Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone ...pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely.
To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA.
Nonrandomized, interventional trial.
Academic clinical research unit.
Ten adolescent girls with HA.
The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed.
Metformin-related change in hypothalamic P4 sensitivity index percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level.
Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use.
Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.
We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal ...treatment for high-risk neuroblastoma.
The effects of the drug combination on cancer growth were examined
and in animal models of
-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction.
The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination.
The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
Like many large-river ecosystems, the Hudson River has been changing rapidly, chiefly as a result of human activities. Many of these changes take place on a decadal timescale, longer than the ...duration of most ecological studies. We use long-term studies of the Hudson to describe decadal-scale change in this ecosystem. Major impacts on the Hudson in the last few decades include biological invasions, climate change and extreme weather events, and changes in harvests of fishes. The effects of these impacts may be manifested at even longer timescales because of slow ecological responses and rapid evolution. Similar changes are occurring in large rivers around the world. We propose a framework based on the abruptness, severity, duration, and novelty of the drivers and responses to organize and understand these highly varied decadal-scale changes. Tracking and managing these rapidly changing ecosystems require an active program of scientific research and monitoring.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We tested the hypothesis that oral NaHCO3 intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) ...to M2 (regulatory) phenotypes, and FOXP3+CD4+ T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO3 ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO3 activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells.
We tested the hypothesis that oral NaHCO
intake stimulates splenic anti-inflammatory pathways. Following oral NaHCO
loading, macrophage polarization was shifted from predominantly M1 (inflammatory) ...to M2 (regulatory) phenotypes, and FOXP3
CD4
T-lymphocytes increased in the spleen, blood, and kidneys of rats. Similar anti-inflammatory changes in macrophage polarization were observed in the blood of human subjects following NaHCO
ingestion. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response in rats and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan-neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements, which visually resembled neuronal structures. Both disruption of the fragile mesothelial connections or transection of the vagal nerves resulted in the loss of capsular mesothelial acetylcholine esterase staining and reduced splenic mass. Our data indicate that oral NaHCO
activates a splenic anti-inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal-like function of mesothelial cells.
During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early ...pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role.
To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls.
Randomized, placebo-controlled, double-blinded crossover study.
Academic clinical research unit.
Eleven normal, postmenarcheal girls, ages 12 to 15 years.
Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover).
LH pulse frequency during waking and sleeping hours.
Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007).
In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.
The increase in obesity and the many educational messages prompting us to eat a healthy diet have heightened people's concerns about the effects of food choice on health and weight. An unintended ...side effect may be that such awareness fuels feelings of guilt and worry about food. Although guilt has the potential to motivate behaviour change, it may also lead to feelings of helplessness and loss of control. The current study examined the relationship between a default association of either 'guilt' or 'celebration' with a prototypical forbidden food item (chocolate cake), indicators of healthy eating and choosing food for mood regulation reasons. Following a 'diathesis-stress' perspective, the moderating roles of depressive symptoms and stress were examined. Although a default association of guilt was found to be harmless under some circumstances (i.e. under low stress), those who associated chocolate cake with guilt (vs. celebration) reported unhealthier eating habits and lower levels of perceived behavioural control over healthy eating when under stress, rated mood regulation reasons for food choice as important irrespective of their current affective state, and did not have more positive attitudes towards healthy eating. Implications for public health messages and interventions will be discussed.
Background Lung cancer stem cells (CSCs) are a subpopulation of cells that drive growth, invasiveness, and resistance to therapy. Inflammatory eicosanoids are critical to maintain this malignant ...subpopulation. Secretory phospholipase A2 group IIa (sPLA2 ) is an important mediator of the growth and invasive potential of human lung cancer cells and regulates eicosanoid production. We hypothesized that sPLA2 plays a role in the maintenance of lung CSCs. Methods Cancer stem cells from lung adenocarcinoma cell lines H125 and A549 were isolated using aldehyde dehydrogenase activity and flow cytometry. Protein and mRNA levels for sPLA2 were compared between sorted cells using Western blotting and quantitative reverse transcriptase–polymerase chain reaction techniques. Chemical inhibition of sPLA2 and short-hairpin RNA knockdown of sPLA2 were used to evaluate effects on tumorsphere formation. Results Lung CSCs were isolated in 8.9% ± 4.1% (mean ± SD) and 4.1% ± 1.6% of H125 and A549 cells respectively. Both sPLA2 protein and mRNA expression were significantly elevated in the CSC subpopulation of H125 ( p = 0.002) and A549 ( p = 0.005; n = 4). Knockdown of sPLA2 significantly reduced tumorsphere formation in H125 ( p = 0.026) and A549 ( p = 0.001; n = 3). Chemical inhibition of sPLA2 resulted in dose-dependent reduction in tumorsphere formation in H125 ( p = 0.003) and A549 ( p = 0.076; n = 3). Conclusions Lung CSCs express higher levels of sPLA2 than the non–stem cell population. Our findings that viral knockdown and chemical inhibition of sPLA2 reduce tumorsphere formation in lung cancer cells demonstrate for the first time that sPLA2 plays an important role in CSCs. These findings suggest that sPLA2 may be an important therapeutic target for human lung cancer.
Background
Cyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling ...and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.
Methods and Results
We assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.
Conclusions
Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.
“Academic genealogy” refers to the linking of scientists and scholars based on their dissertation supervisors. We propose that this concept can be applied to medical training and that this “medical ...academic genealogy” may influence the landscape of the peer‐reviewed literature. We performed a comprehensive PubMed search to identify US authors who have contributed peer‐reviewed articles on a neurosurgery topic that remains controversial: the value of maximal resection for high‐grade gliomas (HGGs). Training information for each key author (defined as the first or last author of an article) was collected (eg, author's medical school, residency, and fellowship training). Authors were recursively linked to faculty mentors to form genealogies. Correlations between genealogy and publication result were examined. Our search identified 108 articles with 160 unique key authors. Authors who were members of 2 genealogies (14% of key authors) contributed to 38% of all articles. If an article contained an authorship contribution from the first genealogy, its results were more likely to support maximal resection (log odds ratio = 2.74, p < 0.028) relative to articles without such contribution. In contrast, if an article contained an authorship contribution from the second genealogy, it was less likely to support maximal resection (log odds ratio = −1.74, p < 0.026). We conclude that the literature on surgical resection for HGGs is influenced by medical academic genealogies, and that articles contributed by authors of select genealogies share common results. These findings have important implications for the interpretation of scientific literature, design of medical training, and health care policy. Ann Neurol 2016;79:169–177
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