Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the ...effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic BH3-domain only PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-beta (TGF-beta) through the intrinsic pathway and to tumor necrosis factor-a (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-beta or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines. J. Cell. Physiol. 227: 1319-1325, 2012. (C) 2011 Wiley Periodicals, Inc.
Abstract Background Women with a false-positive result after a screening mammogram have an increased risk of cancer detection in subsequent participations, especially after assessments involving ...cytology or biopsy. We aimed to compare women's personal characteristics, tumoral features and the radiological appearance of cancers with and without a previous false-positive result generated by additional imaging or invasive procedures. Methods From 1996 to 2007, 111,098 women aged 45–69 years participated in four population-based breast cancer screening programs in Spain, and 1281 cancers were detected. We included all cancers detected in subsequent screenings ( n = 703) and explored the occurrence of previous false-positive results. We identified false-positives requiring additional imaging or invasive procedures. Differences on tumoral features (invasiveness, tumor size, and lymph node status) and radiological appearance were assessed by Chi-square test, and agreement between the location of cancer and prior suspicious by Cohen's kappa coefficient. A multivariate analysis was preformed to evaluate the effect of previous screening results and age on the odds of presenting an in situ carcinoma. Results Among the 703 cancers detected in subsequent screenings, 148 women (21.1%) had a previous false-positive result. Of these, 105 were by additional imaging and 43 by invasive procedures. Women with prior false-positive result requiring invasive assessment, compared to women with negative tests, and women with prior false-positive requiring additional imaging, had a higher proportion of in situ carcinomas (31.7%, 15.3%, 12.9%, respectively; p = 0.014) and microcalcifications (37.2%, 20.2%, 9.5%, respectively; p = 0.003). The proportion of in situ carcinomas was even higher in women over 60 years (39.2%, 12.5%, 13.0%, respectively; p = 0.001). Ipsilateral cancer was observed in 65.7% of cases with prior cytology or biopsy ( k = 0.479; 95%CI: 0.330–0.794). Conclusion A large number of in situ malignancies and calcification patterns were found among women with prior false-positive result in mammography screening requiring cytology or biopsies, suggesting progression from a previously benign lesion.
El programa de apoyo a la exploración judicial va dirigido a víctimas/testigos especialmente vulnerables. Este programa se inició en 1997, siendo su trayectoria ascendente, llegando sólo en el año ...2007 a 266 exploraciones judiciales en la provincia de Barcelona. El objetivo de este programa es recoger la declaración del testigo-víctima: a) Favoreciendo la calidad, tanto cualitativa como cuantitativa de la declaración judicial de los testigos y la aplicación de los derechos de la víctima (evitación de la victimización secundaria). b) Obteniendo la declaración dentro de un marco profesional de contención emocional y reducción del estrés. c) Aplicación posterior de la técnica de credibilidad del testimonio en los casos posibles. Esta exploración judicial se realiza por dos psicólogos forenses del equipo, en una sala con espejo unidireccional. Al otro lado del espejo están presentes aquellas personas necesarias para mantener las garantías procesales. La declaración es grabada en vídeo y se usará siempre que se precise una nueva declaración de la víctima-testigo (en el caso que sea admitido por el juez como prueba preconstituida).
TARDBP (TAR DNA binding protein) is one of the components of neuronal aggregates in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. We have developed a simple ...quantitative method to evaluate TARDBP splicing function that was applied to spinal cord, brainstem, motor cortex, and occipital cortex in ALS (n = 8) cases compared to age- and gender-matched control (n = 17). Then, we quantified the abundance of a TARDBP-spliced cryptic exon present in ATG4B (autophagy related 4B cysteine peptidase) mRNA. Results of these analyses demonstrated that the loss of this TARDBP function in spinal cord, brainstem, motor cortex, and occipital cortex differentiated ALS from controls (area under the curve of receiver operating characteristic: 0.85). Significant correlations were also observed between cryptic exon levels, age, disease duration, and aberrant mRNA levels. To test if TARDBP function in splicing is relevant in ATG4B major function (autophagy) we downregulated TARDBP expression in human neural tissue and in HeLa cells, demonstrating that TARDBP is required for maintaining the expression of ATG4B. Further, ATG4B overexpression alone is sufficient to completely prevent the increase of SQSTM1 induced by TARDBP downregulation in human neural tissue cells and in cell lines. In conclusion, the present findings demonstrate abnormal alternative splicing of ATG4B transcripts in ALS neural tissue in agreement with TARDBP loss of function, leading to impaired autophagy.
Abbreviations: ALS: amyotrophic lateral sclerosis; ATG4B: autophagy related 4B cysteine peptidase; AUC: area under the curve; FTLD: frontotemporal lobar degeneration; iPSC: induced pluripotent stem cells; ROC: receiver operating characteristic; TARDBP: TAR DNA binding protein; RT-qPCR: quantitative RT-PCR
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