Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool.

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.

Subjective social status, race, and metabolic syndrome in women with breast cancer.

PURPOSE: To evaluate the association of subjective social status (SSS) with metabolic syndrome (MetS) severity and its potential contribution to racial health disparities in women with breast cancer. METHODS: Multicenter cross-sectional study (10 US hospitals) in women (n = 1206) with primary diagnosis of invasive breast cancer received during Mar/2013-Feb/2020. Participants, self-identified as non-Hispanic White or Black, underwent physical and laboratory examinations and survey questions assessing socioeconomic parameters, medical history, and behavioral risks. SSS was measured with the 10-rung MacArthur scale. MetS severity was measured with a validated Z-Score. Generalized linear mixed modeling was used to analyze the associations. Missing data were handled using multiple imputation. RESULTS: Average age was 58 years. On average, the SSS of Black women, given equivalent level of income and education, was lower than the SSS of White women: 6.6 (6.1-7.0) vs 7.7 (7.54-7.79) among college graduates and 6.8 (6.4-7.2) vs 7.6 (7.5-7.8) among women in the high-income category (> $75,000). In multivariable analysis, after controlling for age, income, education, diet, and physical activity, increasing SSS was associated with a decrease in MetS-Z score, - 0.10 (- 0.16 to - 0.04) per every 2 rung increase in the MacArthur scale. CONCLUSION: Black women with breast cancer rank their SSS lower than White women with breast cancer do at each level of income and education. As SSS is strongly associated with MetS severity these results identify potentially modifiable factors that contribute to racial disparities.

Management of Type 2 Diabetes Mellitus in the Very Elderly: One Practice's Experience.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) affects 25% of adults over age 65. Nevertheless, few clinical trials include patients over age 75. METHODS: This case series reports retrospective data on a cohort of 85 patients aged 80 and over (mean 88.1, range 80-104) with T2DM, managed by a single endocrinologist. The practice's computerized data base was searched for all patients 80 years of age and older with a diagnosis of T2DM. RESULTS: The major observations were the significant decrease in the use of agents associated with hypoglycemia (sulfonylureas and insulin), and the beneficial and well-tolerated use of glucagon like peptide-1 receptor analogues (GLP-1 RA). The mean A1c in the entire cohort dropped from 7.6% to 6.6% over a mean of 9 months. Nearly one-half of the cohort were treated with GLP1-RA, reflecting studies demonstrating the safety and efficacy of this class of drugs in less elderly patients. At presentation, 75% were on sulfonylurea and/or insulin; this number was reduced to 27%. Furthermore, none of the patients required short-acting (bolus) insulin to achieve the individualized A1c target. CONCLUSION: Patients with T2DM aged 80 and over respond well to GLP1-RA drugs, drastically reducing the need for agents associated with hypoglycemia. The important question, which will require larger and prospective studies, is whether the lowering of A1c, as shown in this paper, and the use of GLP-1 RA specifically, are associated with improved morbidity and mortality in the very elderly.

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.

Distinct cord blood C-peptide, adipokine, and lipidomic signatures by in utero HIV exposure.

BACKGROUND: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (ß = 0.295, p = 0.03) and C-peptide (ß = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

BACKGROUND: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. METHODS: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. RESULTS: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

Higher BMI is associated with smaller regional brain volume in older adults with type 2 diabetes.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.

RNA-binding protein CUGBP1 controls the differential INSR splicing in molecular subtypes of breast cancer cells and affects cell aggressiveness.

The insulin receptor gene (INSR) undergoes alternative splicing to give rise to two functionally related, but also distinct, isoforms IR-A and IR-B, which dictate proliferative and metabolic regulations, respectively. Previous studies identified the RNA-binding protein CUGBP1 as a key regulator of INSR splicing. In this study, we show that the differential splicing of INSR occurs more frequently in breast cancer than in non-tumor breast tissues. In breast cancer cell lines, the IR-A:IR-B ratio varies in different molecular subtypes, knockdown or overexpression of CUGBP1 gene in breast cancer cells altered IR-A:IR-B ratio through modulation of IR-A expression, thereby reversed or enhanced the insulin-induced oncogenic behavior of breast cancer cells, respectively. Our data revealed the predominant mitogenic role of IR-A isoform in breast cancer and depicted a novel interplay between INSR and CUGBP1, implicating CUGBP1 and IR-A isoform as the potential therapeutic targets and biomarkers for breast cancer.

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

The midlife transition and the risk of cardiovascular disease and cancer Part I: magnitude and mechanisms.

Heart disease and cancer are the leading causes of death in the United States. In women, the clinical appearance of both entities-coronary heart disease and cancer (breast, endometrium, and ovary)-escalate during the decades of the midlife transition encompassing the menopause. In addition to the impact of aging, during the interval between the age of 40 and 65 years, the pathophysiologic components of metabolic syndrome also emerge and accelerate. These include visceral adiposity (measured as waist circumference), hypertension, diabetes, and dyslipidemia. Osteoporosis, osteoarthritis, sarcopenia, depression, and even cognitive decline and dementia appear, and most, if not all, are considered functionally related. Two clinical reports confirm the interaction linking the emergence of disease: endometrial cancer and metabolic syndrome. One describes the discovery of unsuspected endometrial cancer in a large series of elective hysterectomies performed in aged and metabolically susceptible populations. The other is from the Women's Health Initiative Observational Study, which found a positive interaction between endometrial cancer and metabolic syndrome regardless of the presence or absence of visceral adiposity. Both provide additional statistical support for the long-suspected causal interaction among the parallel but variable occurrence of these common entities-visceral obesity, heart disease, diabetes, cancer, and the prevalence of metabolic syndrome. Therefore, 2 critical clinical questions require analysis and answers: 1: Why do chronic diseases of adulthood-metabolic, cardiovascular, endocrine-and, in women, cancers of the breast and endometrium (tissues and tumors replete with estrogen receptors) emerge and their incidence trajectories accelerate during the postmenopausal period when little or no endogenous estradiol is available, and yet the therapeutic application of estrogen stimulates their appearance? 2: To what extent should identification of these etiologic driving forces require modification of the gynecologist's responsibilities in the care of our patients in the postreproductive decades of the female life cycle? Part l of this 2-part set of "expert reviews" defines the dimensions, gravity, and interactive synergy of each clinical challenge gynecologists face while caring for their midlife (primarily postmenopausal) patients. It describes the clinically identifiable, potentially treatable, pathogenic mechanisms driving these threats to quality of life and longevity. Part 2 (accepted, American Journal of Obstetrics & Gynecology) identifies 7 objectives of successful clinical care, offers "triage" prioritization targets, and provides feasible opportunities for insertion of primary preventive care initiatives. To implement these goals, a reprogrammed, repurposed office visit is described.

Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment.

BACKGROUND: Early analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC). We previously demonstrated that the IGF-1R acts as a tumor and metastasis suppressor in the Wnt1 mouse model of TNBC. The mechanisms for how reduced IGF-1R contributes to TNBC phenotypes is unknown. METHODS: We analyzed the METABRIC dataset to further stratify IGF-1R expression with patient survival and specific parameters of TNBC. To investigate molecular events associated with the loss of IGF-1R function in breast tumor cells, we inhibited IGF-1R in human cell lines using an IGF-1R blocking antibody and analyzed MMTV-Wnt1-mediated mouse tumors with reduced IGF-1R function through expression of a dominant-negative transgene. RESULTS: Our analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset revealed association between low IGF-1R and reduced overall patient survival. IGF-1R expression was inversely correlated with patient survival even within hormone receptor-positive breast cancers, indicating reduced overall patient survival with low IGF-1R was not due simply to low IGF-1R expression within TNBCs. Inhibiting IGF-1R in either mouse or human tumor epithelial cells increased reactive oxygen species (ROS) production and activation of the endoplasmic reticulum stress response. IGF-1R inhibition in tumor epithelial cells elevated interleukin (IL)-6 and C-C motif chemokine ligand 2 (CCL2) expression, which was reversed by ROS scavenging. Moreover, the Wnt1/dnIGF-1R primary tumors displayed a tumor-promoting immune phenotype. The increased CCL2 promoted an influx of CD11b+ monocytes into the primary tumor that also had increased matrix metalloproteinase (MMP)-2, MMP-3, and MMP-9 expression. Increased MMP activity in the tumor stroma was associated with enhanced matrix remodeling and collagen deposition. Further analysis of the METABRIC dataset revealed an increase in IL-6, CCL2, and MMP-9 expression in patients with low IGF-1R, consistent with our mouse tumor model and data in human breast cancer cell lines. CONCLUSIONS: Our data support the hypothesis that reduction of IGF-1R function increases cellular stress and cytokine production to promote an aggressive tumor microenvironment through infiltration of immune cells and matrix remodeling.

Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice.

Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol 314: R71-R83, 2018. First published September 13, 2017; doi: 10.1152/ajpregu.00157.2017 .-Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS-R1a) in the pancreas has raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signaling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [d-Lys3]-growth hormone-releasing peptide (GHRP)-6, on glucose homeostasis, food intake, and indirect calorimetric parameters in nonobese diabetic MKR mice. Our results showed that [d-Lys3]-GHRP-6 (200 nmol/mouse) reduced pulsatile growth hormone secretion and body fat mass as expected but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and C-peptide levels were observed in MKR mice following long-term [d-Lys3]-GHRP-6 treatment, suggesting a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin-positive cells and a decrease in insulin-positive cells in [d-Lys3]-GHRP-6-treated mice. Furthermore, [d-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of proopiomelanocortin gene expression and antagonized GH secretion via reduced growth hormone-releasing hormone gene expression in hypothalamus. These results demonstrate that [d-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes.

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model.

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth. METHODS: A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle. RESULTS: No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation. CONCLUSIONS/INTERPRETATION: These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours.

CD24 cell surface expression in Mvt1 mammary cancer cells serves as a biomarker for sensitivity to anti-IGF1R therapy.

BACKGROUND: The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival and proliferation and prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies. METHODS: Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knockdown (IGF1R-KD) cells were FACS sorted into CD24(-) and CD24(+) subsets and further characterized in vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of this cell's phenotype. Metastatic capacity of the cells was assessed using the tail vein assay. RESULTS: In this study we demonstrate that downregulation of the IGF1R specifically in cancer cells expressing CD24 on the cell surface membrane affect both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24(+) cells capacity to form mammary tumors and lung metastatic lesions. We found in both cells and tumors a marked upregulation in CTFG and a significant reduction of SLP1 expression in the CD24(+)/IGF1R-KD; tumor-suppressor and tumor-promoting genes respectively. Moreover, we demonstrate here that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in vivo differentiation of the CD24(+) cells toward the CD24(-) phenotype. This further supports the antitumorigenic effects of IGF1R-KD, as we recently published that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24(+) counterparts. CONCLUSIONS: Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies.

Growth hormone receptor signaling is dispensable for HSC function and aging.

Growth hormone receptor (Ghr) signaling is important in a wide variety of cellular processes including aging; however, the role of Ghr signaling in hematopoietic stem cell (HSC) biology remains unexplored. Within the hematopoietic system, Ghr is expressed in a highly HSC-specific manner and is significantly upregulated during aging. Exposure of young and old HSCs to recombinant growth hormone ex vivo led to diminished short-term reconstitution and restored B-cell output from old HSCs. Hematopoietic-specific genetic deletion of Ghr neither impacted steady-state hematopoiesis nor serial transplantation potential. Repeat challenge with 5-fluorouracil showed that Ghr was dispensable for HSC activation and homeostatic recovery in vivo and, after challenge, Ghr-deficient HSCs functioned normally through serial transplantation. Although exogenous Gh induces age-dependent HSC effects, these results indicate that Ghr signaling appears largely dispensable for HSC function and aging.

