cell lines and their exosomes were evaluated using microarray. The result showed that most miRNAs in exosomes had a lower expression level than that in cells, however, some miRNAs expressed higher in exosomes than in cells, suggesting a number of miRNAs is concentrated in exosomes. Among the dysregulated miRNAs, 22 miRNAs were consistently up-regulated in exosomes and their cells of origin. We further found that 12 of the 22 miRNAs were significantly up-regulated after preneoadjuvant chemotherapy. Further study of the role of these 12 miRNAs in acquisition of drug resistance is needed to clarify their contribution to chemoresistance.

Physical Activity and Risk of Lung Cancer: A Meta-analysis.

OBJECTIVE: Previous studies concerning the association between physical activity (PA) and risk of lung cancer yielded mixed results. We investigated the association by performing a meta-analysis. DATA SOURCES: Relevant studies were identified by searching PubMed and EMBASE to January 2014. Twelve cohort studies and 6 case-control studies involving 2 468 470 participants and 26 453 cases of lung cancer were selected for meta-analysis. MAIN RESULTS: We calculated the summary relative risk (RR) and 95% confidence intervals (CIs) using random-effects models. The analyses showed that individuals who participated in any amount of PA had an RR of 0.79 (95% CI, 0.73-0.86) for risk of lung cancer. Those who participated in high PA (vs low PA) had an RR of 0.75 (95% CI, 0.68-0.84). Stratifying by study design (case-control and cohort studies), smoking status (current, former, and never smokers), and gender, similar inverse associations were found for all the subgroups except for never smokers subgroup. CONCLUSIONS: Pooled results from observational studies support a protective effect of PA against lung cancer.

Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222.

Breast cancer (BCa) is one of the major deadly cancers in women. However, treatment of BCa is still hindered by the acquired-drug resistance. It is increasingly reported that exosomes take part in the development, metastasis, and drug resistance of BCa. However, the specific role of exosomes in drug resistance of BCa is poorly understood. In this study, we investigate whether exosomes transmit drug resistance through delivering miR-222. We established an adriamycin-resistant variant of Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line (MCF-7/Adr) from a drug-sensitive variant (MCF-7/S). Exosomes were isolated from cell supernatant by ultracentrifugation. Cell viability was assessed by MTT assay and apoptosis assay. Individual miR-222 molecules in BCa cells were detected by fluorescence in situ hybridization (FISH). Then, FISH was combined with locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH). Individual miR-222 could be detected as bright photostable fluorescent spots and then the quantity of miR-222 per cell could be counted. Stained exosomes were taken in by the receipt cells. MCF-7/S acquired drug resistance after co-culture with exosomes from MCF-7/Adr (A/exo) but did not after co-culture with exosomes from MCF-7/S (S/exo). The quantity of miR-222 in A/exo-treated MCF-7/S was significantly greater than in S/exo-treated MCF-7/S. MCF-7/S transfected with miR-222 mimics acquired adriamycin resistance while MCF-7/S transfected with miR-222 inhibitors lost resistance. In conclusion, exosomes are effective in transmitting drug resistance and the delivery of miR-222 via exosomes may be a mechanism.

Exosomes in development, metastasis and drug resistance of breast cancer.

Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.