Marcatori molecolari di cellule staminali nella cancerogenesi epatica sperimentale

Aim:Evolving under standing on tumor biology has led to the hypothesis that tumors may possess a stem cell–like subpopulation known as Cancer Stem Cells (CSCs) that may be involved in driving tumor pathogenesis and propagation.CSCs as well as normal tissue stem cells possess: self-renewal,unlimited proliferative capacity and pluripotency to differentiate in several cellular types. The aim of our investigation is to identify CSCs molecular markers,both prognostic and diagnostic value,that are associated with tumor initiation, heterogeneity, progression, metastasis, therapy sensitivity usefull potential for innovative therapeutic approaches. Methods:To this purpose we used two rats strains: F344 and BN,susceptible and resistant to chemically induced hepatocarcinogenesis respectively. We induced neoplastic liver lesions accordingly the resistant hepatocyte model. We evaluated,by immunoistochemical staining, CD44 (marker of oval cells and CSCs), CD133 (hematopoietic stem and progenitor cell marker), CK19 (marker of biliary cells and cholangiocytes) and c-Kit (markers of oval cells, CSCs and hepatocytes). Sections were obtained from untreated controls and tumor tissue. Results:Our immunoistochemical observations showed significant differences of basal levels (controls) between the two rat strains, susceptible and resistant, as concernes CK19 (p=0.03);CD133 (p=0.0003) and c-Kit (p=0.0003) expression,but CD44. In BN rats,resistant strain,all 4 markers showed higher levels in tumors compared to their controls (p=0.0001). In F344 rats,susceptible strain, 3 markers showed higher levels in tumors (between 2 and 3 folds) compared to controls, except CK19. Only CD133 and CK19 are significantly higher in HCC from BN rats compared to tumors from F344. Unfortunately at the moment we were able to analyse only few numbers of rats. Conclusion:Based on these data, we may suggest that the stemness markers studied could represent valuable diagnostic and prognostic markers for hepatocellular carcinoma, since stem cells can contribute to tumor progression, as it has already been shown in other several types of tumors

HUBUNGAN SELF CONCEPT DENGAN PENYESUAIAN DIRI PADA ANAK PANTI ASUHAN HARAPAN PUTRA DI KELURAHAN TANGKERANG UTARA KECAMATAN BUKIT RAYA KOTA PEKANBARU

Penyesuaian diri pada anak panti asuhan Harapan Putra di Kelurahan Tangkerang Utara Kecamatan Bukit Raya Kota Pekanbaru. Adapun sampel dalam penelitian ini adalah anak panti asuhan Harapan Putra di Kelurahan Tangkerang Utara Kecamatan Bukit Raya Kota Pekanbaru yang berjumlah 85 anak. Penelitian ini adalah penelitian kuantitatif dengan jenis penelitian korelasi, adapun teknik yang digunakan dalam penelitian ini non probability dengan simple random sampling teknik pengumpulan data yang digunakan yaitu melalui lembar observasi untuk anak. Analisis penelitian menggunakan uji korelasi SPSS for windows ver. 22. Dalam penelitian ini hipotesis yang diajukan adalah terdapat hubungan antara self concept dengan penyesuaian diri pada anak Panti Asuhan Harapan Putra di Kelurahan Tangkerang Utara Kecamatan Bukit Raya Kota Pekanbaru. Pada penelitian ini diperoleh data mengenai penyesuaian diri secara keseluruhannya dengan nilai 58,95% termasuk dalam kategori cukup baik yaitu dalam rentang 54%-70% (dilihat pada table 3.6). Sedangkan data mengenai self concept pada anak secara keseluruhan dengan nilai 64,34% termasuk dalam kategori cukup baik yaitu dalam rentang 54%-70%. Untuk menguji signifikansi hubungan dapat diketahui melalui hasil analisis dengan correlation pearson product moment, dengan melihat nilai probabilitas (sig) yang diperoleh. Sebagai keteria penilaian, apabila >0,05 maka Ho diterima, sedangkan apabila probabilitas < 0,05 maka Ho ditolak. Artinya terdapat hubungan yang signifikan antara dua variabel tersebut

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Leucemias Agudas

Sobre: Leucemia linfoblástica aguda; Linfoma linfoblástico; Leucemia mieloide aguda; Leucemia promielocítica aguda y situaciones especiales.Fil: Agriello, Evangelina Edith. No especifíca;Fil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bullorsky, Laura. No especifíca;Fil: Cazap, Nicolás. No especifíca;Fil: Cranco, Santiago. No especifíca;Fil: Dick, Hernán. No especifíca;Fil: Fernandez, Isolda. No especifíca;Fil: Fischman, Laura. No especifíca;Fil: Funes, María Eugenia. No especifíca;Fil: Gimenez Conca, Alberto. No especifíca;Fil: González, Jacqueline. No especifíca;Fil: Lang, Cecilia. No especifíca;Fil: Mela Osorio, María José. No especifíca;Fil: Navickas, Alicia. No especifíca;Fil: Oliveira, Natalia. No especifíca;Fil: Rey, Irene. No especifíca;Fil: Rivas, Marta. No especifíca;Fil: Suero, Alejandro. No especifíca;Fil: Zanella, Lorena. No especifíca

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

Background and Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a pernicious tumor characterized by a dismal outcome and scarce therapeutic options. To substantially improve the prognosis of iCCA patients, a better understanding of the molecular mechanisms responsible for development and progression of this disease is imperative. In the present study, we aimed at elucidating the role of the maternal embryonic leucine zipper kinase (MELK) protooncogene in iCCA. Materials and Methods: We analyzed the expression of MELK and two putative targets, Forkhead Box M1 (FOXM1) and Enhancer of Zeste Homolog 2 (EZH2), in a collection of human iCCA by real-time RT-PCR and immunohistochemistry (IHC). The effects on iCCA growth of both the multi-kinase inhibitor OTSSP167 and specific small-interfering RNA (siRNA) against MELK were investigated in iCCA cell lines. Results: Expression of MELK was significantly higher in tumors than in corresponding non-neoplastic liver counterparts, with highest levels of MELK being associated with patients&rsquo; shorter survival length. In vitro, OTSSP167 suppressed the growth of iCCA cell lines in a dose-dependent manner by reducing proliferation and inducing apoptosis. These effects were amplified when OTSSP167 administration was coupled to the DNA-damaging agent doxorubicin. Similar results, but less remarkable, were obtained when MELK was silenced by specific siRNA in the same cells. At the molecular level, siRNA against MELK triggered downregulation of MELK and its targets. Finally, we found that MELK is a downstream target of the E2F1 transcription factor. Conclusion: Our results indicate that MELK is ubiquitously overexpressed in iCCA, where it may represent a prognostic indicator and a therapeutic target. In particular, the combination of OTSSP167 (or other, more specific MELK inhibitors) with DNA-damaging agents might be a potentially effective therapy for human iCCA

Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice.

Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT, and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades

PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

It has been suggested that 1&ndash;2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RAR&alpha;) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RAR&alpha; being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RAR&alpha; and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RAR&alpha; and 2 NPM1-RAR&alpha;), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 &times; 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far