Growth hormone-releasing hormone receptor splice variant 1 is frequently expressed in oral squamous cell carcinomas

The expression of growth hormone-releasing hormone (GHRH) splice variant 1 (SV1) receptor in neoplastic lesions of the oral cavity was assessed. The sensitivity of HaCaT keratinocytes to GHRH analogs was also evaluated. Thirty-three benign precancerous oral lesions and 27 squamous cell carcinomas of the oral cavity were evaluated by immunohistochemistry for SV1 expression. SV1 expression in HaCaT keratinocytes was assessed by western blot. HaCaT proliferation was evaluated by cell counting. Anti-SV1 immunoreactivity was detected in only 9% (three of 33) precancerous lesions (one hyperplasia and two dysplasias), while 44% (12 of 27) carcinomas were positive for SV1 (p<0.002). GHRH(1-29)NH(2) and GHRH agonist JI-38 stimulated HaCaT proliferation in vitro, and this effect was blocked by GHRH antagonists. These results indicate that SV1 expression may be associated with the transition of precancerous lesions to carcinomas of the oral epithelium. GHRH antagonists may be useful for the management of the disease.     

FLIP regulation of HO-1 and TNF signalling in human acute myeloid leukemia provides a unique secondary anti-apoptotic mechanism

Acute myeloid leukemia (AML) comprises a heterogeneous group of clonal disorders of hematopoietic progenitors. We previously showed that heme oxygenase-1 (HO-1/Hsp32) underlies resistance of AML to TNF-induced apoptosis. Here we show for the first time that the modulatory protein, FLICE-inhibitory protein (FLIP) indirectly regulates induction of HO-1 in response to TNF in human AML blasts, but not non-cancerous control cells. In AML cells, TNF-induced FLIP expression was an NF-κB-dependent event, and silencing of FLIP isoforms (FLIPL, FLIPS and FLIPR) induced pro-apoptotic responses to TNF, with FLIPL knock-down providing the greatest apoptotic switch. However, FLIPL knock-down consequently increased expression of HO-1; a response that occurred in AML (but not non-cancerous) cells to protect a proportion of them from apoptotic death. Our results show that increases in HO-1 induced an apoptotic-resistant form in AML cells in the absence of FLIPL. This is the first time that FLIPL has been shown to regulate the expression of HO-1. These data reveal unique regulatory networks in cancerous AML cells whereby FLIP regulation of HO-1 provides AML cells with secondary anti-apoptotic protection against extrinsic factors (eg TNF/chemotherapies) that try to switch on death signals in these highly death-resistant cells. Future AML therapies should target these mechanisms.     

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.     

Differentiated thyroid cancer: comparison of therapeutic iodine 131 biological elimination after discontinuation of levothyroxine versus administration of recombinant human thyrotropin

The biological elimination of therapeutic 131I in patients with differentiated thyroid cancer (DTC), post total or near-total thyroidectomy, was compared after withholding levothyroxine suppression against administration of recombinant human thyrotropin without stopping levothyroxine. In 163 patients (group G1) levothyroxine was withheld before 131I therapy: in 138 patients the tumor was limited to the thyroid bed (group G1.1) and in 25 patients metastases were present (group G1.2). A second group of patients (G2; n = 28) received 131I therapy after administration of recombinant human thyrotropin without stopping levothyroxine. Mean retained 131I activity (as a percentage of the administered dose) was 5%-29% (group G1.1), 20%-43% (group G1.2) and 1%-17% (group G2). The effective half-life of 131I was 0.59-0.69 days (group G1.1), 0.87-1.22 days (group G1.2) and 0.38-0.44 days (group G2). In conclusion, the use of recombinant human thyrotropin to prepare patients with thyroid cancer for therapy with 131I shortens its effective half-life and reduces its retained activity compared to preparation with discontinuation of levothyroxine suppression.     

The Conformational Features of Some Biologically Active N-Acylprolyltyrosinamides Studied by 1H NMR Spectroscopy

Pharmaceutical Chemistry Journal -     

Acute disseminated encephalomyelitis after allogeneic bone marrow transplantation for pure red cell aplasia – A case report and review of the literature

ADEM is a rare inflammatory demyelinating disease of the CNS, which usually presents after a viral infection or a vaccination. We report a 15‐yr‐old boy who was diagnosed with ADEM after an HLA‐identical sibling allogeneic BMT for transfusion‐dependent PRCA. His course was complicated with GVHD affecting the skin and lungs. Five months post‐BMT, he developed neurological symptoms including sudden mental status alteration, dysarthria, facial nerve palsy, and acute paraplegia. The MRI revealed multifocal hyperintense lesions mainly in the subcortical white matter of the cerebrum, the brainstem, the basal ganglia, and the thalami. CSF examination was normal. There was no laboratory evidence of infection. The typical MRI findings and an acute monophasic clinical course were consistent with the diagnosis of ADEM. Clinical and radiological improvement was observed after treatment with high‐dose steroids and IVIG. Complete neurologic recovery was achieved six months after the onset of symptoms. We present a rare case of ADEM post‐BMT and review of the literature.     

Effect of dexamethasone on the expression of binding sites for high-density lipoproteins in cultured rat hepatocytes (Independence of the hormone effect on the intracellular cholesterol pool)

It is shown that glucocorticoids play a key regulatory role directed toward the maintenance of an optimal level of binding and internalization of HDL₃ in hepatocytes. Their stimulatory effect on the expression of HDL receptors proves to be independent of changes in the CH content in parenchymal cells. Translated fromByulleten' Eksperimentalnoi Biologii i Meditsiny, Vol. 117, N ^o 1, pp. 50–53, January, 1994     

Glucocorticoid-dependent regulation of the expression of high-density lipoprotein binding sites in rat hepatocytes

It is shown that dexamethasone increases the number of HDL binding sites in cultured hepatocytes bothin vivo andin vitro. The glucocorticoid acts in a dose-dependent and reversible manner within a wide range of concentrations, including physiological and subphysiological doses. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 1, pp. 47–50, January, 1994