Invest in adolescents and young people: it pays

Abstract This year’s Women Deliver conference made a strong call for investing in the health and development of adolescents and young people. It highlighted the unique problems faced by adolescent girls and young women–some of the most vulnerable and neglected individuals in the world–and stressed the importance of addressing their needs and rights, not only for their individual benefit, but also to achieve global goals such as reducing maternal mortality and HIV infection.In response to an invitation from the editors of Reproductive Health, we-the sixteen coauthors of this commentary–put together key themes that reverberated throughout the conference, on the health and development needs of adolescents and young people, and promising solutions to meet them.1. Investing in adolescents and young people is crucial for ensuring health, creating prosperity and fulfilling human rights.2. Gender inequality contributes to many health and social problems. Adolescent girls and boys, and their families and communities, should be challenged and supported to change inequitable gender norms.– Child marriage utterly disempowers girls. It is one of the most devastating manifestations of gender discrimination.– Negative social and cultural attitudes towards menstruation constrain the lives of millions of girls. This may well establish the foundation for lifelong discomfort felt by girls about their bodies and reticence in seeking help when problems arise.3. Adolescents need comprehensive, accurate and developmentally appropriate sexuality education. This will provide the bedrock for attitude formation and decision making.4. Adolescent-centered health services can prevent sexual and reproductive health problems and detect and treat them if and when they occur.5. National governments have the authority and the responsibility to address social and cultural barriers to the provision of sexual and reproductive health education and services for adolescents and young people.6. Adolescents should be involved more meaningfully in national and local actions intended to meet their needs and respond to their problems.7. The time to act is now. We know more now than ever before about the health and development needs of adolescents and young people, as well as the solutions to meeting those needs

Acute liver injury induced by low dose dimethylnitrosamine alters mediators of hepatic vascular flow

Alterations in liver vascular tone play an important role in chronic liver disease. The hepatic stellate cell (HSC) and mediators such as nitric oxide (NO) and hydrogen sulfide (H2S) have been implicated in regulation of vascular tone and intra-hepatic pressure. Though these have been studied in chronic liver damage, changes in response to acute liver injury induced by hepatotoxins such as dimethyl nitrosamine are not well understood. Liver injury was induced in mice by a single intra-peritoneal injection of dimethylnitrosamine (DMN), following which animals were sacrificed at 24, 48 and 72 h. Changes in vascular mediators such as NO and H2S as well as stellate cell activation was then examined. It was found that a single low dose of DMN in mice is sufficient to induce activation of hepatic stellate cells within 24 h, accompanied by oxidative stress, compromised metabolism of H2S and decreased levels of the von Willebrand factor (vWF) cleaving protease; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which functions in intravascular thrombosis. A suppression of hepatic NO levels is also initiated at this time point, which progresses further and is sustained up to 72 h, at which point the HSC activation is still present. Compromised levels of ADAMTS13 and H2S metabolism however, begin to recover by 48 h and are almost similar to control by 72 h. In conclusion, these data suggest that even moderate acute insults in the liver can have far reaching consequences on a number of mediators of vascular flow in the liver

Coexistence of aberrant hematopoietic and stromal elements in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders related to hematopoietic stem and progenitor cell dysfunction. Several studies have shown the role of the bone marrow microenvironment in regulating hematopoietic stem, and progenitor function and their individual abnormalities have been associated with disease pathogenesis. In this study, we simultaneously evaluated hematopoietic stem cells (HSC), hematopoietic stem progenitor cells (HSPCs) and different stromal elements in a cohort of patients with MDS-refractory cytopenia with multilineage dysplasia (RCMD). Karyotyping of these patients revealed variable chromosomal abnormalities in 73.33% of patients. Long-term HSC and lineage-negative CD34 + CD38 − cells were reduced while among the HPCs, there was an expansion of common myeloid progenitor and loss of granulocyte-monocyte progenitors. Interestingly, loss of HSCs was accompanied by aberrant frequencies of endothelial (ECs) (CD31 + CD45 − CD71 −) and mesenchymal stem cells (MSCs) (CD31 − CD45 − 71 −) and its subsets associated with HSC niche. We further demonstrate down-regulation of HSC maintenance genes such as Cxcl12, VEGF in mesenchymal cells and a parallel upregulation in endothelial cells. Altogether we report for the first time quantitative and qualitative de novo changes in hematopoietic stem and its associated niche in a cohort of MDS-RCMD patients. These findings further reinforce the role of different components of the bone marrow microenvironment in MDS pathogenesis and emphasize the need for comprehensive simultaneous evaluation of all niche elements in such studies

Inflammation-induced PELP1 expression promotes tumorigenesis by activating GM-CSF paracrine secretion in the tumor microenvironment

The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel–specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte–macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal–inflammatory–tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel–specific transcriptional regulation of PELP1 in inflammation and possible granulocyte–macrophage colony-stimulating factor–mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies