Partial regression of conventional renal cell carcinoma displays markers of wound repair.

Aims: During detailed analysis of H&E-stained histological slides of 710 unbiased conventional renal cell carcinomas (cRCCs), 141 tumours displayed partial regressive changes showing strong similarity to that of wound healing. We aimed to analyse the molecular processes occurring in regressive tumours.

Methods: Immunohistochemistry was applied to analyse the signalling molecules in 12 selected tumours, and statistical analysis was used to estimate the correlation between regression and the outcome of the disease.

Lack of VEGFA/KDR Signaling in Conventional Renal Cell Carcinoma Explains the Low Efficacy of Target Therapy and Frequent Adverse Events.

It is acknowledged that conventional renal cell carcinoma (cRCC), which makes up 85% of renal malignancies, is a highly vascular tumor. Humanized monoclonal antibodies were developed to inhibit tumor neo-angiogenesis, which is driven by VEGFA/KDR signaling. The results largely met our expectations, and in several cases, adverse events occurred.

Optical Genome Mapping Reveals Disruption of the Gene in a Patient with Developmental Delay Carrying a De Novo Balanced Reciprocal Translocation.

While balanced reciprocal translocations are relatively common, they often remain clinically silent unless they lead to the disruption of functional genes. In this study, we present the case of a boy exhibiting developmental delay and mild intellectual disability. Initial karyotyping revealed a translocation t(5;6)(q13;q23) between chromosomes 5 and 6 with limited resolution.

Impact of cellular morphology and three-tiered nuclear grade on progression of conventional renal cell carcinoma.

Aims And Methods: The aims of this study were to evaluate the prognostic impact of cytomorphology and three-tiered grading on tumour-free survival of patients with conventional renal cell carcinoma (cRCC). Formalin-fixed, paraffin-embedded samples from 710 patients were assessed and the results were evaluated according to the clinical data.

Results: Kaplan-Meier regression model showed that 90.

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities.

Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile.

FAPα and αSMA mark different subsets of fibroblasts in normal kidney and conventional renal cell carcinoma.

Several studies suggested a correlation between cancer associated fibroblasts (CAF) and cancer progression, but data on conventional renal cell carcinoma (cRCC) is still lacking. We aimed to analyse the impact of αSMA positive myo-CAF and FAPα expressing i-CAF on postoperative relapse of cRCC. We applied immunohistochemistry on tissue-multiarray (TMA) containing 736 consecutively operated cRCC without metastasis at the time of diagnosis.

A New Naphthopyran Derivative Combines -Myb Inhibition, Microtubule-Targeting Effects, and Antiangiogenic Properties.

Based on the promising -Myb inhibitor , a series of 2-amino-4-aryl-4-naphtho[1,2-]pyran-3-carbonitriles (, -, -) were repurposed or newly synthesized via a three-component reaction of 1-naphthol, and various aryl aldehydes and malononitrile and screened for their -Myb inhibitory activities. also served as a lead compound for seven new naphthopyran derivatives (-), which were cytotoxic with nanomolar IC values, to inhibit the polymerization of tubulin, and to destabilize microtubules in living cells. Especially, the alkyne , originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed.

Src-Family Protein Kinase Inhibitors Suppress MYB Activity in a p300-Dependent Manner.

Recent studies have disclosed transcription factor MYB as a potential drug target for malignancies that are dependent on deregulated MYB function, including acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often regarded as undruggable, successful targeting of MYB by low-molecular-weight compounds has recently been demonstrated. In an attempt to repurpose known drugs as novel MYB-inhibitory agents, we have screened libraries of approved drugs and drug-like compounds for molecules with MYB-inhibitory potential.

A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells.

C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells.

Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity.

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4-naphtho[1,2-]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300.

Characterization of the MYB-inhibitory potential of the Pan-HDAC inhibitor LAQ824.

A large body of work has shown that MYB acts as a master transcription regulator in hematopoietic cells and has pinpointed MYB as a potential drug target for acute myeloid leukemia (AML). Here, we have examined the MYB-inhibitory potential of the HDAC inhibitor LAQ824, which was identified in a screen for novel MYB inhibitors. We show that nanomolar concentrations of LAQ824 and the related HDAC inhibitors vorinostat and panobinostat interfere with MYB function in two ways, by inducing its degradation and inhibiting its activity.

Matrix metalloproteinase 12 is an independent prognostic factor predicting postoperative relapse of conventional renal cell carcinoma - a short report.

Purpose: Approximately 15% of clinically localised conventional renal cell carcinomas (cRCC) develop metastases within 5 years of follow-up. Sarcomatous cRCC is a highly malignant cancer of the kidney. The aim of our study was to identify biomarkers for estimating the postoperative progression of cRCCs.

Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma.

One of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN).

Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner.

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies.

C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia.

Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ.

The Role of Genetic Analysis in Correct Diagnosis of Eosinophilic Variant of Chromophobe Renal Cell Carcinoma.

Background/aim: It has been suggested that eosinophilic variant of chromophobe renal cell carcinoma (chRCC) with low chromosome number or lack of genomic alteration has an excellent prognosis in comparison to classic chRCC. The aim of our study was to analyse the phenotypical variations of 77 chRCCs, including 7 eosinophilic ones, each diagnosed unequivocally by genetic means.

Materials And Methods: DNA isolated from chRCCs was subjected to array comparative genomic hybridisation (CGH) for establishing the chromosome alteration.

Cytoplasmic Expression of AXL Is Associated With High Risk of Postoperative Relapse of Conventional Renal Cell Carcinoma.

Background/aim: Despite early detection by widespread use of abdominal imaging more than 40% of patients with conventional renal cell carcinoma (RCC) will die due to metastatic disease. Small kinase inhibitors for AXL receptor tyrosine kinase may delay the progression of metastatic cRCC.

Patients And Methods: We analysed AXL expression by immunohistochemistry on tissue multi arrays of 691 conventional RCC without metastasis at the time of nephrectomy.

Expression of RARRES1 and AGBL2 and progression of conventional renal cell carcinoma.

Background: Approximately 15% of clinically localised conventional renal cell carcinoma (RCC) will develop metastasis within 5 years of follow-up. The aim of this study was to identify biomarkers predicting the postoperative tumour relapse.

Methods: Tissue microarrays of conventional RCC from a cohort of 691 patients without metastasis at the time of operation were analysed by immunohistochemistry for the expression of carboxypeptase inhibitor RARRES1 and its substrate carboxypeptidase AGBL2.

M2 Macrophage Marker Chitinase 3-Like 2 (CHI3L2) Associates With Progression of Conventional Renal Cell Carcinoma.

Background/aim: In spite of early detection, appoximately 15% of the small renal cell carcinomas (RCC) will develop metastasis within 5 years follow-up. The aim of this study was to identify new biomarkers to estimate the postoperative relapse of the most common conventional RCC.

Patients And Methods: Tissue multi arrays of conventional RCC without metastasis at the time of operation from a cohort of 634 patients were analysed by immunohistochemistry for expression of the chitinase 3-like protein 2 (CHI3L2).

Dual role of : development of papillary renal cell tumor and progression of conventional renal cell carcinoma.

Expression of has been described in multi-layered epithelia as well as in tumors derived from these cells. In cancers arising from negative single layered epithelia neo-expression of has been associated with tumor progression. To obtain more insight into the biology of kidney cancers we have investigated expression by immunohistochemistry in normal kidney, in papillary preneoplastic lesions and in 151 papillary and 692 conventional renal cell carcinomas placed on tissue microarray.

IL6 Shapes an Inflammatory Microenvironment and Triggers the Development of Unique Types of Cancer in End-stage Kidney.

Background/aim: Chronic inflammation in end-stage kidney is associated with the development of pre-neoplastic lesions and renal cell tumors. The aim of this study was to clarify the role of the inflammatory microenvironment in this process.

Materials And Methods: We used representative microscopic slides from 11 end stage-kidneys containing pre-neoplastic lesions and tumors and applied immunohistochemistry to detect IL-6, SAA1 and LBP expression.

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity.

The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent work has suggested that targeting MYB by small-molecule inhibitors is feasible and that inhibition of MYB has potential as a therapeutic approach against acute myeloid leukemia.

Embryonal Origin of MTSCC of Kidney May Explain its Morphological Heterogeneity: Diagnostic Impact of Genetic Analysis.

Background/aim: Previous genetic and morphologic characterisation of mucinous tubular and spindle cell carcinoma (MTSCC) have yielded controversial results. The aim of this study was to explain the phenotypic heterogeneity of MTSCC diagnosed by genetic means.

Materials And Methods: We analyzed 7 MTSCC by array CGH and microsatellite allelotyping and by histology for morphological variation.

Genomic profiling of papillary renal cell tumours identifies small regions of DNA alterations: a possible role of HNF1B in tumour development.

Aims: Papillary renal cell tumours (RCT) are characterized by specific trisomies. The aim of this study was to identify small regions of duplication marking putative tumour genes.

Methods And Results: Full-tiling path bacterial artificial chromosome (BAC) array hybridization of 20 papillary RCTs confirmed the duplication of chromosomes 7 and 17 and also displayed smaller regions of gains/amplifications of 1.