Showing papers by "Christina Wang published in 2015"

Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials.

Abstract: Context: The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear. Objective: To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormone-binding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials). Design: Cross-sectional study of baseline measures in the TTrials. Setting: The study was conducted at 12 sites in the United States. Participants: The 788 TTrials participants were ≥ 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT < 275 ng/dL. Interventions: None. Main Outcome Measures: Question 4 of Psychosocial Daily Questionnaire (PDQ-...

The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs

Abstract: Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: (1) decreases DOX (ex vivo) and CP (in vivo) induced male germ cell apoptosis; (2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; (3) self-dimerization or binding to IGFBP-3 may not be involved in HN’s effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects.

The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice.

Abstract: Humanin is a peptide that is cytoprotective against stresses in many cell types We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells Young adult male mice were inoculated iv with murine melanoma cells After 1 week, cancer-bearing mice were randomized to receive either: no treatment, daily ip injection of HNG, a single ip injection of cyclophosphamide (CP), or CP+HNG and killed at the end of 3 weeks HNG rescued the CP-induced suppression of leucocytes and protected germ cell from CP-induced apoptosis Lung metastases were suppressed by HNG or CP alone, and further suppressed by CP+HNG treatment Plasma IGF-1 levels were suppressed by HNG with or without CP treatment To investigate whether HNG maintains its protective effects on spermatogonial stem cells, sperm output, and peripheral leucocytes after repeated doses of CP, normal adult male mice received: no treatment, daily sc injection of HNG, 6 ip injections of CP at 5-day intervals, and the same regimens of CP+HNG and killed at the end of 4 weeks of treatment Cauda epididymal sperm counts were elevated by HNG and suppressed by CP HNG rescued the CP-induced suppression of spermatogonial stem cells, sperm count and peripheral leucocytes We conclude that HNG 1) protects CP-induced loss of male germ cells and leucocytes, 2) enhances CP-induced suppression of cancer metastases, and 3) acts as a caloric-restriction mimetic by suppressing IGF-1 levels Our findings suggest that humanin analogues may be promising adjuvants to chemotherapy

Serum Testosterone (T) Level Variability in T Gel-Treated Older Hypogonadal Men: Treatment Monitoring Implications

Abstract: Context: The optimal frequency for on-treatment serum T measurement used for dose adjustment after transdermal T gel application is unknown, especially in older men with thinner skin and slower metabolic clearance. Objectives: The objectives of the study was to determine the variability of postgel application serum T concentrations and assess whether single levels are reflective of average serum T concentrations over 24 hours (Cavg0–24). Design: This was a double-blinded, placebo-controlled randomized trial. Setting: The study was conducted at five academic centers. Participants: Forty-seven symptomatic men 65 years old or older with an average of two morning T concentration less than 275 ng/dL participated in the study. Intervention(s): Transdermal T or placebo gel was applied for 120 ± 14 days. Monthly dose adjustments were made if necessary to target serum T between 400 and 500 to 800 ng/dL. Main Outcome Measures: Variability of serum T 2 hours after the gel application on two outpatient visits and at ...

Recruitment and Screening for the Testosterone Trials

Abstract: © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. Background. We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment. Methods. Men were eligible if they were ≥65 years, had an average of two morning total T values 300 ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality). Results. Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0 kg/m2. Mean (standard deviation) total T (ng/dL) was 212.0 (40.0). Conclusion: Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible.

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

Abstract: Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study—XO, XX, XY and XXY—to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males (“forebrain cholinergic” and “cerebelo-pontine-thalamo-cortical”), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.

Humanin protects against chemotherapy-induced stage-specific male germ cell apoptosis in rats

