Macrophage migration inhibitory factor‐knockout mice are long lived and respond to caloric restriction

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154680/1/fsb2fj09152223.pd

Histotripsy Effects on the Bladder Trigone: Functional and Histologic Consequences in the Canine Model

Background: Histotripsy is an extracorporeal therapeutic ultrasound (US) technology, where high-amplitude acoustic energy is applied to targeted tissue. Previous research has demonstrated the feasibility, safety, and effectiveness of histotripsy tissue homogenization and debulking of the prostate in the canine model. Before translating this technology for human use, it is prudent to examine the susceptibility of critical periprostatic structures to cavitation injury in the event of histotripsy mistargeting. In this study, we sought to characterize the tissue effects and biologic response of directly treating the bladder trigone with histotripsy. Materials and Methods: In eight anesthetized canines, 750,000 histotripsy pulses were applied uniformly across a 2?1.5-cm area encompassing the bladder trigone and ureteral orifices. Prostate and bladder trigone were harvested immediately after treatment (2 subjects) or at 14 days (6 subjects). Flexible cystourethroscopy, US imaging, and creatinine levels were obtained at intervals until harvest, 14 days after treatment. In one control subject, harvested at 2 days, the same treatment algorithm was applied to the prostate. Results: Transrectal US imaging revealed a cavitation bubble cloud on the surface of the bladder trigone and progressive development of tissue edema during treatment. Flexible cystourethroscopy immediately after treatment confirmed edema and erythema of the trigone. In the six subjects survived 2 weeks after treatment, one incidence of transient, self-limited ureteral obstruction was noted based on hydronephrosis and creatinine levels. At harvest, ureteral orifices were confirmed patent by passage of a guide wire. Histologic evaluation revealed hemorrhage acutely with mild localized fibrosis at 14 days. Conclusions: In this study, designed along the lines of a worst-case, destructive testing scenario, direct targeting of the bladder trigone with supratherapeutic histotripsy failed to induce significant tissue damage or clinical complication. These results are reassuring and will guide treatment strategy in upcoming human clinical trials of histotripsy treatment for benign prostatic hyperplasia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140374/1/end.2013.0234.pd

Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106661/1/acel12170.pd

Acarbose improves health and lifespan in aging HET3 mice

To follow‐up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log‐rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%–11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2‐(2‐hydroxyphenyl) benzothiazole (HBX), and INT‐767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose‐control drugs in humans.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148418/1/acel12898.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148418/2/acel12898_am.pd

Pre-Clinical Evaluation of a Novel Nanoemulsion-Based Hepatitis B Mucosal Vaccine

Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg) in a novel nanoemulsion (NE) adjuvant (HBsAg-NE) could be effective with fewer administrations.Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/-17 nm) associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached > or = 10(6) titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu). Normalization showed that HBsAg-NE vaccination correlates with a protective immunity equivalent or greater than 1000 IU/ml. Th1 polarized immune response was indicated by IFN-gamma and TNF-alpha cytokine production and elevated levels of IgG(2) subclass of HBsAg-specific antibodies. The vaccine retains full immunogenicity for a year at 4 degrees C, 6 months at 25 degrees C and 6 weeks at 40 degrees C. Comprehensive pre-clinical toxicology evaluation demonstrated that HBsAg-NE vaccine is safe and well tolerated in multiple animal models.Our results suggest that needle-free nasal immunization with HBsAg-NE could be a safe and effective hepatitis B vaccine, or provide an alternative booster administration for the parenteral hepatitis B vaccines. This vaccine induces a Th1 associated cellular immunity and also may provide therapeutic benefit to patients with chronic hepatitis B infection who lack cellular immune responses to adequately control viral replication. Long-term stability of this vaccine formulation at elevated temperatures suggests a direct advantage in the field, since potential excursions from cold chain maintenance could be tolerated without a loss in therapeutic efficacy

Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice

During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice