Class III β-tubulin expression as a predictor of docetaxel-resistance in metastatic castration-resistant prostate cancer

About half of the patients treated with docetaxel in the setting of metastatic castration-resistant prostate cancer (CRPC) are non-responders. Therefore, a marker of response would be beneficial for clinical decision-making. We evaluated class III β-tubulin (βIII-tubulin) expression as a predictor of resistance in this setting, which previously has been correlated with lack of response to taxanes in other cancers. Patients with CRPC were included if they were treated with at least 3 cycles of docetaxel between 1990 and 2011. βIII-tubulin expression was assessed by immunostaining, which was performed in tissue samples obtained either via biopsy or prostatectomy at the time of diagnosis. Rates of prostate-specific antigen (PSA) response and overall survival (OS) following docetaxel treatment were compared between patients with high (2+ or 3+ staining) vs. low (0 or 1+ staining) βIII-tubulin expression. Of 73 patients, 26 (35%) had a high expression of βIII-tubulin. A PSA decline of 10% or greater occurred in 65% of patients with a high βIII-tubulin expression vs. 89% with a low βIII-tubulin expression (p = 0.0267). The median OS for patients with a high βIII-tubulin expression was 17.4 (95% CI 8.7-21.0) months vs. 19.8 (95% CI 16.6-23.6) months for patients with a low expression (p = 0.039). Our results show that a high βIII-tubulin expression is a negative prognostic factor in metastatic CRPC patients treated with docetaxel

The effects of laterality on obstacle crossing performance in unilateral trans-tibial amputees

yesBackground Unilateral trans-tibial amputees have bilaterally reduced toe clearance, and an increased risk of foot contact, while crossing obstacles compared to the able-bodied. While the able-bodied tend to lead with a ‘preferred’ limb it is equivocal whether amputees prefer to lead with the intact or prosthetic limb. This study determined the effects of laterality, compared to side of amputation, on amputees' obstacle crossing performance. To help understand why laterality could affect performance we also assessed knee proprioception for both limbs. Methods Foot placement and toe clearance parameters were recorded while nine amputees crossed obstacles of varying heights leading with both their intact and prosthetic limbs. Joint-position sense was also assessed. Participants self-reported which limb was their preferred (dominant) limb. Findings There were no significant differences in foot placements or toe clearance variability across lead-limb conditions. There were no significant differences in toe clearance between intact and prosthetic lead-limbs (p = 0.28) but toe clearance was significantly higher when amputees led with their preferred compared to non-preferred limb (p = 0.025). There was no difference in joint-position sense between the intact and residual knees (p = 0.34) but joint-position sense tended to be more accurate for the preferred, compared to non-preferred limb (p = 0.08). Interpretation Findings suggest that, despite the mechanical constraints imposed by use of a prosthesis, laterality may be as important in lower-limb amputees as it is in the able bodied. This suggests that amputees should be encouraged to cross obstacles leading with their preferred limb.Engineering and Physical Sciences Research Counci

Serum Dioxin, Testosterone, and Subsequent Risk of Benign Prostatic Hyperplasia: A Prospective Cohort Study of Air Force Veterans

BACKGROUND: Operation Ranch Hand veterans were involved in spraying herbicides, including Agent Orange, during the Vietnam War in 1962–1971; Agent Orange was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It has been hypothesized that dioxins may be partially responsible for an increase of male reproductive tract disorders such as testicular cancer, cryptorchidism, and hypospadias. OBJECTIVES: In this study, our objective was to assess the effect of serum TCDD concentration on the risk of development of benign prostatic hyperplasia (BPH) and on serum testosterone levels. METHODS: This study was a longitudinal, prospective cohort study made up of U.S. Air Force veterans involved in Operation Ranch Hand. Other Air Force veterans who did not spray herbicides were included as comparisons. BPH was determined by medical record review and by medical examinations conducted during the study. Data were available for 971 Ranch Hand and 1,266 comparison veterans. We investigated the relationship between BPH and serum TCDD level using the Cox proportional hazards models adjusted for testosterone levels, body mass index (BMI), and the percentage change in BMI per year. RESULTS: In univariate and multivariate analyses, the risk of BPH decreased with increasing serum TCDD in the comparison group. The multivariate risk ratio for BPH in the comparison group was 0.84 (95% confidence interval, 0.73–0.98). Excluding men with prostate cancer, inflammatory or other prostatic diseases did not substantially alter the association. Serum testosterone levels were inversely associated with serum TCDD levels in both Ranch Hand and comparison groups. CONCLUSIONS: TCDD exposure at general population levels is associated with a decreasing risk of BPH with higher exposure levels. TCDD exposure is also negatively associated with serum testosterone levels

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Leadership Styles

[First paragraph] Effective schools literature shows clearly that the leadership of the principal is key to the effectiveness of the school (Hoy and Miskell, 1982, and Arnn and Mangieri, 1988). To be effective, principals must use leadership styles appropriate to the situation

Components of Effective Leadership

[First paragraph] The effective schools literature demonstrates that the principal\u27s leadership is key to the revitalization of schools. The purpose of this article is to feature those components of leadership on which principals need to place attention and to provide suggested activities to enhance these components

Grievances

[First Paragraph] The Virginia Board of Education has adopted a procedure for resolving disputes concerning the application of local board policies, rules, and regulations as they impact the work or disciplinary actions of teachers. It is vital that the principal be aware of the process and the timeline involved in the grievance procedure since the solution should be secured at the lowest administrative level in the process. It is beyond the scope of this article to provide every detail of the grievance process. For a complete detailing of procedure, please refer to Chapter 15, Article 3, Sections 22.1-306 through 22.1-314 of the Code of Virginia

Virginia\u27s Plan for Dual Enrollment

[First paragraph] There is a plan where Virginia pays Average Daily Membership (ADM) monies to a school system for a student attending a community college - and the community college collects the Full Time Equivalency (FTE) from the State. Principals must be aware of this dual enrollment plan for secondary students with community colleges approved in September of 1988. This plan provides options for students which were not available before. Dual enrollment allows high school students to accumulate credits for graduation while simultaneously earning college credit. The courses to be offered are to be mutually agreed upon by the school division and the community college

Unit Plans

[First paragraph] Careful unit planning as a framework for daily lesson plans can help teachers individualize instruction, manage time and classroom behavior, bring cohesive-ness to a series of related daily lessons, and ultimately improve student achievement. Principals can help teachers by providing clear expectations and a consistent framework for unit planning. School and district philosophy will help determine the particular model chosen from the wide variety available. Following is one format