Pain Related to Intradetrusor BotulinumtoxinA: A Randomized Clinical Trial.

IMPORTANCE: OnabotulinumtoxinA (BTX-A) is an effective treatment for overactive bladder (OAB), but few studies have been done to evaluate injection techniques. OBJECTIVE: The primary objective was to evaluate procedural discomfort between 2 commonly used injection techniques for BTX-A. STUDY DESIGN: This was a single-blinded, randomized clinical trial of women undergoing injection of 100 U BTX-A for idiopathic OAB. Patients were randomized to 5 mL/5 injection or 10 mL/10 injection groups. Bladder pain was assessed by a validated Numeric Pain Rating Scale. Overactive bladder symptoms were assessed with a standardized questionnaire (Overactive Bladder Questionnaire Short Form). Patient satisfaction, treatment efficacy, and adverse events were assessed at 30 days after procedure. RESULTS: One hundred eight patients were randomized to 52 in the 5 mL/5 injection arm and 56 in the 10 mL/10 injection arm. Mean procedural pain scores were 3.2 (±2.3) in the 5 mL/5 injection group versus 3.6 (±2.1) in the 10 mL/10 injection group (P = 0.21). No difference was found when categorizing pain scores into ordinal outcomes of low (P = 0.55), medium (P = 0.70), and high (P = 1.0) or a binary outcome of low (P = 0.55) versus medium + high (P = 0.55). Multivariate analyses did not effect statistical significance between the 2 groups for the ordinal outcome (odds ratio = 1.86; 95% confidence interval = 0.77 = 4.52; P = 0.17) or the binary outcome (odds ratio = 1.81; 95% confidence interval = 0.68-4.77; P = 0.28). No difference was observed between overall patient satisfaction, global impression of improvement, Overactive Bladder Questionnaire Short Form scores, or adverse outcomes. CONCLUSIONS: Procedural discomfort related to BTX-A injection for idiopathic OAB was not different between 2 injection protocols. Overall satisfaction was high for both groups, and there was no difference in symptom scores or adverse events.

Prospective Evaluation of Intradetrusor Injections of OnabotulinumtoxinA in Adults With Spinal Dysraphism.

OBJECTIVE: To prospectively evaluate the effectiveness of OnabotulinumtoxinA (BTX-A) on neurogenic overactive bladder (nOAB) in adults with congenital spinal dysraphism (CSD). METHODS: We conducted a prospective, nonrandomized pilot study of 24 adults with CSD and neurogenic overactive bladder. Patients were evaluated with baseline video-urodynamics (UDS) and validated questionnaires, underwent injection 200U BTX-A, and then underwent repeat evaluation with questionnaires and UDS 1-3 months postinjection. A high-risk subgroup was separately analyzed based on adverse clinical characteristics (ie, decrease bladder compliance, vesicoureteral reflux, hydronephrosis, chronic kidney disease). RESULTS: BTX-A injection improved patient recorded outcome measures seen in both I-QOL Score total (67.9 vs 75.5, P = .007) and Neurogenic Bladder Symptom Score total (38.0 vs 29.0, P = .001). On UDS, BTX-A injection significantly improved end filling pressure (16.0 vs 8.8, P = .036) and also improved bladder compliance (mL/cm H2O) (89.38 vs 135.81, P = .445). High-risk patients were found to have similar improvements in most subjective questionnaire scoring, a significant decrease in end filling pressures, and improved bladder compliance on UDS. CONCLUSION: BTX-A can be used as an effective treatment in adults with CSD. We found that BTX-A significantly improved quality of life from patient reported outcome measurements as well as improving end filling pressures and bladder compliance. These improvements were seen even within our high-risk subgroup. Further studies are needed to evaluate long-term efficacy and appropriate follow-up of this at-risk population.

Management of Recurrent Urinary Tract Infections in Women: How Providers Can Improve the Patient Experience.

