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Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood.To investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments.Substantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages.Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

Background Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood. Methods To investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments. Findings Substantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages. Interpretation Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

A clinical or radiological worsening of already existing lesions or an emergence of new lesions after beginning treatment in patients with tuberculosis (TB) is referred to as the paradoxical response. This has aroused suspicion regarding the accuracy of diagnosis, the possibilities of treatment failure, or the presence of another underlying disease, and thus it is an important topic for clinicians to understand. In this article, the development of a paradox reaction in a 14-year-old male patient diagnosed with and treated for tuberculosis meningitis is reported. This pediatric patient with a healthy immune system is treated with steroids successfully and reported to elucidate the importance of managing the paradox of TB progression in spite of the appropriate anti-TB medications.

Circulating miRNAs are known to play important roles in intercellular communication.However, the effects of exosomal miRNAs on cells are not fully understood. In this study, substantial expression of oncogenic miR-1246 in sensitive as well as chemoresistant (paclitaxel and multidrug) ovarian cancer (OC) exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFI² receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages. Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemosensitization and tumor progression through exosomal miR-1246 in OC patients. Funding: This study was funded by the NIH Common Fund (UH3 TR000943), through the Office of Strategic Coordination/Office of the NIH Director and MD Anderson’s Cancer Center Support Grant (CCSG) (CA016672) to G. Lopez-Berestein, A.K. Sood, G.A. Calin,, the American Cancer Society Research Professor Award to A.K. Sood, and The Center for RNA Interference and Non-Coding RNA to G.A. Calin, A.K. Sood, and G. Lopez-Berestein and CA166228 from the National Cancer Institute of the NIH to MLG. Declaration of Interest: We have no conflicts of interest to disclose. Ethical Approval: All animal work was approved by the Institutional Animal Use and Care Committee of MD Anderson.

Ovarian cancer is a highly metastatic disease, but no effective strategies to target this metastatic process currently are known. Here, an integrative computational analysis of The Cancer Genome Atlas ovarian cancer dataset coupled with experimental validation identified a novel zinc finger transcription factor ZNF304 as one of the key factors for ovarian cancer metastasis. High tumoral ZNF304 expression was associated with poor overall survival in ovarian cancer patients. Through reverse phase protein array analysis, we demonstrated that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration, and invasion. ZNF304 transcriptionally regulates β1 integrin, which subsequently regulates Src/focal adhesion kinase and paxillin and prevents anoikis. In vivo delivery of ZNF304 siRNA by a novel dual assembly nanoparticle led to sustained gene silencing for 14 days, increased anoikis, and reduced tumor growth in orthotopic mouse models of ovarian cancer. Taken together, ZNF304 is a novel transcriptional regulator of β1 integrin, promotes cancer cell survival, and protects against anoikis in ovarian cancer.

Two effective cytotoxic agents, doxorubicin and trastuzumab, are associated with potentially life-threatening cardiotoxicity. The present study was designed to investigate cardiotoxicity aggravated by the timing of administration of trastuzumab and doxorubicin in rats.Twenty-four rats were randomly assigned to one of four groups. These received one of the following treatment drug regimens administered via intraperitoneal injection: (i) 0.9% saline control (n=6); (ii) doxorubicin (5 mg/kg) on day 1 then trastuzumab 10 mg/kg on day 15 (n=6); (iii) trastuzumab 10 mg/ kg on day 1 then doxorubicin (5 mg/kg) on day 15 (n=6) or (iv) doxorubicin (5 mg/kg) on day 1 and trastuzumab 10 mg/ kg on day 1 (n=6). On the 30th day, the hearts were processed for pathological analysis by electron microscopy.Electron microscopy revealed an ultrastructurally normal heart tissue in the control group. At electron microscopic examination of the tissue samples in the second and fourth group, a mild degree of dilation was observed in the peri-nuclear cisternae of some heart muscle cells. In the third group, pathological changes were detected in mitochondria. These exhibited prominent cristae, which also showed a mild degree of ultrastructural pathology in mitochondria.Based on electron microscopy findings, sequential administration of anthracycline first, followed by trastuzumab is safer in terms of cardiotoxicity, while the most toxic schedule for the rat heart was trastuzumab first, followed by anthracycline.