OBJECTIVE: To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. METHODS: Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan-Meier), clinical remission [28-joint count DAS (DAS28) <2.6; 28 joint Disease Activity index for Psoriatic Arthritis ⩽4] and ACR criteria for 20% improvement (ACR20)/ACR50/ACR70 were calculated, including LUNDEX adjustment. RESULTS: Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. CONCLUSION: Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data.

• Klíčová slova
• DAPSA28, DAS28, TNFi, drug survival, effectiveness, epidemiology, psoriatic arthritis, register, response, spondyloarthritis,
• MeSH
• antirevmatika terapeutické užití   MeSH
• databáze faktografické MeSH
• dospělí MeSH
• inhibitory TNF terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pacientův souhlas se zdravotní péčí * MeSH
• prospektivní studie MeSH
• psoriatická artritida farmakoterapie   MeSH
• registrace MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antirevmatika MeSH
• inhibitory TNF MeSH

OBJECTIVE: Immunotherapy of cancer has the potential to be effective mostly in patients with a low tumour burden. Rising PSA (prostate-specific antigen) levels in patients with prostate cancer represents such a situation. We performed the present clinical study with dendritic cell (DC)-based immunotherapy in this patient population. MATERIALS AND METHODS: The single-arm phase I/II trial registered as EudraCT 2009-017259-91 involved 27 patients with rising PSA levels. The study medication consisted of autologous DCs pulsed with the killed LNCaP cell line (DCVAC/PCa). Twelve patients with a favourable PSA response continued with the second cycle of immunotherapy. The primary and secondary objectives of the study were to assess the safety and determine the PSA doubling time (PSADT), respectively. RESULTS: No significant side effects were recorded. The median PSADT in all treated patients increased from 5.67 months prior to immunotherapy to 18.85 months after 12 doses (p < 0.0018). Twelve patients who continued immunotherapy with the second cycle had a median PSADT of 58 months that remained stable after the second cycle. In the peripheral blood, specific PSA-reacting T lymphocytes were increased significantly already after the fourth dose, and a stable frequency was detected throughout the remainder of DCVAC/PCa treatment. Long-term immunotherapy of prostate cancer patients experiencing early signs of PSA recurrence using DCVAC/PCa was safe, induced an immune response and led to the significant prolongation of PSADT. Long-term follow-up may show whether the changes in PSADT might improve the clinical outcome in patients with biochemical recurrence of the prostate cancer.

• Klíčová slova
• Biochemically recurrent prostate cancer, Dendritic cell, Immunotherapy, PSA doubling time,
• MeSH
• dendritické buňky imunologie   transplantace   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prostaty imunologie   terapie   MeSH
• počet lymfocytů MeSH
• prostatektomie MeSH
• prostatický specifický antigen genetika   imunologie   metabolismus   MeSH
• radioterapie MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• T-lymfocyty imunologie   MeSH
• tumor burden MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• Názvy látek
• prostatický specifický antigen MeSH

PURPOSE: To retrospectively investigate the impact of prostate specific antigen (PSA) level after neoadjuvant androgen- deprivation therapy (ADT) on biochemical relapse-free survival in patients with prostate cancer who received radical radiotherapy (RT). METHODS: Between March 2003 and March 2008, 128 men with localized prostate cancer underwent neoadjuvant ADT for 4-6 months followed by radical RT. Biochemical relapse-free survival was compared between patients with pre-RT PSA ≤ 0.1 vs > 0.1 ng/mL. RESULTS: At a median follow up of 47.3 months, biochemical relapse-free survival was significantly higher in patients with a pre-RT PSA ≤ 0.1 ng/mL compared with pre-RT PSA > 0.1 ng/mL (85.6 vs 63.2%, p = 0.0025). CONCLUSION: The current analysis demonstrating better treatment outcome in patients with excellent biochemical response to neoadjuvant ADT, supports an individualized treatment strategy.

• MeSH
• adjuvantní chemoterapie MeSH
• antagonisté androgenů terapeutické užití   MeSH
• časové faktory MeSH
• hormonální protinádorové látky terapeutické užití   MeSH
• kalikreiny krev   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prostaty krev   farmakoterapie   mortalita   patologie   radioterapie   MeSH
• neoadjuvantní terapie * MeSH
• přežití bez známek nemoci MeSH
• prostatický specifický antigen krev   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výběr pacientů MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté androgenů MeSH
• hormonální protinádorové látky MeSH
• kalikreiny MeSH
• KLK3 protein, human MeSH Prohlížeč
• prostatický specifický antigen MeSH

BACKGROUND AND AIMS: [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks. PATIENTS AND METHODS: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS). RESULTS: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT. CONCLUSION: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.

• Klíčová slova
• PSA, PSMA-RLT, Response prediction, Survival prediction, mCRPC,
• MeSH
• dipeptidy * terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lutecium MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   radioterapie   MeSH
• prostatický specifický antigen MeSH
• radiofarmaka MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy * MeSH
• heterocyklické sloučeniny monocyklické * MeSH
• lutecium MeSH
• Pluvicto MeSH Prohlížeč
• prostatický specifický antigen MeSH
• PSMA-617 MeSH Prohlížeč
• radiofarmaka MeSH

INTRODUCTION: Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. METHODS: In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. RESULTS: Of 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. CONCLUSION: In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed. TRIAL REGISTRATION: NCT03104374.

• Klíčová slova
• Janus kinase inhibitors, Psoriatic arthritis, Upadacitinib,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Upadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD). METHODS: In this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug. RESULTS: At week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively. CONCLUSION: In this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA. CLINICAL TRIAL REGISTRATION NUMBER: NCT03104374.

• Klíčová slova
• arthritis, biological therapy, psoriatic,
• MeSH
• antirevmatika * škodlivé účinky   MeSH
• biologické přípravky * terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• heterocyklické sloučeniny tricyklické MeSH
• lidé MeSH
• psoriatická artritida * chemicky indukované   farmakoterapie   MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antirevmatika * MeSH
• biologické přípravky * MeSH
• heterocyklické sloučeniny tricyklické MeSH
• upadacitinib MeSH Prohlížeč

BACKGROUND: We investigated the response rate and degree of toxicity of a second course of three cycles of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients. METHODS: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87-1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan-Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival. RESULTS: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6-1926 µg/L, p = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer (p = 0.02), whereas the patients with bone metastases had a shorter survival (p = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS (p < 0.05, hazard ratio 2.43, 95% CI 1.01-5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, p = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, p = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded. CONCLUSION: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS.

• Klíčová slova
• 177Lu-PSMA, PSA, PSMA-RLT, mCRPC, prostate cancer,
• Publikační typ
• časopisecké články MeSH

The activities were studied in five kinds of enzymes (aspartate aminotransferase - AST, alanine aminotransferase - ALT, lactate dehydrogenase - LD, the thermally stable fraction of lactate dehydrogenase - LD-1, and alkaline phosphatase - ALP) of 30 male dogs. The dogs, divided into two age categories, were studied during a long-continued training (130 days). Both transaminases exhibit characteristic changes in the activity, with a depression at the beginning between the 30th and 40th days of training, followed by a slow increase in AST and by a rapid increase in ALT, continuing until the end of the training period. A statistically significant activity pattern was recorded in LD: the activity declined continuously in both age groups of dogs. LD-1 exhibited an activity depression continuing until the 70th day of training, followed by an increase which reached statistical significance towards the end of the training. ALP activity varied regularly, but always remained significantly below the starting values. The enzymatic activities can be used as partial tests during the scientific management of the training of dogs in relation to the physiological and pathophysiological processes in the bodies of the dogs subjected to the training stress.

• MeSH
• alanintransaminasa krev   MeSH
• alkalická fosfatasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• enzymy krev   MeSH
• fyziologický stres krev   veterinární   MeSH
• L-laktátdehydrogenasa krev   MeSH
• psi metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• psi metabolismus   MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• alanintransaminasa MeSH
• alkalická fosfatasa MeSH
• aspartátaminotransferasy MeSH
• enzymy MeSH
• L-laktátdehydrogenasa MeSH

Signaling through the androgen receptor (AR) plays a critical role in prostate cancer progression. The AR is a classical nuclear receptor (NR) providing a link between signaling molecule and transcription response. Histone deacetylase inhibitors- (HDACI) have antiproliferative and proapoptotic effects on prostate cancer cells and their implication in silence AR signaling may have potential therapeutic use. We aimed to study the inhibitory effects of the corepressor SMRT (Silencing Mediator for Retinoid and Thyroid -hormone receptors) which forms a complex together with nuclear receptor corepressor (N-CoR) and with histone deacetylase 3 (HDAC3) on AR activity.The androgen-sensitive prostate cancer cell line LNCaP and androgen-insensitive prostate cancer cell line C4-2 both AR-positive, and androgen-insensitive DU145 and PC3 prostate cancer cell lines were treated with two HDACIs, sodium butyrate (NaB) and/or trichostatin A (TSA). We amplified immunoprecipitated DNA by conventional PCR and in the -following step we used the chromatin immunoprecipitation (ChIP) analysis coupled with quantitative PCR for monitoring NaB induced formation of AR-SMRT/N-CoR complex binding on the PSA promoter. The co-immunoprecipitation assay revealed increase in AR-SMRT formation in NaB treated cells. Simultaneously, the Western blot analysis showed a significant decrease in AR protein expression. In conclusion, the inhibitory effect of NaB on AR gene expression seems to be specific and unique for prostate cancer AR-positive cell lines and corresponds with its ability to stimulate AR-SMRT complex formation. We suggest that AR and SMRT/N-CoR corepressors may form a stable complex in vitro and NaB may facilitate the interaction between AR nuclear steroid receptor and SMRT corepressor prote.

• MeSH
• androgenní receptory metabolismus   MeSH
• butyráty farmakologie   MeSH
• histondeacetylasa 2 analýza   MeSH
• histondeacetylasy analýza   metabolismus   MeSH
• inhibitory histondeacetylas terapeutické užití   MeSH
• korepresor 1 jaderného receptoru metabolismus   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• prostatický specifický antigen genetika   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC5 protein, human MeSH Prohlížeč
• androgenní receptory MeSH
• AR protein, human MeSH Prohlížeč
• butyráty MeSH
• HDAC2 protein, human MeSH Prohlížeč
• histondeacetylasa 2 MeSH
• histondeacetylasy MeSH
• histone deacetylase 3 MeSH Prohlížeč
• inhibitory histondeacetylas MeSH
• korepresor 1 jaderného receptoru MeSH
• kyseliny hydroxamové MeSH
• NCOR1 protein, human MeSH Prohlížeč
• prostatický specifický antigen MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• trichostatin A MeSH Prohlížeč

An RNA polymerase-binding 167 bp HinfI fragment from a low-copy Streptomyces plasmid pSA 2201 has been shown to have promoter activity in vivo using a promoter-probe vector. This promoter (A1) is probably involved in expression of the genes responsible for the production of an antibiotic compound, found to be located on this plasmid. A 2600 nucleotides (nt) long transcript starting from this promoter has been identified by Northern hybridization analysis. The transcription start point has been determined using high-resolution S1 mapping and confirmed by in vitro transcription analysis with purified S. aureofaciens 2201 RNA polymerase. The A1 promoter shows no homology in the -10 and -35 consensus sequence of the typical bacterial promoters, and expression from this promoter is temporally dependent on the phase of growth having the maximum transcription activity in the stationary phase.

• MeSH
• autoradiografie MeSH
• bakteriální geny MeSH
• DNA řízené RNA-polymerasy genetika   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• genetická transkripce MeSH
• hybridizace nukleových kyselin MeSH
• molekulární sekvence - údaje MeSH
• northern blotting MeSH
• plazmidy MeSH
• promotorové oblasti (genetika) * MeSH
• regulace genové exprese u bakterií MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie nukleových kyselin MeSH
• Streptomyces aureofaciens enzymologie   genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA řízené RNA-polymerasy MeSH