Angled Vortex Fluidic Mediated Multicomponent Photocatalytic and Transition Metal-Catalyzed Reactions.

The dynamic thin film formed in an angled rapidly rotating tube in a vortex fluidic device (VFD) is effective in facilitating multicomponent reactions (MCRs) as photocatalytic or metal-mediated processes. Here, we demonstrate the utility of the VFD by using two known MCRs, an Ugi-type three component reaction and an A3 -coupling reaction. The Ugi-type reaction can be done in either confined or continuous-flow modes of operation of the microfluidic platform whereas the A3 -coupling reaction was optimized for the confined mode of operation. The examples tested gave excellent yields with short reaction times.

Characterization of Zinc Influx Transporters (ZIPs) in Pancreatic ß Cells: ROLES IN REGULATING CYTOSOLIC ZINC HOMEOSTASIS AND INSULIN SECRETION.

Zinc plays an essential role in the regulation of pancreatic ß cell function, affecting important processes including insulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx transporters (ZIPs). In this study, we examined the ß cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human and mouse islets and MIN6 ß cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic ß cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this dysregulated cytosolic zinc homeostasis led to impaired insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast two-hybrid assay. Knock-down of ZIP6 but not ZIP7 in MIN6 ß cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway. Therefore, our data suggest that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in ß cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on ß cell survival.

A new selective fluorescent probe based on tamoxifen.

Developing targeted validation probes that can interrogate biology is of interest for both chemists and biologists. The synthesis of suitable compounds provides a means for avoiding the costly labeling of cells with specific antibodies and the bias associated with the interpretation of biological validation experiments. The chemotherapeutic agent, tamoxifen has been routinely used in the treatment of breast cancer for decades. Once metabolized, the active form of tamoxifen (4-hydroxytamoxifen) competes with the binding of estrogens to the estrogen receptors (ER). Its selectivity in ER modulation makes it an ideal candidate for the development of materials to be used as chemical probes. Here we report the synthesis of a fluorescent BODIPY®FL conjugate of tamoxifen linked through an ethylene glycol moiety, and present proof-of-principle results in ER positive and ER negative cell lines. Optical microscopy indicates that the fluorescent probe binds selectively to tamoxifen sensitive breast cancer cell lines. The compound showed no affinity for the tamoxifen resistant breast cancer lines. The specificity of the new compound make it a valuable addition to the chemical probe tool kit for estrogen receptors.

Single ultrasound-guided platelet-rich plasma injection for treatment of supraspinatus tendinopathy in dogs.

The effect of a single platelet-rich plasma injection for supraspinatus tendinopathy was assessed in 10 dogs. Subjective (owner-assessed) improvement in lameness and function were seen in 40% of dogs with improved tendon heterogeneity and echogenicity in 60%. There were no significant changes in gait reaction forces 6 wk after treatment.

Injection unique de plasma riche en plaquettes guidée par échographie pour le traitement d'une tendinopathie du muscle sus-épineux chez les chiens. L'effet d'une seule injection de plasma riche en plaquettes pour traiter une tendinopathie du muscle sus-épineux a été évalué chez 10 chiens. L'amélioration subjective (évaluation par les propriétaires) a été observée chez 40 % des chiens et 60 % ont manifesté une amélioration de l'hétérogénécité et de l'échogénicité du tendon. Il n'y a pas eu de changements significatifs des forces de réaction de la démarche 6 semaines après le traitement.(Traduit par Isabelle Vallières).

Gender differences in ergonomics during simulated ureteroscopy.

BACKGROUND: Female urologists report higher rates of work-related physical discomfort compared to male urologists. We compared ergonomics during simulated ureteroscopy, the most common surgery for kidney stones, between male and female urologists. METHODS: Surface electromyography was used to measure muscle activation during common ureteroscopic tasks in urology trainees and staff with different surgeon positions and ureteroscopes. Subjective workload was assessed using the NASA Task Load Index (NASA-TLX). Paired t-tests, Wilcoxon rank-sum tests, and multivariate regressions were used to compare muscle activation by gender for each trial condition. RESULTS: There was no difference in age or distribution of training level between genders, though men had larger glove sizes. Across all conditions, women required greater muscle activation in multiple muscle groups and had greater NASA-TLX scores compared to men. CONCLUSIONS: There may be gender differences in ergonomics during ureteroscopy based on muscle activation and subjective workload, suggesting potential for personalizing surgical ecosystems.

Clinical validation of an audio-based uroflowmetry application in adult males.

INTRODUCTION: Uroflowmetry is a common test to evaluate lower urinary tract symptoms. Audio-based uroflowmetry is a novel, alternative approach that determines urine flow by measuring sound. Available as a smartphone application, it has potential for screening and monitoring common urological pathologies, particularly in out-of-office environments. This study is the first to evaluate audio-based uroflowmetry in a clinical setting against the gold standard. METHODS: Adult male patients (n=44) attending a general urology clinic were recruited. Audio-based uroflowmetry and conventional uroflowmetry were performed concurrently. Pearson correlation and Bland-Altman analysis were used to compare performance with respect to max flow, time to max flow, and total voiding time. Symmetric mean absolute percentage error (SMAPE) was used to compare curve shapes. Repeatability was evaluated separately in three healthy volunteers using repeat measures correlation. RESULTS: Among urology clinic patients, the correlation for max flow was 0.12. Correlation for time to max flow was 0.46, with limits of agreement of -120-165%. Correlation for total voiding time was 0.91, with limits of agreement of -41-38%. The SMAPE for curve shape was 32.6%, with corresponding accuracy of 67.4%. Among healthy volunteers, the repeat measures correlation for max flow was 0.72. CONCLUSIONS: Audio-based uroflowmetry was inconsistent in evaluating flow rate, attributable to high variability and difficult standardization for acoustic signals. Performance improved with respect to temporal variables, as well as flow curve shape. Further work evaluating intra-patient reliability and pathology-specific performance is required to fully evaluate audio-based uroflowmetry as a screening or monitoring tool.

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity.

Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor-associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

Multimodal imaging needle combining optical coherence tomography and fluorescence for imaging of live breast cancer cells labeled with a fluorescent analog of tamoxifen.

SIGNIFICANCE: Imaging needles consist of highly miniaturized focusing optics encased within a hypodermic needle. The needles may be inserted tens of millimeters into tissue and have the potential to visualize diseased cells well beyond the penetration depth of optical techniques applied externally. Multimodal imaging needles acquire multiple types of optical signals to differentiate cell types. However, their use has not previously been demonstrated with live cells. AIM: We demonstrate the ability of a multimodal imaging needle to differentiate cell types through simultaneous optical coherence tomography (OCT) and fluorescence imaging. APPROACH: We characterize the performance of a multimodal imaging needle. This is paired with a fluorescent analog of the therapeutic drug, tamoxifen, which enables cell-specific fluorescent labeling of estrogen receptor-positive (ER+) breast cancer cells. We perform simultaneous OCT and fluorescence in situ imaging on MCF-7 ER+ breast cancer cells and MDA-MB-231 ER- cells. Images are compared against unlabeled control samples and correlated with standard confocal microscopy images. RESULTS: We establish the feasibility of imaging live cells with these miniaturized imaging probes by showing clear differentiation between cancerous cells. CONCLUSIONS: Imaging needles have the potential to aid in the detection of specific cancer cells within solid tissue.

Clinical outcomes of surgically managed ectopic ureters in 33 dogs.

Factors that predict postoperative continence and incontinence were evaluated in 33 female dogs with surgically corrected ectopic ureters. The current study found that intramural or extramural, left- or right-sided, and unilateral or bilateral ectopic ureters were not significant factors influencing postoperative incontinence in affected dogs. The presence of either hydroureter or urinary tract infection was also not significantly associated with postoperative incontinence. Dogs with ectopic ureters that were incontinent postsurgically tended to remain unresolved.

Rating of Pelvic Floor Muscle Training Mobile Applications for Treatment of Urinary Incontinence in Women.

OBJECTIVE: To identify pelvic floor muscle therapy mobile health applications (apps) targeting women with urinary incontinence (UI), and evaluate them in a standardized fashion. METHODS: A systematic search of English language apps on the Canadian App Store (iOS) and Google Play (Android) Store was performed. Eligible apps were evaluated independently by 5 reviewers using the validated Mobile App Rating Scale (MARS) tool. Descriptive characteristics were summarized and MARS subscale and overall quality scores werereported. RESULTS: Of 139 mobile health apps identified, 20 unique apps were included for full review, of which there were 7 iOS only apps, 6 Android only apps, and 7 apps available in both stores. At the time of analysis, most apps had been updated within the last year (60%). Only 1 app had been trialed and verified by evidence in scientific literature. The majority of apps were free to download (80%). The median (interquartile range) MARS overall quality score was 3.7 (0.8) on a 0-5 scale, ranging from 2.7 to 4.1. The highest-rated subscale was "functionality" with a median score of 4.1 (0.6); the lowest-rated was "information" with a median score of 3.4 (0.6). The median MARS subjective quality score was 2.9 (1.0). CONCLUSION: There are both free and paid apps available on-line that deliver pelvic floor muscle therapy programs. Evaluation using the MARS tool identified that many apps are not of high quality, and only 1 was evidence-based and has been trialed clinically. This knowledge is relevant to the choice of apps by both patients and caregivers.

Fluorescent triphenyl substituted maleimide derivatives: synthesis, spectroscopy and quantum chemical calculations.

In this paper we describe a semi-empirical quantum method for predicting the wavelength of maximum fluorescence excitation and emission for several known and new maleimide derivatives. All new maleimides, containing a N-Benzyl attachment, were successfully synthesised via a tandem Suzuki reaction with aryl boronic acids containing either an electron donating, electron withdrawing functional groups. Absorption and emission spectra calculated using the semi-empirical AM1 method with excited state ZINDO calculations proved more reliable than either Hartree-Fock Configuration interaction or time dependent density functional methods. Calculated absorption and emission wavelengths were compared with 26 experimental spectra from known or newly synthesised maleimides and found to have provide reasonable predictions, with an average deviation of less the 6% for absorption maxima and less than 4% for emission peaks. The described method provides a strong benchmark for the accuracy that can be expected from theoretical predictions of fluorescence spectra.

Growth rates and outcomes of observed large renal masses.

INTRODUCTION: The natural history of small renal masses has been well defined, leading to the recommendation of active surveillance in some patients with limited life expectancy. However, this information is less clear for large renal masses (LRM), leading to ambiguity for management in the older, comorbid patient. The objective of this study was to define the natural history, including the growth rate and metastatic risk, of LRM in order to better counsel patients regarding active surveillance. METHODS: This was a retrospective review of patients with solid renal masses >4 cm that had repeated imaging identified from an institutional imaging database. Patient comorbidities and outcomes were obtained through retrospective chart analysis. Outcomes assessed included tumour growth and metastatic rates, as well as cancer-specific (CSS) and overall survival (OS) usimg Kaplan-Meier methodology. RESULTS: We identified 69 patients between 2005 and 2016 who met the inclusion criteria. Mean age at study entry was 75.5 years; mean tumour maximal dimension at study entry was 5.6 cm. CSS was 83% and OS 63% for patients presenting without metastasis, with a mean followup of 57.5 months. The mean growth rate of those that developed metastasis during followup (n=15) was 0.98 cm/year (95% confidence interval [CI] 0.33-1.63) as compared to those that did not develop metastasis (n=46), with a growth rate of 0.67 cm/year (95% CI 0.34-1) (non-significant). Seven patients had evidence of metastasis at the baseline imaging of their LRM and had subsequent growth rate of 1.47 cm/year (95% CI 0.37-2.57) (non-significant) CONCLUSIONS: Compared to small renal masses, LRM are associated with higher metastasis rates and lower CSS and more rapid growth rates. Selection criteria for recommending observation of LRM in older, comorbid patients should be more conservative than for small renal masses.

Benign inverted papilloma at bladder neck causing acute urinary retention.

Inverted papilloma of the urinary tract is a rare benign lesion. A 59-year-old male who presented with the chief complaint of gross hematuria and acute urinary retention is described. Cystoscopy revealed a solitary, papillary tumor at the bladder neck. Transurethral resection was performed, and histological examination revealed a pathological diagnosis of inverted papilloma. Following resection, the patient was able to void without difficulty. This is an interesting case of acute urinary retention secondary to an inverted papilloma at the bladder neck causing intermittent outlet obstruction, and we review the literature on inverted papilloma of the bladder.

A mechanism-based GlcNAc-inspired cyclophellitol inactivator of the peptidoglycan recycling enzyme NagZ reverses resistance to ß-lactams in Pseudomonas aeruginosa.

The development of a potent mechanism-based inactivator of NagZ, an enzyme critical to the production of inducible AmpC ß-lactamase in Gram-negative bacteria, is presented. This inactivator significantly reduces MIC values for important ß-lactams against a clinically relevant strain of Pseudomonas aeruginosa.

HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen-Loss Variants.

Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275. Drug delivery subverted the phenotype of tumor-infiltrating CD11b+ Ly6Chi Ly6G- myeloid cells, favoring NOS2/ROS secretion and pro-inflammatory genes characteristic of M1 polarization. Simultaneously, MS-275 abrogated the immunosuppressive function of tumor-infiltrating myeloid cells and reprogrammed them to eliminate antigen-negative tumor cells in a caspase-dependent manner. Elevated IFN-γ within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-γR/STAT1 signaling axis. Exploiting tumor-infiltrating myeloid cell plasticity thus complements T cell therapy in targeting tumor heterogeneity and immune escape.

Study habits of Canadian urology residents: Implications for development of a competence by design curriculum.

INTRODUCTION: The purpose of this study was to evaluate the study habits of Canadian urology residents throughout their residency training. METHODS: A survey was administered to all final-year Canadian urology residents over a two-year period. Sixty-seven respondents answered a survey consisting of 54 questions scored on a 10-point Likert score. The survey addressed study habits throughout training, motivations for studying, and preferred resources used. RESULTS: Dedication to studying was directly correlated with proximity to the Royal College of Physicians and Surgeons of Canada (RCPSC) exam. Ninety-six percent of residents reported studying over 10 hours per week during their chief year compared to 0% during their junior year. As residents progressed in their training, preparation for the Royal College exam became the greatest motivator for studying. There was considerable variability in study methods and study resources used throughout training. In their chief year, residents found such resources as the textbook Campbell-Walsh, AUA updates, CUA and AUA guidelines, and the study notes of former trainees to be valuable for their preparation. Teaching rounds, journal clubs, and reading current urological literature were found to be les helpful. Forty-six percent of all residents surveyed indicated that they would prefer writing their RCPSC exam one year earlier than the current timing. CONCLUSIONS: This study provides insight into study habits of Canadian urology residents. This data may be helpful in shaping the future of urology training programs and examinations within Canada and elsewhere.

Ovarian vein thrombosis: A complication of percutaneous nephrolithotomy.

The medical and surgical complications of percutaneous nephrolithotomy (PCNL) are well-known, including deep venous thrombosis. Ovarian vein thrombosis (OVT) is a rare, but potentially serious type of venous thrombosis that has not previously been reported as a complication of PCNL or ureteral stent placement. We report a case of OVT associated with ureteral stenting following a tubeless PCNL. This complication was successfully managed conservatively without any short- or long-term sequelae.

TP53-induced glycolysis and apoptosis regulator promotes proliferation and invasiveness of nasopharyngeal carcinoma cells.

The TP53-induced glycolysis and apoptosis regulator (TIGAR) is the protein product of the p53 target gene, C12orf5. TIGAR blocks glycolysis and promotes cellular metabolism via the pentose phosphate pathway; it promotes the production of cellular nicotinamide adenine dinucleotide phosphate (NADPH), which leads to enhanced scavenging of intracellular reactive oxygen species, and inhibition of oxidative stress-induced apoptosis in normal cells. Our previous study identified a novel nucleoside analog that inhibited cellular growth and induced apoptosis in nasopharyngeal carcinoma (NPC) cell lines via downregulation of TIGAR expression. Furthermore, the growth inhibitory effects of c-Met tyrosine kinase inhibitors were ameliorated by the overexpression of TIGAR in the NPC cell lines. These results indicate a significant role for TIGAR expression in the survival of NPCs. The present study aimed to further define the function of TIGAR expression in NPC cells. In total, 36 formalin-fixed, paraffin-embedded NPC tissue samples were obtained for the immunohistochemical determination of TIGAR expression. The effects of TIGAR expression on cell proliferation, NADPH production and cellular invasiveness were also assessed in NPC cell lines. Overall, TIGAR was overexpressed in 27/36 (75%) of the NPC tissues compared with the adjacent non-cancer epithelial cells. Similarly, TIGAR overexpression was also observed in a panel of six NPC cell lines compared with normal NP460 hTert and Het1A cell lines. TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness of the NPC cell lines, whereas a knockdown of TIGAR expression resulted in significant inhibition of cellular growth and invasiveness. The expression of the two mesenchymal markers, fibronectin and vimentin, was increased by TIGAR overexpression, but reduced following TIGAR-knockdown. The present study revealed that TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness, and the maintenance of a mesenchymal phenotype, in NPC tissues.