Citations

Alterations in the extracellular matrix occur during the cardiac hypertrophic process. Because integrins mediate cell-matrix adhesion and β1D-integrin (β1D) is expressed exclusively in cardiac and skeletal muscle, we hypothesized that β1D and focal adhesion kinase (FAK), a proximal integrin-signaling molecule, are involved in cardiac growth. With the use of cultured ventricular myocytes and myocardial tissue, we found the following: 1) β1D protein expression was upregulated perinatally; 2) α1-adrenergic stimulation of cardiac myocytes increased β1D protein levels 350% and altered its cellular distribution; 3) adenovirally mediated overexpression of β1D stimulated cellular reorganization, increased cell size by 250%, and induced molecular markers of the hypertrophic response; and 4) overexpression of free β1D cytoplasmic domains inhibited α1-adrenergic cellular organization and atrial natriuretic factor (ANF) expression. Additionally, FAK was linked to the hypertrophic response as follows: 1) coimmunoprecipitation of β1D and FAK was detected; 2) FAK overexpression induced ANF-luciferase; 3) rapid and sustained phosphorylation of FAK was induced by α1-adrenergic stimulation; and 4) blunting of the α1-adrenergically modulated hypertrophic response was caused by FAK mutants, which alter Grb2 or Src binding, as well as by FAK-related nonkinase, a dominant interfering FAK mutant. We conclude that β1D and FAK are both components of the hypertrophic response pathway of cardiac myocytes.

ObjectiveArtificial urinary sphincter malfunctions can occur in any of the individual components. Preoperative identification of the malfunctioning component can be valuable for patient counseling and surgical planning. The optimal strategy for repair of failed artificial urinary sphincter components is debated given the relative rarity of the situation. The aim of the present study was to evaluate the relationship of time to failure with failed artificial urinary sphincter component and to compare our outcomes of specific component versus complete device replacement.MethodsFrom 1983 to 2011, 1805 artificial urinary sphincter procedures were carried out at Mayo Clinic (Rochester, Minnesota, USA), of which 1072 patients underwent primary artificial urinary sphincter placement. Clinical variables, including time to failure, were evaluated for association with component failure. Bootstrap analysis was used to estimate the differences in time to reach a fixed percentage of component failure.ResultsA total of 115 patients experienced device failure at a median follow up of 4.2 years. Urethral cuff, abdominal reservoir, scrotal pump and tubing malfunction occurred in 53 (4.9%), 26 (2.4%), 11 (1%) and 25 (2.3%) patients, respectively. Increasing age at the time of primary surgery was protective of cuff malfunction (hazard ratio 0.97, P = 0.04). Time to 3% urethral cuff failure outpaced other component failures (P < 0.05). Secondary failure‐free rates after whole device versus specific component revisions were comparable (P = 0.38).ConclusionsClinical predictors for artificial urinary sphincter failure continue to be difficult to establish. Although single component versus entire device replacement have similar outcomes, if pursuing single component revision, we recommend cuff‐first interrogation in devices in place for >3 years, as this represents the most likely component to fail.

Objective The objective of the study was to evaluate the utility of urodynamic studies performed before primary midurethral sling placement for stress urinary incontinence in predicting the need for subsequent sling release for voiding dysfunction. Methods The health records of women managed with primary synthetic midurethral sling placement at Mayo Clinic (Rochester, MN) from January 1, 2002, to December 31, 2012, were reviewed. The primary outcome was surgical sling release for postoperative voiding dysfunction (ie, prolonged retention, elevated postvoid residual volumes with new voiding symptoms, or de novo onset or worsening of overactive bladder symptoms). Logistic regression models were used to evaluate associations between potential clinical risk factors and the primary outcome. Results Overall, 1629 women underwent primary synthetic midurethral sling placement during the study time frame, including 1081 patients (66%) who underwent a preoperative multichannel urodynamic evaluation. A sling release for voiding dysfunction was performed for 51 patients (3.1%) at a median of 1.9 months postoperatively (interquartile range, 1.3–9.3 months). Patients undergoing sling release were significantly more likely to have had retropubic sling placement (P = 0.003) and concomitant prolapse surgery (P = 0.005). On univariate analysis, no urodynamic parameters were associated with the risk of sling release; evaluated parameters included peak flow rate (P = 0.20), postvoid residual volume (P = 0.37), voiding without detrusor contraction (P = 0.96), and detrusor pressure at maximal flow (P = 0.23). Conclusions Sling release for voiding dysfunction was rare in our cohort. No urodynamic parameters were associated with the risk of sling release.

AbstractBackgroundCriteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non‐suppressed. However, there is no standard definition of what constitutes normal non‐suppressed levels, and data are lacking regarding the potential for surgical cure in these patients.MethodsA retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes.ResultsIn total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p < 0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p = 0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p < 0.001). Average follow‐up was 24 months (range 6–55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p = 0.02). Among patients with normal PTH, those with PTH ≤ 55 pg/mL had an 83% cure rate, whereas those with PTH 56–65 had a 96% cure rate (p = 0.12).ConclusionsParathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are > 55 pg/mL.

Abstract Glioblastoma is the most common primary tumor of the CNS in adults, representing approximately 50% of all gliomas and 15% of primary brain tumors. The current standard of care for GBM is safe maximal surgical resection followed by radiotherapy and concurrent Temozolomide (TMZ), but median survival continues to be 15–16 months. Temozolomide is a second-generation DNA alkylating agent that induces thymine mispairing during DNA replication resulting in tumor cell G2/M phase arrest and autophagy, a standard care of therapy against GBM. While the success of TMZ in clinical trials showed great promise for its overall efficacy, emerging TMZ resistance make us to think more for the combination therapy. CD47, a tumor cell surface marker, plays as “don't eat me signal” through binding its receptor SIRPα on macrophages and the antibody against CD47, which blocks interactions of CD47 with SIRPα, has been shown to lead to tumor destruction. Furthermore, CD47 is a prognostic marker as its expression predisposes cancer patients to a poorer survival outcome. This has significant clinical implications since approximately more than 80% of patients with the most GBMs, overexpress CD47. Overexpression of CD47 is also associated with a decreased probability of survival in clinical cohorts of GBM. Our work and that of others demonstrate that CD47 blockade enables tumor cell phagocytosis by antigen presenting cells (APC), establishing this molecule as a viable therapeutic target in GBM. We additionally investigated the combinatorial effect of CD47 blockade with temozolomide. DNA alkylating agents induce sporadic tumor cell necrosis associated with the extracellular release of damage associated molecular patterns (DAMPs) such as calreticulin, a pro-phagocytic protein whose interaction with low density lipoprotein receptor-related protein 1 (LRP1) facilitates recognition by professional antigen-presenting cells (APCs) and acts as a critical molecular component in promoting immunogenic cell. Our results showed that tumor cell treatment with temozolomide induces plasma membrane expression of calreticulin. Combination therapy resulted in amplified tumor cell phagocytosis and antigen presentation by APC. In addition, preclinical assessment of combination therapy in a syngeneic murine model of GBM resulted in significantly improved survival, characterized by increased intra-tumor penetration of APC cells. These results suggest that the combination of CD47 blockade with temozolomide may enhance tumor immunogenicity, and can improve clinical outcomes demonstrated by mono-therapeutic approaches with conventional chemotherapy. Citation Format: Yaqing Qie, Christina Von Roemeling, Yuanxin Chen, Kevin Shih, Xiujie Liu, Wen Jiang, Joshua Knight, Charles Chan, Irving Weissman, Betty Kim. CD47 blockade with temozolomide can enhance the therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-208. doi:10.1158/1538-7445.AM2017-LB-208