Effects of Testosterone Treatment in Older Men Snyder, Peter J; Bhasin, Shalender; Cunningham, Glenn R ...
New England journal of medicine/The New England journal of medicine,
02/2016, Letnik:
374, Številka:
7
Journal Article
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In this study, men 65 years of age or older with low serum testosterone and symptoms of hypoandrogenism received testosterone or placebo for a year. Testosterone had a moderate benefit in sexual ...function and some benefit in mood but no benefit in vitality or walking distance.
Testosterone concentrations in men decrease with increasing age.
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Many symptoms and conditions similar to those that are caused by low testosterone levels in men with pituitary or testicular disease become more common with increasing age. Such symptoms include decreases in mobility, sexual function, and energy. These parallels suggest that the lower testosterone levels in older men may contribute to these conditions.
Previous trials of testosterone treatment in men 65 years of age or older, however, have yielded equivocal results. Although testosterone treatment consistently increased muscle mass and decreased fat mass,
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effects on physical performance,
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sexual function, . . .
An optimal host response against Staphylococcus aureus skin and soft tissue infections (SSTI) is dependent on IL-1β and IL-17 mediated abscess formation. Alpha toxin (AT), an essential virulence ...factor for SSTI, has been reported to damage tissue integrity; however its effect on the immune response has not been investigated. Here, we demonstrate that infection with USA300 AT isogenic mutant (Δhla), or passive immunization with an AT neutralizing mAb, 2A3, 24 h prior to infection with wild type USA300 (WT), resulted in dermonecrotic lesion size reduction, and robust neutrophil infiltration. Infiltration correlates with increase in proinflammatory cytokines and chemokines, as well as enhanced bacterial clearance relative to immunization with a negative control mAb. In addition, infection with Δhla, or with WT +2A3, resulted in an early influx of innate IL-17(+)γδT cells and a more rapid induction of an adaptive immune response as measured by Th1 and Th17 cell recruitment at the site of infection. These results are the first direct evidence of a role for AT in subverting the innate and adaptive immune responses during a S. aureus SSTI. Further, these effects of AT can be overcome with a high affinity anti-AT mAb resulting in a reduction in disease severity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture. OBJECTIVE: To determine whether testosterone ...treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength. DESIGN, SETTING, AND PARTICIPANTS: Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization. INTERVENTIONS: Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year. MAIN OUTCOMES AND MEASURES: Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. RESULTS: There were 211 participants (mean SD age, 72.3 5.9 years; 86% white; mean SD body mass index, 31.2 3.4). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD. CONCLUSIONS AND RELEVANCE: Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00799617
Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified ...individuals with type 2 diabetes (
= 17) as nonresponders (
= 6) or responders (
= 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training.
PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (
P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (
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), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs.
By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA
) worsened. In responders, insulin sensitivity improved.
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improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals.
A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.
IMPORTANCE: In one-third of older men with anemia, no recognized cause can be found. OBJECTIVE: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone ...levels and unexplained anemia would increase their hemoglobin concentration. DESIGN, SETTING, AND PARTICIPANTS: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. INTERVENTIONS: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. MAIN OUTCOMES AND MEASURES: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. RESULTS: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. CONCLUSIONS AND RELEVANCE: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00799617
Purpose: The targeting protein for Xklp2 ( TPX2 ) has recently gained attention as a putative oncogene possibly amplified in several human malignancies, including pancreatic
adenocarcinoma. In this ...work, we sought to evaluate the copy number and expression of TPX2 in pancreatic cancer cell lines and tumor tissues and to further explore the potential of TPX2 as a therapeutic target.
Experimental Design: The DNA copy number and expression of the TPX2 gene were surveyed in pancreatic cancer cell lines and tumor tissues and compared with those of immortalized normal pancreatic
ductal cells and normal pancreatic tissues. The cellular effects of TPX2 knockdown using small interfering RNA oligonucleotides
in pancreatic cancer cells, such as growth in tissue culture, in soft agar, and in nude mice; apoptosis; and sensitivity to
paclitaxel, were also investigated using various assays.
Results: Low-copy-number TPX2 amplification was found in pancreatic cancer cell lines and low-passage pancreatic cancer tumor xenografts. TPX2 expression
was upregulated in pancreatic cancer cell lines at both the mRNA and protein levels relative to the immortalized pancreatic
ductal epithelial cell line HPDE6. Immunohistochemical staining of a tissue microarray showed that TPX2 expression was higher
in pancreatic tumors compared with their normal counterparts. Treatment with TPX2 targeting small interfering RNAs effectively
reduced pancreatic cancer cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar and in nude
mice. Knockdown of TPX2 also sensitized pancreatic cancer cells to paclitaxel treatment.
Conclusions: Our results suggest that TPX2 might be an attractive target for pancreatic cancer therapy. (Clin Cancer Res 2009;15(21):6519â28)
With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria breakdown and the heart becomes less efficient. Heart failure is ...linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the three-dimensional (3-D) networks in cardiac muscle samples of male mice at aging intervals of 3 mo, 1 yr, and 2 yr. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the three-dimensional (3-D) volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of
(some members of the MICOS complex), and
, which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes.
This article shows how mitochondria in murine cardiac changes, importantly elucidating age-related changes. It also is the first to show that the MICOS complex may play a role in outer membrane mitochondrial structure.
Abstract The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling ...pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1 -S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.
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