In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its ...potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules.
Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of ...patients do not respond to cisplatin‐based combination chemotherapy, although it is the standard of care for muscle‐invasive and metastatic bladder cancer. The development of robust predictive biomarkers is expected to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it. Recent advances in the molecular characterization of bladder cancer showed that the basal subtype of bladder cancer and tumors with inactivating mutations in DNA damage repair genes were associated with greater benefit from cisplatin‐based chemotherapy. The present review summarizes current efforts to develop predictive biomarkers for drug response in bladder cancer, focusing on those that predict the response to cisplatin‐based chemotherapy for advanced bladder cancer. We also review the current situation with regard to the identification of predictive biomarkers for response to intravesical therapy, immune checkpoint inhibitors and molecularly‐targeted drugs. We also discuss the future applications of new technologies, including liquid biopsies and patient‐derived organoids that will also serve as resources for the identification of biomarkers in bladder cancer.
Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists ...have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.
Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction. This stress-induced cardiomyopathy appears to be a form of ...myocardial stunning associated with marked sympathetic stimulation.
Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction.
The potentially lethal consequences of emotional stress are deeply rooted in folk wisdom, as reflected by phrases such as “scared to death” and “a broken heart.” In the past decade, cardiac contractile abnormalities and heart failure have been reported after acute emotional stress,
1
–
6
but the mechanism remains unknown. We evaluated 19 patients with “stress cardiomyopathy,” a syndrome of profound myocardial stunning precipitated by acute emotional stress, in an effort to identify the clinical features that distinguish this syndrome from acute myocardial infarction and the cause of transient stress-induced myocardial dysfunction.
Methods
Study Patients
Nineteen previously healthy patients were admitted . . .
Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder ...neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer. In this study, we analyzed 527 cases, including 373 noninvasive and 154 invasive urothelial carcinomas of bladder from transurethral resections or cystectomies performed at four institutions (1991-2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall, 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade noninvasive papillary carcinomas, with a relatively lower incidence of 65% in high-grade noninvasive papillary carcinomas and carcinomas in situ; p = 0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade noninvasive papillary carcinomas compared with high-grade noninvasive papillary carcinomas and carcinomas in situ (p < 0.0001), while the opposite was true for TP53 (p < 0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p = 0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared with those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes, confirming the comprehensive coverage of the panel and supporting its potential utility as a noninvasive urine-based assay.
Non-muscle-invasive bladder cancer (NMIBC) remains one of the most common malignancies and is associated with considerable treatment costs. Patients with intermediate-risk or high-risk disease can be ...treated with intravesical BCG, but many of these patients will experience tumour recurrence, despite adequate treatment. Standard of care in these patients is radical cystectomy with urinary diversion, but this approach is associated with considerable morbidity and lifestyle modification. As an alternative, perioperative intravesical chemotherapy is recommended for low-risk papillary NMIBC, and induction intravesical chemotherapy is an option for patients with intermediate-risk NMIBC and BCG-unresponsive NMIBC. However, poor pharmaceutical absorption and drug washout during normal voiding can limit sustained drug concentrations in the urothelium, which reduces efficacy, and small-molecule chemotherapeutic agents can be absorbed through the urothelium into the bloodstream, leading to systemic adverse effects. Several novel drug delivery methods - including hyperthermia, mechanical sustained released devices and nanoparticle drug conjugation - have been developed to overcome these limitations. These novel methods have the potential to be combined with established chemotherapeutic agents to change the paradigm of NMIBC treatment.
The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in ...morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where >15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.
Urothelial bladder cancer (UBC) remains one of the most common and deadly cancers worldwide, and platinum-based chemotherapy, which has been the standard-of-care in metastatic bladder cancer, has had ...limited success in improving outcomes for patients. The recent development and translation of therapeutic strategies aimed at harnessing the immune system have led to durable and prolonged survival for patients with several different cancers, including UBC. In this review, we discuss new findings in bladder cancer immunotherapy, including recent successes with immune checkpoint blockade. We also discuss therapeutic cancer vaccines and highlight several additional immunotherapy modalities in early stages of development.
Surgical correction of urethral strictures by substitution urethroplasty - the use of grafts or flaps to correct the urethral narrowing - remains one of the most challenging procedures in urology and ...is frequently associated with complications, restenosis and poor quality of life for the affected individual. Tissue engineering using different cell types and tissue scaffolds offers a promising alternative for tissue repair and replacement. The past 30 years of tissue engineering has resulted in the development of several therapies that are now in use in the clinic, especially in treating cutaneous, bone and cartilage defects. Advances in tissue engineering for urethral replacement have resulted in several clinical applications that have shown promise but have not yet become the standard of care.
Priapism: Pathogenesis, Epidemiology, and Management Broderick, Gregory A.; Kadioglu, Ates; Bivalacqua, Trinity J. ...
Journal of sexual medicine,
January 2010, 2010-01, 2010-Jan, 2010-01-01, 20100101, Letnik:
7, Številka:
1pt2
Journal Article
Recenzirano
Priapism describes a persistent erection arising from dysfunction of mechanisms regulating penile tumescence, rigidity, and flaccidity. A correct diagnosis of priapism is a matter of urgency ...requiring identification of underlying hemodynamics.
To define the types of priapism, address its pathogenesis and epidemiology, and develop an evidence-based guideline for effective management.
Six experts from four countries developed a consensus document on priapism; this document was presented for peer review and debate in a public forum and revisions were made based on recommendations of chairpersons to the International Consultation on Sexual Medicine. This report focuses on guidelines written over the past decade and reviews the priapism literature from 2003 to 2009. Although the literature is predominantly case series, recent reports have more detailed methodology including duration of priapism, etiology of priapism, and erectile function outcomes.
Consensus recommendations were based on evidence-based literature, best medical practices, and bench research.
Basic science supporting current concepts in the pathophysiology of priapism, and clinical research supporting the most effective treatment strategies are summarized in this review.
Prompt diagnosis and appropriate management of priapism are necessary to spare patients ineffective interventions and maximize erectile function outcomes. Future research is needed to understand corporal smooth muscle pathology associated with genetic and acquired conditions resulting in ischemic priapism. Better understanding of molecular mechanisms involved in the pathogenesis of stuttering ischemic priapism will offer new avenues for medical intervention. Documenting erectile function outcomes based on duration of ischemic priapism, time to interventions, and types of interventions is needed to establish evidence-based guidance. In contrast, pathogenesis of nonischemic priapism is understood, and largely attributable to trauma. Better documentation of onset of high-flow priapism in relation to time of injury, and response to conservative management vs. angiogroaphic or surgical interventions is needed to establish evidence-based guidance. Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, and Shamloul R. Priapism: Pathogenesis, epidemiology and management.
PDF
