Prenatal Diagnosis of Congenital Dermal Sinus

Background Congenital dermal sinus (CDS) is an uncommon form of spinal dysraphism. Although postdelivery identification in the neonate is aided by several associated physical examination findings, establishing this diagnosis prenatally has proven to be elusive. Case Report We present a case of CDS where the prenatal findings at 20 weeks gestation led to the diagnosis, which was confirmed postnatally. The associated protrusion of fibrotic membranes through the sinus tract helped in the identification of this lesion prenatally, but created confusion with a more common type of lesion, an open neural tube defect. This is the first case report in the literature describing prenatal diagnosis of fetal CDS. Conclusion Prenatal diagnosis with postnatal confirmation of CDS leads to early intervention, better long-term outcomes, and lesser complications

Prenatal Diagnosis of Congenital Dermal Sinus

Background: Congenital dermal sinus (CDS) is an uncommon form of spinal dysraphism. Although postdelivery identification in the neonate is aided by several associated physical examination findings, establishing this diagnosis prenatally has proven to be elusive. Case Report: We present a case of CDS where the prenatal findings at 20 weeks gestation led to the diagnosis, which was confirmed postnatally. The associated protrusion of fibrotic membranes through the sinus tract helped in the identification of this lesion prenatally, but created confusion with a more common type of lesion, an open neural tube defect. This is the first case report in the literature describing prenatal diagnosis of fetal CDS. Conclusion: Prenatal diagnosis with postnatal confirmation of CDS leads to early intervention, better long-term outcomes, and lesser complications

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers

Ovarian cancer modulates the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells via glutamine metabolism

OBJECTIVE: Immature CD11b(+)Gr1(+) myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study\u27s objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: Depletion of Gr1(+) immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b(+)Gr1(+) myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b(+)Gr1(+) myeloid cells. CD11b(+)Gr1(+) myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b(+)Gr1(+) myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer

Prenatal Diagnosis of Congenital Dermal Sinus

Abstract Background Congenital dermal sinus (CDS) is an uncommon form of spinal dysraphism. Although postdelivery identification in the neonate is aided by several associated physical examination findings, establishing this diagnosis prenatally has proven to be elusive. Case Report We present a case of CDS where the prenatal findings at 20 weeks gestation led to the diagnosis, which was confirmed postnatally. The associated protrusion of fibrotic membranes through the sinus tract helped in the identification of this lesion prenatally, but created confusion with a more common type of lesion, an open neural tube defect. This is the first case report in the literature describing prenatal diagnosis of fetal CDS. Conclusion Prenatal diagnosis with postnatal confirmation of CDS leads to early intervention, better long-term outcomes, and lesser complications

Non-native RDF storage engines

The proliferation of heterogeneous Linked Data requires data management systems to constantly improve their scalability and efficiency. Linked Data can be stored according to many different data storage models. Some of these attempt to use general purpose database storage techniques to persist Linked Data, hence they can leverage existing data processing environments (e.g., big Hadoop clusters). We therefore look at the multiplicity of Linked Data storage systems which we categorize into the following classes: relational database-based systems, NoSQL-based systems, massively parallel systems

Myeloid-derived suppressor cell depletion augments antitumor activity in ovarian cancer

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are increased in tumors and create an immunosuppressive environment by inhibiting the T-cell function. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Increased MDSC accumulation in epithelial ovarian cancer (EOC) has been associated with poor prognosis. Our study investigated whether depletion of MDSCs will influence EOC progression and enhance the therapeutic response of programmed death-1 (PD1) immunotherapy. The intraperitoneal ID8 syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study. The ID8 tumor-bearing mice were treated once a week with either the anti-Gr1 specific monoclonal antibody (Ly6G/Ly6C mAb) that targets and depletes MDSCs, or its isotype IgG2b mAb as control (100μg/dose/mouse). Mice were sacrificed at day 60 for tumor burden evaluation. Quantification of various immune cells and their effector cytokines in blood, spleen, bone marrow, ascites, and tumor were performed by fluorescence-activated cell sorter (FACS) using specific cell surface and intracellular markers, ELISA, and by immunohistochemistry (IHC). The preclinical trial of anti-GR1 and anti-PD1 Ab combination was also carried out. ID8-bearing mice exhibited significantly higher levels of MDSCs (CD11bGr1+) (p\u3c0.001) in bone marrow, blood, and spleen compared to mice with no tumors control groups, including its subpopulations, granulocytic (CD11b+Gr1high) and monocytic (CD11b+Gr1low). When compared to MDSCs retrieved from the spleens of control non-tumor bearing mice, MDSCs isolated from tumorbearing mice exhibited higher ability to suppress T-cell proliferation (p\u3c0.01) and function as reflected by lower IFN-gamma production (p\u3c0.01). Depletion of MDSCs using anti-Gr1 antibody significantly retarded the progression of ovarian cancer in mice as reflected by decreased ascites volume (p\u3c0.001) and tumor burden at the diaphragm, peritoneal cavity, and other organs. Ascitic fluid from tumor-bearing mice treated with anti-Gr1 showed decreased MDSC counts associated with an increase in the number of IFN-gammaproducing CD4 and CD8 T cells (p\u3c0.01). Also associated with MDSC depletion and tumor retardation was an increase in T-cytotoxic and T-helper cells, and decreased tumorassociated macrophages and T-regulatory cells. PD-1 immunotherapy response in ID8 tumors was enhanced in combination with MDSC depletion. Overall, our data suggest that reducing MDSCs can improve the antitumor immune response and aids in containing EOC progression and enhancing immunotherapy response. Thus, targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies

Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients

Signal Transducers and Activators of Transcription (STAT) are a group of transcription factors that are known to play a major role in cancer progression. In ovarian cancer, increased STAT3 leads to cancer proliferation in response to cytokines and confers resistance to chemotherapy-induced apoptosis in epithelial malignancies. STAT3 is constitutively activated in patient derived ovarian cancer cells, and increased STAT3 expression is a predictor of poor prognosis. Apart from its function as a transcription factor, recently STAT3 has been shown to modulate mitochondrial function to promote carcinogenesis. The aim of our study was to investigate if STAT3 activation can modulate cellular metabolism of ovarian cancer cells. Stable clones expressing STAT3 were generated in A2780 ovarian cancer cells, along with empty vector clones. Ectopic expression of STAT3 in A2780 ovarian cancer cell line resulted in increased proliferation (p\u3c0.01) and colony formation ability (p\u3c0.001) in vitro and led to large ovarian tumors (p\u3c0.01) compared to parental and vector controls in xenograft mouse model. Bioenergetics profiling showed higher mitochondrial respiration (OCR) and glycolysis (ECAR) in STAT3 clones compared to parental and vector clones. Ratio of ECAR/OCR in the STAT3 overexpressing cells placed them in the \u27metabolically active\u27 phenotype, while parental A2780 and vector clones were in \u27metabolically less active\u27 phenotype. A selective inhibitor of STAT3, STATTIC, inhibited the STAT3 mediated growth of A2780 cells both in vitro (p\u3c0.01) and in vivo (p\u3c0.01). In addition, STATTIC treatments reversed the \u27metabolically active\u27 state of STAT3 overexpressing clones to a \u27lower metabolic state\u27, placing them in the same category as the control cells. In addition, STATTIC inhibited the cell proliferation and modulated bioenergetic phenotype of other ovarian cancer cells lines (PEO4, C200 and OVCAR3) that display a \u27metabolically active\u27 phenotype. Overall, STAT3 can induce metabolic changes in ovarian cancer cells, maybe as survival mechanism and enhances the cellular fitness of the ovarian cancer cell resulting in increased oncogenic abilities

Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients.

