Az áttétes kasztrációrezisztens prosztatarák gyógyszer-rezisztenciájának molekuláris vonatkozásai

A metasztatikus kasztrációrezisztens prosztatarák kezelésére az elmúlt években számos új, különböző hatásmechaniz- musú gyógyszeres kezelés vált elérhetővé. Ez a fejlődés a terápiás döntéshozatalt egyre nehezebbé teszi. Az újabb kezelésekkel szemben is megfigyelhető az alapvonali, a szerzett és a keresztrezisztencia jelensége is. Ezért tehát az elsődleges terápia helyes megválasztása mellett, az azt követő vonalakban alkalmazott kezelések sorrendje és alkalma- zásuk ideje is optimalizálásra szorul. Az újabb kezelésekkel kapcsolatos rezisztenciamechanizmusok egyre nagyobb mértékben válnak ismertté. Ezzel a terápiatervezés az eddigi empirikus – főleg a kipróbálásra építő – irányából egyre inkább a racionális – az adott daganat molekuláris sajátságait is figyelembe vevő –, személyre szabott kezelés irányába mozdul el. Ebben az összefoglaló közleményben ismertetjük azokat a rezisztenciamechanizmusokat, amelyek a me- tasztatikus kasztrációrezisztens prosztatarák kezelésében leggyakrabban használt három gyógyszerrel – docetaxel, abirateron és enzalutamid – kapcsolatosak. Többek között áttekintést nyújtunk a MDR- (multidrogrezisztens) fehér- jéken keresztül megvalósuló, az androgénreceptor-, a Wnt-, a p53-szignálút, valamint a DNS hibajavító mechaniz- musában részt vevő gének (mint például a BRCA és ATM) sérüléseivel összefüggésben kialakuló és a neuroendokrin differenciáció által kiváltott rezisztenciamechanizmusokról

Development of a Multicomponent Microbiological Soil Inoculant and Its Performance in Sweet Potato Cultivation

The cultivation and consumption of sweet potato (Ipomoea batatas) are increasing globally. As the usage of chemical fertilizers and pest control agents during its cultivation may lead to soil, water and air pollution, there is an emerging need for environment-friendly, biological solutions enabling increased amounts of healthy crop and efficient disease management. Microbiological agents for agricultural purposes gained increasing importance in the past few decades. Our goal was to develop an agricultural soil inoculant from multiple microorganisms and test its application potential in sweet potato cultivation. Two Trichoderma strains were selected: Trichoderma ghanense strain SZMC 25217 based on its extracellular enzyme activities for the biodegradation of plant residues, and Trichoderma afroharzianum strain SZMC 25231 for biocontrol purposes against fungal plant pathogens. The Bacillus velezensis strain SZMC 24986 proved to be the best growth inhibitor of most of the nine tested strains of fungal species known as plant pathogens, therefore it was also selected for biocontrol purposes against fungal plant pathogens. Arthrobacter globiformis strain SZMC 25081, showing the fastest growth on nitrogen-free medium, was selected as a component with possible nitrogen-fixing potential. A Pseudomonas resinovorans strain, SZMC 25872, was selected for its ability to produce indole-3-acetic acid, which is among the important traits of potential plant growth-promoting rhizobacteria (PGPR). A series of experiments were performed to test the selected strains for their tolerance to abiotic stress factors such as pH, temperature, water activity and fungicides, influencing the survivability in agricultural environments. The selected strains were used to treat sweet potato in two separate field experiments. Yield increase was observed for the plants treated with the selected microbial consortium (synthetic community) in comparison with the control group in both cases. Our results suggest that the developed microbial inoculant has the potential to be used in sweet potato plantations. To the best of our knowledge, this is the first report about the successful application of a fungal-bacterial consortium in sweet potato cultivation

Circulating syndecan-1 is associated with chemotherapy-resistance in castration-resistant prostate cancer

OBJECTIVES: Docetaxel chemotherapy is a standard treatment for castration-resistant prostate cancer (CRPC). Rapidly expanding treatment options for CRPC provide reasonable alternatives for those who are resistant to docetaxel. Therefore, prediction of docetaxel resistance has become of great clinical importance. Syndecan-1 (SDC1) has been currently shown to be involved in chemotherapy resistance in various malignancies including prostate cancer. The predicting value of serum SDC1 level has not been evaluated yet. PATIENTS AND METHODS: We assessed the baseline levels of SDC1 in serum samples of 75 patients with CRPC who received docetaxel therapy until the appearance of therapy resistance. In one patient who was treated with three treatment series, we assessed also 6 additional serum samples collected during a 1-year treatment period. Serum SDC1 levels were correlated with clinical outcomes as well as with serum levels of MMP7. RESULTS: Pretreatment SDC1 serum levels were not associated with patients' age, the presence of bone or visceral metastases. In univariable analyses, patients' performance status, the presence of bone or visceral metastases, high pretreatment prostate specific antigen and SDC1 levels were significantly associated with cancer-specific survival. In multivariable analysis patients' performance status (P = 0.005), presence of bone or visceral metastases (P = 0.013) and high SDC1 level (P = 0.045) remained independent predictors of patients' survival. In the patient with available follow-up samples serum SDC1 level increased from 50 to 300ng/ml at radiographic progression. Serum concentrations of SDC1 were correlated with those of MMP7 (r = 0.420, P = 0.006). CONCLUSIONS: Our present results together with currently published data suggest a role for SDC1 shedding in chemotherapy resistance. Determination of serum SDC1 may contribute to the prediction of docetaxel resistance and therefore may help to facilitate clinical decision-making regarding the type and timing of therapy for patients with CRPC

Proteome profiling of enzalutamide-resistant cell lines and serum analysis identified ALCAM as marker of resistance in castration-resistant prostate cancer

Enzalutamide (ENZA) is a frequently used therapy in metastatic castration‐resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy‐predictive serum markers. We performed comparative proteome analyses on ENZA‐sensitive parental (LAPC4, DuCaP) and ‐resistant prostate cancer cell lines (LAPC4‐ENZA, DuCaP‐ENZA) using liquid chromatography tandem mass spectrometry (LC‐MS/MS). The top four most promising candidate markers were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in pretreatment samples of 72 ENZA‐treated mCRPC patients using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)‐treated mCRPC patients' baseline samples. Results were correlated with clinical and follow‐up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA‐sensitive and ‐resistant cells and our filtering methods identified four biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI‐ but not in DOC‐treated patients. In LAPC4‐ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA‐ and ABI‐resistant patients and may thereby help to optimize future clinical decision‐making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance

Comparative proteome analysis identified CD44 as a possible serum marker for docetaxel resistance in castration-resistant prostate cancer

Baseline or acquired resistance to docetaxel (DOC) represents a significant risk for patients with metastatic prostate cancer (PC). In the last years, novel therapy regimens have been approved providing reasonable alternatives for DOC‐resistant patients making prediction of DOC resistance of great clinical importance. We aimed to identify serum biomarkers, which are able to select patients who will not benefit from DOC treatment. DOC‐resistant PC3‐DR and DU145‐DR sublines and their sensitive parental cell lines (DU145, PC3) were comparatively analyzed using liquid chromatography‐coupled tandem mass spectrometry (LC‐MS/MS). Results were filtered using bioinformatics approaches to identify promising serum biomarkers. Serum levels of five proteins were determined in serum samples of 66 DOC‐treated metastatic castration‐resistant PC patients (mCRPC) using ELISA. Results were correlated with clinicopathological and survival data. CD44 was subjected to further functional cell culture analyses. We found at least 177 two‐fold significantly overexpressed proteins in DOC‐resistant cell lines. Our bioinformatics method suggested 11/177 proteins to be secreted into the serum. We determined serum levels of five (CD44, MET, GSN, IL13RA2 and LNPEP) proteins in serum samples of DOC‐treated patients and found high CD44 serum levels to be independently associated with poor overall survival (p = 0.001). In accordance, silencing of CD44 in DU145‐DR cells resulted in re‐sensitization to DOC. In conclusion, high serum CD44 levels may help identify DOC‐resistant patients and may thereby help optimize clinical decision‐making regarding type and timing of therapy for mCRPC patients. In addition, our in vitro results imply the possible functional involvement of CD44 in DOC resistance

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