Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated BRAF and NRAS therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.

• MeSH
• chromozomální delece MeSH
• dospělí MeSH
• elementy Alu genetika   MeSH
• exony genetika   MeSH
• glykogenóza typu IIb diagnóza   genetika   patofyziologie   MeSH
• inaktivace chromozomu X genetika   MeSH
• kardiomyopatie genetika   patofyziologie   MeSH
• kulinové proteiny genetika   MeSH
• lidé MeSH
• membránový protein 2 asociovaný s lyzozomy genetika   MeSH
• mentální retardace vázaná na chromozom X genetika   patofyziologie   MeSH
• mutace ztráty funkce genetika   MeSH
• myokard metabolismus   MeSH
• sodíko-draslíková ATPasa genetika   MeSH
• transkripční faktory genetika   MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

The influence of non-thermal plasma (NTP) treatment on the prevention of antibiotic resistance of microbial biofilms was studied. Staphylococcus epidermidis and Escherichia coli bacteria and a yeast Candida albicans, grown on the surface of Ti-6Al-4V alloy used in the manufacture of prosthetic implants, were employed. Their biofilms were exposed to NTP produced by DC cometary discharge and subsequently treated with antibiotics commonly used for the treatment of infections caused by them: erythromycin (ERY), polymyxin B (PMB), or amphotericin B (AMB), respectively. All biofilms displayed significant reduction of their metabolic activity after NTP exposure, the most sensitive was S. epidermidis. The subsequent action of antibiotics caused significant decrease in the metabolic activity of S. epidermidis and E. coli, but not C. albicans, although the area covered by biofilm decreased in all cases. The combined effect of NTP with antibiotics was thus proved to be a promising strategy in bacterial pathogen treatment.

• MeSH
• antibiotická rezistence MeSH
• antiinfekční látky farmakologie   MeSH
• biofilmy účinky léků   růst a vývoj   MeSH
• Candida albicans účinky léků   MeSH
• druhová specificita MeSH
• Escherichia coli účinky léků   MeSH
• mikrobiální testy citlivosti MeSH
• plazmové plyny farmakologie   MeSH
• slitiny MeSH
• Staphylococcus epidermidis účinky léků   MeSH
• titan MeSH
• Publikační typ
• časopisecké články MeSH