Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"

Background. The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues. The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration. Methods. We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques. Results. Our data provide the first evidence of β-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1β) was found to be overexpressed. Conclusion. In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as β-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers

Role of TNF-alpha during central sensitization in preclinical studies

Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaig

Influência do posicionamento de membros superiores sobre os efeitos do treinamento muscular inspiratório de curta duração e alta intensidade em indivíduos jovens sadios

O objetivo do estudo foi analisar os efeitos de um treinamento muscular inspiratório (TMI) de curta duração e alta intensidade, com e sem o apoio de membros superiores, sobre as pressões respiratórias máximas em jovens saudáveis. Trinta jovens do sexo feminino foram aleatoriamente distribuídas em três grupos: o grupo controle (GC) fez treinamento placebo na posição sentada; o grupo GSA treinou em pé sem apoio de membros superiores; e o grupo GCA treinou com apoio de membros superiores. O TMI consistiu em três sessões diárias de 10 minutos em três dias consecutivos. Antes, ao final e após um mês do final do treino foram avaliadas a pressão inspiratória máxima (PImáx) e a pressão expiratória máxima (PEmáx). No GSA, houve aumento significante da PImáx após o treino de -75±10 para -97±14 cmH2O (pThe purpose of the study was to analyse the effects of a short-term, high-intensity inspiratory muscle training (IMT) on healthy youth maximal respiratory pressures, with and without arm bracing postures. Thirty young women were randomly assigned to three groups: control group (CG); group training with no arm bracing (NAB); and group training with arm bracing (AB). The IMT consisted of three 10-minute daily supervised sessions for three consecutive days. Before, at the end, and one month after the end of training, subjects' maximal inspiratory pressures (MIP) and maximal expiratory pressures (MEP) were assessed. In NAB group a significant increase in MIP was found, from -75±10 to -97±14 cmH2O (p0.05). As to MEP, only in AB group a significant increase on final MEP was found, from 99±16 to 112±16 cmH2O, p<0.05), followed by a decrease one month later (101±19 cmH2O, p<0.05). Hence in young healthy women a short-term, high-intensity IMT protocol increases inspiratory muscle strength independently of arm positioning, simultaneous to an increase in expiratory muscle strength when the IMT is performed with arm bracing