BACKGROUNDS: SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity. METHODS: Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival. RESULTS: SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis. CONCLUSIONS: In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.
- MeSH
- chromozomální proteiny, nehistonové * genetika metabolismus MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru patologie metabolismus genetika MeSH
- lymfatické metastázy MeSH
- nádorové biomarkery * genetika metabolismus MeSH
- nádory prostaty rezistentní na kastraci patologie genetika metabolismus MeSH
- nádory prostaty * patologie metabolismus genetika MeSH
- prognóza MeSH
- senioři MeSH
- stupeň nádoru MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND OBJECTIVE: The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy. METHODS: Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data. KEY FINDINGS AND LIMITATIONS: Twenty-five patients (54%) had a response (
- Publikační typ
- časopisecké články MeSH
Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. PATIENT SUMMARY: We compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.
- MeSH
- deoxycytidin * analogy a deriváty farmakologie terapeutické užití MeSH
- gemcitabin * MeSH
- klofarabin * terapeutické užití farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory močového měchýře * farmakoterapie patologie MeSH
- protinádorové antimetabolity terapeutické užití farmakologie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The incidence of nephrolithiasis is rising worldwide. Although it is a multifactorial disease, lifestyle plays a major role in its etiology. Another considerable factor could be an aberrant microbiome. In our observational single-center study, we aimed to investigate the composition of bacteria in kidney stones and urine focusing on patients with features of metabolic syndrome. Catheterized urine and kidney stones were collected prospectively from 100 consecutive patients undergoing endoscopic nephrolithotomy between 2020 and 2021 at our clinic. Microbiome composition was analyzed via 16S rRNA gene amplicon sequencing. Detection of bacteria was successful in 24% of the analyzed kidney stones. These patients had a prolonged length of stay compared to patients without verifiable bacteria in their stones (2.9 vs 1.5 days). Patients with features of metabolic syndrome were characterized by kidney stones colonized with classical gastrointestinal bacteria and displayed a significant enrichment of Enterococcaceae and Enterobacteriaceae. Stones of patients without features of metabolic syndrome characterized by Ureaplasma and Staphylococcaceae. Patients with bacteria in their kidney stones exhibit a longer length of stay, possibly due to more complex care. Patients presenting with features of metabolic syndrome displayed a distinct stone microbiome compared to metabolically fit patients. Understanding the role of bacteria in stone formation could enable targeted therapy, prevention of post-operative complications and new therapeutic strategies.
- MeSH
- Bacteria MeSH
- ledvinové kameny * diagnóza MeSH
- lidé MeSH
- metabolický syndrom * MeSH
- mikrobiota * MeSH
- nefrolitiáza * moč MeSH
- RNA ribozomální 16S genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
Squamous cell carcinoma of the penis (PSC) is a rare disease with limited information on the molecular events leading to malignant transformation. In a third of PSC cases, presence of human papilloma virus (HPV) is found. The APOBEC3 family of proteins is known to play a significant role in defense against HPV infection, but their role in PSC is largely unknown. In this study, we aim to assess mRNA expression levels of APOBEC3 family members in HPV+ and HPV- PSC to get insight into their association with clinicopathological features and to evaluate their prognostic impact. Expression levels of six APOBEC3 family members in tissue from 50 patients with PSC were determined by RT-PCR and correlated with clinical and histopathological features. Lower expression of APOBEC3A, APOBEC3B, and APOBEC3C was observed in advanced PSC stages. Except for APOBEC3D, HPV+ samples showed higher expression of APOBEC3s compared to HPV- samples. In univariate analyses, APOBEC3A and APOBEC3C expression tended to be associated with disease-free survival and APOBEC3A expression with overall survival; however, multivariable analyses failed to confirm these associations with outcome. More extensive external validation and functional laboratory studies are needed to evaluate further their role in PSC development and progression.
- MeSH
- cytidindeaminasa genetika MeSH
- deaminasy APOBEC MeSH
- infekce papilomavirem * komplikace genetika MeSH
- lidé MeSH
- Papillomaviridae genetika MeSH
- penis patologie MeSH
- prognóza MeSH
- spinocelulární karcinom * patologie MeSH
- vedlejší histokompatibilní antigeny genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE OF REVIEW: In this review, we aimed to summarize the available evidence on pretreatment molecular biomarkers that may help to predict oncologic and pathologic outcomes in patients treated with neoadjuvant systemic therapy (NAST) for urothelial carcinoma of the bladder (UCB). RECENT FINDINGS: Several readily available and easily measurable blood-based biomarkers (e.g., neutrophil to lymphocyte or platelet-lymphocyte ratios) seems to help improve the selection of UCB patients who are most likely to benefit from NAST. Recent evidence suggests liquid biopsy including circulating tumor DNA (ctDNA) to be a promising tool to guide the administration of NAST in UCB patients. Pretreatment molecular and genetic characterization of transurethral resection of the bladder tumor samples may also help understand the tumor biology as luminal and basal tumor subtypes seems to be more responsive to NAST, while claudin-low and luminal-infiltrated tumor subtypes are less. In the context of neoadjuvant immunotherapy, programmed death-ligand 1 (PD-L1) status and ctDNA remain the only biomarker with possible value as the clinical utility of tumor mutational burden remains controversial/poor. SUMMARY: Biomarker approach is a necessary step to usher the age of precision/personalized medicine for muscle-invasive UCB with the overarching good to prevent both over- and under-therapy. The present review may offer a robust framework to compare and assess current and future molecular biomarkers for the selection of NAST in muscle-invasive UCB.
- MeSH
- cirkulující nádorová DNA * genetika MeSH
- karcinom z přechodných buněk * farmakoterapie genetika MeSH
- lidé MeSH
- močový měchýř patologie MeSH
- nádorové biomarkery genetika MeSH
- nádory močového měchýře * farmakoterapie genetika MeSH
- neoadjuvantní terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.
- MeSH
- akutní lymfatická leukemie * farmakoterapie metabolismus MeSH
- časná detekce nádoru MeSH
- karcinom z přechodných buněk * MeSH
- klofarabin terapeutické užití MeSH
- lidé MeSH
- myši MeSH
- nádory močového měchýře * patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The gene coding for histone methyltransferase KMT2D is found among the top mutated genes in upper tract urothelial carcinoma (UTUC); however, there is a lack of data regarding its association with clinicopathologic features as well as survival outcomes. Therefore, we aimed to investigate KMT2D expression, mutation patterns, and their utility as prognostic biomarkers in patients with UTUC. A single-center study was conducted on tumor specimens from 51 patients treated with radical nephroureterectomy (RNU). Analysis of KMT2D protein expression was performed using immunohistochemistry (IHC). Customized next-generation sequencing (NGS) was used to assess alterations in KMT2D exons. Cox regression was used to assess the relationship of KMT2D protein expression and mutational status with survival outcomes. KMT2D expression was increased in patients with a previous history of bladder cancer (25% vs. 0%, p = 0.02). The NGS analysis of KMT2D exons in 27 UTUC tumors revealed a significant association between pathogenic KMT2D variants and tumor location (p = 0.02). Pathogenic KMT2D variants were predominantly found in patients with non-pelvic or multifocal tumors (60% vs. 14%), while the majority of patients with a pelvic tumor location (81% vs. 20%) did not harbor pathogenic KMT2D alterations. Both IHC and NGS analyses of KMT2D failed to detect a statistically significant association between KMT2D protein or KMT2D gene alteration status and clinical variables such as stage/grade of the disease or survival outcomes (all p > 0.05). KMT2D alterations and protein expression were associated with UTUC features such as multifocality, ureteral location, and previous bladder cancer. While KMT2D protein expression and KMT2D mutational status do not seem to have prognostic value in UTUC, they appear to add information to improve clinical decision-making regarding the type of therapy.
- Publikační typ
- časopisecké články MeSH
PURPOSE OF REVIEW: Urinary tract infection (UTI) is one of the most common pediatric infections worldwide. Recently introduced 16S rRNA sequencing allows detailed identification of bacteria involved in UTI on a species-based level. The urogenital microbiome in children is scarcely investigated, with underlying conditions differing from adults. Improvement in diagnostic and therapeutic approaches can help to minimize unnecessary antibiotic treatments, thereby protecting the physiological microbiome. RECENT FINDINGS: Healthy bladders of children display a distinct microbiome than those of adults. UTI is characterized by changes in bacterial composition, with a high prevalence of Enterobacterales. There is a correlation between bacterial species and the pH of the urine, so a characteristic age-related pathogen pattern can be found due to the acidic urine in infants and more alkaline urine in older children. Recently, new methods were proposed to overcome the suboptimal diagnostic performance of urine cultures and urine dipstick test. This allows precise treatment decisions and helps to prevent chronification of UTI, related voiding dysfunctions and renal scaring, systemic abiosis, and the development of antibiotic resistance. SUMMARY: Uropathogens involved in UTIs in children should be identified with precision to allow targeted therapeutic decisions. This can also help preventing the destruction of the microbiome homeostasis, which could result in a life-long dysbiosis. New treatment approaches and recolonization with probiotics are necessary due to increasing intrinsic antibiotic resistance of bacteria.
- MeSH
- analýza moči MeSH
- antibakteriální látky terapeutické užití MeSH
- dítě MeSH
- dospělí MeSH
- infekce močového ústrojí * diagnóza farmakoterapie MeSH
- kojenec MeSH
- lidé MeSH
- mikrobiota * MeSH
- RNA ribozomální 16S genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE OF REVIEW: Despite the plethora of publications discussing the severe respiratory coronavirus 2 (SARS-CoV-2), evidence of viral secretion in urine is sparse. RECENT FINDINGS: We could identify 34 publications including a total of 2172 patients. Among those, 549 patients were tested for SARS-CoV-2 secretion in urine, which was detected in only 38 patients (6.9%). Within the seven studies displaying positive results, the majority of positive patients (86.8%) was from not yet peer-reviewed studies including weak data and heterogeneous techniques for sample testing. Furthermore, none of the studies available in the literature addressed the virulence of detected viral RNA in urine. SUMMARY: Overall, only seven studies were able to detect SARS-CoV-2 secretion in urine, all of them with a considerably low rate of positivity. However, these studies were of rather low quality considering their methodology. Despite this, as SARS-CoV-2 has been detected in urine, it is of importance to discuss safety and urinary hygiene protocols. Until further research provides valid data on viral shedding and virulence in urine, potential risk of transmission through urine cannot be ruled out. Therefore, safety and hygiene measures need to be discussed.
- MeSH
- Betacoronavirus izolace a purifikace MeSH
- koronavirové infekce moč MeSH
- lidé MeSH
- pandemie MeSH
- virová pneumonie moč MeSH
- vylučování virů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