Prediabetes and diabetes among HIV-infected adults in Cameroon.

BACKGROUND: Human immunodeficiency virus (HIV) and certain antiretrovirals are associated with diabetes. Few studies have examined the prevalence of and factors associated with diabetes among HIV-infected individuals on combination antiretroviral therapy (cART) in sub-Saharan Africa; some report prevalence estimates between 3.5-26.5% for diabetes in Cameroon and 20.2-43.5% for prediabetes in sub-Saharan Africa. METHODS: In a cross-sectional study, HIV-infected individuals (16-65 years old) were screened for diabetes using haemoglobin A1c (HbA1c ). We further categorized HbA1C as normoglycemia (HbA1c < 5.7%), prediabetes (HbA1c 5.7-6.4%) or diabetes (HbA1c ≥ 6.5%). Dysglycemia was defined as HbA1c ≥ 5.7%. Logistic regression modelling was used to assess factors associated with having dysglycemia. RESULTS: Of 500 participants, 363 (72.6%) were female. Median age was 42.5 years [interquartile range (IQR): 36.5-49.5]. Nineteen patients (3.8%) had diabetes and 170 patients (34%) were classified as having prediabetes. One hundred nine (22%) had a CD4+ count <200 cells/mm(3) , and 464 (93%) had received >28 days of ART at time of screening. Median abdominal circumference for women was 79.5 cm (IQR: 75.5-85.3) and for men, 86.5 cm (IQR: 81.7-90.5). Adjusting for age, sex, socio-economic status, CD4 cell count, being on cART >28 days, body mass index, hypertension, history of hypertension, abdominal circumference and duration of HIV infection, larger abdominal circumference was associated with higher prevalence of prediabetes or diabetes (adjusted odds ratio = 1.07, 95% confidence interval: 1.03-1.11), while being on cART (adjusted odds ratio = 0.46, confidence interval: 0.22-0.99) was associated with lower prevalence. CONCLUSIONS: There was a high prevalence of dysglycemia among Cameroonian HIV-infected adults. Larger abdominal circumference was associated with higher prevalence, while cART was associated with lower prevalence. Copyright © 2016 John Wiley & Sons, Ltd.

Metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer outcomes: hypothesis and proposed pathways.

BACKGROUND: Women with obesity and type 2 diabetes (T2D) are at greater risk of dying from breast cancer than women without these conditions. Obesity and T2D are associated with insulin resistance and endogenous hyperinsulinemia and are more common in Black women. There is increasing disparity in breast cancer mortality between Black and White women in the USA. We hypothesize that insulin resistance and endogenous hyperinsulinemia in Black women with breast cancer contribute to their greater breast cancer mortality and are associated with increased insulin receptor signalling in tumours. METHODS: We will recruit 350 Black women and 936 White women with newly diagnosed breast cancer. We will determine the presence or absence of the metabolic syndrome/pre-diabetes and insulin resistance by measuring body mass index, waist circumference, lipids, blood pressure, glucose, insulin-like growth factor binding protein 1 and insulin. Breast cancer prognosis will be determined by a Nottingham Prognostic Index (NPI), with poor prognosis being defined as NPI >4.4. Tumour insulin receptor signalling will be determined by immunohistochemistry. Insulin receptor subtype expression will be measured using Nanostring. Analysis of these factors will determine whether endogenous hyperinsulinemia is associated with a worse prognosis in Black women than White women and increased tumour insulin receptor signalling. CONCLUSIONS: The results of this study will determine if the metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer mortality. It may provide the basis for targeting systemic insulin resistance and/or tumour insulin receptor signalling to reduce racial disparities in breast cancer mortality. Copyright © 2016 John Wiley & Sons, Ltd.