Abstract: Humanin (HN) has cytoprotective action on male germ cells after testicular stress induced by heat and hormonal deprivation. To examine whether HN has protective effects on chemotherapy-induced male germ cell apoptosis, we treated four groups of adult rats with (i) vehicle (control), (ii) HN, (iii) cyclophosphamide (CP); or (iv) HN+CP. To investigate whether the protective effects of HN on germ cells require the presence of Leydig cells, another four groups of rats were pre-treated with ethane dimethanesulfonate (EDS), a Leydig cell toxicant, to eliminate Leydig cells. After 3 days, when Leydig cells were depleted by EDS, we administered: (i) vehicle, (ii) HN, (iii) CP; or (iv) HN+CP to rats. All rats were killed 12 h after the injection of HN and/or CP. Germ cell apoptosis was detected by TUNEL assay and quantified by numerical count. Compared with control and HN (alone), CP significantly increased germ cell apoptosis; HN +CP significantly reduced CP-induced apoptosis at early (I-VI) and late stages (IX-XIV) but not at middle stages (VII-VIII) of the seminiferous epithelial cycle. Pre-treatment with EDS markedly suppressed serum and intratesticular testosterone (T) levels, and significantly increased germ cell apoptosis at the middle (VII-VIII) stages. CP did not further increase germ cell apoptosis in the EDS-pre-treated rats. HN significantly attenuated germ cell apoptosis at the middle stages in EDS pre-treated rats. To investigate whether HN has any direct effects on Leydig cell function, adult Leydig cells were isolated and treated with ketoconazole (KTZ) to block testosterone synthesis. HN was not effective in preventing the reduction of T production by KTZ in vitro. We conclude that HN decreases CP and/or EDS-induced germ cell apoptosis in a stage-specific fashion. HN acts directly on germ cells to protect against EDS-induced apoptosis in the absence of Leydig cells and intratesticular testosterone levels are very low.

Erratum : The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men (Clinical Trials (2014) 11 (362-375) DOI: 10.1177/1740774514524032)

Abstract: CLINICAL TRIALS DESIGN Clinical Trials 2014; 11: 362–375 The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men Peter J Snyder a , Susan S Ellenberg b , Glenn R Cunningham c , Alvin M Matsumoto d , Shalender Bhasin e , Elizabeth Barrett-Connor f , Thomas M Gill g , John T Farrar h , David Cella i , Raymond C Rosen j , Susan M Resnick k , Ronald S Swerdloff l , Jane A Cauley m , Denise Cifelli h , Laura Fluharty h , Marco Pahor n , Kristine E Ensrud o , Cora E Lewis p , Mark E Molitch q , Jill P Crandall r , Christina Wang l , Matthew J Budoff s , Nanette K Wenger t , Emile R Mohler 3rd u , Diane E Bild v , Nakela L Cook w , Tony M Keaveny x , David L Kopperdahl y , David Lee y , Ann V Schwartz z , Thomas W Storer ab , William B Ershler ac , Cindy N Roy ad , Leslie J Raffel ae , Sergei Romashkan af and Evan Hadley af Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of tes- tosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objec- tive measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concen- trations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Func- tion Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive func- tion (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a sin- gle steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone defi- cient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clini- cally important differences between treatment arms for sample size estimation. Please refer to the Appendix at the end of this paper for individual affiliation details. Author for correspondence: Peter J Snyder, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadel- phia, PA 19104-5160, USA. Email: pjs@mail.med.upenn.edu O The Author(s), 2014 Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav Downloaded from ctj.sagepub.com at AMGEN, INC. on May 22, 2015

Compositions and methods for reducing germ cell death

Abstract: Described herein are methods of protecting germ cells in a subject from cell death induced by a chemotherapeutic agent by, in part, administering a composition comprising one or more humanin polypeptides to the subject. Also described herein are methods of inhibiting a reduction or decrease in fertility in a subject wherein the reduction or decrease in fertility is due to a chemotherapeutic agent.

Humanin, analogs and cancer treatment methods and uses thereof

Abstract: Described herein are methods of enhancing chemotherapeutic treatment of a hyperproliferative disorder by, in part, administering a composition comprising one or more humanin polypeptides to a subject receiving chemotherapy.

Compositions and methods for modulating the effects of chemotherapeutic agents

Abstract: Described herein are methods of protecting germ cells in a subject from cell death induced by a chemotherapeutic agent by, in part, administering a composition comprising one or more humanin polypeptides to the subject. Also described herein are methods of inhibiting a reduction or decrease in fertility in a subject wherein the reduction or decrease in fertility is due to a chemotherapeutic agent. Also described herein are methods of enhancing chemotherapeutic treatment of a hyperproliferative disorder by, in part, administering a composition comprising one or more humanin polypeptides to a subject receiving chemotherapy.