Search

Introduction: COVID-19 has emerged as a global health crisis. It has been established that people with obesity are prone to develop severe manifestations of COVID-19. Since there is no established treatment of the disease, yet, it is essential to increase public awareness toward prevention of infection. This study was aimed to assess the awareness, perception, and practices of obese subjects toward COVID-19 infection. Methods: This cross-sectional study was conducted among 260 obese patients between August 2020 and November 2020 who were enrolled in obesity and metabolic disorders clinic at our institute. A structured questionnaire consisting of 23 questions (15 of knowledge, four of perception, and four of practices) was administered by telephonic interview with the patients. Multiple regression analyses were conducted to identify factors associated with poor knowledge and practice toward COVID-19. Results: The mean age of the participants was 41.7 ± 10.2 years, with 166 (64%) females. Mean awareness score obtained by subjects was 9.1 ± 2.2 out of 15. The scores were categorized into good, moderate, and poor. Subjects with poor awareness constituted 36% of study population. Mean perception score of participants was 14.0 ± 2 out of 20. Majority of patients (69.2%) had moderate perception score. Mean score obtained in practices was 18.5 ± 2.1 out of 20 and 92% of subjects reported good practices. Age was negatively associated with awareness score. Gender and educational qualification had a significant impact on awareness score with males having better awareness then females. Graduates and above had higher awareness score. Increase in awareness score was found to be associated with improved practices but not with perception. Conclusion: The prevalence of good practices toward COVID-19 among obese patients was high (92%) although poor awareness was also highly prevalent (36%). Increasing the awareness through various means should be considered.

To assess the impact of preoperative chronic kidney disease (CKD) on perioperative morbidity and mortality in a contemporary cohort undergoing renal surgery in an era of increased prevalence of minimally invasive surgery and partial nephrectomy.The National Surgery Quality Improvement Program dataset was queried to identify patients undergoing radical nephrectomy (RN) or partial nephrectomy (PN) between 2010 and 2018. CKD staging was assigned based on creatinine clearance calculated using the Cockcroft-Gault formula. Multivariable logistic regression was performed to assess the effect of preoperative CKD stage on postoperative outcomes, including a composite variable encompassing multiple major complications.We analyzed 19,545 patients with CKD undergoing renal surgery. CKD stage ≥ 2 predicted an increase in major perioperative complications, OR 1.54 (95% CI 1.46-1.63); p 0.01. The risk of perioperative morbidity increased linearly with increasing CKD stage. Patients with CKD stage 2 also demonstrated increased 30-day mortality, OR 1.87 (95% CI 1.26-2.48); p 0.01. Adjusting for surgery type, CKD staging predicted perioperative mortality in patients undergoing RN only, and perioperative morbidity in RN and PN.Here, we demonstrate a statistically significant increase in the risk of major postoperative complications following RN and PN with increasing CKD stage. Amongst patients undergoing RN, we also demonstrate increasing 30-day mortality with increasing CKD stage. Importantly, we highlight the ability of CKD staging to predict major perioperative outcomes with greater magnitude of effect than surgery type alone. Thus, we provide a model for translating CKD staging into operative risk amongst patients undergoing surgery for a renal mass.

To determine the response to a virtual educational curriculum in reconstructive urology presented during the COVID-19 pandemic. To assess learner satisfaction with the format and content of the curriculum, including relevance to learners' education and practice.A webinar curriculum of fundamental reconstructive urology topics was developed through the Society of Genitourinary Reconstructive Surgeons and partnering institutions. Expert-led sessions were broadcasted. Registered participants were asked to complete a survey regarding the curriculum. Responses were used to assess the quality of the curriculum format and content, as well as participants' practice demographics.Our survey yielded a response rate of 34%. Survey responses showed50% of practices offer reconstructive urologic services, with 37% offered by providers without formal fellowship training. A difference in self-reported baseline knowledge was seen amongst junior residents and attendings (P.05). Regardless of level of training, all participants rated the topics presented as relevant to their education/practice (median response = 5/5). Responders also indicated that the curriculum supplemented their knowledge in reconstructive urology (median response = 5/5). The webinar format and overall satisfaction with the curriculum was highly rated (median response = 5/5). Participants also stated they were likely to recommend the series to others.We demonstrate success of an online curriculum in reconstructive urology. Given50% of practices surveyed offer reconstruction, we believe the curriculum's educational benefits (increasing access and collaboration while minimizing the risk of in-person contact) will continue beyond the COVID-19 pandemic and that this will remain a relevant educational platform for urologists moving forward.

