OBJECTIVE: To validate the prognostic value of the PAncreatic NeoAdjuvant MAssachusetts (PANAMA) score and to determine its predictive ability for survival benefit derived from adjuvant treatment in patients after resection of pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant FOLFIRINOX. BACKGROUND: The PANAMA score was developed to guide prognostication in patients after neoadjuvant therapy and resection for PDAC. As this score focuses on the risk for residual disease after resection, it might also be able to select patients who benefit from adjuvant after neoadjuvant therapy. METHODS: This retrospective international multicenter study is endorsed by the European-African Hepato-Pancreato-Biliary Association. Patients with PDAC who underwent resection after neoadjuvant FOLFIRINOX were included. Mantel-Cox regression with interaction analysis was performed to assess the impact of adjuvant chemotherapy. RESULTS: Overall, 383 patients after resection of PDAC following neoadjuvant FOLFIRINOX were included of whom 187 (49%), 137 (36%), and 59 (15%) had a low-risk, intermediate-risk, and high-risk PANAMA-score, respectively. Discrimination in median overall survival (OS) was observed stratified by risk groups (48.5, 27.6, and 22.3 months, log-rank Plow-intermediate = 0.004, log-rank Pintermediate-high = 0.027). Adjuvant therapy was not associated with an OS difference in the low-risk group [hazard ratio (HR): 1.50, 95% CI: 0.92-2.50], whereas improved OS was observed in the intermediate (HR: 0.58, 95% CI: 0.34-0.97) and high-risk groups (HR: 0.47, 95% CI: 0.24-0.94; P interaction = 0.008). CONCLUSIONS: The PANAMA 3-tier risk groups (low-risk, intermediate-risk, and high-risk, available through pancreascalculator.com) correspond with differential survival in patients with resected PDAC following neoadjuvant FOLFIRINOX. The risk groups also differentiate between survival benefits associated with adjuvant treatment, with only the intermediate- and high-risk groups associated with improved OS.

• Klíčová slova
• FOLFIRINOX, adjuvant chemotherapy, neoadjuvant treatment, pancreatic neoplasm, prognostic score,
• MeSH
• adjuvantní chemoterapie MeSH
• dospělí MeSH
• duktální karcinom slinivky břišní * mortalita   terapie   farmakoterapie   chirurgie   MeSH
• fluoruracil terapeutické užití   MeSH
• hodnocení rizik MeSH
• irinotekan terapeutické užití   MeSH
• leukovorin terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory slinivky břišní * mortalita   terapie   farmakoterapie   chirurgie   MeSH
• neoadjuvantní terapie MeSH
• oxaliplatin terapeutické užití   MeSH
• pankreatektomie * MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• validační studie MeSH
• Názvy látek
• fluoruracil MeSH
• folfirinox MeSH Prohlížeč
• irinotekan MeSH
• leukovorin MeSH
• oxaliplatin MeSH

Chemoresistance represents a major issue affecting cancer therapy efficacy. Because microRNAs (miRNAs) regulate gene expression on multiple levels, their role in chemoresistance development is reasonably certain. In our previous study, miR-122-5p and miR-142-5p were identified as diagnostic, prognostic, and predictive biomarkers for primary and metastatic rectal cancer. The aim of the present study was to investigate whether these miRNAs can also reflect the disease course of patients with colon cancer (CC). Further, we focused on a deeper understanding of their involvement in 5-fluorouracil (5-FU) chemoresistance development.

• Klíčová slova
• MicroRNA, biomarker, chemoresistance, colon cancer, liquid biopsy,
• MeSH
• chemorezistence * genetika   MeSH
• fluoruracil terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA * krev   genetika   MeSH
• nádorové biomarkery krev   genetika   MeSH
• nádory tračníku * farmakoterapie   genetika   krev   patologie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fluoruracil MeSH
• mikro RNA * MeSH
• MIRN122 microRNA, human MeSH Prohlížeč
• MIRN142 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH

Mismatched nucleobase uracil is commonly repaired through the base excision repair initiated by DNA uracil glycosylases. The data presented in this study strongly indicate that the nuclear uracil-N-glycosylase activity and nuclear protein content in human cell lines is highest in the S phase of the cell cycle and that its distribution kinetics partially reflect the DNA replication activity in replication foci. In this respect, the data demonstrate structural changes of the replication focus related to the uracil-N-glycosylase distribution several dozens of minutes before end of its replication. The analysis also showed that very popular synchronisation protocols based on the double thymidine block can result in changes in the UNG2 content and uracil excision rate. In response, we propose a new method for the description of the changes of the content and the activity of different cell components during cell cycle without the necessity to use synchronisation protocols.

• MeSH
• buněčné jádro metabolismus   MeSH
• buněčný cyklus MeSH
• kinetika MeSH
• lidé MeSH
• oprava DNA MeSH
• replikace DNA * MeSH
• S fáze MeSH
• uracil-DNA-glykosidasa * metabolismus   MeSH
• uracil metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• uracil-DNA-glykosidasa * MeSH
• uracil MeSH

BACKGROUND/AIM: Inflammation-based prognostic scores have shown prognostic significance and have been associated with clinical outcomes in various types of cancer. Inflammation is known to promote tumor progression leading to reduced survival. In pancreatic cancer, systemic inflammation is common and contributes to its dismal prognosis. Although the prognosis of pancreatic cancer is improving with the introduction of new drugs, the prognostic indicators are still poorly understood. The present study aimed to evaluate inflammation-based prognostic scores in patients with metastatic pancreatic cancer receiving first-line chemotherapy. PATIENTS AND METHODS: A total of 43 patients with metastatic pancreatic cancer undergoing first-line chemotherapy (gemcitabine+nab-paclitaxel and mFOLFIRINOX) in our institution were analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using the Kaplan-Meier method and survival differences were evaluated using the log-rank test. RESULTS: In the whole cohort, we identified lymphocyte-to-monocyte ratio ≥3, systemic inflammatory response index <2.3, carcinoembryonic antigen <2.5, neutrophil-to-lymphocyte ratio <5, Memorial Sloane Kettering score <2, and prognostic index <2 as prognostic markers associated with improved overall survival in patients receiving first-line chemotherapy. CONCLUSION: The current analysis showed an association between inflammatory-based prognostic markers and overall survival in patients with metastatic pancreatic cancer treated in a real-world setting at a single institution.

• Klíčová slova
• Metastatic pancreatic cancer, inflammation-based prognostic markers, overall survival, palliative chemotherapy, real-world data,
• MeSH
• albuminy aplikace a dávkování   MeSH
• deoxycytidin analogy a deriváty   aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• fluoruracil aplikace a dávkování   terapeutické užití   MeSH
• gemcitabin MeSH
• irinotekan aplikace a dávkování   terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• leukovorin aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory slinivky břišní * farmakoterapie   mortalita   patologie   MeSH
• neutrofily patologie   MeSH
• oxaliplatin aplikace a dávkování   terapeutické užití   MeSH
• paclitaxel aplikace a dávkování   MeSH
• paliativní péče * metody   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• zánět * patologie   farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 130-nm albumin-bound paclitaxel MeSH Prohlížeč
• albuminy MeSH
• deoxycytidin MeSH
• fluoruracil MeSH
• folfirinox MeSH Prohlížeč
• gemcitabin MeSH
• irinotekan MeSH
• leukovorin MeSH
• oxaliplatin MeSH
• paclitaxel MeSH

Determination of plasma uracil was reported as a method for evaluation of Dihydropyrimidine dehydrogenase (DPD) activity that is highly demanded to ensure the safe administration of 5-fluorouracil (5-FU)-based therapies to cancer patients. This work reports the development of a simple electroanalytical method based on adsorptive stripping square wave voltammetry (AdSWV) at mercury film-coated glassy carbon electrode (MF/GCE) for the highly sensitive determination of uracil in biological fluids that can be used for diagnosis of decreased DPD activity. Due to the formation of the HgII-Uracil complex at the electrode surface, the accuracy of the measurement was not affected by the complicated matrices in biological fluids including human serum, plasma, and urine. The high sensitivity of the developed method results in a low limit of detection (≈1.3 nM) in human plasma samples, falling below the practical cut-off level of 15 ng mL-1 (≈0.14 μM). This threshold concentration is crucial for predicting 5-FU toxicity, as reported in buffer, and ≤1.15% in biological samples), and accuracy (recovery percentage close to 100%).

• Klíčová slova
• 5-Fluorouracil-based therapies, Adsorptive stripping voltammetry, Dihydropyrimidine dehydrogenase phenotyping, Mercury thin film electrode, Uracil determination,
• MeSH
• biosenzitivní techniky * MeSH
• deficit dihydropyrimidindehydrogenázy * MeSH
• dihydrouracildehydrogenasa (NADP) metabolismus   MeSH
• elektrochemické techniky metody   MeSH
• elektrody * MeSH
• fluoruracil * MeSH
• lidé MeSH
• limita detekce MeSH
• rtuť * krev   MeSH
• uracil * krev   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dihydrouracildehydrogenasa (NADP) MeSH
• fluoruracil * MeSH
• rtuť * MeSH
• uracil * MeSH

BACKGROUND: We need to better understand the risk factors and predictors of medication-related weight gain to improve metabolic health of individuals with schizophrenia. This study explores how trajectories of antipsychotic medication (AP) use impact body weight early in the course of schizophrenia. METHODS: We recruited 92 participants with first-episode psychosis (FEP, n = 92) during their first psychiatric hospitalization. We prospectively collected weight, body mass index (BMI), metabolic markers, and exact daily medication exposure during 6-week hospitalization. We quantified the trajectory of AP medication changes and AP polypharmacy using a novel approach based on meta-analytical ranking of medications and tested it as a predictor of weight gain together with traditional risk factors. RESULTS: Most people started treatment with risperidone (n = 57), followed by olanzapine (n = 29). Then, 48% of individuals remained on their first prescribed medication, while 33% of people remained on monotherapy. Almost half of the individuals (39/92) experienced escalation of medications, mostly switch to AP polypharmacy (90%). Only baseline BMI was a predictor of BMI change. Individuals in the top tercile of weight gain, compared to those in the bottom tercile, showed lower follow-up symptoms, a trend for longer prehospitalization antipsychotic treatment, and greater exposure to metabolically problematic medications. CONCLUSIONS: Early in the course of illness, during inpatient treatment, baseline BMI is the strongest and earliest predictor of weight gain on APs and is a better predictor than type of medication, polypharmacy, or medication switches. Baseline BMI predicted weight change over a period of weeks, when other traditional predictors demonstrated a much smaller effect.

• Klíčová slova
• antipsychotics, polypharmacy, predictor, schizophrenia, weight gain,
• MeSH
• antipsychotika * terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• hmotnostní přírůstek * účinky léků   MeSH
• hospitalizace * statistika a číselné údaje   MeSH
• index tělesné hmotnosti * MeSH
• lidé MeSH
• mladý dospělý MeSH
• olanzapin terapeutické užití   MeSH
• polypharmacy MeSH
• prospektivní studie MeSH
• psychotické poruchy * farmakoterapie   MeSH
• risperidon terapeutické užití   škodlivé účinky   MeSH
• rizikové faktory MeSH
• schizofrenie * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• olanzapin MeSH
• risperidon MeSH

Recent studies have highlighted the significant role of 5-hydroxymethylcytosine (5hmC) in carcinogenesis. However, the specific role of 5hmC in osteosarcoma (OS) remains largely unexplored. The-re-fore, this study aimed to investigate the function of 5hmC and TET3 in OS. In this study, we found a decreased total level of 5hmC in OS tissues. The expression of the TET3 protein was also decreased in OS. Importantly, the decreased levels of TET3 were associated with a decreased disease-free survival (DFS) rate in patients. To investigate the role of TET3 and 5hmC in OS, we manipulated the levels of TET3 in MG-63 cells. Silencing TET3 in these cells resulted in a twofold increase in proliferation. Additio-nally, the level of 5hmC decreased in these cells. Con-versely, over-expression of TET3 in MG-63 cells led to the expected inhibition of proliferation and invasion, accompanied by an increase in 5hmC levels. In conclusion, both 5hmC and TET3 protein levels were decreased in OS. Additionally, the over-expression of TET3 inhibited the proliferation of MG-63 cells, while the suppression of TET3 had the opposite effect. These findings suggest that decreased levels of 5hmC and TET3 may serve as potential markers for OS.

• Klíčová slova
• 5hmC, Osteosarcoma, TET3,
• MeSH
• 5-methylcytosin * analogy a deriváty   metabolismus   MeSH
• demetylace DNA * MeSH
• dioxygenasy * metabolismus   MeSH
• epigeneze genetická * MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory kostí genetika   metabolismus   patologie   MeSH
• osteosarkom genetika   metabolismus   patologie   MeSH
• proliferace buněk * MeSH
• protoonkogenní proteiny metabolismus   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 5-hydroxymethylcytosine MeSH Prohlížeč
• 5-methylcytosin * MeSH
• dioxygenasy * MeSH
• protoonkogenní proteiny MeSH
• TET3 protein, human MeSH Prohlížeč

BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

• MeSH
• ABC transportér z rodiny G, člen 2 * metabolismus   antagonisté a inhibitory   MeSH
• apoptóza účinky léků   MeSH
• bortezomib * farmakologie   MeSH
• inhibitory HIV-proteasy * farmakologie   MeSH
• inhibitory proteasomu farmakologie   MeSH
• lidé MeSH
• Lopinavir * farmakologie   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• nelfinavir * farmakologie   MeSH
• oligopeptidy * farmakologie   MeSH
• P-glykoproteiny metabolismus   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• signální dráha UPR * účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• synergismus léků * MeSH
• triple-negativní karcinom prsu * farmakoterapie   patologie   MeSH
• XBP1 metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCB1 protein, human MeSH Prohlížeč
• ABCG2 protein, human MeSH Prohlížeč
• bortezomib * MeSH
• carfilzomib MeSH Prohlížeč
• inhibitory HIV-proteasy * MeSH
• inhibitory proteasomu MeSH
• Lopinavir * MeSH
• nádorové proteiny MeSH
• nelfinavir * MeSH
• oligopeptidy * MeSH
• P-glykoproteiny MeSH
• XBP1 protein, human MeSH Prohlížeč
• XBP1 MeSH

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

• Klíčová slova
• aficamten, cardiac myosin inhibitor, hypertrophic cardiomyopathy,
• MeSH
• benzylaminy MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fibrilace síní farmakoterapie   diagnóza   patofyziologie   MeSH
• funkce levé komory srdeční * účinky léků   MeSH
• hypertrofická kardiomyopatie * patofyziologie   farmakoterapie   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• tepový objem * účinky léků   MeSH
• uracil analogy a deriváty   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• benzylaminy MeSH
• MYK-461 MeSH Prohlížeč
• uracil MeSH

Diabetic nephropathy, characterized by inflammation and oxidative stress, poses a management challenge. This study investigates the effect of Polygonum hyrcanicum extract on diabetic nephropathy in alloxan-induced diabetic mice. In this experimental animal study, the P. hyrcanicum extract was prepared using continuous macerations. Thirty male Albino mice, divided into five groups, were induced with alloxan-induced diabetes. They received intraperitoneal injections of the plant extract (100 and 200 mg/kg) and metformin (300 mg/kg) for four weeks. Kidney and blood samples were collected to assess protein carbonyl, glutathione, lipid peroxidation, TNF-α and IL-6 levels. The amount of total flavonoid and phenolic content in the hydroalcoholic extract of P. hyrcanicum were 7.5 ± 0.3 mg of quercetin and 88.2 ± 1.3 mg gallic acid per gram of extract respectively. The antioxidant activity level of the hydroalcoholic extract was determined to be 1.78 ± 0.51 mM equivalent per gram of extract. Alloxan administration resulted in a significant reduction in glutathione levels and a significant increase in protein carbonyl, lipid peroxidation, TNF-α, and IL-6 levels. Hydroalcoholic extract of P. hyrcanicum effectively reduced oxidative stress markers and inflammatory cytokines (TNF-α, IL-6), indicating its potential in mitigating diabetic nephropathy. However, no significant difference in efficacy was observed between the 100 mg/kg and 200 mg/kg doses in terms of reducing these toxicities.

• Klíčová slova
• Polygonum hyrcanicum, Alloxan, Diabetes, Nephropathy, Oxidative stress,
• MeSH
• alloxan MeSH
• antioxidancia * farmakologie   MeSH
• diabetické nefropatie * farmakoterapie   metabolismus   MeSH
• experimentální diabetes mellitus * farmakoterapie   metabolismus   MeSH
• glutathion metabolismus   MeSH
• interleukin-6 metabolismus   krev   MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• myši MeSH
• oxidační stres * účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• Polygonum * chemie   MeSH
• rostlinné extrakty * farmakologie   chemie   MeSH
• TNF-alfa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alloxan MeSH
• antioxidancia * MeSH
• glutathion MeSH
• interleukin-6 MeSH
• rostlinné extrakty * MeSH
• TNF-alfa MeSH