Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional ...assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.
•Monocytes and macrophages show a protumor phenotype in a human cancer setting•The protumor phenotype is regulated by an IL-1 receptor-dependent mechanism•Targeting this mechanism abrogated macrophage protumor phenotype and tumor in vivo
Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. Biswas and colleagues provide transcriptional, functional, and mechanistic data demonstrating a tumor-promoting phenotype of these cells in a human cancer setting.
Cystoscopy is the gold standard clinical diagnosis of human bladder cancer (BC). As cystoscopy is expensive and invasive, it compromises patients’ compliance toward surveillance screening and ...challenges the detection of recurrent BC. Therefore, the development of a noninvasive method for the diagnosis and surveillance of BC and the elucidation of BC progression become pertinent. In this study, urine samples from 38 BC patients and 61 non-BC controls were subjected to urinary metabotyping using two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC–TOFMS). Subsequent to data preprocessing and chemometric analysis, the orthogonal partial least-squares discriminant analysis (OPLS-DA, R2X = 0.278, R2Y = 0.904 and Q2Y (cumulative) = 0.398) model was validated using permutation tests and receiver operating characteristic (ROC) analysis. Marker metabolites were further screened from the OPLS-DA model using statistical tests. GC×GC–TOFMS urinary metabotyping demonstrated 100% specificity and 71% sensitivity in detecting BC, while 100% specificity and 46% sensitivity were observed via cytology. In addition, the model revealed 46 metabolites that characterize human BC. Among the perturbed metabolic pathways, our clinical finding on the alteration of the tryptophan-quinolinic metabolic axis in BC suggested the potential roles of kynurenine in the malignancy and therapy of BC. In conclusion, global urinary metabotyping holds potential for the noninvasive diagnosis and surveillance of BC in clinics. In addition, perturbed metabolic pathways gleaned from urinary metabotyping shed new and established insights on the biology of human BC.
Objectives
To examine the impact on quality of life of recurrent acute uncomplicated urinary tract infection among premenopausal Singaporean women, and to determine the risk factors for lower quality ...of life among these patients.
Methods
A total of 85 patients with recurrent acute uncomplicated urinary tract infection who were referred to the Urology Department at the National University Hospital, Singapore, were prospectively recruited over a 3‐year period to complete the validated Short Form 36 Health Survey version 1. In addition, demographic and clinical details including symptomology and medical history were analyzed for factors impacting quality of life. Short Form 36 Health Survey version 1 results were compared with published population norms.
Results
After adjusting for age, gender and race, recurrent acute uncomplicated urinary tract infection patients had significantly lower quality of life on seven out of eight Short Form 36 Health Survey version 1 domains when compared with age‐, gender‐ and race‐adjusted population norms for Singapore. Among those with recurrent acute uncomplicated urinary tract infection, those who also reported caffeine consumption had significantly lower Short Form 36 Health Survey version 1 scores than those who did not. Those who reported chronic constipation also had consistently lower Short Form 36 Health Survey version 1 scores across all domains.
Conclusions
Recurrent acute uncomplicated urinary tract infection has a negative impact on the quality of life of premenopausal, otherwise healthy women. Recurrent acute uncomplicated urinary tract infection patients who also have chronic constipation or consume caffeine have lower quality of life than those who do not. More studies are required to understand the relationships between these common problems and risk factors.
Bladder cancer (BC) is a disease that requires lifelong surveillance due to its high recurrence rate. An efficient method for the non-invasive rapid monitoring of patient prognosis and downstream ...phenotype characterization is warranted. Here, we develop an integrated procedure to detect aggressive mesenchymal exfoliated bladder cancer cells (EBCCs) from patients in a label-free manner. Using a combination of filtration and inertial focusing principles, the procedure allowed the focusing of EBCCs in a single stream-line for high-throughput separation from other urine components such as large squamous cells and blood cells using a microfluidic sorting device. Characterization of enriched cells can be completed within hours, suggesting a potential utility for real-time detection. We also demonstrate high efficiency of cancer cell recovery (93.3 ± 4.8%) and specific retrieval of various epithelial to mesenchymal transition (EMT) phenotype cell fractions from respective outlets of the microfluidic device. EMT is closely associated with metastasis, drug resistance and tumor-initiating potential. This procedure is validated with clinical samples, and further demonstrate the efficacy of bladder wash procedure to reduce EBCCs counts over time. Overall, the uniqueness of a rapid and non-invasive method permitting the separation of different EMT phenotypes shows high potential for clinical utility. We expect this approach will better facilitate the routine screening procedure in BC and greatly enhance personalized treatment.
Metabonomic Profiling of Bladder Cancer Chan, Eric Chun Yong; Pasikanti, Kishore Kumar; Hong, Yanjun ...
Journal of proteome research,
02/2015, Letnik:
14, Številka:
2
Journal Article
Recenzirano
Early diagnosis and life-long surveillance are clinically important to improve the long-term survival of bladder cancer patients. Currently, a noninvasive biomarker that is as sensitive and specific ...as cystoscopy in detecting bladder tumors is lacking. Metabonomics is a complementary approach for identifying perturbed metabolic pathways in bladder cancer. Significant progress has been made using modern metabonomic techniques to characterize and distinguish bladder cancer patients from control subjects, identify marker metabolites, and shed insights on the disease biology and potential therapeutic targets. With its rapid development, metabonomics has the potential to impact the clinical management of bladder cancer patients in the future by revolutionizing the diagnosis and life-long surveillance strategies and stratifying patients for diagnostic, surgical, and therapeutic clinical trials. An introduction to metabonomics, typical metabonomic workflow, and critical evaluation of metabonomic investigations in identifying biomarkers for the diagnosis of bladder cancer are presented.
Clinical and pathological predictors of bladder carcinoma recurrence and progression are relatively well defined. However, there is a paucity of genetic data specifically on the association of single ...nucleotide polymorphisms in specific genes for predicting recurrence and progression following immunotherapy. The VDR gene was found to regulate the immunomodulatory effects of vitamin D and it enhances the innate immunity system. We evaluated 3 VDR single nucleotide polymorphisms and their predictive role on the response to immunotherapy.
Patients with bladder cancer at intermediate-high risk who underwent post-transurethral resection intravesical bacillus Calmette-Guérin in Singapore and Hong Kong from 1995 to 2014 were recruited for analysis. We evaluated 3 VDR single nucleotide polymorphisms using polymerase chain reaction. Kaplan-Meier survival curves and relationships with outcomes were analyzed by multivariable Cox regression.
A total of 338 predominantly Chinese patients were included in study. Individuals carrying the VDR genotype Bsm A/G were significantly associated with lower time to recurrence after bacillus Calmette-Guérin therapy (p <0.001). On multivariable analysis the HR of recurrence in patients with the Bsm A allele was 3.95 times that in patients without the allele (p = 0.037). Patients with the VDR GATC subhaplotype were 3.05 times more likely than patients with other subhaplotypes to experience recurrences (p = 0.003). Study limitations include the small sample size and the lack of information on previous bacillus Calmette-Guérin vaccine exposure and on vitamin D levels.
Our findings in this study suggest that various VDR single nucleotide polymorphisms are associated with recurrences after bacillus Calmette-Guérin immunotherapy. Further functional studies should be performed to elucidate the significance of the VDR gene in the management of bladder cancer and the potential therapy implications.
Several studies have reaffirmed the use of regular pentoxifylline therapy in increasing the penile brachial pressure index in men affected by erectile dysfunction when compared to placebo.
The aim of ...this study was to evaluate the efficacy of pentoxifylline as an adjunctive treatment for patients with erectile dysfunction.
This study was a single center, prospective, randomized, double-blind, placebo-controlled trial. Subjects were recruited between April 2014 and November 2016 from the National University Hospital, Singapore. The combination therapy group was given pentoxifylline 400 mg thrice daily orally and the monotherapy group was given placebo capsules thrice daily orally. Both groups continued their on-demand 100 mg sildenafil. The treatment duration was 8 weeks. Efficacy was measured via the International Index of Erectile Function (IIEF-5) questionnaire at the eighth week. Differences in mean IIEF-5 score and the domains of the IIEF at 8 weeks between the 2 treatment groups were compared using independent sample t-test.
Baseline IIEF-5 and the IIEF-15 score vs post-therapy IIEF-5 and the IIEF-15 score.
50 patients were randomized into 2 groups. Patients in the 2 groups were comparable in terms of the demographic and clinical characteristics, comorbidities, and baseline IIEF-5 scores. The mean IIEF-5 score post-therapy of the combination therapy group vs the monotherapy group was 14.11 and 14.87, respectively. There was no significant difference between the outcomes of these 2 groups (unadjusted mean difference -0.76; 95% CI -4.01 to 2.49; P = .641) and the outcomes are the same even after adjusting for baseline IIEF-5 scores. There was a significant improvement in the “overall satisfaction” portion of the IIEF score for the combination therapy group as compared to the monotherapy group (unadjusted mean difference 0.12; 95% CI -1.49 to 1.25) and even after adjustment for baseline scores (adjusted mean difference 1.11; 95% CI 0.10 to 2.12; P = .032) the improvement is significant.
Our trial suggests that the use of combination therapy does not improve the management of patients compared to monotherapy.
Law YXT, Tai BC, Tan YQ et al. A Small Group Randomized Double-Blind Placebo-Controlled Study to Evaluate the Efficacy of Daily Pentoxifylline in the Management of Patients With Erectile Dysfunction with Suboptimal Treatment Response to Sildenafil. Sex Med 2019;8:14–20.
•Bacillus Calmette-Guerin (BCG) immunotherapy is commonly used in bladder cancer.•Rs3759601 is a single nucleotide polymorphism of Autophagy gene ATG2B.•Rs3759601 correlates with BCG response in ...European bladder cancer patients.•Rs3759601 C allele is much less common in Asians compared to Europeans.•Rs3759601 does not correlate with BCG response in Asian bladder cancer patients.
Optimal patient stratification is critical in the era of personalized medicine. Germline polymorphisms play an important role in the treatment response of various human diseases, including bladder cancer. Intravesical BCG therapy is widely-used for bladder cancer. However, tumor recurrence and progression are very common. Stratification based on germline polymorphisms may contribute to circumvent this clinical challenge. Autophagy pathway plays an important role in the nonspecific protective effects of BCG. Patients that carry C allele of rs3759601 in autophagy gene ATG2B showed increased risk of recurrence and progression in European population. We thus sought to analyze rs3759601 and its relevance in BCG response in Asian NMIBC patients.
Functional impact of rs3759601 ATG2B (p.Gln1383Glu) was analyzed by bioinformatics programs including NCBI Conserved Domain Search, Clustal Omega, Polyphen and SIFT. NMIBC patients who received intravesical BCG at multiple hospitals in Singapore from 1995 to 2016 were included. These patients were genotyped for rs3759601 using high resolution melt analysis. The rs3759601 polymorphism was studied in correlation with the bladder cancer recurrence rate and disease progression rate in our cohort. Statistical analysis was conducted using Kaplan-Meier plots and the Chi-squared analysis.
In total, 307 individules were included in the study including 161 NMIBC patients and 146 healthy controls, predominately Chinese. The rs3759601 genotype distributions in our NMIBC patients were (GG 72.1%; GC 27.9%; CC 0%), which were distinct from the Dutch report (GG 32.8%; GC 47.4% and CC 19.8%, Buffen K et al, 2014). Consistently, the C allele frequencies of rs3759601 are 0.171 in our controls and 0.177 in East Asians from 1,000 Genome, but 0.406 in Europeans from 1,000 Genome. In silico analysis suggested rs3759601 ATG2B (p.Gln1383Glu) alteration is unlikely to be functionally deleterious. Statistical analysis revealed no significant association between ATG2B rs3759601 C allele and risk of bladder cancer recurrence (P= 0.353, GC vs. GG: hazard ratio HR= 1.324), or cancer progression (P= 0.454, GC vs. GG: HR = 0.658).
In contrast to European NMIBC patients, ATG2B rs3759601 C allele is much less common in Asians and it not associated with BCG response in Asian NMIBC patients.
Background
Selecting the smaller kidney for donation has been advocated if there is a size difference of > 10% between the 2 kidneys but has never been prospectively evaluated. With increase in donor ...nephrectomies, it is important to evaluate this to minimize loss of renal function to donors.
Methods
75 consecutive donor nephrectomy patients were included in our longitudinal study. The Split Renal Volume (SRV) of bilateral kidneys were measured using contrasted computer tomography scans and patients segregated into 2 groups depending on donated kidney having more (Group 1) or less than (Group 2) 52.5% of SRV.
Results
Patients in Group 1 (n = 19) and 2 (n = 56) were of similar age (43.8 vs. 48.3), BMI (22.4 vs. 25.2), sex (57.9 vs. 55.4% women), respectively. Although total kidney volumes were similar in both groups, Group 1 had significantly smaller right kidney volumes (120.4 ± 24.9 vs. 142.7 ± 28.4 mls, p = 0.003). EGFR pre-operatively (116.3 ± 20.8 vs. 106.3 ± 23.8 mL/min/1.73 m
2
) and at 6-months (65.7 ± 13.3 vs. 66.9 ± 15.5 mL/min/1.73 m
2
) were not different between groups. However, patients in Group 1 had significantly greater absolute (50.6 ± 14.9 vs. 39.5 ± 14.7 mL/min/1.73 m
2
) and relative decline (43.0 ± 8.6 vs. 36.3 ± 10.6%) in eGFR at 6 months (p = 0.06, 0.009).
Conclusion
With a SRV difference of 5% between the 2 sides, removal of the larger kidney for living kidney donation resulted in greater early decline of renal function than kidney donors whose larger or equivalent kidney is preserved.
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