Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents.

Purpose: Vemurafenib, a selective inhibitor of BRAF(V600), has shown significant activity in BRAF(V600) melanoma but not in less than 10% of metastatic BRAF(V600) colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAF(mut) CRC may provide combinatorial strategies.

Experimental Design: We conducted comparative proteomic analysis of BRAF(V600E) melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.

MDM-2 antagonists induce p53-dependent cell cycle arrest but not cell death in renal cancer cell lines.

Renal cell cancers (RCC) are notoriously resistant to chemotherapy and radiotherapy. While mutations of the p53 tumor suppressor gene frequently contribute to therapy resistance in other epithelial cancers, p53 mutations are relatively rare in RCC. To date, there is conflicting evidence as to whether p53 signaling and function are otherwise proficient or defective in tumors with wild-type p53.

Inhibition of Mxi1 suppresses HIF-2alpha-dependent renal cancer tumorigenesis.

In clear cell renal cancers, the primary molecular defect is inactivation of the von Hippel-Lindau (VHL) gene. Loss of pVHL, the VHL gene product, leads to constitutive activation of hypoxia-inducible factor (HIF) signaling. While downregulation of HIF suppresses tumor formation by pVHL-defective renal carcinoma cells, the relative contribution of individual HIF regulated genes to HIF-dependent tumorigenesis remains under investigation.

Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK.

Ceramide is a sphingolipid that activates stress kinases such as p38 and c-JUN N-Terminal Kinase (JNK). Though Chronic Myelogenous Leukemia (CML) derived K562 cells resist killing by short chain C2-ceramide, we report here that longer chain C6-ceramide promotes apoptosis in these cells. C6-ceramide induces cleavage of Caspase-8 and Caspase-9, but only Caspase-8 is required for apoptosis.

AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan.

Literature suggests the involvement of the renin-angiotensin system and transforming growth factor (TGF)-beta in the renal injury that follows chronic ureteric obstruction. SMAD proteins and the JNK1 cascade are essential components of TGF-beta signaling machinery, and recent data suggest cooperative interaction between JNK1 and SMAD proteins in TGF-beta-mediated gene expression. We used a rat model of chronic unilateral ureteric obstruction to study the effects of candesartan, an AT(1A)-receptor blocker, on tissue morphology and the activities of JNK1 and SMAD2 protein in the kidney.

Stanniocalcin-1, an inhibitor of macrophage chemotaxis and chemokinesis.

In macrophages, changes in intracellular calcium have been associated with activation of cellular processes that regulate cell adhesion and motility and are important for the response of macrophages to antigenic stimuli. The mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) is expressed in multiple organs including the thymus and spleen, and hence, we hypothesized that it may have a role in modulating the immune/inflammatory response. Using murine macrophage-like (RAW264.

Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney.

Using morphological and molecular approaches, we characterized cisplatin-induced cell necrosis and apoptosis in rat kidney. Male Sprague-Dawley rats ( n=5 per group) received a single intraperitoneal injection of either cisplatin (5 mg/kg) or saline, and were killed on day 5. Functionally, cisplatin-treated rats developed polyuric acute renal failure.

The remission of post-transplant nephrotic syndrome clinicopathologic characterization.

Among 67 renal transplant recipients with nephrotic syndrome (NS), nine episodes were reversible in eight patients. Biopsies showed minimal-change disease, focal segmental membranous glomerulonephritis and acute glomerulitis, IgA nephropathy and acute glomerulitis or thrombotic microangiopathy, and chronic transplant nephropathy with or without acute glomerulitis. NS developed 1-4 months post transplant in the four patients with minimal-change disease, but later (33-151 months) in the others.

De novo minimal change disease associated with reversible post-transplant nephrotic syndrome. A report of five cases and review of literature.

Nephrotic syndrome (NS) is frequent in renal transplant recipients and may be related to a large variety of glomerular lesions. In some of these cases, the transplant biopsy showed no significant glomerular changes and the NS was reversible, but the primary renal disease was not minimal change disease (MCD), suggesting that MCD may develop de novo in renal transplant setting. Knowledge of this entity, however, is limited.