Overcoming sunitinib resistance with tocilizumab in renal cell carcinoma: Discordance between in vitro and in vivo effects.

Sunitinib is one of the first-line multi-tyrosine kinase inhibitors for metastatic renal cell carcinoma, and resistance to sunitinib continues to be a limiting factor for the successful treatment. As interleukin-6 (IL-6) is overexpressed in sunitinib-resistant cells, the purpose of this study was to explore the potential of IL-6 inhibition with tocilizumab, an IL-6 receptor inhibitor, to overcome resistance. In vitro, two sunitinib-resistant renal cell carcinoma cell lines (Caki-1 and SN12K1) were treated with tocilizumab.

Expression of protease activated receptor-2 is reduced in renal cell carcinoma biopsies and cell lines.

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.

Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney.

Aim: Protease-activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal-regulated kinase signalling and secretion of fibronectin, C-C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis.

Utility of cytokeratin 7, S100A1 and caveolin-1 as immunohistochemical biomarkers to differentiate chromophobe renal cell carcinoma from renal oncocytoma.

Background: Differentiation of chromophobe renal cell carcinoma (chRCC) from benign renal oncocytoma (RO) can be challenging especially when there are overlapping histological and morphological features. In this study we have investigated immunohistochemical biomarkers (cytokeratin 7/CK7, Caveolin-1/Cav-1 and S100 calcium-binding protein A1/S100A1) to aid in this difficult differentiation and attempted to validate their use in human renal tumour tissue to assess their discriminatory ability, particularly for chRCC and RO, in an Australian cohort of patients.

Methods: Retrospective study was carried out of archived formalin-fixed paraffin-embedded renal tumours from tumour nephrectomy specimens of 75 patients: 30 chRCC, 15 RO and 30 clear cell RCC (ccRCC).

Establishment of epithelial and fibroblast cell cultures and cell lines from primary renal cancer nephrectomies.

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.

Pharmacological inhibition of protease-activated receptor-2 reduces crescent formation in rat nephrotoxic serum nephritis.

Glomerular crescent formation is a hallmark of rapidly progressive forms of glomerulonephritis. Thrombosis and macrophage infiltration are features of crescent formation in human and experimental kidney disease. Protease-activated receptor-2 (PAR-2) is a G-protein coupled receptor that links coagulation and inflammation.

Chronic kidney cortical damage is associated with baseline kidney function and albuminuria in patients managed with radical nephrectomy for kidney tumours.

This study evaluated the relationship between histological markers of chronic kidney damage in patients undergoing radical nephrectomy for kidney tumours and preoperative kidney function, degree of albuminuria, and changes in glomerular volume. A schema to grade chronic kidney damage could be used to identify patients at risk of developing CKD following nephrectomy. Non-neoplastic cortical tissue was sourced from 150 patients undergoing radical nephrectomy for suspected kidney cancer.

End-Stage Kidney Disease following Surgical Management of Kidney Cancer.

Background And Objectives: We investigated the incidence of ESKD after surgical management of kidney cancer in the Australian state of Queensland, and described patterns in the initiation of kidney replacement therapy resulting from kidney cancer across Australia.

Design, Setting, Participants, & Measurements: All newly diagnosed cases of kidney cancer in the Australian state of Queensland between January of 2009 and December of 2014 were ascertained through the Queensland Cancer Registry. There were 2739 patients included in our analysis.

Characterisation of the Morphological, Functional and Molecular Changes in Sunitinib-Resistant Renal Cell Carcinoma Cells.

Sunitinib resistance is a major clinical problem hampering the treatment of renal cell carcinoma (RCC). Studies on the comprehensive characterisation of morphological, functional and molecular changes in sunitinib-resistant RCC cells are lacking. The aim of the current study was to develop sunitinib resistance in four human RCC cell lines (786-0, Caki-1, Caki-2 and SN12K1), and to characterise the changed cell biology with sunitinib resistance.

Conditioned medium from stimulated macrophages inhibits growth but induces an inflammatory phenotype in breast cancer cells.

Disparate roles exist for tumor-associated macrophages in breast cancer growth and progression. The aim of this study was to explore the influence of induced macrophages on the growth of breast cancer cells. THP-1 monocytes were differentiated to macrophages using phorbol 12-myristate 13-acetate.

Nuclear factor-kappa B subunits and their prognostic cancer-specific survival value in renal cell carcinoma patients.

Better characterisation and understanding of renal cell carcinoma (RCC) development and progression lead to better diagnosis and clinical outcomes. In this study, expression of nuclear factor-kappa B (NF-κB) subunits: p65 (RelA), p105/p50, p100/p52, and cRel in RCC tissue were compared with corresponding normal kidney, along with tumour characteristics and survival outcome. Ninety-six cases of RCC with paired normal kidney were analysed.

Association between preoperative hydration status and acute kidney injury in patients managed surgically for kidney tumours.

