Distinct functions for the catalytic and hemopexin domains of a Drosophila matrix metalloproteinase.

Human matrix metalloproteinases (MMPs) are believed to contribute to tumor progression. Therapies based on inhibiting the catalytic domain of MMPs have been unsuccessful, but these studies raise the question of whether other MMP domains might be appropriate targets. The genetic dissection of domain function has been stymied in mouse because there are 24 related and partially redundant MMP genes in the mouse genome. Here, we present a genetic dissection of the functions of the hemopexin and catalytic domains of a canonical MMP in Drosophila melanogaster, an organism with only 2 MMPs that function nonredundantly. We compare the phenotypes of Mmp1 null alleles with alleles that have specific hemopexin domain lesions, and we also examine phenotypes of dominant-negative mutants. We find that, although the catalytic domain appears to be required for all MMP functions including extracellular matrix remodeling of the tracheal system, the hemopexin domain is required specifically for tissue invasion events later in metamorphosis but not for tracheal remodeling. Thus, we find that this MMP hemopexin domain has an apparent specialization for tissue invasion events, a finding with potential implications for inhibitor therapies.

Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer.

The mechanistic target of rapamycin (mTOR) integrates environmental inputs to regulate cellular growth and metabolism in tumors. However, mTOR also regulates T-cell differentiation and activation, rendering applications of mTOR inhibitors toward treating cancer complex. Preclinical data support distinct biphasic effects of rapamycin, with higher doses directly suppressing tumor cell growth and lower doses enhancing T-cell immunity. To address the translational relevance of these findings, the effects of the mTOR complex 1 (mTORC1) inhibitor, rapamycin, on tumor and T cells were monitored in patients undergoing cystectomy for bladder cancer. MB49 syngeneic murine bladder cancer models were tested to gain mechanistic insights. Surgery-induced T-cell exhaustion in humans and mice and was associated with increased pulmonary metastasis and decreased PD-L1 antibody efficacy in mouse bladder cancer. At 3 mg orally daily, rapamycin concentrations were 2-fold higher in bladder tissues than in blood. Rapamycin significantly inhibited tumor mTORC1, shown by decreased rpS6 phosphorylation in treated versus control patients (P = 0.008). Rapamycin reduced surgery-induced T-cell exhaustion in patients, evidenced by a significant decrease in the prevalence of dysfunctional programmed death-1 (PD-1)-expressing T cells. Grade 3 to 4 adverse event rates were similar between groups, but rapamycin-treated patients had a higher rate of wound complications versus controls. In conclusion, surgery promoted bladder cancer metastasis and decreased the efficacy of postoperative bladder cancer immunotherapy. Low-dose (3 mg daily) oral rapamycin has favorable pharmacodynamic and immune modulating activity in surgical patients and has the potential to decrease surgery-induced immune dysfunction.

Hormonal manipulation with finasteride or oral contraception does not influence incidence of renal cell carcinoma.

Androgens have been suspected to be involved in the initiation of renal cell carcinoma because of a two-fold increased risk in men compared with women. To investigate the role of self-reported finasteride or oral contraceptive use in the Prostate, Lung, Colorectal, and Ovarian (PCLO) to determine whether the androgen receptor reduces renal cancer development. We query the PCLO trial for predictor variables from the baseline questionnaire and follow-up questionnaires enquiring medication use, specifically the use of 5-α reductase inhibitors (dutasteride or finasteride) and oral contraceptive therapy. The primary outcome of this study was the incidence of renal cancer. Statistical analysis included Student's t-test for continuous variables, χ, or Fisher's exact tests for dichotomous or categorical variables, and multivariable analysis using Cox proportional hazards models. Eight percent (n=6117/73 694) of men in the PCLO trial reported the use of finasteride. 52 (10.6%) of the 492 men diagnosed with renal cancer had self-reported exposure to finasteride and this was not significant in univariable analysis (52/6169; 0.84% vs. 440/66 454; 0.67%, P=0.12) or multivariable main effects analysis (hazard ratio: 1.12; 95% confidence interval: 0.83-1.5; P=0.47). Approximately 54% of women (n=40 997/75 989) in the PCLO trial reported the use of oral contraceptives by questionnaire. 136 (52.1%) of the 261 women diagnosed with renal cancer had self-reported exposure to oral contraceptive therapy and this was not significant in univariable analysis (136/40 997; 0.33% vs. 125/34 992; 0.36%, P=0.36) or in multivariable main effects analysis (hazard ratio: 1.03; 95% confidence interval: 0.97-1.1; P=0.30). Self-reported use of finasteride or oral contraceptives is not associated with a reduced incidence of renal cancer.

Modifiable risk factors to reduce renal cell carcinoma incidence: Insight from the PLCO trial.

INTRODUCTION: Identify modifiable factors contributing to renal cell carcinoma in the PCLO to target disease prevention and reduce health care costs. METHODS: The prostate, lung, colorectal, and ovarian database were queried for the primary outcome of kidney cancer. Demographics were investigated, specifically focusing on modifiable risk factors. Statistical analysis includes the Student t-test for continuous variables, chi-squared or Fisher's exact tests for dichotomous and categorical variables for bivariate analysis. The Cox proportional hazards model was used in a multivariate time-to-event analysis. RESULTS: We investigate existing data relating specifically to renal cancer. After missing data were excluded, we analyzed 149,683 subjects enrolled in the prostate, lung, colorectal, and ovarian trial and noted 0.5% (n = 748) subjects developed renal cancer. Age, male gender, body mass index, diabetes, and hypertension were all significant associated with renal cancer in bivariate analysis (P<0.05). Men have a significant increased risk of kidney cancer over women (hazard ratio [HR] = 1.85; 95% CI: 1.58-2.16; P<0.0001). Nonmodifiable risk factors that are associated with kidney cancer include age (HR = 1.05; 95% CI: 1.01; 1.05, P = 0.001). Modifiable risk factors include obesity measured by body mass index (HR = 1.05; 95% CI: 1.02-1.07; P<0.0001), hypertension (HR = 1.32; 95% CI: 1.13-1.54; P = 0.0004), and smoking in pack-years (HR = 1.04; 95% CI: 1.02-1.07; P = 0.0002). CONCLUSIONS: Obesity, hypertension, and smoking are the 3 modifiable risk factors that could aggressively be targeted to reduce renal cell carcinoma.

