BACKGROUND: Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients. METHODS: In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. RESULTS: Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1-21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency. CONCLUSIONS: Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014-000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

• MeSH
• Benzimidazoles * administration & dosage   adverse effects   pharmacokinetics   MeSH
• Adult MeSH
• Protein Kinase Inhibitors administration & dosage   adverse effects   MeSH
• Colorectal Neoplasms * drug therapy   genetics   pathology   MeSH
• Crizotinib * administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• MAP Kinase Kinase 1 antagonists & inhibitors   MeSH
• MAP Kinase Kinase 2 antagonists & inhibitors   MeSH
• Maximum Tolerated Dose MeSH
• Mutation MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   pharmacokinetics   administration & dosage   MeSH
• Proto-Oncogene Proteins c-met antagonists & inhibitors   genetics   MeSH
• ras Proteins genetics   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH

The parasitic protozoan Entamoeba histolytica secretes extracellular vesicles (EVs), but so far little is known about their function in the interaction with the host immune system. Infection with E. histolytica trophozoites can lead to formation of amebic liver abscesses (ALAs), in which pro-inflammatory immune responses of Ly6Chi monocytes contribute to liver damage. Men exhibit a more severe pathology as the result of higher monocyte recruitment and a stronger immune response. To investigate the role of EVs and pathogenicity in the host immune response, we studied the effect of EVs secreted by low pathogenic EhA1 and highly pathogenic EhB2 amebae on monocytes. Size and quantity of isolated EVs from both clones were similar. However, they differed in their proteome and miRNA cargo, providing insight into factors potentially involved in amebic pathogenicity. In addition, EVs were enriched in proteins with signaling peptides compared with the total protein content of trophozoites. Exposure to EVs from both clones induced monocyte activation and a pro-inflammatory immune response as evidenced by increased surface presentation of the activation marker CD38 and upregulated gene expression of key signaling pathways (including NF-κB, IL-17 and TNF signaling). The release of pro-inflammatory cytokines was increased in EV-stimulated monocytes and more so in male- than in female-derived cells. While EhA1 EV stimulation caused elevated myeloperoxidase (MPO) release by both monocytes and neutrophils, EhB2 EV stimulation did not, indicating the protective role of MPO during amebiasis. Collectively, our results suggest that parasite-released EVs contribute to the male-biased immunopathology mediated by pro-inflammatory monocytes during ALA formation.

• MeSH
• Liver Abscess, Amebic immunology   parasitology   MeSH
• Cytokines metabolism   MeSH
• Entamoebiasis immunology   parasitology   MeSH
• Entamoeba histolytica * immunology   pathogenicity   genetics   MeSH
• Extracellular Vesicles * immunology   metabolism   MeSH
• Humans MeSH
• Monocytes * immunology   parasitology   MeSH
• Signal Transduction * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.

• MeSH
• Deoxycytidine * analogs & derivatives   administration & dosage   adverse effects   therapeutic use   MeSH
• Lymphoma, Large B-Cell, Diffuse * drug therapy   mortality   pathology   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Oxaliplatin administration & dosage   adverse effects   MeSH
• Antibodies, Bispecific * administration & dosage   adverse effects   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   administration & dosage   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Salvage Therapy MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH

BACKGROUND: Research on the possible influence of lateralised basal ganglia dysfunction on speech in Parkinson's disease is scarce. This study aimed to compare speech in de-novo, drug-naive patients with Parkinson's disease (PD) with asymmetric nigral dopaminergic dysfunction, predominantly in either the right or left hemisphere. METHODS: Acoustic analyses of reading passages were performed. Asymmetry of nigral dysfunction was defined using dopamine transporter-single-photon emission CT (DAT-SPECT). RESULTS: From a total of 135 de novo patients with PD assessed, 47 patients had a lower right and 36 lower left DAT availability in putamen based on DAT-SPECT. Patients with PD with lower left DAT availability had higher dysarthria severity via composite dysarthria index compared with patients with lower right DAT availability (p=0.01). CONCLUSION: Our data support the crucial role of DAT availability in the left putamen in speech. This finding might provide important clues for managing speech following deep brain stimulation.

• MeSH
• Basal Ganglia * physiopathology   diagnostic imaging   MeSH
• Dysarthria physiopathology   diagnostic imaging   etiology   MeSH
• Functional Laterality * physiology   MeSH
• Tomography, Emission-Computed, Single-Photon MeSH
• Middle Aged MeSH
• Humans MeSH
• Parkinson Disease * physiopathology   diagnostic imaging   complications   MeSH
• Dopamine Plasma Membrane Transport Proteins metabolism   MeSH
• Putamen diagnostic imaging   metabolism   physiopathology   MeSH
• Speech * physiology   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Článek se soustředí na farmakoterapii farmakorezistentní schizofrenie. Nejprve je uvedena definice farmakorezistentní schizofrenie a způsoby vyloučení pseudorezistence. Detailněji jsou rozebrány možnosti léčby, tj. změna stávající léčby, augmentace a kombinace antipsychotik. Na závěr je krátce zmíněna perspektivní léčba.

The paper is focused on pharmacotherapy of treatment-resistant schizophrenia and exclusion of pseudoresistance. The treatment options including switch, augmentation and combination of antipsychotics are described. Finally, perspective substances are briefly mentioned.

• MeSH
• Antipsychotic Agents MeSH
• Clozapine therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Drug Resistance * MeSH
• Humans MeSH
• Schizophrenia, Treatment-Resistant * drug therapy   MeSH
• Drug Synergism MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Tento přehledový článek se zabývá nejen historickým, ale také současným přístupem k velmi závažné medicínské problematice, kterou je transgender identita. Věnuje se procesu psychiatrizace transgender identity, ale také změnám v diagnostických klasifikacích a vývoji afirmativní péče. Zabývá se úlohou psychiatrie v procesu tranzice a také kontroverzemi, spojenými s diagnostikou tzv. genderové dysforie. Zaměřuje se také na vztah mezi transgender osobami a zdravotní péčí. Článek by měl přinést pohled na moderní přístupy a trendy, které povedou k podpoře transgender problematiky a k její depatologizaci.

This review article addresses not only historical but also contemporary approaches to the significant medical problem of transsexuality. It examines the psychiatric processes associated with transsexuality, as well as changes in diagnostic classifications and the evolution of affirmative care practices. The role of psychiatry in the transition process is explored, along with the controversies surrounding the diagnosis of gender dysphoria. It also focuses on the relationship between transgender people and health care. The article aims to present modern perspectives and trends that support the transgender community and advocate for the depathologization of transgender identity.

• Keywords
• afirmativní péče,
• MeSH
• Gender Dysphoria * MeSH
• Gender Identity * MeSH
• Humans MeSH
• Transgender Persons MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Článek má za cíl seznámit čtenáře s problematikou farmakogenetického (PGx) vyšetření v oboru psychiatrie, které dnes představuje dostupný a významný nástroj personalizované medicíny. PGx testování umožňuje upravit farmakoterapii na základě genetických predispozic pacientů. V rámci oboru psychiatrie se zaměřuje zejména na polymorfismy v genech odpovědných za metabolismus léčiv, především enzymy cytochromu P450, jako jsou CYP2C19 a CYP2D6. Toto vyšetření může v praxi pomoci predikovat účinnost nebo toxicitu léčiv, a tím zlepšit bezpečnost a efektivitu farmakoterapie. Ve studii realizované v Psychiatrické nemocnici Bohnice byli testováni pacienti, kteří vykazovali známky farmakorezistence, odlišnost ve výsledcích vyšetření monitorování plazmatických hladin (TDM) nebo např. výrazné nežádoucí účinky při terapii běžnými dávkami. Až 75 % testovaných pacientů mělo změněnou funkci jednoho nebo obou testovaných izoenzymů CYP, tedy fenotyp pomalého, ultrarychlého, rychlého nebo intermediárního metabolizéra. Interpretace výsledků PGx vyšetření je klíčová a měla by být prováděna odborníkem, který má zkušenosti v této oblasti, hluboké znalosti farmakokinetiky a také veškeré potřebné informace o konkrétním pacientovi. Pouze v takovém případě může PGx vyšetření významně ovlivnit správný výběr a dávkování psychofarmak, jejichž účinnost závisí na fenotypu pacientů (zejm. risperidon, haloperidol, venlafaxin, tricyklická antidepresiva, es-/citalopram aj.). Správná interpretace výsledků také umožňuje optimalizaci medikace. To přispívá k minimalizaci rizika vzniku vedlejších účinků a zajištění lepších výstupů léčby. Na závěr je uvedena jedna kazuistika reflektující reálnou situaci, kdy PGx vyšetření sehrálo důležitou roli při rozhodování o výběru farmakoterapie.

