Neoadjuvant Chemotherapy as a Risk Factor for Urinary Anastomotic Leak in Patients Undergoing Radical Cystectomy

Muscle-invasive bladder cancer (MIBC) represents approximately 25% of all bladder cancer and carries a significant risk of mortality. Neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) is the standard of care for MIBC. One complication associated with RC is ureteral anastomotic leak with a predicted rate of 3%. The objective of this National Surgical Quality Improvement Project (NSQIP) database analysis is to determine if correlations exist between radiation (RAD) and/or NAC before RC and anastomotic leak in the treatment of MIBC

Association of Prematurity and Urogenital Comorbidities with Postoperative Outcomes of Ureteroneocystostomy for Vesicoureteral Reflux

Background: It is estimated that 20-30% of congenital anomalies involve the kidney and ureter, and these rates are even higher in infants with low birth weights. Vesicoureteral reflux (VUR) occurs when there is a backflow of urine from the bladder to the kidney. Depending on severity, this condition may require surgical correction with ureteroneocystostomy (UNC). The impact of premature birth and presence of urogenital comorbidities on outcomes of UNC is not known. The objective of this study is to determine the relationship between premature birth and urogenital comorbidities with operative outcomes of UNC for VUR. Methods: The 2020 American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database was analyzed for patients undergoing UNC for VUR. 1742 patients were evaluated with 1623 meeting inclusion criteria. The patients were divided into full term (\u3e37 weeks gestation at birth) and preterm (birth). Patient demographics, comorbid conditions, urogenital comorbidities, and outcomes were evaluated. Further analysis of factors associated with ectopic ureter was performed. Results: Out of 1623 UNC patients analyzed, 8.6% were preterm and 91.4% were full term. In basic statistics, bronchopulmonary dysplasia, esophageal/gastric/intestinal disease, developmental delay, structural CNS abnormality, neuromuscular disorder, nutritional support, congenital malformation, cardiac risk factors, ASA classification, gestational age, and urogenital comorbidities were significantly associated with prematurity. Univariate and multivariate analysis revealed that congenital malformation (p=0.007), major cardiac risk factors (p=0.002), and gestational age of 35-36 weeks are significantly associated with risk of ectopic ureter (p\u3c0.001). Conclusion: While prematurity alone is not associated with incidence of VUR, preterm patients undergoing UNC have a significantly higher risk of postoperative complications despite no differences in operative approach, VUR disease severity, and prior VUR procedure compared to full term patients undergoing this procedure. Preterm patients tend to have more comorbidities which may contribute to this finding. Ectopic ureter is associated with prematurity and factors such as congenital malformations and major cardiac risk factors may increase the risk for ectopic ureter in this population

Cardioprotective Effects of Selective Mitochondrial-Targeted Antioxidants in Myocardial Ischemia/Reperfusion (I/R) Injury

During myocardial ischemia, coronary blood flow interruption deprives cardiomyocytes of oxygen, glucose and fatty acids. Ischemic damage is exacerbated by a burst of reactive oxygen species (ROS) generated at reperfusion when oxygen interacts with damaged mitochondrial electron transport chains (ETC), especially uncoupled complexes I and III (Fig. 1,2). Nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity can also release ROS, inducing additional tissue/organ damage. Surgical intervention or thrombolytic treatments can restore coronary blood flow. However, as blood flow reestablishes, oxidative stress leads to I/R injury. Clinical treatment remains a challenge as no pharmaceutical agents effectively limit I/R-induced damage. Mitochondria are implicated in I/R as a major source of ROS3,4,5. Excess ROS leads to mitochondrial and cardiac contractile dysfunction6. Conventional antioxidants have limited efficacy in myocardial I/R because they are not targeted selectively to where most I/R damage occurs, in mitochondria (Fig. 3)3,4,5. Mitoquinone (mitoQ, MW=600 g/mol), a coenzyme Q analog, easily crosses phospholipid bilayers and is driven by the large electrochemical membrane potential to concentrate mitoQ several hundred-fold within mitochondria. The respiratory chain reduces mitoQ to its active ubiquinol antioxidant form to limit myocardial I/R injury5. The SS-31 (Szeto-Schiller) peptide ((D-Arg)-Dmt-Lys-Phe-Amide, MW=640 g/mol, Genemed Synthesis, Inc., San Antonio, TX) is also of interest since it is cellpermeable, specifically targeted to inner mitochondrial membranes based on its alternating cationic aromatic residue sequence, with an antioxidant dimethyltyrosine moeity. SS peptides scavenge ROS in I/R models. Although mitochondrial-targeted antioxidant pretreatment can effectively limit I/R injury, pretreatment is not always possible in cases of myocardial infarction. Therefore, evaluating cardioprotective efficacy of mitochondrialtargeted antioxidants when given at reperfusion is of high significanc

Cardioprotective Effects of Cell Permeable NADPH oxidase inhibitors in Myocardial Ischemia/Reperfusion Injury

During myocardial ischemia/reperfusion (I/R), the generation of reactive oxygen species (ROS) contributes to post-reperfused cardiac injury and contractile dysfunction. Activation of NADPH oxidase (NOX) during reperfusion generates ROS, and exacerbates I/R injury. We hypothesize that reducing ROS formation through inhibition of NOX will attenuate myocardial I/R injury in isolated perfused rat hearts subjected to I(30min)/R(45min) compared to untreated I/R hearts. The cell-permeable NOX inhibiting peptide, gp91 ds/tat (RKKRRQRRR-CSTRIRRQL-Amide, MW=2452 g/mol, 20μM, n=5), significantly improved post-reperfused cardiac function compared to controls (n=15,

American Choral Directors Association Preview Concert with Guest Artist Ola Gjeilo, composer

Kennesaw State University School of Music presents the ACDA National Conference American Choral Directors Association Preview Concert with guest artist Ola Gjeilo, composer.https://digitalcommons.kennesaw.edu/musicprograms/1337/thumbnail.jp

Genotoxicity of multi-walled carbon nanotubes at occupationally relevant doses

Carbon nanotubes are commercially-important products of nanotechnology; however, their low density and small size makes carbon nanotube respiratory exposures likely during their production or processing. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to single-walled carbon nanotubes (SWCNT). In this study, we examined whether multi-walled carbon nanotubes (MWCNT) cause mitotic spindle damage in cultured cells at doses equivalent to 34 years of exposure at the NIOSH Recommended Exposure Limit (REL). MWCNT induced a dose responsive increase in disrupted centrosomes, abnormal mitotic spindles and aneuploid chromosome number 24 hours after exposure to 0.024, 0.24, 2.4 and 24 μg/cm2 MWCNT. Monopolar mitotic spindles comprised 95% of disrupted mitoses. Three-dimensional reconstructions of 0.1 μm optical sections showed carbon nanotubes integrated with microtubules, DNA and within the centrosome structure. Cell cycle analysis demonstrated a greater number of cells in S-phase and fewer cells in the G2 phase in MWCNT-treated compared to diluent control, indicating a G1/S block in the cell cycle. The monopolar phenotype of the disrupted mitotic spindles and the G1/S block in the cell cycle is in sharp contrast to the multi-polar spindle and G2 block in the cell cycle previously observed following exposure to SWCNT. One month following exposure to MWCNT there was a dramatic increase in both size and number of colonies compared to diluent control cultures, indicating a potential to pass the genetic damage to daughter cells. Our results demonstrate significant disruption of the mitotic spindle by MWCNT at occupationally relevant exposure levels

Effects of steroids and angiotensin converting enzyme inhibition on circumferential strain in boys with Duchenne muscular dystrophy: a cross-sectional and longitudinal study utilizing cardiovascular magnetic resonance

<p>Abstract</p> <p>Background</p> <p>Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (ε_cc).</p> <p>Methods</p> <p>We used CMR to assess effects of corticosteroids alone (Group A) or in combination with ACEI or ARB (Group B) on heart rate (HR), left ventricular ejection fraction (LVEF), mass (LVM), end diastolic volume (LVEDV) and circumferential strain (ε_cc) in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results.</p> <p>Results</p> <p>Patients in Group A (114 studies) were younger than those in Group B (92 studies)(10 ± 2.4 vs. 12.4 ± 3.2 years, p < 0.0001), but HR, LVEF, LVEDV and LVM were not different. Although ε_ccmagnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004), age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, ε_ccworsened regardless of treatment group.</p> <p>Conclusions</p> <p>These results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.</p

Identification and Characterization of Nucleolin as a COUP-TFII Coactivator of Retinoic Acid Receptor β Transcription in Breast Cancer Cells

The orphan nuclear receptor COUP-TFII plays an undefined role in breast cancer. Previously we reported lower COUP-TFII expression in tamoxifen/endocrine-resistant versus sensitive breast cancer cell lines. The identification of COUP-TFII-interacting proteins will help to elucidate its mechanism of action as a transcriptional regulator in breast cancer.FLAG-affinity purification and multidimensional protein identification technology (MudPIT) identified nucleolin among the proteins interacting with COUP-TFII in MCF-7 tamoxifen-sensitive breast cancer cells. Interaction of COUP-TFII and nucleolin was confirmed by coimmunoprecipitation of endogenous proteins in MCF-7 and T47D breast cancer cells. In vitro studies revealed that COUP-TFII interacts with the C-terminal arginine-glycine repeat (RGG) domain of nucleolin. Functional interaction between COUP-TFII and nucleolin was indicated by studies showing that siRNA knockdown of nucleolin and an oligonucleotide aptamer that targets nucleolin, AS1411, inhibited endogenous COUP-TFII-stimulated RARB2 expression in MCF-7 and T47D cells. Chromatin immunoprecipitation revealed COUP-TFII occupancy of the RARB2 promoter was increased by all-trans retinoic acid (atRA). RARβ2 regulated gene RRIG1 was increased by atRA and COUP-TFII transfection and inhibited by siCOUP-TFII. Immunohistochemical staining of breast tumor microarrays showed nuclear COUP-TFII and nucleolin staining was correlated in invasive ductal carcinomas. COUP-TFII staining correlated with ERα, SRC-1, AIB1, Pea3, MMP2, and phospho-Src and was reduced with increased tumor grade.Our data indicate that nucleolin plays a coregulatory role in transcriptional regulation of the tumor suppressor RARB2 by COUP-TFII