Validation of 3D volumetric-based renal function prediction calculator for nephron sparing surgery.

OBJECTIVE: To evaluate a recently published volume-based renal function prediction calculator intended to be used in small renal mass surgical counseling. METHODS: Retrospective data collection included three-dimensional calculation of renal mass and parenchyma of patients who have undergone extirpative therapy. The predicted glomerular filtration rate (GFR) was calculated using the online calculator. The predicted GFR was compared with the actual 6-month GFR. The Pearson correlation coefficient, paired t test and root-mean-square error (RMSE) are utilized for statistical analysis. RESULTS: After institutional review board approval, three institutions provided data for analysis. After patients with renal mass size >300 cc, renal size >400 cc or preoperative CKD ≥stage 3 had been excluded, we retrospectively analyzed data from 136 patients. The median mass volume was 22.2 cc (IQR 7-49). In multiple linear regression analysis, the most significant variables predicting postoperative GFR were partial versus radical nephrectomy and preoperative GFR with an overall R2 of .68 (F = 26.13, P < .001). The predicted GFR was 75.4 mL/min/1.73 m2 compared to an actual GFR of 70.7 mL/min/1.73 m2 (P < .001, paired t test). The predicted GFR was highly correlated with the actual postoperative GFR at 6 months (Pearson correlation, r = .65, P < .001). RMSE of the validation cohort was 16.87. CONCLUSIONS: The predictive tool to determine renal function benefit of nephron sparing surgery compared to radical nephrectomy online calculator effectively predicts GFR and could potentially be used to help urologists and patients discuss renal function prior to extirpative renal surgery.

Screening for depression and anxiety in childhood neurogenic bladder dysfunction.

INTRODUCTION: Patients with chronic illnesses are known to have anxiety disorders and are likely to be depressed. Anxiety and depression (A/D) has been studied in adults with spina bifida (SB), however, no study has directly screened for A/D in pediatric patients with neurogenic bladder (NB) and their caregivers. OBJECTIVE: The aims of our study were to determine the prevalence of A/D in caregivers of all children with SB and other NB dysfunction and in adolescents with validated screening measures. STUDY DESIGN & PATIENTS: This was a preliminary cross-sectional screening investigation for A/D in pediatric patients with NB and their caregivers and adolescents with NB. Pediatric patients were defined as ages birth to 19 years and adolescents as ages 10 years-19 years. A caregiver was self-defined as a primary parent/guardian who took care of the pediatric patient for a majority of their time on a daily basis. MATERIALS AND METHODS: We contacted 75 families by mail, of which 15 returned the consent and completed the questionnaires. Subsequently, 25 consecutive families whose children were seen for routine office appointments by the pediatric urology service at the Albany Medical Center in New York participated in person. 22 adolescents completed the Hospital Anxiety and Depression Scale (HADS). 47 caregivers completed both the HADS and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Depression among adolescents: Of the 22 adolescents who completed the HADS, the median HADS score was 5.5 (Inter-quartile range (IQR): 1.75-8.75) for anxiety and 1.5 (IQR: 0-4.25) for depression; both scores were within the normal range (<8/21). Individual abnormal HADS scores (≥8/21) were seen in 6/22 (27%) for anxiety and 1/22 (5%) for depression. Anxiety and depression among caregivers: Of the 47 caregivers who completed the HADS and CES-D, the median HADS score was 7 (IQR: 4-11) for anxiety and 4 (IQR: 1-7) for depression; both scores were within the normal range. Individual abnormal HADS scores were seen in 23/47 (49%) for anxiety and 10/47 (21%) for depression. Abnormal CES-D scores (>15) were seen in 15/47 (32%). The median CES-D scores were 8 (IQR: 3-19). DISCUSSION: In this preliminary screening study, we found considerable anxiety in adolescents with NB and both A/D in caregivers. When screening by two validated surveys, adolescents with NB had median scores for A/D that were normal; yet 27% of these patients exhibited scores for anxiety that outwit the normal range. For the caregivers, the median scores were also normal; yet 49% and 32% had scores for A/D, respectively, that were abnormal. SB among pediatric patients has been shown to result in alterations in daily functioning and to increase the dependency on adult care, factors that are associated with altered self-concept, psychological distress, including A/D. Our findings underscore such results from previous studies. In caregivers, we observed a higher prevalence of anxiety than adolescents; similar findings have been reported for caregivers of other chronic conditions. Surprisingly, in caregivers, a lower percentage of scores for depression was observed. Although we have no data on the cause of this finding this may be related to a caregiver's ability to adapt to the demands of the situation in chronic illness or perhaps, lower expectations. The cross-sectional nature of our study limited us to draw any causal relationships for anxiety or depression between neurogenic patients and their caregivers. CONCLUSION: Despite our study limitations, the prevalence of anxiety in adolescents and in the caregivers is striking. Our data highlight that clinicians should screen for A/D more aggressively in pediatric patients with NB dysfunction and in their caregivers.