OBJECTIVE: To provide guidance to providers on how to improve the patient experience for women with recurrent urinary tract infections (rUTIs). METHODS: The recently updated 2019 American Urological Association (AUA) guidelines for recurrent uncomplicated acute cystitis and other contemporary publications pertaining to recurrent UTIs in women were reviewed. These data were used to summarize practice-based methodology to formulate recommendations with an emphasis on education to enhance the patient experience. RESULTS: We summarize the guideline-based management of patients with rUTI and augment this with a patient-focused perspective to provide recommendations for how to best counsel patients regarding evaluation, treatment using antibiotic stewardship practices, and a comprehensive prevention plan. We focus on patient education as the foundation for successful provider-patient relationships as well as patient compliance with care pathways. CONCLUSION: rUTIs are costly, time-consuming, and painful for patients. For providers, rUTIs represent a frustrating aspect of clinical care facing the balance of antibiotic stewardship with effective treatment and patient expectations with limited data supporting nonantibiotic therapies. Urologists have the skills and knowledge to provide this patient population with competent and compassionate care. By investing in these patients, being responsive to their concerns and offering education, patients will have a better overall experience with this chronic condition.

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.

Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors.

Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in in vivo cancer models harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 wild-type, or acquired mutations G595R and G667C in vitro and in vivo. Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naïve patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.

Procedure Choice in Primary Versus Recurrent Prolapse: A Study of Fellowship-Trained Surgeons.

OBJECTIVE: This retrospective study describes procedures of choice in management of patients with primary prolapse compared with recurrence prolapse patients by fellowship-trained surgeons. METHODS: Surgically managed primary and recurrent prolapse cases from 2012 to 2015 at Houston Methodist Hospital were reviewed. Baseline characteristics, compartment defects, and stage were compared. Mean interval from the index surgeries to management of prolapse recurrence was recorded. In recurrence cases, mesh complaints were noted if present. Primary outcome was the procedure type used to manage cases of recurrence and primary prolapse. Logistic regression was used to determine odds ratio (OR) for the procedure of choice in recurrence and primary repairs of prolapse. RESULTS: Of 386 cases reviewed, 379 met criteria for inclusion; 25.8% of repairs were for recurrence. Recurrence patients were significantly older than primary cases (mean, 63.6 vs 60.5; P = 0.03) and had been postmenopausal for longer (P = 0.004). Median time interval to surgical management of recurrence was 8 years. Thirty percent of recurrence patients treated previously by mesh had mesh complaints. There was no difference in the distribution of defects or stage. Sacrocolpopexy was more frequently used to manage recurrent prolapse (OR, 2.6334; P < 0.0005). Vaginal mesh repairs showed no difference in utilization. Uterosacral ligament fixation (OR, 0.347; P = 0.002) was used more often in primary prolapse. Anterior colporrhaphy (OR, 0.398; P = 0.0005) and uterosacral ligament fixation (OR, 0.347; P = 0.002) were performed less in recurrence cases. CONCLUSION: Fellowship-trained urogynecologists at this institution utilize sacrocolpopexy mesh more frequently in recurrent prolapse, and uterosacral ligament fixation was used more frequently in primary prolapse cases.

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2-M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma.Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma.Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature.Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR.

Outcomes in Pelvic Organ Prolapse Surgery in Women Using Chronic Antithrombotic Therapy.

INTRODUCTION: Chronic antithrombotic therapy is common among patients requiring surgery for pelvic organ prolapse because of age and comorbidities. The impact of chronic anticoagulation on postoperative complications in pelvic organ prolapse surgery has not been investigated. This study aims to determine if patients on chronic antithrombotic therapy are at increased risk for postoperative complications. METHODS: This retrospective cohort study included women having prolapse surgery from 2012 to 2015, identified by Current Procedural Terminology codes, excluding patients undergoing concomitant major nonurogynecologic procedures. Baseline characteristics were compared and all procedures performed, operative duration, estimated blood loss, and length of hospitalization. Complications (blood transfusion, intensive care unit admission, reoperation, readmission, hematoma, thromboembolic event, and infection) were compared in women on chronic antithrombotic therapy and controls. Logistic regression determined odds ratio (OR) for complications in patients on chronic antithrombotics. Complications were graded by the Clavien-Dindo classification. RESULTS: A total of 388 charts were reviewed, and 386 patients met inclusion criteria. Twenty-one of the 386 patients were on chronic antithrombotic therapy. Chronic antithrombotic therapy increased overall complications (OR, 6.8; P < 0.0005), blood transfusion (OR, 165; P < 0.001), intensive care unit admission (OR, 19.10; P < 0.004), hospital readmission (OR, 20.7; P < 0.0005), vaginal hematoma (OR, 554.1; P < 0.001), infection (OR, 22.44; P < 0.004), and complications that required specific additional follow-up (OR, 9.42; P < 0.0005). There were no thromboembolic events. Antithrombotic therapy did not significantly increase reoperation rates (OR, 3.8; P = 0.275). Findings were maintained when adjusting for covariates of age and body mass index. CONCLUSIONS: Postoperative surgical complications after prolapse repair procedures are increased in patients who use chronic antithrombotic medication, the majority of cases are successfully managed conservatively.

Stromal-Based Signatures for the Classification of Gastric Cancer.

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.

Inhibition of CXCR4 by LY2624587, a Fully Humanized Anti-CXCR4 Antibody Induces Apoptosis of Hematologic Malignancies.

SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin's lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies.

Does Sexual Assault Nurse Examiner (SANE) Training Affect Attitudes of Emergency Department Nurses Toward Sexual Assault Survivors?

There are over 243,800 female sexual assaults in the United States annually. Of those who seek healthcare services after being sexually assaulted, 90% present to hospitals. Unfortunately, care and services for women who have been sexually assaulted are inconsistent. Increased burnout, frustration, and feelings of inadequacy can lead healthcare providers to exhibit personal biases or negative attitudes toward their patients. The Joint Commission, responsible for accreditation of healthcare organizations, has stated that nurses must provide competent care to all patients. Therefore, Sexual Assault Nurse Examiner (SANE) training needs to be available for emergency department (ED) nurses who care for patients who have been sexually assaulted. A survey using the Attitude Toward Rape Victims Scale was sent to 1503 ED nurses throughout the United States, from the Emergency Nursing Association's mailing list. The results of the survey showed that there was a significant difference in attitudes toward the patients between SANE-trained emergency nurses and those without training. This study also showed that 35.5% of hospitals represented by the respondents did not have SANE services available for adult patients who had been sexually assaulted, and furthermore, 85.5% of the respondents who cared for adult patients who had been sexually assaulted were not SANE trained. The negative attitudes held toward such patients as found in this study, coupled with a lack of training provides evidence that ED nurses may benefit from education related to appropriate treatment for patients who have been sexually assaulted. As evidence-based practice becomes the gold standard of care, ensuring that nurses are properly trained to care for all patients must be the goal.

The Single-Incision Sling to Treat Female Stress Urinary Incontinence: A Dynamic Computational Study of Outcomes and Risk Factors.

Dynamic behaviors of the single-incision sling (SIS) to correct urethral hypermobility are investigated via dynamic biomechanical analysis using a computational model of the female pelvis, developed from a female subject's high-resolution magnetic resonance (MR) images. The urethral hypermobility is simulated by weakening the levator ani muscle in the pelvic model. Four positions along the posterior urethra (proximal, midproximal, middle, and mid-distal) were considered for sling implantation. The α-angle, urethral excursion angle, and sling-urethra interaction force generated during Valsalva maneuver were quantitatively characterized to evaluate the effect of the sling implantation position on treatment outcomes and potential complications. Results show concern for overcorrection with a sling implanted at the bladder neck, based on a relatively larger sling-urethra interaction force of 1.77 N at the proximal implantation position (compared with 0.25 N at mid-distal implantation position). A sling implanted at the mid-distal urethral location provided sufficient correction (urethral excursion angle of 23.8 deg after mid-distal sling implantation versus 24.4 deg in the intact case) with minimal risk of overtightening and represents the optimal choice for sling surgery. This study represents the first effort utilizing a comprehensive pelvic model to investigate the performance of an implanted sling to correct urethral hypermobility. The computational modeling approach presented in the study can also be used to advance presurgery planning, sling product design, and to enhance our understanding of various surgical risk factors which are difficult to obtain in clinical practice.

Pelvic Organ Prolapse in Female Patients Presenting to Transitional Urology Care Clinic.

PURPOSE: Patients with congenital genitourinary abnormalities are growing into adulthood and their expectations, especially in the areas of sexual function and fertility are creating unforeseen challenges for health care providers. We review the incidence and management of pelvic organ prolapse at our Transitional Urology Clinic. MATERIALS AND METHODS: This study is a retrospective chart review of the presentation and treatment of patients with clinically bothersome pelvic organ prolapse seen at our tertiary Transitional Urology Clinic during 2012 to 2015. RESULTS: Seven patients with a mean age of 22.8 years presented to our clinic with clinically bothersome prolapse. Four patients had myelomeningocele, 2 had sacral agenesis and 1 had bladder exstrophy. All were on self-catheterization. Three patients were sexually active and 1 had an intact uterus and desired fertility. Bothersome symptoms included vaginal bulge in 6 cases, difficult vaginal intercourse in 1 and difficult catheterization in 1. For the leading edge of Bp (anterior compartment) prolapse the median POP-Q (Pelvic Organ Prolapse Quantification System) stage was 3 (range 1 to 3), for Bp (posterior compartment) prolapse it was 1 (range 0 to 3) and for C (vaginal vault or cervical) prolapse it was 2 (range 1 to 3). Management included pessary in 1 case, hysterectomy with bilateral uterosacral ligament suspension in 4, sacrocolpopexy in 1 and observation in 1. Mean followup was 17.6 months (range 1 to 92). One of the 5 patients treated with surgical intervention had recurrence in the anterior compartment and vaginal vault. CONCLUSIONS: Females with congenital genitourinary anomalies present with pelvic organ prolapse at a much younger age and a more advanced stage. There is a paucity of literature on the epidemiology, presentation and management of pelvic organ prolapse in this patient population.

Robotic Intracorporeal Continent Cutaneous Urinary Diversion: Primary Description.

The purpose is to present the first report and describe our novel technique for intracorporeal continent cutaneous diversion after robotic cystectomy. After completion of robot-assisted cystectomy using a standard six-port transperitoneal technique, three additional ports are placed, and the robot is redocked laterally over the patient's right side in the modified lateral position. Our technique replicates step-by-step the principles of the open approach. Ileocolonic anastomosis, ureteroenteral anastomoses, and construction of a hand-sewn right colonic pouch are all performed intracorporeally. Tapering of efferent ileal limb and reinforcement of the ileocecal valve are performed via the extraction site, while the stoma is matured through a prospective port site. Successful robotic intracorporeal creation of a modified Indiana pouch was achieved. Operative time for diversion was 3 hours, with negligible blood loss, and without any intraoperative complications. No major (Clavien III-V) 90-day complications were observed. At a follow-up of 1 year, the patient continues to catheterize without difficulty. We demonstrate the first description of robotic intracorporeal continent cutaneous urinary diversion after robot-assisted cystectomy. We present a systematic minimally invasive approach, replicating the principles of open surgery, which is technically feasible and safe with a good functional result.

The association of urinary nerve growth factor levels with bladder outlet obstruction in women.

OBJECTIVES: Nerve growth factor (NGF) has been proposed as a urinary biomarker and previously shown to be elevated in male patients with bladder outlet obstruction (BOO) and other lower urinary tract symptoms. No published studies have examined NGF as a potential urinary biomarker in women with BOO. The aims of this prospective study were to evaluate NGF levels in urine from women with anatomic BOO resulting from pelvic organ prolapse (POP) and/or previous incontinence surgery and to measure the effect associated with surgical or conservative management. METHODS: From January to September 2012, all female patients referred for evaluation and management of BOO from POP or previous incontinence surgery were screened for enrollment. Inclusion criteria included elevated postvoid residual, valsalva voiding on urodynamics, or urinary peak flow (Qmax) of 12 mL/s or less. A control group of 10 asymptomatic age-matched female volunteers was also recruited. In all subjects, urinary NGF and creatinine (Cr) levels were measured and normalized to the urinary Cr concentrations (NGF/Cr). Urinary NGF levels were measured at 1 month and 3 months after either surgical correction or initiation of clean intermittent catheterization. RESULTS: A total of 10 female patients with anatomic BOO (mean [SD] age of 66.2 [3.88] years) and 10 female control subjects (mean [SD] age of 62 [7] years) were recruited. Nine patients had POP. Six patients had undergone a previous anti-incontinence procedure. Five patients had both POP and undergone a previous anti-incontinence procedure. The urinary NGF/Cr levels in the study patients with BOO (mean [SE] 20.8 [4.31] pg/mg) were significantly higher (P = 0.0001) than the levels in the age-matched control group (5.6 [0.65] pg/mg). After treatment, the urinary NGF/Cr level significantly decreased to 6.50 (0.57) pg/mg (P = 0.01) CONCLUSIONS: In this study, female patients with anatomic BOO resulting from POP and/or previous incontinence surgery had significantly higher urinary NGF/Cr levels when compared with age-matched controls. After treatment, the urinary NGF/Cr levels significantly decreased.

Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models.

Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.

Emotional intelligence and spiritual well-being: implications for spiritual care.

Understanding factors that influence spiritual well-being may improve nurses' spiritual caregiving. This study examined relationships between emotional intelligence (EI) and spiritual well-being (SWB) in undergraduate and graduate nursing students. Using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and the spiritual well-being scale (SWBS) relationships were found between managing emotion and spiritual well-being, and managing emotion and existential well-being. Implications for education and practice are discussed.

A method to assess target gene involvement in angiogenesis in vitro and in vivo using lentiviral vectors expressing shRNA.

Current methods to study angiogenesis in cancer growth and development can be difficult and costly, requiring extensive use of in vivo methodologies. Here, we utilized an in vitro adipocyte derived stem cell and endothelial colony forming cell (ADSC/ECFC) co-culture system to investigate the effect of lentiviral-driven shRNA knockdown of target genes compared to a non-targeting shRNA control on cord formation using High Content Imaging. Cord formation was significantly reduced following knockdown of the VEGF receptor VEGFR2 in VEGF-driven cord formation and the FGF receptor FGFR1 in basic FGF (bFGF)-driven cord formation. In addition, cord formation was significantly reduced following knockdown of the transcription factor forkhead box protein O1 (FOXO1), a protein with known positive effects on angiogenesis and blood vessel stabilization in VEGF- and bFGF-driven cord formation. Lentiviral shRNA also demonstrated utility for stable knockdown of VEGFR2 and FOXO1 in ECFCs, allowing for interrogation of protein knockdown effects on in vivo neoangiogenesis in a Matrigel plug assay. In addition to interrogating the effect of gene knockdown in endothelial cells, we utilized lentiviral shRNA to knockdown specificity protein 1 (SP1), a transcription factor involved in the expression of VEGF, in U-87 MG tumor cells to demonstrate the ability to analyze angiogenesis in vitro in a tumor-driven transwell cord formation system and in tumor angiogenesis in vivo. A significant reduction in tumor-driven cord formation, VEGF secretion, and in vivo tumor angiogenesis was observed upon SP1 knockdown. Therefore, evaluation of target gene knockdown effects in the in vitro co-culture cord formation assay in the ADSC/ECFC co-culture, ECFCs alone, and in tumor cells translated directly to in vivo results, indicating the in vitro method as a robust, cost-effective and efficient in vitro surrogate assay to investigate target gene involvement in endothelial or tumor cell function in angiogenesis.