A Unique Pattern Of Pmn-Mdsc Migration In Cancer

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of pathologically activated immature myeloid cells that expand and accumulate in cancer, and are categorized as M-MDSC or PMN-MDSC. The role of MDSC to suppress T-cell activation and proliferation in the tumor microenvironment has been clarified over the past 15 years. Our lab has previously demonstrated that an inflammatory environment can lead to the expansion of “MDSC-like” cells that lack immunosuppressive capability. However, the role of these MDSC-like cells in cancer has not been elucidated. First, we hypothesized that PMN-MDSC-like cells will develop in relatively low inflammatory conditions, such as the early stages of tumor development. Next, we hypothesized that because bona fide PMN-MDSC must migrate into tissues to exert their immunosuppressive effects, PMN-MDSC-like cells that lack immunosuppressive capability will exhibit altered migratory behavior. Finally, because many immune cells undergo metabolic reprogramming to meet the energetic demands of their functionality, we hypothesized that PMN-MDSC-like cells would alter their metabolic profile compared to na�ve PMN and bona fide PMN-MDSC. We have demonstrated that PMN-MDSC-like cells develop in the early stages of tumor development and in transgenic models, but not in the late stages of tumor development or in transplantable models. Moreover, we have found that PMN-MDSC-like cells spontaneously migrate 2-3 fold more than na�ve PMN, and that this motility is characterized by increased speed, persistence time, mean squared displacement and an overall increased random motility coefficient. We demonstrated that PMN-MDSC-like cell spontaneous migration is dependent upon pannexin-1 hemichannel-mediated ATP release, autocrine ATP signaling through the P2X1 purinergic receptor, and increased pMLC2 levels. Additionally, we have shown that PMN-MDSC-like cells increase cell surface expression of the glucose transporter Glut1. Finally, we have shown that, in comparison to na�ve PMN and bona fide PMN-MDSC, PMN-MDSC-like cells increase their glycolytic rate to meet the energetic demands of their altered migratory behavior. Collectively, these studies have shed insight on the development of bona fide PMN-MDSC in cancer, and have suggested a role for PMN-MDSC-like cells in pre-metastatic niche development

Adolescents’ Acceptance of Long-Acting Reversible Contraception After an Educational Intervention in the Emergency Department: A Randomized Controlled Trial

Introduction: Adolescents who seek care in the emergency department (ED) are a cohort at increased risk of unintended pregnancy. Although adolescents are interested in learning about pregnancy prevention in the ED, there is a lack of effective educational interventions in this setting. Long-acting reversible contraceptives (LARC) are highly effective and safe in teens, yet are underutilized. This study assessed contraception use among adolescents in the ED and evaluated the impact of an educational video on their interest in and uptake of LARCs.Methods: We conducted a two-arm randomized controlled trial on a convenience sample of sexually active females 14 to 21 years old in an urban pediatric ED. Participants were randomized to an educational video or standard care. All participants completed a survey and were given an informational card about affiliated teen clinics with the option to schedule an appointment. We assessed pre-post mean differences between control and intervention participants and pre-post differences among intervention participants. Participants were followed three months after their ED visit to examine use of contraception.Results: A total of 79 females were enrolled (42 control and 37 intervention). The mean age was 17 years, and most were youth of color. The proportion of participants with a prior pregnancy was 18%. Almost all participants reported wanting to avoid pregnancy, yet 18% reported not using contraception at last intercourse. At baseline, 17.7% of participants were somewhat or very interested in the intrauterine device (IUD) or implant. After watching the video, 42.3% were somewhat or very interested in the IUD and 35.7% in the implant. Among those who watched the video, there were significant increases in interest in using an IUD or implant (p<.001). Compared to controls, adolescents who watched the video were also significantly more likely to report wanting an IUD (p<0.001) or implant (p=0.002). A total of 46% were reached for follow-up. Of these, 16% had initiated a LARC method after their ED visit (p=NS).Conclusion: Most adolescent females in the ED want to avoid pregnancy, but are using ineffective methods of contraception. A brief educational video on LARCs was acceptable to adolescents and feasible to implement in a busy urban ED setting. Adolescents who watched the video had significantly greater interest in using LARCs, but no demonstrated change in actual adoption of contraception

Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis

MAP (MUTYH-associated polyposis) is a syndrome, described in 2002, which is associated with colorectal adenomas, with enhanced colorectal carcinogenesis. This review synthesizes the available literature on MAP and outlines its pathogenesis, association with colorectal tumorigenesis, screening, treatment, and the subtle differences between it and its close cousins—FAP and AFAP. The preponderance of data is collected using MAP guidelines. However, although AFAP and MAP appear similar, potentially important distinctions exist, warranting targeted diagnostic criteria and treatment approaches. We suggest that it may be prudent to screen for MAP earlier than in current clinical practice, as it has been shown that sequence variants are associated with more severe disease, presenting with an earlier onset of colorectal cancer. Finally, we issue a call-to-action for much-needed further data to establish clear clinical and diagnostic criteria

Higher Tetanus Toxoid Immunity 2 Years After PsA-TT Introduction in Mali.

BACKGROUND: In 2010, mass vaccination with a then-new meningococcal A polysaccharide-tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. METHODS: Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. RESULTS: Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre-PsA-TT, significantly higher GMCs in all age-sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6-36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7-43.3; P < .0001) pre- and postvaccination. CONCLUSIONS: Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity

Healing Spaces: A Design Framework for Care Centres for Human Trafficking Survivors

"The primary goal of this project is to establish a framework for a new human-centred, evidence-based and user-led approach to the design of facilities – including shelters and care centres – aimed at specifically supporting survivors of human trafficking as part of their psychological rehabilitation. The project will draw on the memory and direct testimony of survivors in Uganda, and of those currently resident in a recovery facility, to investigate and establish how the physical environment can promote their healing. Data collected through creative workshops and the use of observational, participatory and digital media methods will outline key architectural and landscaping design aspects of facilities that positively impact the survivors’ psychological health. The findings of this research will be disseminated as a design framework setting out evidence-based approaches for purpose-built, human-centred facilities aimed at supporting survivors." Extract from Final Publication by BuildXStudi

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins

BACKGROUND: The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. METHODS AND FINDINGS: Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 ((213)Bi) and rhenium 188 ((188)Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a (213)Bi- or (188)Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the (188)Re-labeled antibody to gp41 compared with those treated with the (188)Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice. CONCLUSIONS: The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin