Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

P53, CK20, and FGFR3 Overexpression is Associated with the Characteristics of Urothelial Cell Carcinoma of the Bladder

OBJECTIVES: The aim of this study was to investigate the association between the overexpression of tumor protein (P53), cytokeratin 20 (CK20), fibroblast growth factor receptor 3 (FGFR3), biomarkers and the grading, prognosis, heterogeneity, and relapse tendency of urothelial cell carcinomas (UCCs) of the bladder. METHODS: A cross-sectional study was conducted using 413 samples of Iranian patients diagnosed with UCC of the bladder. The tissue microarray technique was used to evaluate the patterns of tumor tissue. Two pathologists scored tissue staining using a semi-quantitative scoring system. RESULTS: The results showed that P53 was a predictor of a high-grade pattern (the area under the curve (AUC)=0.620) with a best cut-off value of 95.0 using the receiver operating characteristic (ROC) curve. CK20 was another predictor of a high-grade pattern (AUC=0.745) with a best cut-off value of 15. However, the overexpression of both biomarkers was not associated with a heterogeneous pattern and could not predict tumor-associated death or relapse. The heterogeneous (odds ratio (OR)=4.535, p-value=0.001) and non-papillary (OR= 6.363, p-value= 0.001) patterns were effective predictors of tumor recurrence among all baseline variables, including patient and tumor characteristics. FGFR3 was positive in all specimens and was not a valuable biomarker for differentiating patterns. None of the variables predicted tumor prognosis. CONCLUSION: The study findings indicate that the intensity and percentage of cell staining for P53 and CK20 in the UCC of the bladder can aid in differentiating the grading patterns. The tendency of tumor relapse can be predicted by demonstrating heterogeneous and non-papillary patterns.

The Added Value of Crescents on Oxford Classification Score in Risk Stratification of End-stage Kidney Disease in Patients with IgA Nephropathy.

INTRODUCTION: Crescents (C) have been recently added to the Oxford classification of IgA nephropathy (IgAN) consisting of mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S) and tubular atrophy/ interstitial fibrosis (T) (MEST). The aim of the study was to assess the added impact of crescents, on development of end-stage kidney disease (ESKD) in IgAN patients Methods. On-hundred fifteen IgAN patients (76% male, mean age: 37 ± 13 years, mean serum creatinine: 4.0 ± 4.3 mg/dL, mean proteinuria: 3.4 ± 2.5 g/d) were followed for 43 ± 29 months. MEST score was defined according to Oxford classification (M0/M1, E0/ E1, S0/S1). To increase the power, T was defined as T0 ≤ 25% and T1 > 25%. Crescents were defined as C0, "absence" and C1 "at least one" crescent. In sensitivity analysis, the risk of ESKD was estimated at different cut-off levels of at least 10, 20, and 30% crescents. RESULTS: Forty patients (35%) developed ESKD. Among those 14% with at least one crescent, 21 patients (46%) developed ESKD. In 11 patients with C ≥ 30%, 66% and among 57 patients with T1, 60% and in 27 patients with T1 + C1 74% developed ESKD. In adjusted model, only C ≥ 30% (HR = 3.15, 95% CI: 1.15 to 11.00; P = 0.027) and the presence of T1+ C1 (HR = 7.18, 95% CI: 1.90 to 27.10, P = 0.004) were associated with increased risk of ESKD. The median kidney survival was 78.0 months (95% CI: 70.5 to 85.6 months), in patients with T0 + C0 and 32.3 months (95% CI: 19.3 to 45.3 months) in patients with T1 + C1. CONCLUSION: In this study T ≥ 25%, and the presence of crescents ≥ 30%, were independently associated with increased risk of ESKD. This risk was strongly increased in the combined presence of at least one crescent and T1 ≥ 25%, that predicted a high ESKD rate.  DOI: 10.52547/ijkd.6685.

Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer.

BACKGROUND: The crucial oncogenic role of cancer stem cells (CSCs) in tumor maintenance, progression, drug resistance, and relapse has been clarified in different cancers, particularly in colorectal cancer (CRC). The current study was conducted to evaluate the co-expression pattern and clinical significance of epithelial cell adhesion molecules (EpCAM) and activated leukocyte cell adhesion (CD166 or ALCAM) in CRC patients. METHODS: This study was carried out on 458 paraffin-embedded CRC specimens by immunohistochemistry on tissue microarray (TMA) slides. RESULTS: Elevated expression of EpCAM and CD166 was observed in 61.5% (246/427) and 40.5% (164/405) of CRC cases. Our analysis showed a significant positive association of EpCAM expression with tumor size (P = 0.02), tumor stage (P = 0.007), tumor differentiate (P = 0.005), vascular (P = 0.01), neural (P = 0.01), and lymph node (P = 0.001) invasion. There were no significant differences between CD166 expression and clinicopathological parameters. Moreover, the combined analysis demonstrated a reciprocal significant correlation between EpCAM and CD166 expression (P = 0.02). Interestingly, there was a significant positive correlation between EpCAM/CD166 phenotypes expression and tumor stage (P = 0.03), tumor differentiation (P = 0.05), neural, and lymph node invasion (P =0.01). CONCLUSIONS: The significant correlation of EpCAM and CD166 expression and their association with tumor progression and aggressive behavior is the reason for the suggestion of these two CSC markers as promising targets to promote novel effective targeted-therapy strategies for cancer treatment in the present study.

Kidney Outcome in Primary Focal Segmental Glomerulosclerosis (FSGS) by Using a Predictive Model.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is one of the important causes of end stage kidney disease (ESKD). We evaluated the progression risk factors of primary FSGS to chronic kidney disease (CKD) or ESKD with a predictive model including clinical and histological predictors. METHODS: 201 patients with primary FSGS (59% male, mean age: 38 ± 15 years), were studied. Time-dependent Cox model and C statistics were used for the predictive model. Interaction and correlation between independent variables were estimated. RESULTS: During 55 ± 27 months of follow-up, 82 patients (41%) developed CKD (46) or ESKD (36) patients. In adjusted model, 1 unit of higher serum creatinine (SCr) at baseline (HR = 1.39, 95% CI: 1.15 to 1.70) and 1% increase in glomeruli with segmental glomerulosclerosis (SGS) (HR = 1.03, 95% CI: 1.02 to 1.04) or interstitial fibrosis/tubular atrophy (IF/TA) (HR = 1.03, 95% CI: 1.01 to 1.05) increased the risk of CKD/ESKD. In adjusted model, higher baseline proteinuria and collapsing variant were not associated with risk of CKD/ESKD. By adding SGS and IF/TA scores to baseline SCr in the model, discrimination by C statistics was 0.83 (95% CI: 0.77 to 0.90). Median renal survival was 3.1 years (95% CI: 2.2 to 4.1 years) in patients with highest risk score (baseline eGFR < 25 mL/min/1.73m2 + IF/TA/SGS > 50%), and 8.1 years (95% CI: 7.7 to 8.6 years).in those with lowest score (baseline eGFR > 75 mL/ min/1.73m2 + IF/TA/SGS < 5%). CONCLUSION: In primary FSGS, higher baseline SCr, increased SGS and IF/TA, but not baseline proteinuria and collapsing pathology, were the predictors for CKD/ESKD. These findings indicated the importance of timely detection and referral in prognosis of primary FSGS. DOI: 10.52547/ijkd.6442.

SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes.

Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-ß (Transformis growth factorß)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFß1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFß1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis.

Low level expression of human telomerase reverse transcriptase predicts cancer-related death and progression in embryonal carcinoma.

INTRODUCTION: hTERT (human telomerase reverse transcriptase) is a catalytic subunit of the enzyme telomerase and has a role in cell proliferation, cellular senescence, and human aging. MATERIALS AND METHODS: The purpose of this study was to evaluate the expression and significance of hTERT protein expression as a prognostic marker in different histological subtypes of testicular germ cell tumors (TGCTs), including 46 embryonal carcinomas, 46 yolk sac tumors, 38 teratomas, 84 seminomas as well as two main subtypes of seminomas and non-seminomas using tissue microarray (TMA) technique. RESULTS: The results showed that there is a statistically significance difference between the expression of hTERT and various histological subtypes of TGCTs (P < 0.001). In embryonal carcinoma, low level expression of hTERT protein was significantly associated with advanced pT stage (P = 0.023) as well as tunica vaginalis invasion (P = 0.043). Moreover, low level expression of hTERT protein was found to be a significant predictor of worse DSS (log rank: P = 0.011) and PFS (log rank: P = 0.011) in the univariate analysis. Additionally, significant differences were observed (P =0.021, P =0.018) with 5-year survival rates for DSS and PFS of 66% and 70% for moderate as compared to 97% and 97% for high hTERT protein expression, respectively. CONCLUSION: We showed that hTERT protein expression was associated with more aggressive tumor behavior in embryonal carcinoma patients. Also, hTERT may be a novel worse prognostic indicator of DSS or PFS, if the patients are followed up for more time periods.

Cytoplasmic expression of B7-H3 and membranous EpCAM expression are associated with higher grade and survival outcomes in patients with clear cell renal cell carcinoma.

B7-H3 and EpCAM are overexpressed in cancer and play a role in tumorigenesis and metastasis. In this study, the membranous, cytoplasmic and nuclear expression levels of B7-H3 and EpCAM biomarkers were mapped in three major subtypes of renal cell carcinoma (RCC). Expression of B7-H3 and EpCAM were evaluated using immunohistochemistry in RCC samples on tissue microarrays (TMAs), including clear cell RCCs (ccRCCs), type I and II papillary RCCs (pRCCs), and chromophobe RCCs (chRCCs). The association between B7-H3 and EpCAM expression and clinicopathological features as well as survival outcomes was determined. There was a statistically significant difference between B7-H3 and EpCAM expression among the different RCC subtypes. In ccRCC, higher cytoplasmic expression of B7-H3 was significantly associated with increase in nucleolar grade, lymph node invasion (LNI), invasion of the Gerota's fascia, and tumor necrosis, while no association was found with the membranous and nuclear expression. Moreover tumors with cytoplasmic expression of B7-H3 tended to have a worse prognosis for disease-specific survival (DSS) than those with membranous expression. In case of EpCAM, increased membranous expression of EpCAM was associated with nucleolar grade and tumor necrosis in ccRCC. Additionally, membranous EpCAM expression added prognostic value in patients with ccRCC who had high nucleolar grade versus low nucleolar grade. Moreover, membranous EpCAM expression was found to be an independent favorable prognostic marker for progression-free survival (PFS) in ccRCC. Our results demonstrated that higher cytoplasmic B7-H3 and membranous EpCAM expression are clinically significant in ccRCC and are associated with more aggressiveness tumor behavior.

Policy Analysis Of Iranian Pharmaceutical Sector; A Qualitative Study.

INTRODUCTION: Improving public health through providing affordable and accessible pharmaceuticals is among the concerns of governments worldwide. This study aimed to analyze Iran's pharmaceutical sector policies in order to identify the challenges and suggest some strategic solutions to overcome such challenges. METHODS: Top managers (15), middle managers (10), and operational managers (5) working in the Food and Drug Administration of Iranian Ministry of Health along with community pharmacists (5) participated in a qualitative study using semi-structured in-depth interviews. Data were recorded, transcribed, and then analyzed via MAXQDA 10 software. RESULTS: Policies for national pharmaceutical sector were divided into four groups of "research & development", "import & export", "pharmaceutical procurement", and "pharmaceutical supply and distribution". Then, the challenges faced by each sector were extracted. Considering the challenges, some policy options were recommended for growth and development of national pharmaceutical sector. CONCLUSION: Iran's pharmaceutical sector has managerial and administrative differences compared with overseas pharmaceutical sectors. These differences are the main reasons for the current status of Iran's pharmaceutical sector and have put Iran behind foreign pharmaceutical sectors. Iran's pharmaceutical sector has endured many critical periods during recent decades and has gained great experience during these stages. Therefore, it is believed that Iran's pharmaceutical sector, with its experience and potential, is capable of producing world-level medicines.

Spheroid-Derived Cells From Renal Adenocarcinoma Have Low Telomerase Activity and High Stem-Like and Invasive Characteristics.

Cancer stem cells (CSCs) are a theorized small subpopulation of cells within tumors thought to be responsible for metastasis, tumor development, disease progression, treatment-resistance, and recurrence. The identification, isolation, and biological characterization of CSCs may therefore facilitate the development of efficient therapeutic strategies targeting CSCs. This study aims to compare the biology and telomerase activity of CSCs to parental cells (PCs) in renal cancer. Renal CSCs were enriched from the ACHN cell line using a sphere culture system. Spheroid-derived cells (SDCs) and their adherent counterparts were compared with respect to their colony and sphere formation, expression of putative CSC markers, tumorigenicity in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and invasiveness. The expression of genes associated with CSCs, stemness, EMT, apoptosis, and ABC transporters was also compared between the two populations using quantitative real-time PCR (qRT-PCR). Finally, telomerase activity, hTERT expression, and sensitivity to MST-312, a telomerase inhibitor, was investigated between the two populations. We demonstrated that a subpopulation of ACHN cells was capable of growing as spheroids with many properties similar to CSCs, including higher clonogenicity, superior colony- and sphere-forming ability, and stronger tumorigenicity and invasiveness. In addition, SDCs demonstrated a higher expression of markers for CSCs, stemness, EMT, apoptosis, and ABC transporter genes compared to PCs. The expression of hTERT and telomerase activity in SDCs was significantly lower than PCs; however, the SDC population was more sensitive to MST-312 compared to PCs. These findings indicate that the SDC population exhibits stem-like potential and invasive characteristics. Moreover, the reduced expression of hTERT and telomerase activity in SDCs demonstrated that the expressions of hTERT and telomerase activity are not always higher in CSCs. Our results also showed that MST-312 treatment inhibited SDCs more strongly than PCs and may therefore be useful as a complementary targeted therapy against renal CSCs in the future.

Human telomerase reverse transcriptase protein expression predicts tumour aggressiveness and survival in patients with clear cell renal cell carcinoma.

Human telomerase reverse transcriptase (hTERT) is an active component of telomerase and responsible for its catalytic activity, associated with cell proliferation and differentiation. For the first time, the present study was conducted to evaluate the expression and prognostic significance of hTERT in different histological subtypes of renal cell carcinoma (RCC). Expression of hTERT was examined in 176 well-defined renal tumour samples including clear cell RCCs (ccRCCs), papillary and chromophobe RCCs using immunohistochemistry on tissue microarrays. The association between hTERT expression and clinicopathological parameters as well as survival outcomes were then analysed. There was a statistically significant difference in terms of hTERT expression among various RCC subtypes. In ccRCC, increased expression of hTERT was significantly associated with advanced stage, higher grade, presence of microvascular invasion, lymph node invasion, and metastasis. Moreover, in the multivariate analysis, tumour stage and tumour size were independent predictors of the disease-specific survival (DSS). Additionally, expression of hTERT was found to be a significant predictor of worse DSS (p = 0.012) in the univariate analysis. In papillary carcinoma samples (type I and II), significant association was detected between hTERT expression and the tumour stage (p = 0.010, p = 0.050), respectively. In chromophobe RCC, no significant association was detected between expression of hTERT and clinicopathological parameters and survival data. We showed that hTERT protein expression was associated with more aggressive tumour behaviour and more advanced disease in ccRCC patients. Also, hTERT may be a novel poor prognostic indicator of DSS, if the patients are followed for more prolonged time periods.

Co-expression of Cancer Stem Cell Markers OCT4 and NANOG Predicts Poor Prognosis in Renal Cell Carcinomas.

Many renal cancer patients experience disease recurrence after combined treatments or immunotherapy due to permanence of cancer stem cells (CSCs). This study was conducted to evaluate the expression patterns and clinical significance of octamer-binding transcription factor 4 (OCT4) and NANOG as the key stem cell factors in renal cell carcinoma (RCC). A total of 186 RCC tissues were immunostained on a tissue microarray (TMA) for the putative CSC markers OCT4 and NANOG. Subsequently, the correlation among the expression of these markers, the clinicopathological variables and survival outcomes were determined. OCT4 and NANOG were expressed in both the nucleus and the cytoplasm of RCC cells. Coexpression of OCT4 and NANOG in renal cancer was significantly associated with RCC subtypes. A significant association was found among nuclear coexpression of OCT4 and NANOG, worse PFS in RCC, and the clear cell renal cell carcinomas (ccRCC) subtype. The OCT4-nuclear high/NANOG-nuclear high phenotype in RCC and ccRCC subtype indicated aggressive tumor behavior and predicted a worse clinical outcome, which may be a useful biomarker to identify patients at high risk of postoperative recurrence and metastasis. Cytoplasmic expression of NANOG could be considered as a novel independent prognostic predictor in patients with renal cancer.

Downregulation of miR-1266-5P, miR-185-5P and miR-30c-2 in prostatic cancer tissue and cell lines.

Over the latest decade, the role of microRNAs (miRNAs/miRs) has received more attention. miRNAs are small non-coding RNAs that may serve a role as oncogenes or tumor suppressor genes. Certain miRNAs regulate the apoptosis pathway by influencing pro- or anti-apoptotic genes. We hypothesized that increases in the expression of B cell lymphoma 2 (BCL2) and BCL2-like 1 (BCL2L1) genes, which have been reported in various types of cancer tissues, may be due to the downregulation of certain miRNAs. The present study aimed to identify miRNAs that target BCL2 and BCL2L1 anti-apoptotic genes in prostate cancer (PCa) clinical tissue samples. Certain candidate miRNAs were selected bioinformatically and their expression in PCa samples was analyzed and compared with that in benign prostatic hyperplasia (BPH) tissue samples. The candidate miRNAs that targeted BCL2 and BCL2L1 genes were searched in online databases (miRWalk, microRNA.org, miRDB and TargetScan). A total of 12 miRNAs that target the 3'-untranslated region of the aforementioned genes and/or for which downregulation of their expression has previously been reported in cancer tissues. A total of 30 tumor tissue samples from patients with PCa and 30 samples tissues from patients with BPH were obtained and were subjected to reverse transcription-quantitative polymerase chain reaction for expression analysis of 12 candidate miRNAs, and the BCL2 and BCL2L1 genes. Additionally, expression of 3 finally selected miRNAs and genes was evaluated in prostate cancer PC3 and DU145 cell lines and human umbilical vein endothelial cells. Among 12 miRNA candidates, the expression of miR-1266, miR-185 and miR-30c-2 was markedly downregulated in PCa tumor tissues and cell lines. Furthermore, downregulation of these miRNAs was associated with upregulation of the BCL2 and BCL2L1 genes. An inverse association between three miRNAs (miR-1266, miR-185 and miR-30c-2) and two anti-apoptotic genes (BCL2 and BCL2L1) may be considered for interventional miRNA therapy of PCa.

Aberrant expression of miR-141 and nuclear receptor small heterodimer partner in clinical samples of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the second most common cancer in men worldwide. Currently, prostate-specific antigen (PSA) test and digital rectal exam are the main screening tests used for PCa diagnosis. However, due to the low specificity of these tests, new alternative biomarkers such as deregulated RNAs and microRNAs have been implemented. OBJECTIVES: Aberrant expressions of small heterodimer partner gene (SHP, NR0B2) and mir-141 are reported in various cancers. The aim of this study was to investigate the SHP and miR-141 expression level in tissue samples of prostate cancer. METHODS: The expression level of SHP gene and miR-141 was assessed by real time PCR and their relative amounts were calculated by the Δ⁢ΔCT method. Also, IHC technique was used to determine the expression level of SHP protein. RESULTS: The miR-141 was significantly up-regulated in the samples of metastatic tumors compared to localized tumor samples (P< 0.001, 31.17-fold change). Tumor samples showed lower SHP mRNA expression levels than BPH samples (p= 0.014, 4.7-fold change). The results of paired t-test analysis showed there was no significant difference between the SHP gene expression in PCa samples and their matched tumor-adjacent normal tissue (p= 0.5). CONCLUSIONS: The data obtained in our study confirm the involvement of miR-141 in PCa progression and metastasis. These effects could be mediated by AR via down-regulation of its co-repressor protein, i.e., SHP.

Expression of CD105 cancer stem cell marker in three subtypes of renal cell carcinoma.