To evaluate patient outcomes in a contemporary cohort of patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN). The NSQIP database was used to identify patients undergoing PN or RN for renal neoplasms between 2010 and 2018. The SEER database was also queried to assess changes in tumor staging during the study period. Logistic regression was used to assess the independent relationship between surgery year and approach on postoperative complications. Between 2010 and 2018, NSQIP captured 58,020 cases, including 26,745 (46%) PN and 31,275 (54%) RN. The proportion of PN increased annually, from 39.8% in 2010 to 48.7% in 2018. This rise in PN coincided with a decrease in the proportion of patients experiencing complications, irrespective of surgical approach (20.4% of total cases to 14.2% of total cases). While limited by a lack of information on tumor characteristics, multivariable analysis controlling for patient characteristics demonstrated that RN was associated with an increased risk of complications, OR 1.42 (95% CI 1.35–1.49). Here, we report an 8.9% increase in the proportion of patients undergoing PN between 2010 and 2018, with no associated increase in perioperative morbidity/mortality. Given that there was no concurrent shift in stage or size of kidney tumors undergoing resection during the study period, these data therefore suggest markedly improved surgical technique and perioperative management nationally. Furthermore, the relative burden of complications has shifted from patients undergoing PN to those undergoing RN. Therefore PN, when technically feasible, should be increasingly considered.

Laparoscopic prostatectomy was technically challenging and not widely adopted. Robotics led to the widespread adoption of minimally invasive prostatectomy, which has been used heavily, supplanting the open and traditional laparoscopic approach. The benefits of robotic prostatectomy are disputed. Data suggest that robotic prostatectomy outcomes have improved over time.

Introduction: Limited data guide urological practice when employing prostate magnetic resonance imaging (MRI) in active surveillance protocols. To determine the ability of prostate MRI to predict pathological progression in active surveillance patients, we correlated findings of serial MRI with results of surveillance biopsies. Methods: Patients on active surveillance with greater than or equal to two prostate MRI and greater than or equal to two prostate biopsies were included. Prostate Imaging-Reporting and Data System (PI-RADS) score upgrade, as assigned by experienced radiologists, was used to assess the ability of imaging to predict pathological biopsy progression. Imaging test statistics and the odds ratio of pathological progression according to MRI upgrade were calculated. Results: Of 121 patients meeting criteria, 36 (30%) demonstrated MRI upgrade. Biopsy progression was noted in 55 patients (46%). Of these, 20 patients (37%) had biopsy progression predicted by MRI upgrade, while the remaining (n=35) had no lesion upgrade on prostate MRI. Conversely, among those with no biopsy progression (n=66), 16 patients (24%) had a false-positive upgrade on serial MRI. We report a sensitivity and specificity of MRI change for pathological progression of 36% and 76%, respectively. Although MRI change was associated with a positive predictive value of 56% for pathological progression, patients with a high-suspicion lesion (PI-RADS >3) at any time were more likely to experience disease progression, (odds ratio 3.3, 95% confidence interval 1.6–8.0, p3 lesion, a high index of suspicion should be maintained, as these patients are more likely to progress on active surveillance.

Background: Cortical bone trajectory (CBT) screws have been recently described as a method of lumbosacral fixation. These screws are typically inserted under fluoroscopic guidance with a medial-to-lateral trajectory in the axial plane and a caudal-to-cephalad trajectory in the sagittal plane. In an effort to reduce surgeon radiation exposure and improve accuracy, CBT screws may be inserted under navigation with intraoperative cone beam computed tomography (CT). However, the accuracy of CBT screw placement under intraoperative navigation has yet to be assessed in the literature. The purpose of the study was to evaluate the accuracy of CBT screw placement using intraoperative cone beam CT navigation. Methods: One hundred and thirty-four consecutive patients who underwent CBT fixation with 618 screws under intraoperative navigation were analyzed from May 2016 through May 2018. Screws were placed by one of three senior spine surgeons using the Medtronic O-Arm Stealth Navigation. Screw position and accuracy were assessed on intraoperative and postoperative CT scans using 2D and 3D reconstructions with VitreaCore software. Results: The majority of surgeries were primary cases (73.1%). The mean age at the time of surgery was 61.5±10.0 years and the majority of patients were female (61.2%). Most patients underwent surgery for a diagnosis of degenerative spondylolisthesis (47.8%) followed by mechanical collapse with foraminal stenosis (22.4%). Ten violations of the vertebral cortex were noted with an average breach distance of 1.0±0.7 mm. Three breaches were lateral (0.5%) and seven were medial (1.1%). The overall navigated screw accuracy rate was 98.3%. The accuracy to within 1 mm of error was 99.2%. There were no intra-operative neurologic, vascular, or visceral complications related to the placement of the CBT screws. Conclusions: CBT screw fixation under an intraoperative cone beam CT navigated insertion technique is safe and reliable. Despite five breaches greater than 1mm, there were no complications related to the placement of the CBT screws in this series.

Study Design: Literature review. Objectives: Posterior cervical interfacet cages are an alternative to lateral mass fixation in patients undergoing cervical spine surgery. Recently, a percutaneous, tissue-sparing system for interfacet cage placement has been developed, however, there is limited clinical evidence supporting its widespread use. The aim was to review studies published on this system for patient reported outcomes, radiographic outcomes, intraoperative outcomes, and complications. Methods: Four electronic databases (PubMed, EMBASE, Scopus, and MEDLINE) were queried for original published studies that evaluated the percutaneous, tissue-sparing technique for posterior cervical fusion with interfacet cage placement. All studies reporting on open techniques and purely biomechanical studies were excluded. Results: The extensive literature search returned 7852 studies. After systematic review, a total of 7 studies met inclusion criteria. Studies were independently classified as retrospective or prospective cohort studies and each assessed by the GRADE criteria. Patient reported outcomes, radiographic outcomes, intraoperative outcomes, and complications were extracted from each study and presented. Conclusions: Tissue-sparing, posterior cervical fusion with interfacet cages may be considered a safe and effective surgical intervention in patients failing conservative management for cervical spondylotic disease. However, the quality of evidence in the literature is lacking, and controlled, comparative studies are needed for definitive assessment.

Testosterone deficiency is known to affect men with increasing incidence throughout their lifespan. The clinical manifestations of testosterone deficiency, in turn, negatively impact men's quality of life and perception of overall health. The interaction of chronic systemic disease and androgen deficiency represent an area for potential intervention. Here, we explore the topic of testosterone deficiency amongst men with end-stage organ failure requiring transplantation in order to elucidate the underlying pathophysiology of androgen deficiency of chronic disease and discuss whether intervention, including testosterone replacement and organ transplantation, improve patients' outcomes and quality of life.

To evaluate patient outcomes in a contemporary cohort of patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN).The NSQIP database was used to identify patients undergoing PN or RN for renal neoplasms between 2010 and 2018. The SEER database was also queried to assess changes in tumor staging during the study period. Logistic regression was used to assess the independent relationship between surgery year and approach on postoperative complications.Between 2010 and 2018, NSQIP captured 58,020 cases, including 26,745 (46%) PN and 31,275 (54%) RN. The proportion of PN increased annually, from 39.8% in 2010 to 48.7% in 2018. This rise in PN coincided with a decrease in the proportion of patients experiencing complications, irrespective of surgical approach (20.4% of total cases to 14.2% of total cases). While limited by a lack of information on tumor characteristics, multivariable analysis controlling for patient characteristics demonstrated that RN was associated with an increased risk of complications, OR 1.42 (95% CI 1.35-1.49).Here, we report an 8.9% increase in the proportion of patients undergoing PN between 2010 and 2018, with no associated increase in perioperative morbidity/mortality. Given that there was no concurrent shift in stage or size of kidney tumors undergoing resection during the study period, these data therefore suggest markedly improved surgical technique and perioperative management nationally. Furthermore, the relative burden of complications has shifted from patients undergoing PN to those undergoing RN. Therefore PN, when technically feasible, should be increasingly considered.

Bladder agenesis is a rare congenital anomaly infrequently reported in the literature, with an incidence of 1/600,000 patients. 1 Commonly associated with other fatal malformations, the condition is often incompatible with life. 2 Prior reports estimate that over 90% of living children born with this malformation are female, owing to renal preservation resulting from low pressure drainage of urine into the vagina, uterus, and vestibule. 3 , 4 Herein we report a rare case of an infant male born with penoscrotal transposition and end stage renal disease secondary to bilateral cystic renal dysplasia found to have concurrent bladder agenesis and bilateral ureteral ectopia.

About 70% of eye drops contain benzalkonium chloride (BAK) to maintain sterility. BAK is an effective preservative but it can cause irritation and toxicity. We propose to mitigate ocular toxicity without compromising sterility by incorporating a filter into an eye drop bottle to selectively remove BAK during the process of drop instillation. The filter is a packed bed of particles made from poly(2-hydroxyethyl methacrylate) (pHEMA), which is a common ophthalmic material. We showed that pHEMA particle prepared by using ethoxylated trimethylolpropane triacrylate as crosslinker can be incorporated into a modified eyedrop bottle tip to selectively remove the preservative as the formulation is squeezed out of the bottle. Hydraulic permeability of the plug is measured to determine the resistance to eye drop squeezing, and % removal of BAK and drugs are determined. The modified tip has a hydraulic permeability of about 2 Darcy, which allows eyedrops formulations to flow through without excessive resistance. The tip is designed such that the patients can create an eyedrop of solution of 1–10 cP viscosity in 4 s with a nominal pressure. During this short contact time, the packed particles removed nearly 100% of benzalkonium chloride (BAK) from a 15 mL, 0.012% BAK solution but have only minimal impact on the concentration of contained active components. Our novel design can eliminate the preservative induced toxicity from eye drops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases like glaucoma and dry eyes.

Background Previous studies have shown that Magnetic Resonance Imaging (MRI) techniques can be used to non-invasively assess lung disease in CF patients. In this study, we compare the sensitivity of normalized T1 (nT1) and non-contrast perfusion MRI techniques to detect regional lung disease in CF patients. Materials and methods MRI data were obtained for eight adult CF patients without overt pulmonary exacerbation (FEV1=45–127%) and six healthy volunteers on a Siemens Espree 1.5T MRI scanner. Sagittal nT1 and perfusion data were acquired for each subject's left and right lungs. A region-of-interest analysis was used to calculate mean nT1 and perfusion values in the individual lobes of the left and right lungs for each subject. Results In comparison to healthy controls, CF subjects showed a significant decrease in nT1 values in the upper lobe of the left lung as well as in the upper and anterior lobes of the right lung (p

The transition from castration resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with over-expression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc over-expression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of AR signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

For many years outpatient surgery centers have been used to perform procedures such as microlumbar discectomy, lumbar laminotomy, decompressions, and fusions. These procedures have been shown to be safe and cost-effective in the outpatient setting while also demonstrating better outcomes and patient satisfaction. An important component of outpatient spine surgery is patient selection and safety. Factors affecting patient safety include the patient’s general health status, the risk profile of the approach, and the familiarity of the surgeon with the operative procedure. Patient selection factors include age, comorbidities, diagnosis, treatment levels, hemoglobin levels, body mass index (BMI), and patient disposition. If a patient maintains anxiety about outpatient spine surgery, this should be considered a contraindication. Literature has shown that lumbar fusion surgery in outpatient settings has had positive outcomes when compared to traditional spine surgery or spine surgery in an inpatient setting, such as shorter operating room (OR) time, less blood loss, and reduced procedure cost. Those electing for outpatient surgery are also often discharged sooner and experience greater satisfaction with their outcomes.

Dietary and lifestyle factors play an important role in human health, as nutritional imbalances are major determinants of various diseases including cancer. Emerging literature suggests that diet and lifestyle factors have a major impact on gene expression through epigenetic mechanisms. Epigenetic modifications are heritable and cause potentially reversible changes in gene expression without altering the DNA sequence. Epigenetic inscriptions include changes in DNA methylation, histone modifications, and small noncoding microRNAs. Atypical epigenetic alterations possibly occur at an early stage during neoplastic development and are widely recognized as essential players in cancer progression. Additionally, environmental cues might lead to epigenetic modifications, thus providing a link between susceptible genes and environmental factors in the etiology of cancer. This chapter primarily highlights the role of various epigenetic mechanisms in the regulation and maintenance of the mammalian genome. This chapter also discusses the impact of endogenous factors including diet, lifestyle, environment, and socioeconomic status on the process of carcinogenesis through various epigenetic modifications. Elucidating the impact of dietary and lifestyle factors on epigenetic mechanisms may serve as a personalized prognostic tool for gauging cancer susceptibility and providing recommendations and guidance for the prevention of cancer.

Large vessel vasculitis (LVV) is characterized by immune-mediated injury of predominantly large vessels. Histopathologic features include mononuclear cell infiltration of the vessel wall that often includes granuloma formation. Within this group of diseases, Takayasu arteritis (TAK) affects younger individuals (younger than 50 years; mean age ~26 years at onset), whereas giant cell arteritis (GCA) is unique to older patients (older than 50 years; mean age ~74 years at onset) (1). Both predominantly affect women. Included within the LVV spectrum is isolated focal aortic disease, which is usually limited to the thoracic aorta. Isolated focal aortic disease is a form of vasculitis within the larger category of single-organ vasculitis (1). Patients with isolated focal aortic disease who do not have histories or features of GCA or TAK at presentation may later develop TAK or GCA, but that is infrequent (2). It has been suggested that GCA (prevalence 1 in 500 in the population older than 50 years) and TAK (annual incidence ~3 per million) may be the same disease with the same etiology, but with phenotypic variations due to immune and substrate senescence that occur with aging (3,4). How and whether isolated focal aortic disease fits into the spectrum of GCA and TAK have not been explored. Limited availability of aorta specimens has been a major deterrent to designing studies that may provide a better understanding of LVV pathogenesis. TAK and GCA are primarily considered Th1 and Th17 cell–mediated diseases (5,6). In both, certain vascular territories are commonly affected (e.g., aorta and aortic arch vessels) and others mostly spared (e.g., arteries distal to the elbows and knees), begging the question of what might be targeted antigens or shared immune vulnerabilities within affected sites (7). Vascular dendritic cells (DCs) are a component of the resident cell population in muscular arteries (6,8). It has been proposed that resident-sentinel DCs within the adventitia–media border of muscular arteries become activated by unknown antigen(s), leading to the recruitment of CD4+ T cells and release of proinflammatory cytokines (8,9). The inflammatory cascade includes endothelial cell activation, recruitment of macrophages and neutrophils, enhanced production of matrix metalloproteinases, and oxidative products that cause extracellular matrix disruption and reorganization (10,11). Previous attempts to identify autoantigens and infectious agents in the temporal arteries of patients with GCA have implicated numerous organisms, including parainfluenza virus type 1 (12), herpes simplex virus (13), parvovirus B19 (14), Varicella zoster virus (15), Chlamydia pneumonia (16), and Mycobacterium tuberculosis (17). In a previous study, microbial fragments present in the giant cells of temporal arteries were isolated and found to contain signatures of multiple bacterial species to which patients produced antibodies (18). Other studies have failed to identify suspected microbial agents in temporal arteries. Our study is unique in addressing the issues of autoantigens within sterile, snapfrozen, thoracic aorta specimens. Within our Heart Vascular Institute, the Center for Aortic Diseases performs thoracic aorta surgeries for >650 patients per year. This has provided opportunities to study specimens from patients with a variety of noninflammatory conditions and LVV. We have explored LVV pathogenesis by asking questions about extractable antigens in the aneurysmal aorta of surgical specimens that may elicit autologous immune responses. The question of antigen reactivity was explored in patients with GCA, TAK, or isolated focal aortic disease, and in disease controls (i.e., patients with thoracic aneurysms who had matrix disorders and no clinical or pathologic evidence of vasculitis). We found that patients with LVV, including GCA, TAK, and isolated focal aortic disease, produce antibodies to select isoforms of 14-3-3 proteins.

Catalase is a tetrameric heme-containing enzyme with essential antioxidant functions in biology. Multiple factors including nitric oxide (NO) have been shown to attenuate its activity. However, the possible impact of NO in relation to the maturation of active catalase, including its heme acquisition and tetramer formation, has not been investigated. We found that NO attenuates heme insertion into catalase in both short-term and long-term incubations. The NO inhibition in catalase heme incorporation was associated with defective oligomerization of catalase, such that inactive catalase monomers and dimers accumulated in place of the mature tetrameric enzyme. We also found that GAPDH plays a key role in mediating these NO effects on the structure and activity of catalase. Moreover, the NO sensitivity of catalase maturation could be altered up or down by manipulating the cellular expression level or activity of thioredoxin-1, a known protein-SNO denitrosylase enzyme. In a mouse model of allergic inflammatory asthma, we found that lungs from allergen-challenged mice contained a greater percentage of dimeric catalase relative to tetrameric catalase in the unchallenged control, suggesting that the mechanisms described here are in play in the allergic asthma model. Together, our study shows how maturation of active catalase can be influenced by NO, S-nitrosylated GAPDH, and thioredoxin-1, and how maturation may become compromised in inflammatory conditions such as asthma.

Chemoprevention is defined as a means of cancer control in which the occurrence of clinical cancer can be prevented, slowed or reversed by the administration of one or more synthetic or naturally occurring biologic compounds [1-5]. In contrast to cancer treatment, the goal of chemoprevention is to reduce the incidence of clinical cancer. Preventing the onset of clinical cancer is desirable because therapy for established cancer is not uniformly effective. Chemoprevention also implies the prevention of precancerous lesions, which are called pre-invasive neoplasia, dysplasia, or intraepithelial neoplasia, depending on the organ system [5, 6]. The process of carcinogenesis involves the accumulation of multiple sequential genetic alterations and mutations that transforms a normal cell to a malignant cell capable of stromal invasion and ultimately metastasis. Carcinogenesis is traditionally separated into three phases: initiation, promotion and progression [6]. The initiation stage is relatively rapid and involves carcinogen binding and damage to DNA. The promotion phase is reversible, as tumor promoters act as mitogens to induce clones of initiated cells to expand. The promotion phase is a consequence of the functional loss of regulatory proteins and cellular checkpoints important for cellular proliferation and apoptosis. Progression is a stage in which phenotypically and genotypically altered cells develop irreversible macroscopic and microscopic changes. Because initiation and progression are irreversible, the promotion phase of carcinogenesis may be the best target for chemoprevention.

Research in cancer chemoprevention provides convincing evidence that increased intake of vegetables and fruits may reduce the risk of several human malignancies. Phytochemicals present therein provide beneficial anti-inflammatory and antioxidant properties that serve to improve the cellular microenvironment. Compounds known as flavonoids categorized anthocyanidins, flavonols, flavanones, flavonols, flavones, and isoflavones have shown considerable promise as chemopreventive agents. Apigenin (4', 5, 7-trihydroxyflavone), a major plant flavone, possessing antioxidant, anti-inflammatory, and anticancer properties affecting several molecular and cellular targets used to treat various human diseases. Epidemiologic and case-control studies have suggested apigenin reduces the risk of certain cancers. Studies demonstrate that apigenin retain potent therapeutic properties alone and/or increases the efficacy of several chemotherapeutic drugs in combination on a variety of human cancers. Apigenin's anticancer effects could also be due to its differential effects in causing minimal toxicity to normal cells with delayed plasma clearance and slow decomposition in liver increasing the systemic bioavailability in pharmacokinetic studies. Here we discuss the anticancer role of apigenin highlighting its potential activity as a chemopreventive and therapeutic agent. We also highlight the current caveats that preclude apigenin for its use in the human trials.

We sought to determine whether disease volume at prostate biopsy would correlate with genomic scores among men with favorable risk prostate cancer.We identified all men with NCCN® (National Comprehensive Cancer Network®) very low and low risk disease who underwent Oncotype DX® prostate testing at our institution from 2013 to 2016. Disease volume was characterized as the percent of positive cores, the number of cores with greater than 50% involvement, the largest involvement of any single core and prostate specific antigen density. Nonparametric testing was performed to compare the median Genomic Prostate Score™ and the likelihood of favorable pathology findings between quartiles of disease volume.We identified 112 (37.8%) and 184 men (62.2%) at NCCN very low and low risk, respectively. Median scores did not differ significantly between disease volume quartiles (all p0.05). However, the median likelihood of favorable pathology findings statistically differed between volume quartiles (all 0.05). Seven of the 105 men (6.3%) with very low risk disease were reclassified at low risk and 13 of 181 (7.2%) with low risk disease were reclassified at intermediate risk. Genomic disease reclassification did not depend on biopsy tumor volume.In patients with NCCN very low and low risk prostate cancer genomic scores did not demonstrate meaningfully significant differences by volume based on clinically established cutoff points. Moreover, genomic scores identified and reclassified men with higher risk disease despite generally acceptable surveillance characteristics in this group according to grade and volume. This suggests that in patients at low risk the tumor biological potential measured by genomics rather than by volume should inform decisions on active surveillance candidacy.

Pyelonephritis is a bacterial infection of the kidney and is most commonly caused by Escherichia coli. Recurrent infections can cause significant renal inflammation and fibrosis ultimately resulting in declining kidney function. Before improved clinical management and prevention of pyelonephritis can be instituted, a reliable animal model must be established in order to study the mechanisms of progression, recurrence, and therapeutic efficacy. The transurethral infection model closely mimics human pyelonephritis but exhibits considerable variation due to its reliance on urethral reflux to transport the bacteria to the kidney. Herein, a detailed surgical protocol for performing bacterial injections into the rat renal pelvis is provided and confirmed by non-invasive Magnetic Resonance Imaging (MRI). Using this protocol, animals receive direct exposure to a desired concentration of E. coli bacteria and can fully recover from the surgical procedure with adequate post-operative care. This facilitates subsequent longitudinal MRI assessments of the experimental animal models for comparison with saline (sham) controls. Using this direct delivery approach, the severity of infection is controllable and applicable for mechanistic studies of progression as well as development of novel treatment strategies.

Pyelonephritis is a bacterial infection of the kidney and is most commonly caused by Escherichia coli. Recurrent infections can cause significant renal inflammation and fibrosis ultimately resulting in declining kidney function. Before improved clinical management and prevention of pyelonephritis can be instituted, a reliable animal model must be established in order to study the mechanisms of progression, recurrence, and therapeutic efficacy. The transurethral infection model closely mimics human pyelonephritis but exhibits considerable variation due to its reliance on urethral reflux to transport the bacteria to the kidney. Herein, a detailed surgical protocol for performing bacterial injections into the rat renal pelvis is provided and confirmed by non-invasive Magnetic Resonance Imaging (MRI). Using this protocol, animals receive direct exposure to a desired concentration of E. coli bacteria and can fully recover from the surgical procedure with adequate post-operative care. This facilitates subsequent longitudinal MRI assessments of the experimental animal models for comparison with saline (sham) controls. Using this direct delivery approach, the severity of infection is controllable and applicable for mechanistic studies of progression as well as development of novel treatment strategies.

Tea is the second most consumed beverage in the world reported to have multiple health benefits. Preventive and therapeutic benefits of tea polyphenols include enhanced general well being and anti-neoplastic effects. The pharmacologic action of tea is often attributed to various catechins present therein. Experiments conducted in cancer cell lines and animal models demonstrate that tea polyphenols protect against cellular damage caused by oxidative stress and altered immunity. Tea polyphenols modify various metabolic and signaling pathways in the regulation of proliferation, apoptosis, angiogenesis, and metastasis and therefore restrict clonal expansion of cancer cells. Tea polyphenols have been shown to reactivate tumor suppressors, block the unlimited replicative potential of cancer cells, and physically bind to nucleic acids involved in epigenetic alterations of gene regulation. Remarkable interest in green tea as a potential chemopreventive agent has been generated since recent epigenetic data showed that tea polyphenols have the potential to reverse epigenetic modifications which might otherwise be carcinogenic. Like green tea, black tea may also possess chemopreventive and chemotherapeutic potential; however, there is still not enough evidence available to make any conclusive statements. Here we present a brief description of tea polyphenols and discuss the findings of various in vitro and in vivo studies of the anticancer effects of tea polyphenols. Detailed discussion of various studies related to epigenetic changes caused by tea polyphenols leading to prevention of oncogenesis or cancer progression is included. Finally, we discuss on the scope and development of tea polyphenols in cancer prevention and therapy.

Green tea polyphenols (GTPs) reactivate epigenetically silenced genes in cancer cells and trigger cell cycle arrest and apoptosis; however, the mechanisms whereby these effects occur are not well understood. We investigated the molecular mechanisms underlying the antiproliferative effects of GTP, which may be similar to those of histone deacetylase (HDAC) inhibitors. Exposure of human prostate cancer LNCaP cells (harboring wild-type p53) and PC-3 cells (lacking p53) with 10-80 μg/ml of GTP for 24 h resulted in dose-dependent inhibition of class I HDAC enzyme activity and its protein expression. GTP treatment causes an accumulation of acetylated histone H3 in total cellular chromatin, resulting in increased accessibility to bind with the promoter sequences of p21/waf1 and Bax, consistent with the effects elicited by an HDAC inhibitor, trichostatin A. GTP treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. Furthermore, treatment of cells with proteasome inhibitor, MG132 together with GTP prevented degradation of class I HDACs, compared with cells treated with GTP alone, indicating increased proteasomal degradation of class I HDACs by GTP. These alterations were consistent with G(0)-G(1) phase cell cycle arrest and induction of apoptosis in both cell lines. Our findings provide new insight into the mechanisms of GTP action in human prostate cancer cells irrespective of their p53 status and suggest a novel approach to prevention and/or therapy of prostate cancer achieved via HDAC inhibition.

Background: Impact of cardiac disease on pregnancy is significant. Impact of hypertension on pregnancy is also significant. “Does occurrence of hypertension along with cardiac disease worsen the outcomes?” forms the crux of this study. The aim of the present study was to determine the impact of pregnancy-associated hypertension on the clinical outcomes of pregnant patients with cardiac disease.Methods: Retrospective, observational, comparative, case control study of one and half year duration conducted in a tertiary care referral hospital. The various medical and obstetric parameters were studied and compared.Results: Among 143 patients studied, 36 were hypertensive and 107 were non-hypertensive. Non-severe hypertension was seen in 17%, severe hypertension in 4% and eclampsia in 4%. Average age was 26 years and majority were first or second gravida. Valvular heart disease was the most common cardiac disease encountered. Gestational age at delivery, perinatal outcome and occurrence of pulmonary hypertension were all similar in both the hypertensive and non-hypertensive groups. The most common mode of delivery was vaginal delivery. The cesarean section rate was 29% and was similar among both hypertensive and non-hypertensive groups. Requirement for induction of labor, occurrence of small-for- gestational age among the newborns, intensive care unit admission due to heart failure and maternal death was higher (statistically significant (p

93 Background: To determine if disease volume at biopsy correlates with GPS among men with favorable risk prostate cancer. Methods: All men with NCCN very low (VLR) and low risk (LR) and GPS from 2013-2016 were identified. Disease volume was characterized by percent of positive cores, number of cores with >50% involvement, and largest involvement of any single core. Nonparametric equality of medians was performed to compare the median likelihood of favorable pathology between quartiles. Results: 112 (37.8%) with VLR and 184 (62.2%) with LR disease were identified. The likelihood of favorably pathology by quartile are listed in Table 1. 7/105 (6.3%) with VLR were reclassified as LR, and 13/181 (7.2%) with LR were reclassified as intermediate risk (IR). Patients reclassified to IR by GPS had a median likelihood favorable pathology of 63.0% (IQR 62.0-63.0), 20.0% positive cores (IQR 13.0-29.0), 0 cores with > 50% involved (IQR 0-1), largest core involvement of 20.0% (IQR 10.0-20.0), and PSA density of 0.12 ng/ml/cc (IQR 0.10-0.14). Conclusions: Differences in the likelihood of favorable pathology by disease volume were not clinically significant in men with favorable risk disease. [Table: see text]

Epigenetic and genetic alterations contribute to cancer initiation and progression. Epigenetics refers to the study of heritable changes in gene expression without alterations in DNA sequences. Epigenetic changes are reversible and include key processes of DNA methylation, chromatin modifications, nucleosome positioning, and alterations in noncoding RNA profiles. Disruptions in epigenetic processes can lead to altered gene function and cellular neoplastic transformation. Epigenetic modifications precede genetic changes and usually occur at an early stage in neoplastic development. Recent technological advances offer a better understanding of the underlying epigenetic alterations during carcinogenesis and provide insight into the discovery of putative epigenetic biomarkers for detection, prognosis, risk assessment, and disease monitoring. In this chapter we provide information on various epigenetic mechanisms and their role in carcinogenesis, in particular, epigenetic modifications causing genetic changes and the potential clinical impact of epigenetic research in the future.

Epigenetic and genetic alterations contribute to cancer initiation and progression. Epigenetics refers to the study of heritable changes in gene expression without alterations in DNA sequences. Epigenetic changes are reversible and include key processes of DNA methylation, chromatin modifications, nucleosome positioning, and alterations in noncoding RNA profiles. Disruptions in epigenetic processes can lead to altered gene function and cellular neoplastic transformation. Epigenetic modifications precede genetic changes and usually occur at an early stage in neoplastic development. Recent technological advances offer a better understanding of the underlying epigenetic alterations during carcinogenesis and provide insight into the discovery of putative epigenetic biomarkers for detection, prognosis, risk assessment, and disease monitoring. In this chapter we provide information on various epigenetic mechanisms and their role in carcinogenesis, in particular, epigenetic modifications causing genetic changes and the potential clinical impact of epigenetic research in the future.

Large vessel vasculitides (LVV) are a group of autoimmune diseases characterized by injury to and anatomic modifications of large vessels, including the aorta and its branch vessels. Disease etiology is unknown. This study was undertaken to identify antigen targets within affected vessel walls in aortic root, ascending aorta, and aortic arch surgical specimens from patients with LVV, including giant cell arteritis, Takayasu arteritis, and isolated focal aortitis.Thoracic aortic aneurysm specimens and autologous blood were acquired from consenting patients who underwent aorta reconstruction procedures. Aorta proteins were extracted from both patients with LVV and age-, race-, and sex-matched disease controls with noninflammatory aneurysms. A total of 108 serum samples from patients with LVV, matched controls, and controls with antinuclear antibodies, different forms of vasculitis, or sepsis were tested.Evaluation of 108 serum samples and 22 aortic tissue specimens showed that 78% of patients with LVV produced antibodies to 14-3-3 proteins in the aortic wall (93.7% specificity), whereas controls were less likely to do so (6.7% produced antibodies). LVV patient sera contained autoantibody sufficient to immunoprecipitate 14-3-3 protein(s) from aortic lysates. Three of 7 isoforms of 14-3-3 were found to be up-regulated in aorta specimens from patients with LVV, and 2 isoforms (ε and ζ) were found to be antigenic in LVV.This is the first study to use sterile, snap-frozen thoracic aorta biopsy specimens to identify autoantigens in LVV. Our findings indicate that 78% of patients with LVV have antibody reactivity to 14-3-3 protein(s). The precise role of these antibodies and 14-3-3 proteins in LVV pathogenesis deserves further study.

Acetylation of the tumor suppressor gene p53 at the carboxy-terminal lysine (Lys) residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis. Histone deacetylases (HDACs), a family of evolutionarily conserved enzymes, counterbalance the acetylation of lysine residues on histone and non-histone proteins. In this study, we demonstrate that green tea polyphenols (GTPs) and their major constituent, (-) epigallocatechin-3-gallate (EGCG), activate p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in LNCaP human prostate cancer cells. Treatment of cells with GTPs (2.5-10 µg/ml) and EGCG (5-20 µM) resulted in dose- and time-dependent inhibition of class I HDACs (HDAC1, 2, 3 and 8), albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with increased accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs, a function that is likely to be part of the mechanisms that control the physiological activity of p53.

Tumor suppressor gene p53 is frequently inactivated in a variety of human cancers including prostate cancer and is associated with therapeutic resistance. We have previously demonstrated that green tea polyphenols (GTP) induces apoptosis in prostate cancer cells irrespective of p53 status (Carcinogenesis 33:377-84, 2012). However, the molecular mechanisms underlying these observations are not properly understood. In the present study we investigated the mechanisms of GTP-induced apoptosis in human prostate cancer cells with and without functional p53. Human prostate cancer LNCaP cells were stably transfected with short hairpin-53 (LNCaPshp53) and control vector (LNCaPshV), exposed to GTP in dose and time dependent manner. GTP exposure induced p53 stabilization and activation of downstream targets p21/waf1 and Bax in dose-dependent manner specifically in LNCaPshV cells. However, GTP-induced FAS upregulation through the activation of c-jun N-terminal kinase resulting in FADD phosphorylation, caspase-8 activation and truncation of BID leading to apoptosis was common in both LNCaPshV and LNCaPshp53 cells. In parallel, treatment of cells with GTP resulted in inhibition of survival pathway, mediated by Akt deactivation and loss of BAD phosphorylation more prominently in LNCaPshp53 cells. These distinct routes of cell death converged to a common pathway leading to loss of mitochondrial transmembrane potential, cytochrome c release and activation of terminal caspases resulting in PARP cleavage. GTP-induced apoptosis was attenuated with JNK inhibitor, SP600125 in both cell lines; whereas PI3K-Akt inhibitor, LY294002 resulted in increased cell death in LNCaPshp53 cells, establishing the role of two distinct pathways of GTP-mediated apoptosis. Furthermore, GTP exposure resulted in the inhibition of class I HDAC protein, accumulation of acetylated histone H3 in total cellular chromatin resulting in increased accessibility to bind with the promoter sequences of p21/waf1 and Bax irrespective of p53 status of cells, consistent with the effects elicited by HDAC inhibitor, trichostatin A. These results demonstrate that GTP induces prostate cancer cell death by two distinct mechanisms irrespective of p53 status, thus identifying for the first time through defined molecular targets for their chemopreventive and/or therapeutic actions. Citation Format: Karishma Gupta, Vijay S. Thakur, Natarajan Bhaskaran, Akbar Nawab, Melissa A. Babcook, Mark W. Jackson, Sanjay Gupta. Differential mechanisms of green tea polyphenols-induced apoptosis in human prostate cancer cells: Role of p53. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3684. doi:10.1158/1538-7445.AM2013-3684

p53, a major tumor suppressor and transcription factor protects the cells from both internal and external stress by modulating cell cycle and apoptotic pathways. p53 is mutated in more than 50% of human cancer and in most others, its pathway is defective. p53 undergoes a number of posttranslational modifications including acetylation of lysine (Lys) residues on its C-terminal. Acetylation of p53 at Lys373 and Lys382 has been reported to decrease its degradation and increased binding to DNA, leading to increased transcription of its downstream targets such as p21/waf1 and Bax. The process of acetylation is regulated by a group of opposing enzymes histone acetyltransferase (HATs) and histone deacetylases (HDACs). Class I HDACs (HDAC 1, 2, 3 and 8) are shown to be upregulated in a variety of human cancers including prostate cancer and their inhibition by HDAC inhibitors leads to cell cycle arrest and apoptosis in cancer cells. In pursuit of safe and effective HDAC inhibitors, we earlier demonstrated that green tea polyphenols (GTP) and its major constituent, (-) epigallocatechin-3-gallate (EGCG) has ability to inhibit class I HDACs in human prostate cancer cells. Here we demonstrate that GTP and EGCG activates p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in human prostate cancer LNCaP cells. Treatment of cells with GTP (2.5-10μg/ml) and EGCG (5-20μM) resulted in dose and time dependent inhibition of class I HDACs, albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with the increase accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Taken together, our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs which is likely to be part of the mechanism that control the physiological activity of p53. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2583. doi:1538-7445.AM2012-2583