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Cardiovascular diseases (CVD) are a leading cause of human death worldwide. Over the past two decades, the emerging field of cardioimmunology has demonstrated how cells of the immune system play vital roles in the pathogenesis of CVD. MicroRNAs (miRNAs) are critical regulators of cellular identity and function. Cell-intrinsic, as well as cell-extrinsic, roles of immune and inflammatory cell-derived miRNAs have been, and continue to be, extensively studied. Several ‘immuno-miRNAs’ appear to be specifically expressed or demonstrate greatly enriched expression within leucocytes. Identification of miRNAs as critical regulators of immune system signalling pathways has posed the question of whether and how targeting these molecules therapeutically, may afford opportunities for disease treatment and/or management. As the field of cardioimmunology rapidly continues to advance, this review discusses findings from recent human and murine studies which contribute to our understanding of how leucocytes of innate and adaptive immunity are regulated—and may also regulate other cell types, via the actions of the miRNAs they express, in the context of CVD. Finally, we focus on available information regarding miRNA regulation of regulatory T cells and argue that targeted manipulation of miRNA regulated pathways in these cells may hold therapeutic promise for the treatment of CVD and associated risk factors.

When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.

Organ transplantation is often lifesaving, but the long-term deleterious effects of combinatorial immunosuppression regimens and allograft failure cause significant morbidity and mortality. Long-term graft survival in the absence of continuing immunosuppression, defined as operational tolerance, has never been described in the context of multiple major histocompatibility complex (MHC) mismatches. Here, we show that miR-142 deficiency leads to indefinite allograft survival in a fully MHC mismatched murine cardiac transplant model in the absence of exogenous immunosuppression. We demonstrate that the cause of indefinite allograft survival in the absence of miR-142 maps specifically to the T cell compartment. Of therapeutic relevance, temporal deletion of miR-142 in adult mice prior to transplantation of a fully MHC mismatched skin allograft resulted in prolonged allograft survival. Mechanistically, miR-142 directly targets Tgfbr1 for repression in regulatory T cells (TREG ). This leads to increased TREG sensitivity to transforming growth factor - beta and promotes transplant tolerance via an augmented peripheral TREG response in the absence of miR-142. These data identify manipulation of miR-142 as a promising approach for the induction of tolerance in human transplantation.

Autism is a severe neurodevelopmental disorder with prevalence varies from 0.6 to 1 %. Autism is at least four times more common in males. It is characterized by disorders in social interactions, communication and behavior, which must appear under 3 years. We don't know the exact reason of rising incidence of autism but one of the factors we attribute is increasing access to electronic media on the daily basis than those of previous generation. This study is being done to establish if there is any direct/indirect correlation between exposure to screen time, its duration, involvement of parent care at the time when its needed the most exists. Funding Statement: The authors declare that no funding or grant has been received for conducting the study. Declaration of Interests: The authors declared no competing interest. Ethics Approval Statement: This study was approved by ethics and research committee and that it complied with all measures.

Introduction: Cell therapy using unselected mononuclear cell populations has had modest benefits in patients with critical limb ischemia (CLI). We hypothesized that tissue-remodeling monocytes, identified by their expression of CD16 (CD16+ Mo), may be a novel cellular therapy for CLI. Methods and Results: Flow cytometry showed that the proportion of circulating CD16+ Mo was greater in CLI patients (n=25) compared with matched controls (n=15, P6 cells injected into the adductor muscles of nude athymic mice following femoral artery excision. More ischemic hindlimbs were salvaged when treated with CD16+ compared with CD16- Mo (83% [10/12] vs 17% [2/12] limbs, P Conclusion: Circulating CD16+ Mo from CLI patients have increased expression of adhesion markers, are preferentially retained within ischemic muscle and promote robust arteriogenesis and limb salvage in experimental HLI. This monocyte subset may be an effective cellular therapy for CLI.

Breast involution following pregnancy has been implicated in the high rates of metastasis observed in postpartum breast cancers; however, it is not clear how this remodeling process promotes metastasis. Here, we demonstrate that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. Moreover, lymphatic vessel density was increased in normal postpartum breast tissue compared with tissue from nulliparous women. In rodents, mammary lymphangiogenesis was upregulated during weaning-induced mammary gland involution. Furthermore, breast cancer cells exposed to the involuting mammary microenvironment acquired prolymphangiogenic properties that contributed to peritumor lymphatic expansion, tumor size, invasion, and distant metastases. Finally, in rodent models of postpartum breast cancer, cyclooxygenase-2 (COX-2) inhibition during the involution window decreased normal mammary gland lymphangiogenesis, mammary tumor-associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Our data indicate that physiologic COX-2–dependent lymphangiogenesis occurs in the postpartum mammary gland and suggest that tumors within this mammary microenvironment acquire enhanced prolymphangiogenic activity. Further, our results suggest that the prolymphangiogenic microenvironment of the postpartum mammary gland has potential as a target to inhibit metastasis and suggest that further study of the therapeutic efficacy of COX-2 inhibitors in postpartum breast cancer is warranted.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that are increased in the peripheral blood of cancer patients and limit productive immune responses against tumors. Immunosuppressive MDSCs are well characterized in murine splenic tissue and are found at higher frequencies in spleens of tumor-bearing mice. However, no studies have yet analyzed these cells in parallel human spleens. We hypothesized that MDSCs would be increased in the spleens of human cancer patients, similar to tumor-bearing mice. We compared the frequency and function of MDSC subsets in dissociated human spleen from 16 patients with benign pancreatic cysts and 26 patients with a variety of cancers. We found that total MDSCs (Linneg CD11bpos CD33pos HLA-DRneg), granulocytic MDSCs (additional markers CD14neg CD15pos), and monocytic MDSCs (CD14pos CD15neg) were identified in human spleen. The monocytic subset was the most prominent in both spleen and peripheral blood and the granulocytic subset was expanded in the spleen relative to matched peripheral blood samples. Importantly, the frequency of CD15pos MDSCs in the spleen was increased in patients with cancer compared to patients with benign pancreatic cysts and was associated with a significantly increased risk of death and decreased overall survival. Finally, MDSCs isolated from the spleen suppressed T cell responses, demonstrating for the first time the functional capacity of human splenic MDSCs. These data suggest that the human spleen is a potential source of large quantities of cells with immunosuppressive function for future characterization and in-depth studies of human MDSCs.

Coordination and biocidal aspects of lanthanide(III) complexes with 3-formyl-4-chlorocoumarin hydrazinecarbothioamide (L1H) and 3-formyl-4-chlorocoumarin hydrazinecarboxamide (L2H) are described with the support of elemental analyses, molecular weight, melting point, and molar conductance determinations along with the IR, 1H NMR, EPR, UV spectral, and X-ray powder diffraction studies. The spectral data suggest that the ligands are monobasic bidentate, coordinating through nitrogen and sulfur/oxygen. The isolated products are colored solids, soluble in DMSO, DMF, and methanol. All the complexes are monomeric, as indicated by their molecular weight determinations. Conductivity measurements in dry DMF show them to be non-electrolytes. The antimicrobial, DNA cleavage, pesticidal, and nematicidal activities were examined and are discussed.

Microwave-assisted synthesis and spectroscopic studies of trimethyl and triphenyl germanium(IV) chelates derived from the reactions of organogermanium chlorides with the sodium salt of a biologically active nitrogen donor ligand are described. The resulting products have been isolated and characterized by elemental analyses, molecular weight determinations and conductance measurements, Systronics-Vadodara, India. On the basis of electronic, infrared, 1H and 13C NMR spectral studies, trigonal bipyramidal geometry has been suggested for the resulting complexes. The biologically active ligand and its corresponding complexes have been examined with regard to antifungal and antibacterial activity against pathogenic fungi and bacteria, and the results are rather encouraging. Both the compounds have also been found to act as nematicides by reducing the number of nematodes (Meloidogyne incognita).

Although tumor cell dissemination via the lymphatic vasculature is thought to be a common pathway of metastasis for solid human cancers, the mechanisms of lymphatic mediated metastasis remain poorly understood1. For breast cancer patients, lymph node involvement remains a very important indicator of patient prognosis and is utilized clinically for therapeutic choices2,3. A recent study has shown that the incidence of being diagnosed with stage IV breast cancer, i.e. breast cancer that has spread outside the breast, is increasing in young women4. Furthermore, young women's breast cancers diagnosed within 5 years postpartum are more likely to be metastatic5-7. Given that 35-45% of young women's breast cancers are likely to be diagnosed within 5 years of giving birth, we predict that postpartum cases may be driving the observed increase in breast cancers with distant involvement in young women. Here, we hypothesized that the postpartum period promotes lymphangiogenesis, which leads to breast tumor metastasis. To test this hypothesis we have generated xenograft and isograft mouse models of postpartum breast cancer that show increased metastasis in postpartum animals8,9. We utilized these rodent models and a cohort of young women's breast tissues to investigate lymphatic mediated metastasis in the postpartum period. In our rodent models, we show that 1) lymphangiogenesis is enhanced during normal postpartum involution, 2) tumor cells can utilize the lymphatic vasculature to escape the mammary gland during postpartum involution, 3) postpartum tumors display increased lymphatic vessel density and lymphatic vessel invasion in the tumor periphery, and 4) that postpartum tumor cells promote lymphangiogenesis and express high levels of pro-lymphangiogenic molecules VEGF-C and Sem7a ex vivo. Importantly, we show that both normal and tumor associated lymphangiogenesis in vivo are dependent upon COX-2 and that COX-2 inhibitors can block metastasis of postpartum tumors. In our young women's breast cancer cohort we also report increased mammary lymphangiogenesis tissues from women within one year of childbirth, increased lymphatic vessel density at the tumor periphery of postpartum breast cancers, as well as a positive correlation between lymphatic vessel density and lymphatic vessel invasion. Thus, we suggest that lymphatic mediated metastasis in young women may be decreased by COX-2 inhibitor or NSAID use. 1. Stacker, S.A., Baldwin, M.E. & Achen, M.G. The role of tumor lymphangiogenesis in metastatic spread. Faseb J 16, 922-934 (2002). 2. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer cell 1, 219-227 (2002). 3. Pepper, M.S., Tille, J.C., Nisato, R. & Skobe, M. Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314, 167-177 (2003). 4. Johnson, R.H., Chien, F.L. & Bleyer, A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. Jama 309, 800-805 (2013). 5. Callihan, E.B., et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res Treat (2013). 6. Johansson, A.L., Andersson, T.M., Hsieh, C.C., Cnattingius, S. & Lambe, M. Increased Mortality in Women with Breast Cancer Detected during Pregnancy and Different Periods Postpartum. Cancer Epidemiol Biomarkers Prev 20, 1865-1872 (2011). 7. Stensheim, H., Moller, B., van Dijk, T. & Fossa, S.D. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol 27, 45-51 (2009). 8. McDaniel, S.M., et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. The American journal of pathology 168, 608-620 (2006). 9. Lyons, T.R., et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17, 1109-1115 (2011). Citation Format: Traci R. Lyons, Virginia F. Borges, Courtney B. Betts, Puja Kapoor, Holly A. Martinson, Sonali Jindal, Pepper Schedin. Postpartum mammary gland involution promotes COX-2 dependent tumor cell invasion of lymphatics. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B099.

Women diagnosed with breast cancer within five years postpartum have worse prognosis than age-matched nulliparous women, independent of tumor stage1,2. While lymph node involvement, lymphatic vessel presence at the tumor margin, and invasion of tumor cells into peritumor lymphatics are all poor prognostic factors for breast cancer patients1-3; it is unknown if lymphatic vessel invasion plays a role in the poor prognosis of postpartum breast cancer. To address this question, we utilized a cohort of young women's breast cancer cases balanced for patient age, tumor stage, and tumor biologic subtype. We observe increased lymph vessel density (LVD) and lymph vessel specific invasion (LSI) in the peritumor region of tumors from postpartum cases compared to nulliparous cases, consistent with a role for lymphatic vessel invasion in postpartum breast cancer metastasis. In addition, we observe increased LVD in normal mammary tissue from postpartum women suggesting that lymphangiogenesis is activated in the postpartum gland. We hypothesize that expansion of the lymphatic vasculature occurs during normal postpartum mammary gland regression, known as postpartum involution, and that tumor cells exposed to the involution microenvironment similarly upregulate lymphangiogenesis, providing increased opportunity for metastasis. To test this hypothesis, we measured LVD in normal rodent mammary tissues and observed a significant increase in LVD during postpartum mammary gland involution. We then utilized our mouse xenograft model of postpartum breast cancer to test whether postpartum tumors have increased LVD and LSI. In this model, postpartum tumors invade the surrounding mammary stroma and peripheral blood, and infiltrate the lung at increased frequency compared to nulliparous tumors4. Here, we also observe increased LVD and LSI in the peritumor region in the postpartum group. Furthermore, we utilized COX-2 inhibitors to show that COX-2 activity during involution is required for the increased LVD, LSI, and lung infiltration associated with postpartum tumors. COX-2 inhibitors also significantly reduced LVD in the normal gland during involution without interfering with morphological gland regression. Finally, tumor cells exposed to postpartum involution appear to be stably altered, as transplantation of postpartum tumor cells into nulliparous mice show elevated levels of tumor associated lymphatics. We conclude that tumor cells exploit the normal lymphangiogenesis programs of postpartum involution to persistently upregulate lymphangiogenesis, which may explain the increased metastasis observed in postpartum tumors. This work was funded by DOD, ACS, Komen, and Cancer League of Colorado. References: 1. Schedin P. Pregnancy-associated breast cancer and metastasis. Nature reviews 2006;6:281-91. 2. Lyons TR, Schedin PJ, Borges VF. Pregnancy and breast cancer: when they collide. Journal of mammary gland biology and neoplasia 2009;14:87-98. 3. Jain RK, Padera TP. Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. Journal of the National Cancer Institute 2002;94:785-7. 4. Lyons TR, O'Brien J, Borges VF, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 2011;17:1109-15. Citation Format: Traci R. Lyons, Courtney Betts, Sonali Jindal, Puja Kapoor, Virginia Borges, Pepper Schedin. Postpartum mammary gland involution drives COX-2-dependent lymphangiogenesis and lymphatic vessel invasion in a model of postpartum breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B79.