Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome.

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS.

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.

Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland.

Comparative Analysis of Small-Molecule LIMK1/2 Inhibitors: Chemical Synthesis, Biochemistry, and Cellular Activity.

LIM domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics and subsequently key cellular functions such as proliferation and migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading to increased actin polymerization. As a result, LIMK inhibitors are emerging as a promising treatment strategy for certain cancers and neurological disorders.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy.

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.

Methods: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

Background: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy).

An anthropomorphic phantom study of visualisation of surgical clips for partial breast irradiation (PBI) setup verification.

Surgical clips were investigated for partial breast image-guided radiotherapy (IGRT). Small titanium clips were insufficiently well visualised. Medium tantalum clips were best for megavoltage IGRT and small tantalum clips were best for floor mounted kilovoltage IGRT (ExacTrac).

Segmental urethral dosimetry and urinary toxicity in patients with no urinary symptoms before permanent prostate brachytherapy.

Purpose: To determine whether segmental urethral dosimetry is predictive for the degree of urinary morbidity after prostate brachytherapy in patients with no urinary symptoms before prostate brachytherapy.

Methods And Materials: Between May 2000 and November 2005, 1,107 patients underwent iodine-125 monotherapy with urethral sparing techniques. A total of 166 patients fulfilled the selection criteria: baseline (International Prostate Symptom Score) IPSS < or =5, no androgen deprivation therapy, and prostate ultrasound planning volumes (PUTV) <45 mL.

Assessing Efficacy of Stuttering Treatments.

Efficacy has been defined as the extent to which a specific intervention, procedure, regimen or service produces a beneficial result under ideally controlled conditions when administered or monitored by experts. Studies on efficacy can be divided into those that study methods of conducting treatment (treatment process research) and those that are concerned with the effects of treatments (treatment outcome research). This reviews both of these areas, emphasizes the former and considers such key determinants of efficacy as measurement, treatment integrity and design issues.

Hearing preservation following fractionated stereotactic radiotherapy for vestibular schwannomas: prognostic implications of cochlear dose.

Object: The goal in this study was to evaluate hearing preservation rates and to determine prognostic factors for this outcome following fractionated stereotactic radiotherapy (FSRT) of vestibular schwannoma.

Methods: Thirty-four consecutive patients with serviceable hearing who received FSRT between May 1998 and December 2003 were identified. Clinical and audiometry data were collected prospectively.

Clinical impact of second pathology opinion: a longitudinal study of central genitourinary pathology review before prostate brachytherapy.

Purpose: To evaluate the clinical impact of pathology review before prostate brachytherapy.

Methods And Materials: Original and reviewing pathologists' reports were retrospectively collected from 1323 men treated with prostate brachytherapy between July 1998 and October 2005 at one institution. Statistical analysis was performed pre- and post-January 2002.

Prostate brachytherapy post-implant dosimetry: a comparison between higher and lower source density.

Background And Purpose: To compare post-implant dosimetry between high density source implants (HDI) and low density source implants (LDI).

Materials And Method: Dosimetric analysis of the whole prostate (V200, V150, V100, D90, D80, contiguous V200 and V150, external index), prostate quadrants (V200, V150, V100, D90), rectum (V150, V120, V100, V80, V60) and deviated surrogate urethra (V200, V150, V120, V100, V80) was performed on 39 consecutive prostate brachytherapy LDI and 39 volume matched HDI over the same time period. The distinction between LDI and HDI was based on differing prescribed dose using 125-Iodine sources, with MPD of 115 and 144 Gy, respectively, using a fixed source strength of 0.