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.cancer ͉ genetics ͉ tissue remodeling

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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 towards treating cancer complex. Preclinical data supports 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 (BC). MB49 syngeneic murine BC 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 BC. 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 3-4 adverse event rates were similar between groups, but rapamycin-treated patients had a higher rate of wound complications versus controls. In conclusion, surgery promoted BC metastasis and decreased the efficacy of post-operative BC immunotherapy. Low dose (3 mg daily) oral rapamycin has favorable pharmacodynamic and immune modulating activity in surgical patients and has potential to decrease surgery-induced immune dysfunction.

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 3-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, 3 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 vs. radical nephrectomy and preoperative GFR with an overall R2 of 0.68 (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 post-operative GFR at 6 months (Pearson correlation, r=0.65, 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.