Our article aims to introduce the reader to pharmacogenetic (PGx) testing in psychiatry, where it currently represents an available and significant tool in personalized medicine. PGx testing enables the adjustment of pharmacotherapy based on patients' genetic predispositions. In psychiatry, PGx testing focuses on polymorphisms in genes responsible for drug metabolism, primarily cytochrome P450 enzymes such as CYP2C19 and CYP2D6. In clinical practice, these tests can help predict drug efficacy or toxicity, thereby improving the safety and effectiveness of pharmacotherapy. PGx testing, which was conducted at the Bohnice Psychiatric Hospital, was done on patients who exhibited signs of drug resistance, discrepancies in therapeutic drug monitoring (TDM), or significant adverse effects during therapy with standard doses. Results showed that up to 75% of the tested patients had altered function of one or both CYP isoenzymes (i. e., slow, ultra-rapid, rapid, or intermediate metabolizer phenotypes). The interpretation of PGx test results is crucial and should be performed by professionals with expertise in this field. Additionally, a thorough understanding of pharmacokinetics, as well as comprehensive patient-specific information, is required. Only under these conditions can PGx testing significantly influence the correct selection and optimal dosing of psychotropic drugs, especially those whose effectiveness depends on the patient's phenotype (e.g., risperidone, haloperidol, venlafaxine, tricyclic antidepressants, es-/citalopram, etc.). Correct interpretation of PGx results also enables medication optimization, contributing to individualized therapy. This minimizes the risk of side effects and ensures better treatment outcomes. Our article concludes with a case report illustrating a real-life situation in which PGx testing played a key role in guiding pharmacotherapy decisions.

• MeSH
• Cytochrome P-450 CYP2D6 genetics   metabolism   MeSH
• Cytochrome P-450 CYP2C19 genetics   metabolism   MeSH
• Pharmacogenetics * MeSH
• Middle Aged MeSH
• Humans MeSH
• Schizophrenia, Paranoid drug therapy   pathology   MeSH
• Pilot Projects MeSH
• Polymorphism, Genetic MeSH
• Amphetamine-Related Disorders drug therapy   MeSH
• Psychotropic Drugs * administration & dosage   metabolism   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Review MeSH

Cílem článku je rozšíření povědomí o oboru muzikoterapie, možnostech aplikací muzikoterapeutických přístupů, metod a technik u dětí s poruchou autistického spektra (PAS). Zahrnuje vývoj vědeckého poznání včetně aktuálních poznatků z výzkumu a praxe. V závěru nechybí konkrétní muzikoterapeutická cvičení.

The aim of the article is to broaden the awareness of the field of music therapy and the possibilities of applying music therapy approaches, methods and techniques to children with autism spectrum disorder (ASD). It covers the development of scientific knowledge including current findings from research and practice. The article concludes with specific music therapy exercises.

• MeSH
• Humans MeSH
• Music Therapy * methods   MeSH
• Autism Spectrum Disorder * therapy   MeSH
• Sensorimotor Cortex MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• Publication type
• Editorial MeSH

Úzkostné poruchy jsou v současnosti nejčetnější skupinou duševních poruch, postihují světově více než 300 milionů lidí. Rozpočty směřující na léčení a prevenci těchto poruch jsou velmi omezené. Článek se zaměřuje na soucit se sebou, který je dostupným přístupem snižování úzkostných příznaků i potenciálního léčení úzkostných poruch. Uvedený text se opírá zejména o teorii tří systémů regulace emocí, doplněnou o rešerši studií zaměřujících se na vztah mezi soucitem se sebou, úzkostnými příznaky, citovou vazbou a oxytocinem. Pro budoucí rozvoj tohoto oboru je zapotřebí více randomizovaných kontrolovaných longitudinálních studií a komplexnějších výzkumných modelů, zkoumajících zejména roli mediačních/moderačních faktorů, jako je citová vazba či emoční regulace. Autoři v oboru by také měli zvážit adaptování a validaci většího množství intervencí v rámci klinické populace. Významný potenciál budoucího výzkumu lze spatřit ve zkoumání role oxytocinu, který dle některých studií vykazuje příznivé efekty pro snižování úzkostí. V poslední části jsou prezentována doporučení pro podporu praxe pracovníků v oblasti duševního zdraví.

Anxiety disorders are currently the most common group of mental disorders, affecting more than 300 million people worldwide. Budgets for the treatment and prevention of these disorders are very limited. The article focuses on self-compassion, which is an available approach to reducing anxiety symptoms as well as potentially treating anxiety disorders. The above text is mainly based on the theory of three systems of emotion regulation, as well as studies focusing on the relationship between self-compassion, anxiety symptoms, emotional attachment and oxytocin. Based on this, recommendations for future studies are presented. For the future development of this field, more randomized controlled longitudinal studies and more complex research models are needed, especially investigating the role of mediating/moderating factors such as emotional attachment, personality characteristics or emotional regulation. Authors in the field should also consider adapting and validating more interventions within a clinical population. Significant potential for future research can be seen in examining the role of oxytocin, which according to some studies shows beneficial effects for reducing anxiety. In the last part, recommendations for supporting the practice of mental health workers are presented.

• MeSH
• Humans MeSH
• Oxytocin physiology   MeSH
• Psychotherapy MeSH
• Self-Compassion * MeSH
• Anxiety psychology   MeSH
• Anxiety Disorders * pathology   psychology   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH