In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Methodology: We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-Angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-Angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis

Quantitative magnetic resonance arthrography in patients with femoroacetabular impingement

PURPOSE: Quantitative magnetic resonance imaging (QMRI) of the hip with sequences such as T1(ρ) and T2 mapping has been utilized to detect early changes in cartilage matrix composition. However, QMRI has not been performed in the presence of intra-articular contrast. Thus the purpose of this study was to evaluate the feasibility and use of QMRI during MR-arthrography (MRA) in femoracetabular impingement (FAI) patients. MATERIALS AND METHODS: Using a 3T MR-scanner, ten FAI patients underwent a unilateral MRA and standard MRI of the hip joint. Global and sub-regional T1(ρ) and T2 relaxation times of the acetabular and femoral articular cartilage were computed in the MRA and MRI assessments and agreement of these values were assessed using the Krippendorff’s alpha (α) coefficient and linear regression (μ). T1(ρ) and T2 relaxation times between the MRA and MRI were compared using a repeated measures analysis of variance. RESULTS: Both global and sub-regional T1(ρ) and T2 relaxation times demonstrated strong agreement (α>0.83; μ>0.85) independent of intra-articular contrast. Also, global and sub-regional acetabular T1(ρ) (p=0.72) and T2 (p=0.94), as well as femoral T1(ρ), relaxation times were similar between MRA and MRI (p=0.73) yet femoral T2 relaxation times decreased when using intra-articular contrast (p=0.04). CONCLUSION: This study demonstrated the feasibility of T1ρ and T2 mapping for use in hip MRA with FAI patients. The inclusion of QMRI in MRA provides a quantitative assessment of the effects of FAI on hip joint articular cartilage while allowing for detailed assessment of labral pathology with the use of intra-articular contrast

Clusterin from human clinical tear samples: Positive correlation between tear concentration and Schirmer strip test results

Purpose: To investigate the relationship between tear concentration of the homeostatic protein clusterin (CLU) and dry eye signs and symptoms, and to characterize tear CLU protein. Methods: Two independent studies were conducted, one in Tucson (44 subjects), the other in Los Angeles (52 subjects). A cohort study design was employed to enroll patients without regard to dry eye diagnosis. Dry eye signs and symptoms were assessed using clinical tests. Tear samples were collected by Schirmer strip, and also by micropipette at slit lamp when possible. CLU from both sample types was quantified by immunoassay. The relationship between CLU concentration and clinical test scores was determined by Pearson\u27s correlation coefficient (for individual eyes) and multiple linear regression analysis (including both eyes). CLU was also evaluated biochemically by western blotting. Results: In the Tucson cohort, a positive correlation was observed between tear CLU concentration and results of the Schirmer strip test, a measure of tear flow (p = 0.021 includes both eyes). This result was corroborated in the Los Angeles cohort (p = 0.013). The mean tear CLU concentration was 31 ± 14 μg/mL (n = 18 subjects, 33 eyes; range = 7-48 μg/mL). CLU from clinical tear samples appeared biochemically similar to CLU from a non-clinical tear sample and from blood plasma. Conclusions: Results support the hypothesis that an optimal concentration of tear CLU is important for ocular surface health, and that this drops below the effective threshold in dry eye. Tear CLU measurement might identify patients that could benefit from supplementation. Information about concentration will aid development of therapeutic dosage parameters

Phase 1 Trial of Stereotactic Body Radiation Therapy Neoadjuvant to Radical Prostatectomy for Patients With High-Risk Prostate Cancer

PurposeThis study aimed to evaluate the feasibility and safety of prostate stereotactic body radiation therapy (SBRT) neoadjuvant to radical prostatectomy (RP) in a phase 1 trial. The primary endpoint was treatment completion rate without severe acute surgical complications. Secondary endpoints included patient-reported quality of life and physician-reported toxicities.Methods and materialsPatients with nonmetastatic high-risk or locally advanced prostate cancer received 24 Gy in 3 fractions to the prostate and seminal vesicles over 5 days, completed 2 weeks before RP. Patients with pN1 disease were treated after multidisciplinary discussion and shared decision making. Patient-reported quality of life (International Prostate Symptom Score and Expanded Prostate Cancer Index Composite 26-item version questionnaires) and physician-reported toxicity (Common Terminology Criteria for Adverse Events, version 4.03) were assessed before SBRT, immediately before surgery, and at 3-month intervals for 1 year.ResultsTwelve patients were enrolled, and 11 completed treatment (1 patient had advanced disease on prostate-specific membrane antigen positron emission tomography after enrollment but before treatment). There were no significant surgical complications. After RP, 2 patients underwent additional radiation therapy to nodes with androgen suppression for pN1 disease. Median follow-up after completion of treatment was 20.1 months, with 9 of 11 patients having a follow-up period of >12 months. Two patients had biochemical recurrence (prostate-specific antigen ≥0.05) within the first 12 months, with an additional 2 patients found to have biochemical recurrence after the 12-month period. The highest Common Terminology Criteria for Adverse Events genitourinary grades were 0, 1, 2, and 3 (n = 1, 4, 4, and 2, respectively), and the highest gastrointestinal grades were 0, 1, and 2 (n = 9, 1, and 1, respectively). At 12 months, incontinence was the only grade ≥2 toxicity. One and 2 of 9 patients had grade 2 and 3 incontinence, respectively. On the Expanded Prostate Cancer Index Composite (26-item version), the mean/median changes in scores from baseline to 12 months were -32.8/-31.1 for urinary incontinence, -1.6/-6.2 for urinary irritative/obstructive, -2.1/0 for bowel, -34.4/-37.5 for sexual function, and -10.6/-2.5 for hormonal. The mean/median change in International Prostate Symptom Score from baseline to 12 months was 0.5/0.5.ConclusionsRP after neoadjuvant SBRT appears to be feasible and safe at the dose tested. The severity of urinary incontinence may be higher than RP alone