Interferon alpha and rapamycin inhibit the growth of pheochromocytoma PC12 line in vitro

Wstęp: Guzy chromochłonne (pheochromocytoma/paraganglioma) należą do łagodnych lub złośliwych nowotworów neuroendokrynnych.Wobec niezadowalającej skuteczności standardowych sposobów leczenia pacjentów z rozsianą postacią choroby, wciąż poszukuje się nowych metod terapii, w tym możliwości skutecznego leczenia celowanego. W związku ze wzmożonym unaczynieniem tych nowotworów, preparaty o działaniu antyangiogennym mogą potencjalnie stanowić nową grupę leków stosowanych w leczeniu pheochromocytoma/paraganglioma.Materiał i metody: W badaniu oceniano wpływ różnych angiomodulatorów: VEGF (naczyniowo-środbłonkowy czynnik wzrostu) orazpięciu endo- i egzogennych czynników antyangiogennych (endostatyna; IFN-alfa [interferon alfa]; rapamycyna — inhibitor szlaku mTOR[mammalian target of rapamycin]; JV1-36 and SU5416 [semaxinib]) na wzrost szczurzej linii pheochromocytoma PC12.Wyniki: IFN-alfa (105 U/mL) silnie hamował wzrost komórek PC12 w hodowli 72 h, nasilając apoptozę i hamując cykl komórkowy. Rapamycynaw szerokim zakresie stężeń (10-5 to 10-8 M) nieznacznie zmniejszała żywotność komórek PC12, a w stężeniu 10-5 M także hamowałaich proliferację. VEGF, endostatyna oraz JV1-36 nie wpływały na wzrost lini PC12.Wnioski: W badaniu po raz pierwszy wykazano, że IFN-alfa hamuje wzrost linii komórkowej pheochromocytoma PC12, a także potwierdzonohamujący wpływ rapamycyny wobec tej linii komórkowej. Uzyskane wyniki sugerują zatem, że IFN-alfa oraz inhibitory szlakumTOR mogą być potencjalnie skuteczne w leczeniu złośliwych postaci guzów chromochłonnych i zachęcają do dalszych badań w tymkierunku.(Endokrynol Pol 2013; 64 (5): 368–374)Introduction: Pheochromocytomas are benign or malignant neuroendocrine tumours. The unsatisfactory efficacy of the traditionaltherapeutic methods for patients with metastatic disease results in a continuing search for more effective and targeted agents. Due to theincreased vascularisation of these tumours, inhibitors of angiogenesis could be potentially a new group of drugs in pheochromocytoma/paraganglioma therapy.Material and methods: The aim of this study was to evaluate the influence of angiomodulators: VEGF (vascular endothelial growth factor)and five endogenous and exogenous antiangiogenic compounds (endostatin; IFN-alpha [interferon alpha]; rapamycin — mTOR [mammaliantarget of rapamycin] inhibitor; JV1-36 and SU5416 (semaxinib]) on the growth of rat pheochromocytoma PC12 cell line.Results: IFN-alpha (105 U/mL) strongly inhibited PC12 growth in a 72 h culture, increasing apoptosis and arresting the cell cycle. Rapamycinin a wide range of concentrations (10-5 to 10-8 M) induced a slight inhibitory effect on PC12 viability and decreased cell proliferation at theconcentration of 10-5 M. VEGF, endostatin and JV1-36 did not influence the growth of PC12.onclusions: The study has shown for the first time that IFN-a inhibited the growth of pheochromocytoma PC12 line and confirmed theinhibitory action of rapamycin on these cells. The results suggest that IFN-alpha and mTOR inhibitors could be potentially effective in thetherapy of malignant pheochromocytoma, and encourage further study in this field.(Endokrynol Pol 2013; 64 (5): 368–374

Elevated Peripheral Blood Plasma Concentrations of Tie-2 and Angiopoietin 2 in Patients with Neuroendocrine Tumors

Background: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. Methods: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. Results: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. Conclusions: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases

The Rise and Fall of Hypertension: Lessons Learned from Eastern Europe

Hypertension is a progressive cardiovascular syndrome that arises from many differing, but interrelated, etiologies. Hypertension is the most prevalent cardiovascular disorder, affecting 20% to 50% of the adult population in developed countries. Arterial hypertension is a major risk factor for cardiovascular diseases and death. Epidemiologic data have shown that control of hypertension is achieved in only a small percentage of hypertensive patients. Findings from the World Health Organization project Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) showed a remarkably high prevalence (about 65%) of hypertension in Eastern Europeans. There is virtually no difference however, between the success rate in controlling hypertension when comparing Eastern and Western European populations. Diagnosing hypertension depends on both population awareness of the dangers of hypertension and medical interventions aimed at the detecting elevated blood pressure, even in asymptomatic patients. Medical compliance with guidelines for the treatment of hypertension is variable throughout Eastern Europe. Prevalence of hypertension increases with age, and the management of hypertension in elderly is a significant problem. The treatment of hypertension demands a comprehensive approach to the patient with regard to cardiovascular risk and individualization of hypertensive therapy

Transgresión y polaridad: autorretrato de la intimidad femenina en el contexto contemporáneo

Esta tesis es un trabajo que nació de la motivación personal y de la experiencia práctica en el área del arte visual, y ha obtenido su forma final en la investigación entorno a la mujer, sus trastornos sexuales y la transgresión de estos trastornos a través de las prácticas visuales. Este trabajo "en arte y género" ha englobado diversos ámbitos de estudio y ha trabajado con múltiples tipos de recursos e iniciativas para alcanzar sus objetivos. Estas iniciativas se han emplazado en un ámbito internacional

Balance between Transcription and RNA Degradation Is Vital for Saccharomyces cerevisiae Mitochondria: Reduced Transcription Rescues the Phenotype of Deficient RNA Degradation

The Saccharomyces cerevisiae SUV3 gene encodes the helicase component of the mitochondrial degradosome (mtEXO), the principal 3′-to-5′ exoribonuclease of yeast mitochondria responsible for RNA turnover and surveillance. Inactivation of SUV3 (suv3Δ) causes multiple defects related to overaccumulation of aberrant transcripts and precursors, leading to a disruption of mitochondrial gene expression and loss of respiratory function. We isolated spontaneous suppressors that partially restore mitochondrial function in suv3Δ strains devoid of mitochondrial introns and found that they correspond to partial loss-of-function mutations in genes encoding the two subunits of the mitochondrial RNA polymerase (Rpo41p and Mtf1p) that severely reduce the transcription rate in mitochondria. These results show that reducing the transcription rate rescues defects in RNA turnover and demonstrates directly the vital importance of maintaining the balance between RNA synthesis and degradation

Active 5′ splice sites regulate the biogenesis efficiency of Arabidopsis microRNAs derived from intron-containing genes

Arabidopsis, miR402 that is encoded within the first intron of a protein-coding gene At1g77230, is induced by heat stress. Its upregulation correlates with splicing inhibition and intronic proximal polyA site selection. It suggests that miR402 is not processed from an intron, but rather from a shorter transcript after selection of the proximal polyA site within this intron. Recently, introns and active 5′ splice sites (5′ss’) have been shown to stimulate the accumulation of miRNAs encoded within the first exons of intron-containing MIR genes. In contrast, we have observed the opposite effect of splicing inhibition on intronic miR402 production. Transient expression experiments performed in tobacco leaves revealed a significant accumulation of the intronic mature miR402 when the 5′ss of the miR402-hosting intron was inactivated. In contrast, when the miR402 stem-loop structure was moved into the first exon, mutation of the first-intron 5′ss resulted in a decrease in the miRNA level. Thus, the 5′ss controls the efficiency of miRNA biogenesis. We also show that the SERRATE protein (a key component of the plant microprocessor) colocalizes and interacts with several U1 snRNP auxiliary proteins. We postulate that SERRATE-spliceosome connections have a direct effect on miRNA maturation