INTRODUCTION: The use of signal dogs for cancer detection is not yet routinely performed,but dogs and their powerful olfactory system have proven to be a unique and valuable tool for many lineages and are beginning to be incorporated into medical practice. This method has great advantages; the dog can detect a tumour in the human body already in preclinical stages, when the patient has no symptoms yet. The identification of cancer biomarkers to enable early diagnosis is a need for many types of cancer, whose prognosis is strongly dependent on the stage of the disease. However, this method also has its various pitfalls that must be taken into account. AIM: The aim of the study was to identify and highlight the factors that affect the level of detection accuracy, but also the conditions associated with olfactometric diagnosis. METHODS: The study included 48 dogs and 48 handlers, that were part of the training between 2016 and 2023.All those who started olfactometry training and remained in training for at least one year were included in the study. The dogs ranged in age from 8 months to 12 years and were of different races and sexes. After long-term observation, a qualitative analysis was performed and factors that may play a role in the early detection of the disease were listed. RESULTS: The results of the search for the different factors have been compiled into two groups, focussing on the actual handling of the patient biological sample from collection, processing, storage until transport, preparation of the sample,and detection. Focus on the actual work and behaviour of the dog and handler. CONCLUSION: There are many factors; however, it is worth addressing them because the canine sense of smell is one of the possible uses as a diagnostic method.
- Publikační typ
- časopisecké články MeSH
UNLABELLED: The aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 μL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used (P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE: Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform.
- MeSH
- diagnostické techniky molekulární normy metody MeSH
- DNA fungální * krev genetika MeSH
- kvantitativní polymerázová řetězová reakce * normy metody MeSH
- lidé MeSH
- Mucorales * genetika izolace a purifikace MeSH
- mukormykóza * diagnóza mikrobiologie krev MeSH
- senzitivita a specificita * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
INTRODUCTION: Appendectomy for acute appendicitis is the most common surgical procedure performed during pregnancy. The primary treatment for acute appendicitis is emergency surgery, which can be particularly challenging due to altered anatomical conditions. Preoperative and postoperative care may require certain examinations due to pregnancy that are not standard within surgical practice or may be overlooked by the attending gynecologist. CASE PRESENTATION: A patient at 31 weeks of gestation presented to the obstetric clinic with an acute onset of acute appendicitis. After completing all necessary examinations and a thorough multidisciplinary evaluation, a successful laparoscopic appendectomy was performed. The subsequent hospitalization was complicated by the onset of uterine contractions, for which tocolysis was administered in combination with corticosteroid therapy to induce fetal lung maturity. CONCLUSION: In the presented case report, we demonstrate an example of the appropriate multidisciplinary approach with an analysis of the specific steps that should be taken to maximize the benefit for both the fetus and the mother, as well as the surgical team. In the discussion, we outline the steps that should be followed for patient benefit and forensic reasons.
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.
Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.
- MeSH
- chinoliny * aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- fenylmočovinové sloučeniny * aplikace a dávkování terapeutické užití MeSH
- humanizované monoklonální protilátky * aplikace a dávkování terapeutické užití MeSH
- karcinom z renálních buněk * farmakoterapie patologie mortalita sekundární MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory ledvin * farmakoterapie patologie mortalita MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sunitinib * aplikace a dávkování terapeutické užití MeSH
- výsledek terapie 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
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
2. české vydání xii, 488 stran : ilustrace (převážně barevné) ; 21 cm
Atlas a přehled, který se zaměřuje na biochemii a fyziologii člověka. Určeno odborné veřejnosti.; Biochemie člověka přehledně na 223 barevných schématech. Grafické znázornění je základem knihy – texty slouží především k rozšíření a doplnění legendy k vyobrazením. Autoři krátce uvádějí čtenáře do hlavní problematiky chemie a biochemie, zmiňují provázanost mezi chemickou strukturou a biologickou funkcí nebo patologickými procesy. V knize čtenář najde aktuální informace, vývoj a poznatky z oboru, strukturu důležitých molekul a mnohé další informace. Nejvíce místa je v tomto atlasu samozřejmě věnováno biochemii člověka, zahrnuje však i biochemii dalších živočichů, rostlin a mikroorganismů. Didaktické přednosti, které je nutné ocenit: * Efektivní poměr mezi barevnou grafikou a vysvětlujícím textem. * Unifikované barevné zobrazení atomů, koenzymů, chemických tříd a buněčných organel, umožňující rychlou orientaci a pochopení ve všech zobrazených systémech. * Moderní zobrazení mnoha důležitých molekul. * Rychlé orientaci pomáhá barevné kódování a užití různých symbolů, vysvětlivky jsou umístěny na vnitřních stranách obálky. O úspěšnosti knihy vypovídá i seznam předchozích vydání: české 2012; německé 1994, 1997, 2003, 2009; francouzské 1994, 1999, 2004, 2011; anglické 1996, 2004, 2012; japonské 1997, 2007, 2015; portugalské 2005, 2013; ruské 2000, 2017; řecké 1999, 2007; španělské 2004, 2012; turecké 2002, 2016; čínské 2008; indonéské 2002; italské 1997; korejské 2008; nizozemské 2004; polské 2005.
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biochemie
Gambling encompasses a wide variety of activities, and the structural characteristics of each form contribute to its potential risk. However, the literature does not fully agree on the risk levels of certain gambling forms. In this study, we classify less risky gambling forms (soft forms) based on public perceptions of their riskiness. We examine the link between gambling experience and problem gambling prevalence. A survey was conducted in a model region of the Czech Republic, a post-socialist country with high gambling availability, with N = 2,498 respondents. A typology of gambling forms (lotteries, betting, and casino games) was created based on perceived risk similarities. Lotteries are the most frequently played gambling form, with 86.3% reporting lifetime participation. Among those who exclusively engage in lottery-type forms, 15 percentage points more women than men participated in the last year, and the gap widens to 31 points over a lifetime. Forms of gambling perceived as more risky show a lower proportion of non-problem gamblers, both for recent and lifetime participation. Furthermore, individuals who gambled within the past month or year are at higher risk of developing gambling problems compared to those whose gambling experiences were less recent.
- MeSH
- dospělí MeSH
- hráčství * psychologie klasifikace epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- návykové chování * psychologie epidemiologie klasifikace MeSH
- prevalence MeSH
- průzkumy a dotazníky MeSH
- riskování * MeSH
- rizikové faktory MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.
- MeSH
- dospělí MeSH
- epigeneze genetická MeSH
- epigenomika MeSH
- fúze genů * MeSH
- genetická predispozice k nemoci MeSH
- genomika MeSH
- imunohistochemie MeSH
- jednonukleotidový polymorfismus MeSH
- juxtaglomerulární aparát patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA MeSH
- nádorové biomarkery * genetika MeSH
- nádory ledvin * genetika patologie chemie MeSH
- sekvenování celého genomu 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
The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.
- MeSH
- dlouhověkost * fyziologie MeSH
- kardiovaskulární nemoci patofyziologie epidemiologie MeSH
- lidé MeSH
- oxidační stres fyziologie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- stárnutí * fyziologie MeSH
- střevní mikroflóra fyziologie MeSH
- zdravé stárnutí fyziologie MeSH
- životní styl MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 (37) targeting CK1δ and CK1ε with excellent selectivity over the highly related CK1α isoform. The developed PROTAC, AH078 (37) selectively degraded CK1δ and CK1ε with a DC50 of 200 nM. Characterization of AH078 (37) revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 (37) represents a versatile chemical tool to study CK1δ and CK1ε function in cellular systems.
- MeSH
- inhibitory proteinkinas * farmakologie chemie metabolismus MeSH
- kaseinkinasa Idelta * antagonisté a inhibitory metabolismus MeSH
- kaseinkinasa Iepsilon * antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- objevování léků MeSH
- proteolýza * účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
