Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• Autophagy * genetics   MeSH
• White People genetics   MeSH
• Carcinoma, Pancreatic Ductal * genetics   pathology   MeSH
• Forkhead Transcription Factors MeSH
• Genetic Predisposition to Disease * MeSH
• Hepatocyte Nuclear Factor 3-alpha genetics   metabolism   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Cohort Studies MeSH
• Humans MeSH
• Biomarkers, Tumor * genetics   MeSH
• Tumor Suppressor Proteins * genetics   MeSH
• Pancreatic Neoplasms * genetics   pathology   MeSH
• Case-Control Studies MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

Super- and low-shedding phenomena have been observed in genetically homogeneous hosts infected by a single bacterial strain. To decipher the mechanisms underlying these phenotypes, we conducted an experiment with chicks infected with Salmonella Enteritidis in a non-sterile isolator, which prevents bacterial transmission between animals while allowing the development of the gut microbiota. We investigated the impact of four commensal bacteria called Mix4, inoculated at hatching, on chicken systemic immune response and intestinal microbiota composition and functions, before and after Salmonella infection. Our results revealed that these phenotypes were not linked to changes in cell invasion capacity of bacteria during infection. Mix4 inoculation had both short- and long-term effects on immune response and microbiota and promoted the low-shedder phenotype. Kinetic analysis revealed that Mix4 activated immune response from day 4, which modified the microbiota on day 6. This change promotes a more fermentative microbiota, using the aromatic compounds degradation pathway, which inhibited Salmonella colonization by day 11 and beyond. In contrast, control animals exhibited a delayed TNF-driven pro-inflammatory response and developed a microbiota using anaerobic respiration, which facilitates Salmonella colonization and growth. This strategy offers promising opportunities to strengthen the barrier effect against Salmonella and possibly other pathogens.

• MeSH
• Bacteria * classification   genetics   isolation & purification   MeSH
• Chickens * microbiology   immunology   MeSH
• Poultry Diseases * microbiology   immunology   prevention & control   MeSH
• Salmonella enteritidis * immunology   growth & development   MeSH
• Salmonella Infections, Animal * microbiology   immunology   prevention & control   MeSH
• Gastrointestinal Microbiome * MeSH
• Symbiosis MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Candida species are the predominant cause of fungal infections in patients treated in hospital, contributing substantially to morbidity and mortality. Candidaemia and other forms of invasive candidiasis primarily affect patients who are immunocompromised or critically ill. In contrast, mucocutaneous forms of candidiasis, such as oral thrush and vulvovaginal candidiasis, can occur in otherwise healthy individuals. Although mucocutaneous candidiasis is generally not life-threatening, it can cause considerable discomfort, recurrent infections, and complications, particularly in patients with underlying conditions such as diabetes or in those taking immunosuppressive therapies. The rise of difficult-to-treat Candida infections is driven by new host factors and antifungal resistance. Pathogens, such as Candida auris (Candidozyma auris) and fluconazole-resistant Candida parapsilosis, pose serious global health risks. Recent taxonomic revisions have reclassified several Candida spp, potentially causing confusion in clinical practice. Current management guidelines are limited in scope, with poor coverage of emerging pathogens and new treatment options. In this Review, we provide updated recommendations for managing Candida infections, with detailed evidence summaries available in the appendix.

• MeSH
• Antifungal Agents * therapeutic use   MeSH
• Candida classification   drug effects   isolation & purification   MeSH
• Global Health MeSH
• Drug Resistance, Fungal MeSH
• Candidiasis * diagnosis   drug therapy   microbiology   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

OBJECTIVE: patients with type 2 diabetes (T2DM) and obesity are generally known to have increased risk of various types of cancer, though studies addressing associations between T2DM/obesity and thyroid cancer are inconclusive. The aim of our study was to evaluate the risk of thyroid cancer focusing on diabetic patients under conditions of euthyroid status. A retrospective study in 184 patients was performed. Three cohorts were established according to tumor histology: malignant (M), benign (B) and low-risk carcinoma (MB). Fisher's exact test and Kruskal-Wallis one-way ANOVA of ranks were used for statistical analysis. The M (39.1 %), B (57.6 %) and MB (3.3 %) cohorts had comparable age (p=0.4), BMI (p=0.452), glycaemia (p=0.834), Hb1AC (p=0.157) and HOMA-IR (p=0.235). T2DM patients had larger thyroid gland volumes (28.8 vs 17.6 mL;p=0.001) compared to the cohort with normal glucose tolerance. Compared to women, men had more frequently present distal metastases (p=0.017), minimally invasive disease (p=0.027), more advanced staging (p=0.01) and positive pathogenic mutations in the TERT gene (p=0.009);these results were also significant for the diabetic male cohort (p=0.026). Type 2 diabetes and obesity are not risk factors for thyroid cancer, but a subgroup of males seems to have thyroid cancers of poorer prognosis. In general, diabetic patients with insulin resistance and hyperinsulinemia are also prone to have a goiter. KEY WORDS: Thyroid cancer, Type 2 diabetes, Obesity, Thyroid nodule, Insulin resistance.

• MeSH
• Diabetes Mellitus, Type 2 * epidemiology   complications   MeSH
• Adult MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Thyroid Neoplasms * epidemiology   pathology   MeSH
• Obesity * complications   epidemiology   MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The ApxIVA protein belongs to a distinct class of a "clip and link" activity of Repeat-in-ToXin (RTX) exoproteins. Along with the three other pore-forming RTX toxins (ApxI, ApxII and ApxIII), ApxIVA serves as a major virulence factor of Actinobacillus pleuropneumoniae, the causative agent of porcine pneumonia. The gene encoding ApxIVA is located on a bicistronic operon downstream of the orf1 gene and is expressed exclusively under in vivo conditions. Both ApxIVA and ORF1 are essential for full virulence of A. pleuropneumoniae, but the molecular mechanisms by which they contribute to the pathogenicity are not yet understood. Here, we provide a comprehensive structural and functional analysis of ApxIVA and ORF1 proteins. Our findings reveal that the N-terminal segment of ApxIVA shares structural similarity with colicin M (ColM)-like bacteriocins and exhibits an antimicrobial activity. The ORF1 protein resembles the colicin M immunity protein (Cmi) and, like Cmi, is exported to the periplasm through its N-terminal signal peptide. Additionally, ORF1 can protect bacterial cells from the antimicrobial activity of ApxIVA, suggesting that ORF1 and ApxIVA function as an antibacterial toxin-immunity pair. Moreover, we demonstrate that fetal bovine serum could elicit ApxIVA and ORF1 production under in vitro conditions. These findings highlight the coordinated action of various RTX determinants, where the fine-tuned spatiotemporal production of ApxIVA may enhance the fitness of A. pleuropneumoniae, facilitating its invasion to a resident microbial community on the surface of airway mucosa.

• MeSH
• Actinobacillus pleuropneumoniae * genetics   immunology   MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Bacterial Proteins * genetics   metabolism   immunology   MeSH
• Bacterial Toxins genetics   metabolism   immunology   MeSH
• Virulence Factors genetics   MeSH
• Actinobacillus Infections microbiology   veterinary   MeSH
• Colicins genetics   metabolism   MeSH
• Operon * MeSH
• Swine MeSH
• Gene Expression Regulation, Bacterial MeSH
• Virulence MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

• MeSH
• Child MeSH
• Adult MeSH
• Pheochromocytoma * genetics   therapy   diagnosis   MeSH
• Humans MeSH
• Adrenal Gland Neoplasms * genetics   therapy   diagnosis   MeSH
• Paraganglioma * genetics   therapy   MeSH
• Succinate Dehydrogenase genetics   MeSH
• Germ-Line Mutation genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

nfekce způsobené bakterií Streptococcus pneumoniae představují stále závažný zdravotnický problém. Projevují se širokou škálou příznaků, od méně závažných neinvazivních, které jsou lokalizovány na sliznicích, po tzv. invazivní onemocnění. V důsledku stárnutí populace, a tudíž i rostoucího počtu rizikových pacientů, narůstá riziko častějšího výskytu invazivních forem pneumokokových infekcí, s dopady na zdraví jednotlivců a na zdravotnický systém. Ačkoli léčba antibiotiky je dostupná, v posledních letech narůstá riziko vzniku nežádoucí antibiotické rezistence. Význam včasné prevence je tak zcela na místě. Současné pneumokokové vakcíny jsou schopny ovlivňovat výskyt jak invazivních, tak i některých neinvazivních onemocnění. Rozeznáváme přes sto sérotypů bakterie Streptococcus pneumoniae, které jsou pro člověka patogenní. Řada z nich je dnes již pokryta v konjugovaných nebo polysacharidových vakcínách.

Pneumococcal infections remain a serious problem in many countries around the world. They manifest themselves in a wide range of symptoms, from less serious non-invasive ones localized on the mucous membranes, to so-called invasive diseases. As a result of the aging of the population, and therefore the growing number of patients at risk, the risk of more frequent occurrence of invasive forms of pneumococcal infections is increasing, with impacts on the health of individuals and the healthcare system. Although antibiotic treatment is available, the risk of unwanted antibiotic resistance has been increasing in recent years. Early prevention is very important. Current pneumococcal vaccines are able to influence the occurrence of both invasive and some non-invasive diseases. We recognize over one hundred serotypes of the Streptococcus pneumoniae, pathogenic for humans. A number of them are already covered today in conjugated or polysaccharide vaccines.

Background: Recent studies have suggested that pathogenic variants of the DICER1 gene could be a driver of alterations in some pediatric thyroid nodules, but data are still limited. The aim of this study was to detect variants in the DICER1 gene in a large cohort of pediatric thyroid nodules and then correlate them with clinicopathological data, with a focus on the disease prognosis in patients with thyroid carcinoma. Methods: This retrospective cohort study consisted of 350 pediatric and young adult patients (aged 2-21 years) with thyroid nodules, from whom 275 fresh-frozen thyroid nodule samples and 92 fine-needle aspiration biopsy (FNAB) samples were collected. After an analysis of variants in major genetic alterations of thyroid tumors, variants in the DICER1 gene were identified using next-generation sequencing and multiplex ligation-dependent probe amplification methods. Peripheral blood was analyzed from patients with DICER1-positive tumors. The results of genetic analysis were then correlated with clinicopathological data. Results: Variants in the DICER1 gene were detected in a total of 24/350 (6.9%; 95%CI [4.4;10.0]) pediatric and young adult patients, respectively, in 10/119 (8.4%; [4.1;14.9]) patients with benign fresh-frozen tissue, in 8/141 (5.7%; [1.9;9.5]) with papillary thyroid carcinoma (PTC) and in 6/86 (7.0%; [4.1;14.6]) patients with FNAB. No other gene alteration was found in DICER1-positive samples. Germline DICER1 variants were identified in 11/24 (45.8%; [25.6;67.2]) patients. Two somatic (biallelic) variants in the DICER1 gene were found in 9/24 (37.5%; [18.8;59.4]) thyroid nodules. Somatic deletions of at least 3 Mbp long were revealed in 2/24 (8.3%; [1.0;27.0]) cases. DICER1-positive PTCs were significantly associated with the follicular subtype of PTC (p = 0.001), encapsulation (p = 0.006) and were larger in size (p = 0.035), but with no extrathyroidal extension (p = 0.039), and less frequent lymph node metastases (p = 0.003) compared with DICER1-negative PTCs. Patients with DICER1-positive PTC had an excellent response to treatment in 75% of cases. Conclusions: Variants of the DICER1 gene are frequently found in the thyroid nodules of pediatric and young adult patients. In our patients, DICER1-positive PTCs showed low invasiveness. Our findings support considering more conservative management for DICER1-positive low-risk PTCs.

• MeSH
• DEAD-box RNA Helicases * genetics   MeSH
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Thyroid Neoplasms * genetics   pathology   MeSH
• Thyroid Cancer, Papillary genetics   pathology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Ribonuclease III * genetics   MeSH
• Biopsy, Fine-Needle MeSH
• Thyroid Nodule * genetics   pathology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Background/Objectives: PET imaging of bacterial infection could potentially provide added benefits for patient care through non-invasive means. [68Ga]Ga-desferrioxamine B-a radiolabelled siderophore-shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa and sufficient serum stability for clinical application. In this report, we present data for automated production of [68Ga]Ga-desferrioxamine B on two different cassette-based synthesis modules (Modular-Lab PharmTracer and GRP 3V) utilising commercially obtainable cassettes together with a licensed 68Ge/68Ga radionuclide generator. Methods: Quality control, including the determination of radiochemical purity, as well as a system suitability test, was set up via RP-HPLC on a C18 column. The two described production processes use an acetic acid/acetate buffer system with ascorbic acid as a radical scavenger for radiolabelling, yielding ready-to-use formulations with sufficient activity yield. Results: Batch data analysis demonstrated radiochemical purity of >95% by RP-HPLC combined with ITLC and excellent stability up to 2 h after synthesis. Specifications for routine production were set up and validated with four masterbatches for each synthesis module. Conclusions: Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable automated production of [68Ga]Ga-desferrioxamine B in-house with high reproducibility for clinical application.

• Publication type
• Journal Article MeSH

Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [68Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (μPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [68Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by μPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [68Ga]Ga-DOTA-puromycin-μPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [68Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [18F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [68Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity.

• MeSH
• Heterocyclic Compounds, 1-Ring chemistry   MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Mycobacterium bovis * MeSH
• Mycobacterium Infections diagnostic imaging   microbiology   MeSH
• Mice, SCID MeSH
• Mice MeSH
• Organometallic Compounds MeSH
• Positron-Emission Tomography * methods   MeSH
• Radiopharmaceuticals * chemistry   MeSH
• Gallium Radioisotopes * MeSH
• Tuberculosis diagnostic imaging   microbiology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH