Preclinical pharmacokinetic,toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator

Purpose  

SR16157 is a novel dual-acting inhibitor of estrogen action that irreversibly inhibits the estrogen biosynthetic enzyme steroid sulfatase (STS) and releases the selective estrogen receptor modulator SR16137, which blocks the estrogen receptor. SR16157 is a promising agent for the endocrine therapy of breast cancer. We conducted preclinical in vivo toxicity evaluations to determine the maximum-tolerated dose (MTD), target organ(s) of toxicity, reversibility, dose-limiting toxicity, no observable adverse effect level (NOAEL), and toxicokinetics (TK) and to investigate a potential biomarker for use in SR16157 clinical trials.     

Peer Reviewed: Design and National Dissemination of the StrongWomen Community Strength Training Program

Background

Physical activity is essential for maintaining health and function with age, especially among women. Strength training exercises combat weakness and frailty and mitigate the development of chronic disease. Community-based programs offer accessible opportunities for strength training.

Program Design

The StrongWomen Program is an evidence-informed, community-based strength training program developed and disseminated to enable women aged 40 or older to maintain their strength, function, and independence. The StrongWomen Workshop and StrongWomen Tool Kit are the training and implementation tools for the StrongWomen Program. Program leaders are trained at the StrongWomen Workshop. They receive the StrongWomen Tool Kit and subsequent support to implement the program in their communities.

Dissemination

Program dissemination began in May 2003 with a three-part approach: recruiting leaders and forming key partnerships, soliciting participant interest and supporting implementation, and promoting growth and sustainability.

Assessment

We conducted site visits during the first year to assess curriculum adherence. We conducted a telephone survey to collect data on program leaders, participants, locations, and logistics. We used a database to track workshop locations and program leaders. As of July 2006, 881 leaders in 43 states were trained; leaders from 35 states had implemented programs.

Conclusion

Evidence-informed strength training programs can be successful when dissemination occurs at the community level using trained leaders. This research demonstrates that hands-on training, a written manual, partnerships with key organizations, and leader support contributed to the successful dissemination of the StrongWomen Program. Results presented provide a model that may aid the dissemination of other community-based exercise programs.     

The Carbohydrate Metabolism and Respiration of Isolated Small Lymphocytes: In Vitro Studies of Normal and Phytohemagglutinin Stimulated Cells

1. A homogeneous population of small lymphocytes with an average size of6.7 micra was isolated from equine blood.

2. These cells could be maintained in vitro, with essentially complete survivalfor 24 hours, and with a 50% viability for five days.

3. The small lymphocytes consumed glucose at a rate of 1.87 mµmoles/1 x10⁷ cells/minute, and produced lactic acid at a rate of 2.30 mµmoles/1 x 10⁷cells/minute.

4. The oxygen consumption of small equine lymphocytes was 1.023 ± .165mµmo1es oxygen 1 x 10⁷ cells/minute, and that of mixed peripheral bloodleukocytes, 1.25 ± .07 mµmoles oxygen/1 x 10⁷ cells/minute, as determined, using a Clark oxygen electrode.

5. Lymphocyte glycolysis was stimulated under anaerobic conditions (Pasteur effect), and viability appeared unimpaired after 24 hours in a N₂ environment.

6. Uncoupling of oxidative phosphorylation by the addition of 2,4, dinitrophenol stimulated both respiration and glycolysis.

7. The glycogen content of the normal small horse lymphocyte was 7.45 ±1.04 µg glucose equivalents per 1 x 10⁷ cells.

8. Many of the initial cell population were transformed into "blasts" followingthe addition of phytohemagglutin to the tissue culture medium. Thisresponse was associated with an increase in the rate of glycolysis andrespiration by 24 hours, and a rise in intracellular glycogen by 48 hours.

Submitted on December 7, 1966 Accepted on May 22, 1967     

Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI

Purpose

To investigate the association of Progesterone Receptor (PR) gene variations and male infertility

Methods

DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI.

Results

Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele.

Conclusion

PR gene alterations are not associated with male infertility or ICSI outcome.     

Intracranially recorded interictal spikes: Relation to seizure onset area and effect of medication and time of day

Objective

The relationship between seizures and interictal spikes remains undetermined. We analyzed intracranial EEG (icEEG) recordings to examine the relationship between the seizure onset area and interictal spikes.

Methods

80 unselected patients were placed into 5 temporal, 4 extratemporal, and one unlocalized groups based on the location of the seizure onset area. We studied 4-h icEEG epochs, removed from seizures, from day-time and night-time during both on- and off-medication periods. Spikes were detected automatically from electrode contacts sampling the hemisphere ipsilateral to the seizure onset area.

Results

There was a widespread occurrence of spikes over the hemisphere ipsilateral to the seizure onset area. The spatial distributions of spike rates for the different patient groups were different (p < 0.0001, chi-square test). The area with the highest spike rate coincided with the seizure onset area only in half of the patients.

Conclusion

The spatial distribution of spike rates is strongly associated with the location of the seizure onset area, suggesting the presence of a distributed spike generation network, which is related to the seizure onset area.

Significance

The spatial distribution of spike rates, but not the area with the highest spike rate, may hold value for the localization of the seizure onset area.     

A population-based study of surgery for spinal metastases. Survival rates and complications

The management of spinal metastases is palliative and aimed at improving quality of life at an acceptable risk. This population study uses administrative databases and measures survivorship and complication rates after surgery for spinal metastases. The effects of various potential predictor variables were evaluated. We identified 987 patients with a median survival for all types of cancer of 227 days. The one and three-month mortality was 9% and 29%, respectively. Increasing age, male gender and primary lung cancer were significant risk factors for death within 30 days of surgery. A preoperative neurological deficit contributed a 19% increase in mortality and a 71% increase in the risk of postoperative wound infection. We found an overall major complication rate of 27%. This information will provide patients, families and clinicians with objective data which will help in the choice of treatment and the understanding of the surgical risk and outcome.     

Sentinel lymphnode biopsy in early breast cancer using methylene blue dye and radioactive sulphur colloid — a single institution Indian experience

Background  

Axillary lymph node dissection is an established procedure in breast cancer staging. However, it is associated with unpleasant side effects. A promising alternative to assess axillary lymph node status in early breast cancer patients is Sentinel Lymph Node Biopsy (SLNB). Isosulfan blue has traditionally been the dye used to identify the Sentinel Lymph Node (SLN). This article is a validation study of SLNB using methylene blue dye and radioactive sulphur colloid in early breast cancer Indian patients.