Purpose: The purpose of this study was to investigate whether preoperative dehydration and intraoperative hypotension were associated with postoperative acute kidney injury in patients managed surgically for kidney tumours.

Methods: A retrospective analysis of 184 patients who underwent nephrectomy at a single centre was performed, investigating associations between acute kidney injury after nephrectomy, and both intraoperative hypotension and preoperative hydration/volume status. Intraoperative hypotension was defined as mean arterial pressure < 60 mmHg for ≥ 5 min.

Outcome Measures Used to Report Kidney Function in Studies Investigating Surgical Management of Kidney Tumours: A Systematic Review.

Context: Most practice decisions relevant to preserving kidney function in patients managed surgically for kidney tumours are driven by observational studies. A wide range of outcome measures are used in these studies, which reduces comparability and increases the risk of reporting bias.

Objective: To comprehensively and succinctly describe the outcomes used to evaluate kidney function in studies evaluating surgical management of kidney tumours.

Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells.

Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with declining kidney function. Although generally thought of as a consequence of declining kidney function, emerging evidence demonstrates direct cytotoxic role of IS on endothelial cells and cardiomyocytes, largely through the expression of pro-inflammatory and pro-fibrotic factors. The direct toxicity of IS on human kidney proximal tubular epithelial cells (PTECs) remains a matter of debate.

N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses.

Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice.

The Correlates of Kidney Dysfunction – Tumour Nephrectomy Database (CKD-TUNED) Study: Protocol for a Prospective Observational Study.

Background: Tumour nephrectomy conveys a significant risk of adverse renal functional outcomes postoperatively, however there are limited strategies for predicting patients at increased risk of these outcomes. The Correlates of Kidney Dysfunction – Tumour Nephrectomy Database (CKD-TUNED) study is a prospective observational study evaluating the risk of chronic kidney disease and end-stage kidney disease in tumour nephrectomy patients. Methods: The CKDTUNED study involves analysis of clinical data and collection of tissue, urine and blood samples for the purposes of forming a tissue repository resource for future investigation.

Factors associated with acutely elevated serum creatinine following radical tumour nephrectomy: the Correlates of Kidney Dysfunction-Tumour Nephrectomy Database study.

Background: To identify factors associated with acutely elevated serum creatinine (SCr) within 7 days of radical tumour nephrectomy.

Methods: The study population consisted of 130 consecutive patients managed for renal tumours. The primary outcome was acute kidney injury (AKI) (defined as SCr increase ≥50% above baseline), assessed using multivariable logistic regression analysis.

MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance.

Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers.

The stress response of human proximal tubule cells to cadmium involves up-regulation of haemoxygenase 1 and metallothionein but not cytochrome P450 enzymes.

Enzymes of the cytochrome P450 (CYP) super-family are implicated in cadmium (Cd) -induced nephrotoxicity, however, direct evidence is lacking. This study investigated the endogenous expression of various CYP proteins together with the stress-response proteins, heme oxygenase-1 (HO-1) and metallothionein (MT) in human kidney sections and in cadmium-exposed primary cultures of human proximal tubular epithelial cells (PTC). By immunohistochemistry, the CYP members 2B6, 4A11 and 4F2 were prominently expressed in the cortical proximal tubular cells and to a lesser extent in distal tubular cells.

Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways.

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.

A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma.

Background: Numerous immunohistochemical (IHC) biomarkers have been employed to aid in the difficult differentiation between chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO). A systematic review and meta-analysis of the published literature was carried out to summarise and analyse the evidence for discriminatory IHC biomarkers to differentiate the two entities.

Methods: PubMed database was used to identify relevant literature.

Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus.

Ethnopharmacological Relevance: Astragalus membranaceus either alone or in combination with Angelica sinensis has been used traditionally for kidney disease in East Asia and China for thousands of years. Previous studies using in vivo animal models have shown the benefits of these medicinal herbs in kidney diseases that involve oxidative stress. However, the mechanisms by which these medicinal herbs protect kidney cells remain largely unknown.

Indoxyl sulphate and kidney disease: Causes, consequences and interventions.

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m(2) ) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest-growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes).

Expression of Bcl-xL and Mcl-1 in the nonmelanoma skin cancers of renal transplant recipients.

Objectives: This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients.

Methods: NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression.

Results: NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .

O-GlcNAc protein modification in C2C12 myoblasts exposed to oxidative stress indicates parallels with endogenous antioxidant defense.

A growing body of evidence demonstrates the involvement of protein modification with O-linked β-N-acetylglucosamine (O-GlcNAc) in the stress response and its beneficial effects on cell survival. Here we investigated protein O-GlcNAcylation in skeletal muscle cells exposed to oxidative stress and the crosstalk with endogenous antioxidant system. The study focused on antioxidant enzymes superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPX1), and transcriptional regulators proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and forkhead box protein O1 (FOXO1), which play important roles in oxidative stress response and are known to be O-GlcNAc-modified.