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
• Molecular Diagnostic Techniques standards   methods   MeSH
• DNA, Fungal * blood   genetics   MeSH
• Real-Time Polymerase Chain Reaction * standards   methods   MeSH
• Humans MeSH
• Mucorales * genetics   isolation & purification   MeSH
• Mucormycosis * diagnosis   microbiology   blood   MeSH
• Sensitivity and Specificity * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH

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.

• Publication type
• Journal Article 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
• Quinolines * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Phenylurea Compounds * administration & dosage   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   mortality   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sunitinib * administration & dosage   therapeutic use   MeSH
• Treatment Outcome 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 III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

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.

• MeSH
• Biochemistry MeSH
• Physiology MeSH
• Publication type
• Atlas MeSH
• Review MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• NML Fields
• biochemie

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
• Longevity * physiology   MeSH
• Cardiovascular Diseases physiopathology   epidemiology   MeSH
• Humans MeSH
• Oxidative Stress physiology   MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aging * physiology   MeSH
• Gastrointestinal Microbiome physiology   MeSH
• Healthy Aging physiology   MeSH
• Life Style MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Protein Kinase Inhibitors * pharmacology   chemistry   metabolism   MeSH
• Casein Kinase Idelta * antagonists & inhibitors   metabolism   MeSH
• Casein Kinase 1 epsilon * antagonists & inhibitors   metabolism   MeSH
• Humans MeSH
• Drug Discovery MeSH
• Proteolysis * drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Adult MeSH
• Epigenesis, Genetic MeSH
• Epigenomics MeSH
• Gene Fusion * MeSH
• Genetic Predisposition to Disease MeSH
• Genomics MeSH
• Immunohistochemistry MeSH
• Polymorphism, Single Nucleotide MeSH
• Juxtaglomerular Apparatus pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation MeSH
• Biomarkers, Tumor * genetics   MeSH
• Kidney Neoplasms * genetics   pathology   chemistry   MeSH
• Whole Genome Sequencing MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study 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
• Healthcare Disparities statistics & numerical data   MeSH
• Health Status Disparities MeSH
• Health Services Accessibility statistics & numerical data   MeSH
• Humans MeSH
• Life Expectancy * MeSH
• Delivery of Health Care statistics & numerical data   MeSH
• Health Equity MeSH
• Sex Factors MeSH
• Men's Health * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• United States 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
• Circadian Rhythm MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   MeSH
• Neoplasms * pathology   therapy   MeSH
• Gastrointestinal Microbiome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review 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
• Child MeSH
• Electroencephalography * methods   MeSH
• Epilepsy MeSH
• Focal Cortical Dysplasia MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Malformations of Cortical Development, Group I * surgery   complications   diagnostic imaging   MeSH
• Malformations of Cortical Development surgery   complications   diagnostic imaging   MeSH
• Adolescent MeSH
• Positron-Emission Tomography MeSH
• Child, Preschool MeSH
• Drug Resistant Epilepsy * surgery   diagnostic imaging   physiopathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH