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

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

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

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

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

PURPOSE OF REVIEW: Men face distinctive health-related challenges as a result of biological, behavioral, and sociocultural factors. In addition, the modern healthcare system does not offer men equal opportunities and options to ensure sex-specific access and delivery to health services. Men's health concerns are, indeed, often not addressed or even forgotten. In this review, we wanted to assess the impact of biology and sociocultural effects on sex-specific life-expectancy. RECENT FINDINGS: Globally, men have a shorter life expectancy than women. With a 5.8 years gender gap in the USA and 5.4 in the EU-27 (both in 2022). Cardiovascular disease, cancer, and accidents continue to represent the primary causes of mortality for both genders with all having disproportional preponderance in men. In recent years, there has been a notable decline in age-adjusted mortality rates related to cancer, while there has been an increase in deaths from accidental and intentional self-harm. Moreover, in the United States, men are more likely than women to develop and die from nonsex-specific cancers. As a result, men's poor health affects productivity, absenteeism, and employment. SUMMARY: The status of men in healthcare is complex. It is rooted in history, culture, and institutions. To address disparities, we need a comprehensive approach that includes policy reforms, sociocultural changes, and a fair and equitable public discourse. Grassroots and top-down strategies are needed to ensure a value-based societal healthcare system acknowledging the unique health needs of men.

• MeSH
• disparity zdravotní péče statistika a číselné údaje   MeSH
• disparity zdravotního stavu MeSH
• dostupnost zdravotnických služeb statistika a číselné údaje   MeSH
• lidé MeSH
• naděje dožití * MeSH
• poskytování zdravotní péče statistika a číselné údaje   MeSH
• rovnost ve zdraví MeSH
• sexuální faktory MeSH
• zdraví mužů * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Spojené státy americké MeSH

OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

• MeSH
• dítě MeSH
• elektroencefalografie * metody   MeSH
• epilepsie MeSH
• fokální kortikální dysplazie MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• malformace mozkové kůry, skupina I * chirurgie   komplikace   diagnostické zobrazování   MeSH
• malformace mozkové kůry chirurgie   komplikace   diagnostické zobrazování   MeSH
• mladiství MeSH
• pozitronová emisní tomografie MeSH
• předškolní dítě MeSH
• refrakterní epilepsie * chirurgie   diagnostické zobrazování   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The tumor microenvironment (TME) is a complex, highly structured, and dynamic ecosystem that plays a pivotal role in the progression of both primary and metastatic tumors. Precise assessment of the dynamic spatiotemporal features of the TME is crucial for understanding cancer evolution and designing effective therapeutic strategies. Cancer is increasingly recognized as a systemic disease, influenced not only by the TME, but also by a multitude of systemic factors, including whole-body metabolism, gut microbiome, endocrine signaling, and circadian rhythm. In this review, we summarize the intrinsic, extrinsic, and systemic factors contributing to the formation of 'cold' tumors within the framework of the cancer-immunity cycle. Correspondingly, we discuss potential strategies for converting 'cold' tumors into 'hot' ones to enhance therapeutic efficacy.

• MeSH
• cirkadiánní rytmus MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * patologie   terapie   MeSH
• střevní mikroflóra MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• MeSH
• dieta s vysokým obsahem tuků * MeSH
• inzulinová rezistence MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• obezita * chemicky indukované   MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• průmyslové fungicidy * toxicita   MeSH
• triazoly * toxicita   MeSH
• triglyceridy krev   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• ztučnělá játra * chemicky indukované   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH