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Fulltext A Study on the Immunohistochemical Expressions of Leptin and Leptin Receptor in Clear Cell Renal Cell Carcinoma

Perumal K, Mun KS, Yap NY, Razack AHA, Gobe GC, Ong TA, et al.

Biomed Res Int, 2020;2020:3682086.
PMID: 32802842 DOI: 10.1155/2020/3682086

Background: The mechanisms that link obesity and cancer development are not well-defined. Investigation of leptin and leptin receptor expressions may help define some of the mechanisms. These proteins are known for associating with the immune response, angiogenesis and, signalling pathways such as JAK2/STAT3, PI3K, and AKT pathways. Tissue proteins can be easily detected with immunohistochemistry (IHC), a technique widely used both in diagnostic and research laboratories. The identification of altered levels of leptin and leptin receptor proteins in tumour tissues may lead to targeted treatment for cancer.
Objective: The objective of this study was to use IHC to compare leptin and leptin receptor expressions in clear cell renal cell carcinomas (ccRCC) in non-obese and obese patients to determine the association between these proteins with the clinicopathological features and prognosis of ccRCC. Patients and Methods. The study involved 60 patients who underwent nephrectomy of which 34 were obese, as assessed using body mass index (BMI). Nephrectomy samples provided tissues of ccRCC and adjacent non-cancerous kidney. The intensity and localization of leptin and leptin receptor protein expressions were evaluated using IHC and correlated with clinicopathological features and clinical outcomes. Aperio ImageScope morphometry and digital pathology were applied to assess the IHC results. The chi-square test was used to determine if there was any significant association between the proteins and the clinicopathological features. The Kaplan-Meier test was used to determine the overall survival, disease-free survival, and recurrence-free survival. A value of p < 0.05 was considered significant.
Results: There was neither significant difference in the overall cellular and nuclear expressions of leptin and leptin receptor between non-cancerous kidney and ccRCC tissues nor in non-obese and obese individuals with ccRCC.
Conclusion: In this present study, it was revealed that leptin and leptin receptor were not associated with tumour characteristics and progression of ccRCC patients. Interestingly, nuclear expression of leptin was significantly associated with overall survival. However, the significance of these proteins as biomarkers in other RCC histotypes is still unclear.
Fulltext Automatic ICD-10 multi-class classification of cause of death from plaintext autopsy reports through expert-driven feature selection

Mujtaba G, Shuib L, Raj RG, Rajandram R, Shaikh K, Al-Garadi MA

PLoS One, 2017;12(2):e0170242.
PMID: 28166263 DOI: 10.1371/journal.pone.0170242

OBJECTIVES: Widespread implementation of electronic databases has improved the accessibility of plaintext clinical information for supplementary use. Numerous machine learning techniques, such as supervised machine learning approaches or ontology-based approaches, have been employed to obtain useful information from plaintext clinical data. This study proposes an automatic multi-class classification system to predict accident-related causes of death from plaintext autopsy reports through expert-driven feature selection with supervised automatic text classification decision models.
METHODS: Accident-related autopsy reports were obtained from one of the largest hospital in Kuala Lumpur. These reports belong to nine different accident-related causes of death. Master feature vector was prepared by extracting features from the collected autopsy reports by using unigram with lexical categorization. This master feature vector was used to detect cause of death [according to internal classification of disease version 10 (ICD-10) classification system] through five automated feature selection schemes, proposed expert-driven approach, five subset sizes of features, and five machine learning classifiers. Model performance was evaluated using precisionM, recallM, F-measureM, accuracy, and area under ROC curve. Four baselines were used to compare the results with the proposed system.
RESULTS: Random forest and J48 decision models parameterized using expert-driven feature selection yielded the highest evaluation measure approaching (85% to 90%) for most metrics by using a feature subset size of 30. The proposed system also showed approximately 14% to 16% improvement in the overall accuracy compared with the existing techniques and four baselines.
CONCLUSION: The proposed system is feasible and practical to use for automatic classification of ICD-10-related cause of death from autopsy reports. The proposed system assists pathologists to accurately and rapidly determine underlying cause of death based on autopsy findings. Furthermore, the proposed expert-driven feature selection approach and the findings are generally applicable to other kinds of plaintext clinical reports.
Carbonic anhydrase IX immunohistochemistry has potential to predict renal cell carcinoma outcomes: A systematic review and meta-analyses

Samberkar S, Rajandram R, Mun KS, Samberkar P, Danaee M, Zulkafli IS

Malays J Pathol, 2019 Dec;41(3):233-242.
PMID: 31901907

INTRODUCTION: Tissue biomarker carbonic anhydrase IX (CAIX) is purported to have prognostic value for renal cell carcinoma (RCC) but contradicting findings from previous studies have also been documented. This study aims to perform a systematic review and meta-analysis on the role of CAIX in RCC disease progression.
MATERIALS AND METHODS: Following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, online searches of multiple databases were performed to retrieve articles from their inception until December 2017. Inclusion criteria included all English-based original articles of immunohistochemistry (IHC) studies investigating CAIX expression in human RCC tissue. Four articles were finally selected for meta-analysis with a total of 1964 patients. Standard meta-analysis methods were applied to evaluate the role of CAIX in RCC prognosis. The relative risk (RR) and its 95% confidence interval (CI) were recorded for the association between biomarker and prognosis, and data were analysed using MedCalc statistical software.
RESULTS: The meta-analysis showed that high CAIX expression was associated with low tumour stage (RR 0.90%, 95% CI 0.849-0.969, p= 0.004), low tumour grade (RR 0.835%, 95% CI 0.732-0.983, p= 0.028), absence of nodal involvement (RR 0.814%, 95% CI 0.712-0.931, p= 0.003) and better ECOS-PS index (RR 0.888%, 95% CI 0.818-0.969, p= 0.007). The high tissue CAIX expression in RCC is hence an indication of an early malignancy with a potential to predict favourable disease progression and outcome.
CONCLUSION: The measurement of this marker may be beneficial to determine the course of the illness. It is hoped that CAIX can be developed as a specific tissue biomarker for RCC in the near future.
Fulltext Chromosome 7 aneuploidy in clear cell and papillary renal cell carcinoma: detection using silver in situ hybridization technique

Pailoor J, Rajandram R, Yap NY, Ng KL, Wang Z, Iyengar KR

Indian J Pathol Microbiol, 2013 Apr-Jun;56(2):98-102.
PMID: 24056643 DOI: 10.4103/0377-4929.118688

Chromosome 7 aberrations in renal cell carcinoma (RCC) have been reported in papillary renal cell carcinoma (pRCC) and clear cell renal cell carcinoma (ccRCC). However, the implication of these anomalies on prognosis and survival is still unclear. RCC Chromosome 7 aberrations have commonly been detected by fluorescent in situ hybridization and chromogenic in situ hybridization but not silver in situ hybridization (SISH).
Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis

Yap NY, Yap FN, Perumal K, Rajandram R

Biomarkers, 2019 Sep;24(6):607-614.
PMID: 31215811 DOI: 10.1080/1354750X.2019.1634763

Context: Metabolic imbalance in renal cell carcinoma (RCC) can lead to abnormal adiponectin levels. Objective: To evaluate circulating adiponectin as a detection or predictive marker for RCC. Methods: A comprehensive literature search and meta-analysis was performed on studies reporting circulating adiponectin levels and RCC. The meta-analysis was performed using RevMan. Results: Seven studies compared the circulating adiponection levels between RCC cases and controls. Adiponectin level was significantly lower in RCC cases compared to controls at pre-diagnosis and pre-operative time-points. RCC stage, grade and subtype did not affect adiponectin levels. Conclusion: Low circulating adiponectin could be a predictive or risk factor for RCC.
Fulltext Classification of forensic autopsy reports through conceptual graph-based document representation model

Mujtaba G, Shuib L, Raj RG, Rajandram R, Shaikh K, Al-Garadi MA

J Biomed Inform, 2018 06;82:88-105.
PMID: 29738820 DOI: 10.1016/j.jbi.2018.04.013

Text categorization has been used extensively in recent years to classify plain-text clinical reports. This study employs text categorization techniques for the classification of open narrative forensic autopsy reports. One of the key steps in text classification is document representation. In document representation, a clinical report is transformed into a format that is suitable for classification. The traditional document representation technique for text categorization is the bag-of-words (BoW) technique. In this study, the traditional BoW technique is ineffective in classifying forensic autopsy reports because it merely extracts frequent but discriminative features from clinical reports. Moreover, this technique fails to capture word inversion, as well as word-level synonymy and polysemy, when classifying autopsy reports. Hence, the BoW technique suffers from low accuracy and low robustness unless it is improved with contextual and application-specific information. To overcome the aforementioned limitations of the BoW technique, this research aims to develop an effective conceptual graph-based document representation (CGDR) technique to classify 1500 forensic autopsy reports from four (4) manners of death (MoD) and sixteen (16) causes of death (CoD). Term-based and Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) based conceptual features were extracted and represented through graphs. These features were then used to train a two-level text classifier. The first level classifier was responsible for predicting MoD. In addition, the second level classifier was responsible for predicting CoD using the proposed conceptual graph-based document representation technique. To demonstrate the significance of the proposed technique, its results were compared with those of six (6) state-of-the-art document representation techniques. Lastly, this study compared the effects of one-level classification and two-level classification on the experimental results. The experimental results indicated that the CGDR technique achieved 12% to 15% improvement in accuracy compared with fully automated document representation baseline techniques. Moreover, two-level classification obtained better results compared with one-level classification. The promising results of the proposed conceptual graph-based document representation technique suggest that pathologists can adopt the proposed system as their basis for second opinion, thereby supporting them in effectively determining CoD.
Clinical prognostic factors and survival outcome in renal cell carcinoma patients--a malaysian single centre perspective

Yap NY, Ng KL, Ong TA, Pailoor J, Gobe GC, Ooi CC, et al.

Asian Pac J Cancer Prev, 2013;14(12):7497-500.
PMID: 24460324

BACKGROUND: This study concerns clinical characteristics and survival of renal cell carcinoma (RCC) patients in University Malaya Medical Centre (UMMC), as well as the prognostic significance of presenting symptoms.
MATERIALS AND METHODS: The clinical characteristics, presenting symptoms and survival of RCC patients (n=151) treated at UMMC from 2003-2012 were analysed. Symptoms evaluated were macrohaematuria, flank pain, palpable abdominal mass, fever, lethargy, loss of weight, anaemia, elevated ALP, hypoalbuminemia and thrombocytosis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic significance of these presenting symptoms. Kaplan Meier and log rank tests were employed for survival analysis.
RESULTS: The 2002 TNM staging was a prognostic factor (p<0.001) but Fuhrman grading was not significantly correlated with survival (p=0.088). At presentation, 76.8% of the patients were symptomatic. Generally, symptomatic tumours had a worse survival prognosis compared to asymptomatic cases (p=0.009; HR 4.74). All symptoms significantly affect disease specific survival except frank haematuria and loin pain on univariate Cox regression analysis. On multivariate analysis adjusted for stage, only clinically palpable abdominal mass remained statistically significant (p=0.027). The mean tumour size of palpable abdominal masses, 9.5±4.3cm, was larger than non palpable masses, 5.3±2.7cm (p<0.001).
CONCLUSIONS: This is the first report which includes survival information of RCC patients from Malaysia. Here the TNM stage and a palpable abdominal mass were independent predictors for survival. Further investigations using a multicentre cohort to analyse mortality and survival rates may aid in improving management of these patients.
Fulltext Comparing CxBladder to Urine Cytology as Adjunct to Cystoscopy in Surveillance of Non-muscle Invasive Bladder Cancer-A Pilot Study

Chai CA, Yeoh WS, Rajandram R, Aung KP, Ong TA, Kuppusamy S, et al.

Front Surg, 2021;8:659292.
PMID: 34055868 DOI: 10.3389/fsurg.2021.659292

Purpose: Guidelines advocate cystoscopy surveillance (CS) for non-muscle invasive bladder cancer (NMIBC) post-resection. However, cystoscopy is operator dependent and may miss upper tract lesions or carcinoma in-situ (CIS). Urine cytology is a common adjunct but lacks sensitivity and specificity in detecting recurrence. A new mRNA biomarker (CxBladder) was compared with urine cytology as an adjunct to cystoscopy in detecting a positive cystoscopy findings during surveillance cystoscopy in our center. Materials and Methods: Consented patients older than 18, undergoing CS for NMIBC, provide paired urine samples for cytology and CxBladder test. Patients with positive cystoscopy findings would undergo re-Trans Urethral Resection of Bladder Tumor (TURBT). Results: Thirty-five patients were enrolled from April to June 2019. Seven contaminated urine samples were excluded. The remaining cohort of 23 (82%) and 5 (18%) females had a mean age of 66.69 (36-89). Eight (29%) patients with positive cystoscopy finding underwent TURBT. All 8 patients also had positive CxBladder result. This shows that CxBladder has a sensitivity and negative predictive value (NPV) of 100%, specificity of 75% and positive predictive value (PPV) of 62% in predicting a positive cystoscopy finding. TURBT Histo-pathological findings showed Low-grade Ta NMIBC in one patient (4%), and 7 (25%) patients had inflammatory changes. Urine cytology was only positive in one patient with a positive cystoscopy finding. This led to a sensitivity of merely 13% and NPV of 74%, while specificity and PPV was 100% in predicting a positive cystoscopy finding. Conclusion: CxBladder had high NPV and sensitivity which accurately predicted suspicious cystoscopy findings leading to further investigation. It has great potential for use as adjunct to cystoscopy for surveillance of NMIBC.
Corrigendum to "Role of leptin as a biomarker for early detection of renal cell carcinoma? No evidence from a systematic review and meta-analysis" [Med. Hypotheses 129 (2019) 1-6]

Perumal K, Kit Huin W, Yi Yap N, Aik Ong T, Carolyn Gobe G, Rajandram R

Med Hypotheses, 2019 Oct;131:109284.
PMID: 31443767 DOI: 10.1016/j.mehy.2019.109284
Fulltext Decreased Expression of Inhibitor of Caspase-Activated DNase (ICAD) in Renal Cell Carcinoma - Tissue Microarray of Human Samples

Rajandram R, Razack AH, Ng KL, Gobe GC

J Kidney Cancer VHL, 2016;3(1):1-11.
PMID: 28326275 DOI: 10.15586/jkcvhl.2016.47

Although primary localised tumours of renal cell carcinoma (RCC) can be treated relatively successfully with surgery, metastatic RCC has poor prognosis because of late diagnosis and resistance to therapies. In the present study, we were interested in profiling the protein expression of "inhibitor of caspase-activated DNase" (ICAD), an apoptosis inhibitor, in kidney cancer and its paired normal kidney. Immunohistochemistry with automated batch staining and morphometry using digital pathology were used to compare ICAD in 121 RCC specimens with their paired normal kidney tissue. Tissue microarray of formalin-fixed, paraffin-embedded archival tissue was used. Intensity and localisation of ICAD were compared between normal and cancer samples, and against grading within the cancers. The results demonstrated that, in this cohort, ICAD was highly expressed in the proximal tubular epithelium of normal kidney, and significantly decreased in clear cell RCC tissue (p < 0.05) as well as other subtypes of RCC (p < 0.01) compared with normal kidney. There was a tendency towards nuclear localisation of ICAD in clear cell RCC, but not in other subtypes of RCC. No significant association was found between ICAD intensity and grade of RCC. In summary, down-regulation of ICAD occurs in RCC. ICAD normally inhibits DNA fragmentation and apoptosis; thus, its down-regulation was unexpected in a cancer known for its resistance to apoptosis. However, these RCC samples were from primary, not metastatic, RCC sites, and down-regulated ICAD may be part of a progressive pathway that promotes RCC metastasis.
Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways

Gobe GC, Ng KL, Small DM, Vesey DA, Johnson DW, Samaratunga H, et al.

Biochem Biophys Res Commun, 2016 Apr 22;473(1):47-53.
PMID: 26995091 DOI: 10.1016/j.bbrc.2016.03.048

Apoptosis repressor with caspase recruitment domain (ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human cancers, thereby conferring drug resistance and giving a rationale for the inhibition of ARC to overcome drug resistance. Our hypothesis was that ARC would be similarly upregulated and targetable for therapy in renal cell carcinoma (RCC). Expression of ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations, ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of ARC with shRNA in the RCC cell line (SN12K1) that had shown increased ARC expression conferred resistance to Sunitinib, and upregulated interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). We therefore propose that decreased ARC, particularly in clear cell RCC, confers resistance to targeted therapy through restoration of tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that ARC is decreased in RCC.
Demethylases of H3 lysine 27 (H3K27) expression in urothelial carcinoma (UC) of the urinary bladder

Anthony R, Rajandram R, Yap NY, Mun KS, Samberkar PN, Kuppusamy S

Malays J Pathol, 2023 Aug;45(2):261-269.
PMID: 37658535

BACKGROUND: Ubiquitously Transcribed Tetracopeptide Repeat on X Chromosome (UTX) and Jumonji Domain-Containing Protein 3 (JMJD3) are histone H3 lysine 27 (H3K27) demethylases that are found to play tumour suppressor or oncogenic roles in many cancers. However, their roles in urothelial carcinoma (UC) have not been well studied.
OBJECTIVE: This study investigated UTX and JMJD3 protein expression patterns in UC and assess their clinical significance.
PATIENTS AND METHODS: Immunohistochemistry (IHC) method was performed on formalin-fixed paraffin-embedded (FFPE) of UC tissues and compared to the normal bladder tissues from the autopsy specimen. The staining intensity of FFPE tissues were captured with the nuclear and overall positive pixels quantified using Aperio ImageScope software.
RESULTS: JMJD3 protein uptake was present in both nucleus and cytoplasm but UTX protein was predominantly seen in the cytoplasm of UC tissue. UTX was under expressed whereas JMJD3 was over expressed in UC compared to normal bladder. UTX and JMJD3 were not related to clinical stage and grade. However, significant association between JMJD3 expression and invasiveness of tumour (p<0.05) was noted, especially in MIBC group (88.9%). UTX and JMJD3 did not yield any significance as prognostic factors for diseasespecific survival.
CONCLUSIONS: Low expression of UTX protein in UC may indicate possible loss of its tumour suppressor activity and higher JMJD3 protein expression may indicate oncogenic activity. Hence, JMJD3 protein could be a potential diagnostic biomarker in detecting bladder UC of higher stages. Further investigation needed to study the dysregulation of this protein expression with associated gene expression.
Fulltext Efficacy of microbial cell preparation in improving chronic constipation: a randomized, double-blind, placebo-controlled trial

Jayasimhan S, Yap NY, Roest Y, Rajandram R, Chin KF

Clin Nutr, 2013 Dec;32(6):928-34.
PMID: 23561636 DOI: 10.1016/j.clnu.2013.03.004

Probiotics is an emerging therapeutic agent which may alleviate the symptoms of constipation. We evaluated the effectiveness of microbial cell preparation (Hexbio(®)) containing fructooligosaccharide, Bifidobacterium and Lactobacillus in improving stool frequency and symptoms of chronic constipation.
Establishment of epithelial and fibroblast cell cultures and cell lines from primary renal cancer nephrectomies

Yap NY, Ong TA, Morais C, Pailoor J, Gobe GC, Rajandram R

Cell Biol Int, 2019 Jun;43(6):715-725.
PMID: 31062478 DOI: 10.1002/cbin.11150

Renal cell carcinoma (RCC) is one of the most lethal urogenital cancers and effective treatment of metastatic RCC remains an elusive target. Cell lines enable the in vitro investigation of molecular and genetic changes leading to renal carcinogenesis and are important for evaluating cellular drug response or toxicity. This study details a fast and easy protocol of establishing epithelial and fibroblast cell cultures or cell lines concurrently from renal cancer nephrectomy tissue. The protocol involves mechanical disaggregation, collagenase digestion and cell sieving for establishing epithelial cells while fibroblast cells were grown from explants. This protocol has been modified from previous published reports with additional antibiotics and washing steps added to eliminate microbial contamination from the surgical source. Cell characterisation was carried out using immunofluorescence and quantitative polymerase chain reaction. Eleven stable epithelial renal tumour cell lines of various subtypes, including rare subtypes, were established with a spontaneous immortalisation rate of 21.6% using this protocol. Eight fibroblast cell cultures grew successfully but did not achieve spontaneous immortalisation. Cells of epithelial origin expressed higher expressions of epithelial markers such as pan-cytokeratin, cytokeratin 8 and E-cadherin whereas fibroblast cells expressed high α-smooth muscle actin. Further mutational analysis is needed to evaluate the genetic or molecular characteristics of the cell lines.
Ethnic differences in serum testosterone concentration among Malay, Chinese and Indian men: A cross-sectional study

Rajandram R, Koong JK, Quek KF, Lee EG, Razack AHA, Kuppusamy S

Clin Endocrinol (Oxf), 2022 Feb 02.
PMID: 35107834 DOI: 10.1111/cen.14682

OBJECTIVE: To investigate non-urological patients with multiple comorbidities for factors contributing towards differences in testosterone concentration in multiethnic Malaysian men.
DESIGN: An observational study.
PATIENTS: Sexually active men, ≥40 years, with no known urological problems, were recruited at the phlebotomy clinic at our centre.
MEASUREMENTS: A brief history along with latest fasting lipid profile and plasma glucose levels were obtained. An Aging Male Symptoms questionnaire was administered; waist circumference (WC) and serum testosterone concentration were measured.
STATSTICAL ANALYSIS: Analysis of testosterone concentration between Malay, Indian and Chinese men was performed. Statistical tests such as analysis of variance, χ2 test, univariate and multivariable regression were performed. Any p .05). In the multivariable analysis only Malay ethnicity, WC ≥ 90 cm and low high-density lipoprotein (HDL) were associated with lower testosterone concentration.
CONCLUSION: In this study, Malaysian men of Malay origin had lower testosterone concentration compared with Indian and Chinese men. WC and low HDL were also associated with lower testosterone concentrations.
Fulltext Evaluation of steroid hormones and their receptors in development and progression of renal cell carcinoma

Bennett NC, Rajandram R, Ng KL, Gobe GC

J Kidney Cancer VHL, 2014;1(2):17-25.
PMID: 28326246 DOI: 10.15586/jkcvhl.2014.9

Steroid hormones and their receptors have important roles in normal kidney biology, and alterations in their expression and function help explain the differences in development of kidney diseases, such as nephrotic syndrome and chronic kidney disease. The distinct gender difference in incidence of renal cell carcinoma (RCC), with males having almost twice the incidence as females globally, also suggests a role for sex hormones or their receptors in RCC development and progression. There was a peak in interest in evaluating the roles of androgen and estrogen receptors in RCC pathogenesis in the late 20th century, with some positive outcomes for RCC therapy that targeted estrogen receptors, especially for metastatic disease. Since that time, however, there have been few studies that look at use of steroid hormone modulators for RCC, especially in the light of new therapies such as the tyrosine kinase inhibitors and new immune therapies, which are having some success for treatment of metastatic RCC. This review summarises past and current literature and attempts to stimulate renewed interest in research into the steroid hormones and their receptors, which might be used to effect, for example, in combination with the other newer targeted therapies for RCC.
Fulltext Expression of osteopontin, matrix metalloproteinase-2 and -9 proteins in vascular instability in brain arteriovenous malformation

Anbarasen L, Lim J, Rajandram R, Mun KS, Sia SF

PeerJ, 2019;7:e7058.
PMID: 31275742 DOI: 10.7717/peerj.7058

Background: Matrix metalloproteinase (MMP)-2 and -9 are Osteopontin (OPN) dependent molecules implicated in the destabilization of blood vessels. OPN and MMPs have been studied in brain arteriovenous malformation (BAVM) patients' tissues and blood samples before intervention. In this study, we compared the serum level of these markers before and after treatment, as well as assessed their protein expressions in BAVM tissues to evaluate their roles in this disease.
Methodology: Serum samples from six BAVM patients and three control subjects were analyzed using enzyme-linked immunoabsorbent assay (ELISA) for OPN. A total of 10 BAVM patients and five control subjects were analyzed using Multiplex ELISA for MMPs. A total of 16 BAVM tissue samples and two normal brain tissue samples were analyzed using immunohistochemistry.
Result: MMP-2 and -9 were significantly higher in the serum of BAVM patients before and after treatment than in control patients. There were no significant differences of OPN and MMP-9 serum level in BAVM patients before and after treatment. MMP-2 showed a significant elevation after the treatment. Expression of OPN, MMP-2 and -9 proteins were seen in endothelial cells, perivascular cells and brain parenchyma of BAVM tissues.
Conclusion: Findings revealed that the level of MMP-2 and -9 in the serum correlated well with the expression in BAVM tissues in several cases. Knockdown studies will be required to determine the relationships and mechanisms of action of these markers in the near future. In addition, studies will be required to investigate the expression of these markers' potential applications as primary medical therapy targets for BAVM patients.
Fulltext Expression of protease activated receptor-2 is reduced in renal cell carcinoma biopsies and cell lines

Morais C, Rajandram R, Blakeney JS, Iyer A, Suen JY, Johnson DW, et al.

PLoS One, 2021;16(3):e0248983.
PMID: 33765016 DOI: 10.1371/journal.pone.0248983

Expression of the protease sensing receptor, protease activated receptor-2 (PAR2), is elevated in a variety of cancers and has been promoted as a potential therapeutic target. With the development of potent antagonists for this receptor, we hypothesised that they could be used to treat renal cell carcinoma (RCC). The expression of PAR2 was, therefore, examined in human RCC tissues and selected RCC cell lines. Histologically confirmed cases of RCC, together with paired non-involved kidney tissue, were used to produce a tissue microarray (TMA) and to extract total tissue RNA. Immunohistochemistry and qPCR were then used to assess PAR2 expression. In culture, RCC cell lines versus primary human kidney tubular epithelial cells (HTEC) were used to assess PAR2 expression by qPCR, immunocytochemistry and an intracellular calcium mobilization assay. The TMA revealed an 85% decrease in PAR2 expression in tumour tissue compared with normal kidney tissue. Likewise, qPCR showed a striking reduction in PAR2 mRNA in RCC compared with normal kidney. All RCC cell lines showed lower levels of PAR2 expression than HTEC. In conclusion, we found that PAR2 was reduced in RCC compared with normal kidney and is unlikely to be a target of interest in the treatment of this type of cancer.
Fulltext Genetic and Chromosomal Aberrations and Their Clinical Significance in Renal Neoplasms

Yap NY, Rajandram R, Ng KL, Pailoor J, Fadzli A, Gobe GC

Biomed Res Int, 2015;2015:476508.
PMID: 26448938 DOI: 10.1155/2015/476508

The most common form of malignant renal neoplasms is renal cell carcinoma (RCC), which is classified into several different subtypes based on the histomorphological features. However, overlaps in these characteristics may present difficulties in the accurate diagnosis of these subtypes, which have different clinical outcomes. Genomic and molecular studies have revealed unique genetic aberrations in each subtype. Knowledge of these genetic changes in hereditary and sporadic renal neoplasms has given an insight into the various proteins and signalling pathways involved in tumour formation and progression. In this review, the genetic aberrations characteristic to each renal neoplasm subtype are evaluated along with the associated protein products and affected pathways. The potential applications of these genetic aberrations and proteins as diagnostic tools, prognostic markers, or therapeutic targets are also assessed.
Fulltext Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Rajandram R, Ong TA, Razack AH, MacIver B, Zeidel M, Yu W

Am J Physiol Renal Physiol, 2016 05 01;310(9):F885-94.
PMID: 26911853 DOI: 10.1152/ajprenal.00483.2015

Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.

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