Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually diagnosed in children. In advanced and metastatic stages the prognosis is often poor. RMS cell lines were used for evaluation of the role of MET receptor inhibition on chemotaxis and invasion. In vivo studies were performed using NOD-SCID xenograft model. This study shows that blocking of MET expression has strong influence on metastatic behavior of RMS. MET negative cells possess a reduced potential to migrate and to invade. Downregulation of MET suppressed the ability of RMS cells to populate bone marrow. Inhibition of MET negative tumor cells engraftment into bone marrow was observed. MET negative tumors were also two to four times smaller than their wild type counterparts. Since MET receptor plays a very important role in facilitating metastasis of RMS cells, blocking of HGF-MET axis might be considered as a therapeutic option for RMS patients, at more advanced and metastatic stages

TP53 polymorphism in plasma cell myeloma

Introduction. Significant and accessible predictive factors for bortezomib treatment in plasma cell myeloma (PCM) are still lacking. TP53 codon 72 polymorphism (P72R) results in proline (P) or arginine (R) at 72 amino acid position, which causes synthesis of proteins with distinct functions. The aims of our study were to: 1) analyze whether this polymorphism is associated with an increased risk of PCM; 2) study whether the P72R polymorphism affects overall survival (OS) among PCM patients; 3) assess the possible association of the P72R polymorphism with sensitivity to bortezomib in cell cultures derived from PCM patients. Material and methods. Genomic DNA from newly diagnosed 59 patients (without IgVH gene rearrangements and TP53 deletions) and 50 healthy blood donors were analyzed by RFLP-PCR to identify TP53 polymorphism. Chromosomal aberrations were detected by use of cIg-FISH. The lymphocyte cell cultures from a subgroup of 40 PCM patients were treated with bortezomib (1, 2 and 4 nM). Results. The P allele of the P72R polymorphism was more common than the R allele in PMC patients compared to controls (39% vs. 24%), and the difference was significant (p = 0.02). The PP and PR genotypes (in combina­tion) were more frequent among cases than in controls (65% vs. 42%, OR = 2.32, p = 0.04). At the cell culture level and 2 nM bortezomib concentration the PP genotype was associated with higher necrosis rates (10.5%) compared to the PR genotype (5.7%, p = 0.006) or the RR genotype (6.3%, p = 0.02); however, no effect of genotypes was observed at bortezomib concentrations of 1 and 4 nM. The shortest OS (12 months) was observed in patients with the PP genotype compared to patients with the PR or RR genotypes (20 months) (p = 0.04). Conclusions. The results suggest that P72R polymorphisms may be associated with an increased PCM risk and may affect OS of PCM patients. However, we saw no consistent results of the polymorphism effect on apoptosis and necrosis in cell cultures derived from PCM patients. Further studies are need in this regard

Role of interpeduncular nucleus of midbrain in addictions development, controlling novelty preference and processes connected with brain arousal.

Streszczenie Jądro międzykonarowe (interpeduncular nucleus, IPN) leżące w śródmózgowiu, jest niewielką strukturą zaangażowaną w kontrolę wzbudzenia mózgowia. Niewiele wiadomo na temat rodzajów neuronów budujących IPN oprócz faktu, że większośćz nich syntetyzuje kwas gamma-aminomasłowy (gamma-aminobutric acid, GABA). Postuluje się istnienie co najmniej dwóch typów neuronów w IPN, ale nie zostały one do tej pory jednoznacznie scharakteryzowane elektrofizjologicznie. Głównym pobudzającym wejściem do IPN są aksony acetylocholinergicznez przyśrodkowych części uzdeczki (medial habenula, mHb). Pętla mHb-IPN jest uważana za kluczową w syndromie odstawienia substancji uzależniających (alkoholu, nikotyny i opiatów). Uzależnienia stanowią ogromny problem społeczny i każdego roku są przyczyną wielu możliwych do uniknięcia śmierci. Istnieje wiele leków umożliwiających odstawienie uzależniających substancji, ale nie niwelują one negatywnych skutków psychofizycznych syndromu odstawienia, który jest najczęstszą przyczyną powrotu do nałogu. Stąd też IPN stosunkowo niedawno zwrócił na siebie uwagę naukowców pod kątem jego roli w powodowaniu negatywnych symptomówpo odstawieniu substancji uzależniających. Ponadto IPN ma ogromną rolę w sygnalizacji preferencji nowości, konserwatywnego ewolucyjnie mechanizmu umożliwiającego zwierzętom rozróżnienie czy nowy bodziec (zarówno ożywiony jak i nieożywiony) jest dla nich zagrożeniem, czy też nie. W normalnych warunkach zwierzęta powinny naturalnie poświęcać więcej uwagi nowym obiektom i osobnikom w celu zbadania ich pożyteczności. Zostało wykazane, że IPN pełni rolę swoistego rodzaju hamulca dla nowości. Stwierdzono, że podczas kontaktu ze znajomym bodźcem (zarówno socjalnym jak i nie socjalnym) jego komórki GABAergiczne były aktywne. Ponadto optogenetyczne wyciszenie komórek IPN powodowało, że zwierzęta przestały rozróżniać nowego osobnikaod znajomego. W niniejszej pracy przedstawiono charakterystykę IPN’u, jego położeniaw mózgu, unerwienia zarówno wstępującego jak i zstępującego oraz rodzajów komórek i neurotransmiterów. Ponadto praca opisuje rolę jądra międzykonarowegow uzależnieniach oraz syndromie odstawienia alkoholu, nikotyny i opiatów. Osobny rozdział stanowi udział struktury w sygnalizacji preferencji nowości.Abstract Interpeduncular nucleus is a small, oval midbrain structure laying mediallyand ventrally from VTA. It is anatomically divided into seven subnuclei. Little is known about its cells apart from the fact that majority of them is GABAergic. Some authors suggest that there are more than one electrophysiological type of cells within the structure, but still, more research is needed to characterise them. IPN has a strong acetylocholinergic innervation arriving from medial habenula and the role of this axis was described as crucial for signalling novelty preferenceand has been proposed as a cause of withdrawal syndrome occurring after cessationof different drugs of abuse. IPN sends its axons to multiple structures suchas hippocampus, preoptic area and nucleus incertus but its most dense fibers projectto raphe nuclei – serotoninergic-rich structure responsible for signalling emotional states, such as anxiety. Recently, besides the traditional reward circuit IPN-VTA-mHb axis has gained attention in the research concerning the mechanism of addiction and withdrawal syndrome of nicotine, opiates and alcohol. The CRF receptors have been identifiedas crucial for this process. Furthermore, IPN was shown to play an important role in signalling novelty preference, evolutionary conserved mechanism allowing an animal to identify whether the new stimulus is safe and useful or dangerous. IPN in this case was shown to actas a brake for novelty, it’s GABAergic neurons become active when the animalis exposed to familiar stimuli (both social and non-social). Optogenetic silencing of this particular structure renders mice do not differentiate between novel and familiar objects. The focus of this work was to get the low-down on the structure. The review contains a description of the IPN, its descending and ascending axons, location in the brain, types of cells and neurotransmitters. Furthermore the paper describes the roleof IPN in nicotine, alcohol and opiates addictions and a withdrawal syndrome after their cessation and role of the structure in novelty preference signalling

Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually diagnosed in children. In advanced and metastatic stages the prognosis is often poor. RMS cell lines were used for evaluation of the role of MET receptor inhibition on chemotaxis and invasion. In vivo studies were performed using NOD-SCID xenograft model. This study shows that blocking of MET expression has strong influence on metastatic behavior of RMS. MET negative cells possess a reduced potential to migrate and to invade. Downregulation of MET suppressed the ability of RMS cells to populate bone marrow. Inhibition of MET negative tumor cells engraftment into bone marrow was observed. MET negative tumors were also two to four times smaller than their wild type counterparts. Since MET receptor plays a very important role in facilitating metastasis of RMS cells, blocking of HGF-MET axis might be considered as a therapeutic option for RMS patients, at more advanced and metastatic stages

Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel

Metronomic agents reduce the effective doses and adverse effects of cytostatics in cancer chemotherapy. Therefore, they can enhance the treatment efficiency of drug-resistant cancers. Cytostatic and anti-angiogenic effects of fenofibrate (FF) suggest that it can be used for the metronomic chemotherapy of drug-resistant prostate tumors. To estimate the effect of FF on the drug-resistance of prostate cancer cells, we compared the reactions of naïve and drug-resistant cells to the combined treatment with docetaxel (DCX)/mitoxantrone (MTX) and FF. FF sensitized drug-resistant DU145 and PC3 cells to DCX and MTX, as illustrated by their reduced viability and invasive potential observed in the presence of DCX/MTX and FF. The synergy of the cytostatic activities of both agents was accompanied by the inactivation of P-gp-dependent efflux, dysfunction of the microtubular system, and induction of polyploidy in DCX-resistant cells. Chemical inhibition of PPARα- and reactive oxygen species (ROS)-dependent pathways by GW6471 and N-acetyl-L-cysteine, respectively, had no effect on cell sensitivity to combined DCX/FF treatment. Instead, we observed the signs of adenosine triphosphate (ATP) deficit and autophagy in DCX/FF-treated drug-resistant cells. Furthermore, the cells that had been permanently propagated under DCX- and DCX/FF-induced stress did not acquire DCX/FF-resistance. Instead, relatively slow proliferation of DCX-resistant cells was efficiently inhibited by FF. Collectively, our observations show that FF reduces the effective doses of DCX by interfering with the drug resistance and energy metabolism of prostate cancer cells. Concomitantly, it impairs the chemotherapy-induced microevolution and expansion of DCX/FF-resistant cells. Therefore, FF can be applied as a metronomic agent to enhance the efficiency of palliative chemotherapy of prostate cancer