Citations

Abstract Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

Abstract Theiler's murine encephalomyelitis virus (TMEV) infection of the CNS is cleared in C57BL/6 mice by a CD8 T cell response restricted by the MHC class I molecule H-2Db. The identity and function of the APC(s) involved in the priming of this T cell response is (are) poorly defined. To address this gap in knowledge, we developed an H-2Db LoxP-transgenic mouse system using otherwise MHC class I–deficient C57BL/6 mice, thereby conditionally ablating MHC class I–restricted Ag presentation in targeted APC subpopulations. We observed that CD11c+ APCs are critical for early priming of CD8 T cells against the immunodominant TMEV peptide VP2121-130. Loss of H-2Db on CD11c+ APCs mitigates the CD8 T cell response, preventing early viral clearance and immunopathology associated with CD8 T cell activity in the CNS. In contrast, animals with H-2Db–deficient LysM+ APCs retained early priming of Db:VP2121-130 epitope–specific CD8 T cells, although a modest reduction in immune cell entry into the CNS was observed. This work establishes a model enabling the critical dissection of H-2Db–restricted Ag presentation to CD8 T cells, revealing cell-specific and temporal features involved in the generation of CD8 T cell responses. Employing this novel system, we establish CD11c+ cells as pivotal to the establishment of acute antiviral CD8 T cell responses against the TMEV immunodominant epitope VP2121-130, with functional implications both for T cell–mediated viral control and immunopathology.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Introduction: Infants in neonatal intensive care units require painful and noxious stimuli as part of their care. Judicious use of analgesic medications, including opioids, is necessary. However, these medications have long- and short-term side effects, including potential neurotoxicity. This quality improvement project’s primary aim was to decrease opioid exposure by 33% in the first 14 days of life for infants less than 1,250 g at birth within 12 months. Methods: A multidisciplinary care team used Define, Measure, Analyze, Improve, Control methodology to identify root causes of the quality gap including: (1) inconsistent reporting of objective pain scales; (2) variable provider prescribing patterns; and (3) variable provider bedside assessment of pain. These root causes were addressed by two interventions: (1) standardized reporting of the premature infant pain profile scores and (2) implementation of an analgesia management pathway. Results: Mean opioid exposure, measured in morphine equivalents, in infants less than 1,250 g at birth during their first 14 days of life decreased from 0.64 mg/kg/d (95% confidence interval 0.41–0.87) at baseline to 0.08 mg/kg/d (95% confidence interval 0.03–0.13) during the postintervention period (P < 0.001). There was no statistical difference in rates of days to full feedings, unintentional extubations, or central line removals between epochs. Conclusions: Following the implementation of consistent pain score reporting and an analgesia management pathway, opioid exposure in the first 14 days of life for infants less than 1,250 g was significantly reduced by 88%, exceeding the project aim.

Abstract Background: Hyperinsulinemia is considered to be important in the development of colon cancer, but few studies have investigated the associations of hyperinsulinemia with colon cancer survival via dietary scores. Methods: Empirical dietary index for hyperinsulinemia (EDIH) was derived to assess the insulinemic potential of daily diets reflecting the long-term insulin exposure, with higher (more positive) scores indicating higher insulinemic diets. We prospectively estimated the HRs and 95% confidence intervals (CI) to investigate the association of EDIH with disease-free, recurrence-free, and overall survival among patients with stage III colon cancer (1999–2009) enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803). Results: Of 1,024 patients (median follow-up: 7.3 years), 311 died, 350 had recurrences, and 394 had events for disease-free survival. Compared with patients in the lowest quintile of EDIH, the corresponding HRs of patients in the highest quintile for disease-free survival events, cancer recurrence, and overall mortality were 0.80 (95% CI, 0.56–1.15), 0.76 (95% CI, 0.51–1.11), and 0.77 (95% CI, 0.52–1.14). Conclusions: Higher EDIH was not associated with the risk of colon cancer recurrence or mortality in this population of patients with stage III colon cancer. Impact: EDIH, as a measure of dietary insulinemic potential, may be associated with colon cancer risk but not survival in patients with late-stage colon cancer.