HIV/AIDS peer counselors\u27 perspectives on intervention delivery formats

This research sought to elicit HIV/AIDS peer counselors’ perspectives about delivery formats for a counseling intervention. Peer counselors identified personal contact as the major advantage of the face-to-face format. Personal contact afforded counselors better opportunities to understand and assess clients’ physical, emotional, and environmental status and allowed them to connect with peers in more concrete and personal ways. Being physically present was also a very direct and effective way to role model for other HIVpositive women. Peer counselors identified a number of inherent barriers and challenges to telephone interventions but also recognized potential logistic and personal advantages. Despite the overwhelming preference for the faceto- face intervention format, counselors acknowledged the potential for conducting successful peer counseling over the telephone. A significant finding was that the value and meaning of HIV/AIDS peer counselors’ work transcended the limitations of either delivery format

Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma

Despite improvements in cancer patient outcomes seen in the past decade, tumor resistance to therapy remains a major impediment to achieving durable clinical responses. Intratumoral heterogeneity related to genetic, epigenetic, transcriptomic, proteomic, and metabolic differences between individual cancer cells has emerged as a driver of therapeutic resistance. This cell to cell heterogeneity can be assessed using single cell profiling technologies that enable the identification of tumor cell clones that exhibit similar defining features like specific mutations or patterns of DNA methylation. Single cell profiling of tumors before and after treatment can generate new insights into the cancer cell characteristics that confer therapeutic resistance by identifying intrinsically resistant sub-populations that survive treatment and by describing new cellular features that emerge post-treatment due to tumor cell evolution. Integrative, single cell analytical approaches have already proven advantageous in studies characterizing treatment-resistant clones in cancers where pre- and post-treatment patient samples are readily available, such as leukemia. In contrast, little is known about other cancer subtypes like pediatric high grade glioma, a class of heterogeneous, malignant brain tumors in children that rapidly develop resistance to multiple therapeutic modalities, including chemotherapy, immunotherapy, and radiation. Leveraging single cell multi-omic technologies to analyze naïve and therapy-resistant glioma may lead to the discovery of novel strategies to overcome treatment resistance in brain tumors with dismal clinical outcomes. In this review, we explore the potential for single cell multi-omic analyses to reveal mechanisms of glioma resistance to therapy and discuss opportunities to apply these approaches to improve long-term therapeutic response in pediatric high grade glioma and other brain tumors with limited treatment options

Embodied work: Insider perspectives on the work of HIV/AIDS peer counselors

Our aim in this study was to explore HIV/AIDS peer counseling from the perspective of women actively engaged in this work within the context of a community-based program in rural areas of the southeastern United States. Based on this research we suggest that the embodied work of HIV/AIDS peer counselors is constructed around their personal identities and experiences. This work involves gaining entry to other HIV-positive women’s lives, building relationships, drawing on personal experiences, facing issues of fear and stigma, tailoring peer counseling for diversity, balancing risks and benefits, and terminating relationships. Peer counselors recognize the personal and collective value of their work, which, like much of women’s work within the context of family and community, lacks public visibility and acknowledgment. We discuss implications for the training and support of peer-based interventions for HIV and other women’s health issues across diverse contexts and settings

Embodied work: Insider perspectives on the work of HIV/AIDS peer counselors

Our aim in this study was to explore HIV/AIDS peer counseling from the perspective of women actively engaged in this work within the context of a community-based program in rural areas of the southeastern United States. Based on this research we suggest that the embodied work of HIV/AIDS peer counselors is constructed around their personal identities and experiences. This work involves gaining entry to other HIV-positive women’s lives, building relationships, drawing on personal experiences, facing issues of fear and stigma, tailoring peer counseling for diversity, balancing risks and benefits, and terminating relationships. Peer counselors recognize the personal and collective value of their work, which, like much of women’s work within the context of family and community, lacks public visibility and acknowledgment. We discuss implications for the training and support of peer-based interventions for HIV and other women’s health issues across diverse contexts and settings

Predictors of quality of life in HIV-infected rural women: Psychometric test of the Chronic Illness Quality of Life Ladder

The Chronic Illness Quality of Life Ladder (CIQOLL) underwent psychometric testing in a sample of 278 women with HIV disease. The CIQOLL, a self-anchoring striving scale based on Cantril’s Ladder, measures seven domains (physical , emotional, financial, family and friends, spiritual well-being, peace of mind, and overall life satisfaction) across four time periods (present, past, future, life without a diagnosis of HIV). The domains were derived from focus groups with persons with HIV disease. Women with a diagnosis of HIV Infection, age 18 or older, residing in rural areas in the southeastern United States, completed questionnaires that measured physical functioning, HIV related symptom frequency and distress, depressive symptoms, social support, and quality of life. Procedures used to assess reliability included item–item, item–total, and subscale–subscale correlations, and Chronbach’s coefficient a. Criterion-related (concurrent) validity was assessed by correlating the CIQOLL with HIV symptoms, functional status and social support. Construct validity was estimated using factor analysis and predictive modeling. Results provide preliminary evidence that the CIQOLL is a reliable and valid scale that may provide meaningful information about persons living with a chronic illness, such as HIV disease, especially low literacy and unacculturated populations. Additional research is needed to weight the domains, test the sensitivity of the scale to changes over time, and explore the usefulness of discrepancy scores

Using Cryo-Et to Distinguish Platelets During Pre-acute Myeloid Leukemia From Steady State Hematopoiesis

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes in the overall shape and depletion of organelles in AML. Notably, 23% of platelets in pre-leukemic cells exhibit abnormal, round mitochondria with unfolded cristae, accompanied by a significant drop in ATP levels and altered expression of metabolism-related gene signatures. Our study demonstrates that detectable structural changes in pre-leukemic platelets may serve as a biomarker for the early diagnosis of AML

Increased Iron Uptake by Splenic Hematopoietic Stem Cells Promotes TET2-Dependent Erythroid Regeneration

Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs reveals that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increases upon anemia and these HSCs exhibit enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promotes DNA demethylation and expression of erythroid genes. Suppressing iron uptake or TET2 expression impairs erythroid genes expression and erythroid differentiation of HSCs; iron supplementation, however, augments these processes. These results establish that the physiological level of iron taken up by HSCs has an instructive role in promoting erythroid-biased differentiation of HSCs

SOD1 Is a Synthetic-Lethal Target in PPM1D-Mutant Leukemia Cells

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers

Effects of Insulin Detemir and NPH Insulin on Body Weight and Appetite-Regulating Brain Regions in Human Type 1 Diabetes: A Randomized Controlled Trial

Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli.ClinicalTrials.gov NCT00626080