Signal Transducers and Activators of Transcription (STAT) are a group of transcription factors that are known to play a major role in cancer progression. In ovarian cancer, increased STAT3 leads to cancer proliferation in response to cytokines and confers resistance to chemotherapy-induced apoptosis in epithelial malignancies. STAT3 is constitutively activated in patient derived ovarian cancer cells, and increased STAT3 expression is a predictor of poor prognosis. Apart from its function as a transcription factor, recently STAT3 has been shown to modulate mitochondrial function to promote carcinogenesis. The aim of our study was to investigate if STAT3 activation can modulate cellular metabolism of ovarian cancer cells. Stable clones expressing STAT3 were generated in A2780 ovarian cancer cells, along with empty vector clones. Ectopic expression of STAT3 in A2780 ovarian cancer cell line resulted in increased proliferation (p\u3c0.01) and colony formation ability (p\u3c0.001) in vitro and led to large ovarian tumors (p\u3c0.01) compared to parental and vector controls in xenograft mouse model. Bioenergetics profiling showed higher mitochondrial respiration (OCR) and glycolysis (ECAR) in STAT3 clones compared to parental and vector clones. Ratio of ECAR/OCR in the STAT3 overexpressing cells placed them in the \u27metabolically active\u27 phenotype, while parental A2780 and vector clones were in \u27metabolically less active\u27 phenotype. A selective inhibitor of STAT3, STATTIC, inhibited the STAT3 mediated growth of A2780 cells both in vitro (p\u3c0.01) and in vivo (p\u3c0.01). In addition, STATTIC treatments reversed the \u27metabolically active\u27 state of STAT3 overexpressing clones to a \u27lower metabolic state\u27, placing them in the same category as the control cells. In addition, STATTIC inhibited the cell proliferation and modulated bioenergetic phenotype of other ovarian cancer cells lines (PEO4, C200 and OVCAR3) that display a \u27metabolically active\u27 phenotype. Overall, STAT3 can induce metabolic changes in ovarian cancer cells, maybe as survival mechanism and enhances the cellular fitness of the ovarian cancer cell resulting in increased oncogenic abilities

Role of myeloid derived suppressor cells in promoting ovarian cancer

Myeloid Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that are increased in tumors and create an immunosuppressive environment by inhibiting the T-cell function. In addition, MDSCs promote angiogenesis, tumor invasion, and metastasis. Increased MDSC accumulation in epithelial ovarian cancer (EOC) has been associated with poor prognosis. Our study investigated whether depletion of MDSCs will influence EOC progression and enhance the therapeutic response of programmed death-1 (PD1) immunotherapy. The intraperitoneal ID8-luciferase syngeneic mouse epithelial ovarian cancer cell model in B6 mice was used for the study ID8 bearing mice exhibited significantly higher levels of MDSCs (CD11bGr1+) (p\u3c0.001) in bone marrow, blood and spleen compared to mice with no tumors control groups, including its sub-populations; granulocytic and monocytic as the tumor progressed. Additionally, the MDSCs isolated from tumor-bearing mice exhibited higher ability to suppress T cell proliferation (p\u3c0.01) and function as reflected by lower IFN-gamma production (p\u3c0.01). Adoptive transfer of tumor educated MDSCs resulted in earlier and aggressive ovarian tumor progression. The adoptively transferred MDSCs (from 45.2 mice) were found to infiltrate in the ovarian tumors of the donor mice (45.1 mice). Once a week treatment of the ID8 tumor bearing mice with the anti-Gr1 specific monoclonal antibody (Ly6G/Ly6C mAb) that targets and depletes MDSCs, resulted in significant retardation in the progression of ovarian cancer in mice as reflected by luciferase based quantification of tumor images (p\u3c0.01), decreased ascites volume (p\u3c0.001) and tumor burden at diaphragm, peritoneal cavity and other organs. Ascitic fluid from tumor bearing mice treated with anti-Gr1 showed decreased MDSC counts associated with an increase in the number of IFN-gamma producing CD4 and CD8 T cells (p\u3c0.01). Also, associated with MDSC depletion and tumor retardation was increase in T-cytotoxic and Thelper cells, and decreased tumor associated macrophages and T-regulatory cells. PD-1 immunotherapy response in ID8 tumors was enhanced in combination with MDSC depletion as seen from decreased tumor burden and restoration of anti-tumor response. Overall, our data suggests that targeting immunosuppression by reducing MDSCs can improve the anti-tumor immune response and aids in containing EOC progression and enhance immunotherapy response. Thus targeting of MDSCs represents a potential therapeutic modality in ovarian cancer and may be considered in combination with other immunotherapies