Neuroprotective effects of novel small peptides in vitro and after brain injury

Thyrotropin-releasing hormone (TRH) and TRH analogues have been reported to be neuroprotective in experimental models of spinal cord injury and head injury. We have previously shown that a diketopiperazine structurally related to the TRH metabolite cyclo-his-pro reduces neuronal cell death in vitro and in vivo. Here we report the neuroprotective activity of other cyclic dipeptides in multiple in vitro models of neuronal injury and after controlled cortical impact (CCI) in mice. Using primary neuronal cultures, three novel dipeptides were compared to the previously reported diketopiperazine as well as to vehicle controls; each of the compounds reduced cell death after direct physical trauma or trophic withdrawal. Two of these peptides also protected against glutamate toxicity and beta-amyloid-induced injury; the latter also strongly inhibited glutamate-induced increases in intracellular calcium. Treatment with each of the test compounds resulted in highly significant improvement of motor and cognitive recovery after CCI, as well as markedly reducing lesion volumes as shown by high field magnetic resonance imaging. DNA microarray studies following fluid percussion induced traumatic brain injury (TBI) in rats showed that treatment with one of these dipeptides after injury significantly down-regulated expression of mRNAs for cell cycle proteins, aquaporins, cathepsins and calpain in ipsilateral cortex and/or hippocampus, while up-regulating expression of brain-derived neurotrophic factor, hypoxia-inducible factor and several heat-shock proteins. Many of these mRNA expression changes were paralleled at the protein level. The fact that these small peptides modulate multiple mechanisms favoring neuronal cell survival, as well as their ability to improve functional outcome and reduce posttraumatic lesion size, suggests that they may have potential utility in clinical head injury.     

Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the processes of extracellular matrix degradation. Changes in their expression levels have been observed in various tumor types, including lung carcinoma. However, their clinical significance and their prognostic importance in the progression of nonsmall cell lung carcinoma (NSCLC) remain to be specified. In this study, mRNA expression levels of MMP-1, MMP-9, TIMP-1, and TIMP-2 were evaluated in patients with resected NSCLC, and their associations with disease progression and prognosis were determined. METHODS: Between June 1996 and December 1999, 116 patients underwent resection for NSCLC. Expression levels of MMPs and TIMPs were evaluated using Northern blot analysis in these NSCLC tissue samples and in 39 matched samples of normal lung tissue. RESULTS: MMP-1, MMP-9, and TIMP-1 expression levels were increased in tumor samples compared with matched, corresponding normal tissues. In contrast, TIMP-2 expression was decreased in tumor samples. MMP-1 tumor expression was correlated significantly with the evolution of lymph node status and tumor-lymph node-metastasis (TNM) stage. In contrast, MMP-9 tumor expression was correlated significantly with increased T stage. TIMP-1 overexpression was an independent predictor of worse survival in patients with NSCLC that was not associated with other prognosis factors, such as TNM stage. CONCLUSIONS: The overexpression of TIMP-1 was an independent prognostic marker in patients with NSCLC, and evaluating TIMP-1 may be important for identifying patients who are at greater risk of disease recurrence.     

Anorectal malignant melanoma. Report of three cases

The authors report three cases of primary anorectal malignant melanoma in order to discuss the various diagnostic problems, therapeutic modalities and to remind of the prognostic factors of this rare and unknown affliction. The diagnosis is unfortunately realized in the advanced stage. Mrs B.O, 55 years old, presented rectal hemorrhages and false meeds since a year, the clinical examination showed rectal tumor that bleeds with touch. The mass has been biopsed during the rectoscopy and the diagnosis of the malignant melamoma has been confirmed. Abdominoperitoneal amputation had been realized. Mr F.K, 35 years old, hospitalized because of constipation and rectal hemorrhages that evolve since 7 months with loss of weight and alteration of the general state. The rectal touch emphasizes a budy rectal polypoid tumor about 6 cm that the biopsies confirmed the diagnosis of invasive malignant. A Hartman's operation has been realized. A resection of the tumoral bud has been realized 3 months later, the patient died 4 months after that. Mrs F.K, 50 years old, presented since 50 days relapsing rectorrhages. The rectal touch showed a rectal tumor far about 6 cm from the amal margin, the biopsy during the rectoscopy confirmed the diagnosis of the pigmented and little invasive malignant melanoma. The abdominal exhography showed hepatic metastases and a resection by endo-mal way in order to reduce the tumor has been realized. The inclusion of the primary anorectal malignant melanoma in the diagnosis of the afflictins of the anorectal region would permit an improvement of this affliction prognosis, this is still unfortunate when the diagnosis is late. Its treatment is still surgical, the role of the other therapies still needs to be defined.