The transcription factor FOXF1 promotes prostate cancer by stimulating the mitogen-activated protein kinase ERK5.

Forkhead box F1 (FOXF1) is a stromal transcription factor that is not expressed in epithelial cells of normal prostate tissue. The role of FOXF1 in cancer is conflicting; its loss in some cancers suggests a tumor suppressive function, but its abundance in others is associated with protumorigenic and metastatic traits. Extracellular signal-regulated kinase 5 (ERK5) is associated with advanced-stage prostate adenocarcinoma (PCa) in patients. We detected a population of FOXF1-positive tumor cells in aggressive mouse and human PCa. Using two murine orthotopic models of PCa, we found that overexpression of FOXF1 in Myc-CaP and TRAMP prostate tumor cells induced tumor growth in the prostate and progression to peritoneal metastasis. Increased growth of FOXF1-positive prostate tumors was associated with increased phosphorylation of ERK5, a member of the mitogen-activated protein kinase (MAPK) family. FOXF1 transcriptionally induced and directly bound to promoter regions of genes encoding the kinases MAP3K2 and WNK1, which promoted the phosphorylation and activation of ERK5. Knockdown of ERK5 or both MAP3K2 and WNK1 in FOXF1-overexpressing PCa cells reduced cell proliferation in culture and suppressed tumor growth and tumor metastasis when implanted into mice. In human tumors, FOXF1 expression correlated positively with that of MAP3K2 and WNK1 Thus, in contrast to some tumors where FOXF1 may function as a tumor suppressor, FOXF1 promotes prostate tumor growth and progression by activating ERK5 signaling. Our results also indicate that ERK5 may be a new therapeutic target in patients with FOXF1-positive PCa.

Utility of frozen section analysis for fungal organisms in soft tissue wound debridement margin determination.

BACKGROUND: Zygomycetes cause different patterns of infection in immunosuppressed individuals, including sino-orbito-cerebral, pulmonary, skin/soft tissue infection and disseminated disease. Infections with Zygomycetes have a high mortality rate, even with prompt treatment, which includes anti-fungal agents and surgical debridement. In some centers, clear margins are monitored by serial frozen sections, but there are no specific guidelines for the use of frozen sections during surgical debridement. Studies in fungal rhinosinusitis found 62.5-85 % sensitivity of frozen section analysis in margin assessment. However, the utility of frozen section analysis for margin evaluation in debridement of skin/soft tissue infection has not been published. METHODS: We present a case of zygomycosis of decubitus ulcers in which we assessed statistical measures of performance of frozen section analysis for presence of fungal organisms on the margin, compared with formalin-fixed paraffin embedded (FFPE) sections as gold standard. A total of 33 specimens (94 blocks) were sectioned, stained with H&E and evaluated by both frozen and FFPE analysis. Negative interpretations were confirmed by Gomori methenamine silver stain on FFPE sections. RESULTS: H&E staining of frozen sections had 68.4 % sensitivity and 100 % specificity for assessing margins clear of fungal organisms. The negative and positive predictive values were 70.0 % and 100 %, respectively. Using presence of acute inflammation and necrosis as markers of fungal infection improved sensitivity (100 %) at the expense of specificity (42.9 %). CONCLUSION: Use of intraoperative assessment of skin and soft tissue margins for fungal infection is a valuable tool in the management of skin and soft tissue fungal infection treatment.

Fine-needle aspiration diagnosis of high grade adenoid cystic carcinoma metastatic to the pancreas.

Pancreatic tumors are mostly primary tumors, with only rare metastatic tumors described in the literature. Here we report an unusual case of fine-needle aspiration (FNA) diagnosis of high grade adenoid cystic carcinoma of the parotid gland metastatic to the pancreas. The aspirate smears were moderately cellular and revealed numerous basaloid neoplastic cells. The cytomorphologic differential diagnosis included primary pancreatic tumor with small cell morphology as well as metastatic tumors. By immunocytochemistry, the tumor cells were positive for cytokeratins (AE1/AE3, CAM5.2, and CK7), and CD117 (C-KIT), and negative for CD45, WT1, synaptophysin, chromogranin, CD56, TTF-1, and CK20. The cytomorphologic features and immunoprofile in our case were consistent with high-grade carcinoma metastases from patient's known salivary gland primary. To the best of our knowledge, this case is the first reported encounter of FNA diagnosis of pancreatic metastasis with small cell morphology from a salivary gland neoplasm as primary site.

Expression of a novel tropomyosin isoform in axolotl heart and skeletal muscle.

TPM1kappa is an alternatively spliced isoform of the TPM1 gene whose specific role in cardiac development and disease is yet to be elucidated. Although mRNA studies have shown TPM1kappa expression in axolotl heart and skeletal muscle, it has not been quantified. Also the presence of TPM1kappa protein in axolotl heart and skeletal muscle has not been demonstrated. In this study, we quantified TPM1kappa mRNA expression in axolotl heart and skeletal muscle. Using a newly developed TPM1kappa specific antibody, we demonstrated the expression and incorporation of TPM1kappa protein in myofibrils of axolotl heart and skeletal muscle. The results support the potential role of TPM1kappa in myofibrillogenesis and sarcomeric function.

Male gender and not the severity of hypertension is associated with end-organ damage in aged stroke-prone spontaneously hypertensive rats.

BACKGROUND: It is well-known that gender affects the progression of kidney failure. Male patients exhibit faster development of age-dependent renal disease than do women. In the present study, we examined arterial blood pressure (BP), proteinuria, and end-organ damage in male and female retired breeders from our colony of stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: Male (n = 7) and female (n = 11) SHRSP littermates maintained on Purina Laboratory Chow 5008 and water were studied starting at 53 weeks of age. Systolic BP was measured by tail-cuff plethysmography and 24-h urinary protein excretion was quantified while animals were housed in metabolic cages. Blood was obtained by retro-orbital bleeding. Mean arterial pressure (MAP) was then monitored by radiotelemetry. Organs were preserved for histopathologic assessment. RESULTS: Tail-cuff systolic BP did not differ between the sexes. Male SHRSP exhibited greater proteinuria (128 +/- 7 mg/d) than females (21 +/- 5 mg/d, P < .001). Blood urea nitrogen was higher in males (22 +/- 2 mg%) v females (15 +/- 1 mg%, P < .005). The MAP by radiotelemetry did not differ between the sexes (179 +/- 3 mm Hg in males v 192 +/- 6 mm Hg in females, 2 weeks after probe implantation). Stroke-related mortality was greater in males (83%) than females (10%). Renal vascular disease including thrombotic microangiopathy affecting glomeruli and microvessels and cardiac damage were more prominent in male SHRSP. CONCLUSIONS: These findings demonstrate that male gender is a major risk factor for multisystem end-organ damage associated with aging and hypertension in SHRSP, despite comparable degrees of hypertension among males and females.