Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement ...treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p < 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma Schmitz, Roland; Wright, George W; Huang, Da Wei ...
New England journal of medicine/The New England journal of medicine,
04/2018, Letnik:
378, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Gene-expression profiling of 574 cases of diffuse large B-cell lymphoma revealed four new subtypes based on the co-occurrence of mutation patterns. The subtypes had prognostic influence beyond the ...usual clinical prognostic factors and may aid in directing targeted therapy.
Wolbachia
-based biocontrol has recently emerged as a potential method for prevention and control of dengue and other vector-borne diseases. Major vector species, such as
Aedes aegypti
females, when ...deliberately infected with
Wolbachia
become less capable of getting viral infections and transmitting the virus to human hosts. In this paper, we propose an explicit sex-structured population model that describes an interaction of uninfected (wild) male and female mosquitoes and those deliberately infected with
wMelPop
strain of
Wolbachia
in the same locality. This particular strain of
Wolbachia
is regarded as the best blocker of dengue and other arboviral infections. However,
wMelPop
strain of
Wolbachia
also causes the loss of individual fitness in
Aedes aegypti
mosquitoes. Our model allows for natural introduction of the decision (or control) variable, and we apply the optimal control approach to simulate
wMelPop Wolbachia
infestation of wild
Aedes aegypti
populations. The control action consists in continuous periodic releases of mosquitoes previously infected with
wMelPop
strain of
Wolbachia
in laboratory conditions. The ultimate purpose of control is to find a tradeoff between reaching the population replacement in minimum time and with minimum cost of the control effort. This approach also allows us to estimate the number of
Wolbachia
-carrying mosquitoes to be released in day-by-day control action. The proposed method of biological control is safe to human health, does not contaminate the environment, does not make harm to non-target species, and preserves their interaction with mosquitoes in the ecosystem.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between ...Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.
Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We ...assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6-25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.
This randomized, open-label trial compared two regimens for the initial treatment of human immunodeficiency virus (HIV) infection: tenofovir disoproxil fumarate and emtricitabine plus efavirenz or a ...fixed dose of zidovudine and lamivudine plus efavirenz. Through week 48, the first regimen was superior in terms of viral suppression, CD4-cell response, and adverse events leading to discontinuation of the medication. As this trial continues, it will be important to assess any differences in long-term toxic effects, especially with regard to lipoatrophy and hyperlipidemia.
For the initial treatment of HIV, a regimen of tenofovir and emtricitabine plus efavirenz was superior in terms of viral suppression, CD4-cell response, and adverse events through week 48.
Highly active antiretroviral therapy has fundamentally altered the course of human immunodeficiency virus (HIV) infection by making it possible to suppress the plasma viral load below the limit of detection and to increase the number of CD4 cells.
1
The cornerstone of durable suppression of HIV replication is maintenance of a potent and tolerable regimen to which the patient can adhere. Adherence is necessary to prevent the emergence and replication of drug-resistant strains of the virus.
2
Current guidelines for the management of HIV infection recommend the use of zidovudine or tenofovir disoproxil fumarate (DF) with lamivudine or emtricitabine as preferred nucleoside . . .
To complement the existing treatment guidelines for all tumour types, ESMO organizes consensus conferences to focus on specific issues in each type of tumour. In this setting, a consensus conference ...on the management of lymphoma was held on 18 June 2011 in Lugano, next to the 11th International Conference on Malignant Lymphoma. The conference convened ∼30 experts from all around Europe, and selected six lymphoma entities to be addressed; for each of them, three to five open questions were to be addressed by the experts. For each question, a recommendation should be given by the panel, referring to the strength of the recommendation based on the level of evidence. This consensus report focuses on the three less common lymphoproliferative malignancies: marginal zone lymphoma, mantle cell lymphoma, and peripheral T-cell lymphomas. A first report had focused on diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukaemia.
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