BACKGROUND: CD105 is recently described as a cancer stem cell (CSC) marker. OBJECTIVE: The present study was aimed to investigate the expression and prognostic significance of the CSC marker CD105 in different histological subtypes of renal cell carcinoma (RCC). METHODS: Expression of CD105 was evaluated using immunohistochemistry in RCC samples on tissue microarrays including clear cell RCCs (ccRCCs), papillary, and chromophobe RCCs. The association between CD105 expression and clinicopathological features as well as survival outcomes was determined. RESULTS: In ccRCC, increased tumoral cytoplasmic and endothelial expression of CD105 were significantly associated with advanced stage, renal vein invasion, and microvascular invasion (MVI). In addition, MVI was associated with a worse overall survival (OS). Moreover, in multivariate analysis tumor stage and nuclear grade were independent prognostic factors for OS both in case of tumoral cytoplasmic and endothelial CD105 expression. Additionally, CD105 expression was found to be a predictor of worse OS in univariate analysis. However, in papillary and chromophobe RCC, no significant association was found between CD105 expression and clinicopathological parameters or prognosis. CONCLUSIONS: We showed that CD105 expression was associated with more aggressive tumor behavior, more advanced disease, and worse prognosis in ccRCC but not in the other RCC subtypes.

Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma.

Twist1 is a key transcription factor, which confers tumor cells with cancer stem cell (CSC)-like characteristics and enhances epithelial-mesenchymal transition in pathological conditions including tumor malignancy and metastasis. This study aimed to evaluate the expression patterns and clinical significance of Twist1 in renal cell carcinoma (RCC). The cytoplasmic and nuclear expression of Twist1 were examined in 252 well-defined renal tumor tissues, including 173 (68.7%) clear cell renal cell carcinomas (ccRCC), 45 (17.9%) papillary renal cell carcinomas (pRCC) and 34 (13.5%) chromophobe renal cell carcinoma, by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters and survival outcomes were then analyzed. Twist1 was mainly localized to the cytoplasm of tumor cells (98.8%). Increased cytoplasmic expression of Twist1 was associated with higher grade tumors (P = 0.045), renal vein invasion (P = 0.031) and microvascular invasion (P = 0.044) in RCC. It was positively correlated with higher grade tumors (P = 0.026), shorter progression-free survival time (P = 0.027) in patients with ccRCC, and also with higher stage in pRCC patients (P = 0.036). Significantly higher cytoplasmic expression levels of Twist1 were found in ccRCC and pRCC subtypes, due to their more aggressive tumor behavior. Increased cytoplasmic expression of Twist1 had a critical role in worse prognosis in ccRCC. These findings suggest that cytoplasmic, rather than nuclear expression of Twist1 can be considered as a prognostic and therapeutic marker for targeted therapy of RCC, especially for ccRCC patients.

Increased expression of CD44 is associated with more aggressive behavior in clear cell renal cell carcinoma.

AIM: Although CD44 has been suggested as a prognostic marker in renal cell carcinoma (RCC), the prognostic significance of this marker in three main subtypes of RCC is still unclear. Thus, the present study was conducted to evaluate the expression and prognostic significance of CD44 as a cancer stem cell marker in different histological subtypes of RCC. Methodology & results: CD44 expression was evaluated in 206 well-defined renal tumor samples using immunohistochemistry on tissue microarrays. Higher CD44 expression was associated with more aggressive behavior, tumor progression and worse prognosis in clear cell RCC (ccRCC) but not in papillary and chromophobe RCC subtypes. DISCUSSION & CONCLUSION: Cancer stem cell marker CD44 may be a promising target for cancer treatment only in ccRCC.

Seropositivity of Rheumatoid Arthritis Specific Tests in a Patient With Nephrotic Syndrome: Successful Treatment With Rituximab.

Presentation of rheumatoid arthritis (RA) with renal complications is very rare without articular symptoms. We here report a case of a 23-year-old woman, presenting with the edema of the extremities, no relevant previous medical history, and the features of acute tubular injury in her percutaneous kidney biopsy. Following the incidental notification of a positive rheumatoid factor test, other immunologic tests including anticyclic citrullinated peptide and antimutated citrullinated vimentin were performed, the positive results of which favored the diagnosis of RA. Administration of rituximab led to the complete remission of the disease. Six weeks later, along with steroid dose reduction, the symptoms of arthralgia was observed, which was managed with methotrexate. Nephrotic syndrome could be rarely the first manifestation of RA, and screening of specific RA autoantibodies might be considered as part of diagnostic evaluations in nephrotic syndrome workup.

Cytoplasmic expression of CD133 stemness marker is associated with tumor aggressiveness in clear cell renal cell carcinoma.

Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression.