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
A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.
- MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Colorectal Neoplasms * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Repair genetics MeSH
- Pedigree MeSH
- Exome Sequencing * methods MeSH
- Aged MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.
- MeSH
- Bendamustine Hydrochloride * administration & dosage therapeutic use MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy mortality MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Piperidines therapeutic use administration & dosage adverse effects MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects MeSH
- Pyrazoles * therapeutic use administration & dosage adverse effects MeSH
- Pyrimidines * therapeutic use administration & dosage adverse effects MeSH
- Rituximab * administration & dosage therapeutic use adverse effects MeSH
- Aged, 80 and over MeSH
- Aged 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
- Comparative Study MeSH
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
- MeSH
- Alzheimer Disease * genetics MeSH
- Genome-Wide Association Study methods MeSH
- Genetic Predisposition to Disease genetics MeSH
- X Chromosome Inactivation genetics MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Humans MeSH
- Chromosomes, Human, X * genetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.
- MeSH
- Immunotherapy * methods MeSH
- Papillomavirus Infections immunology virology MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Mutation * MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Tumor Microenvironment * immunology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Exome Sequencing MeSH
- Tumor Escape genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Tailocins are nano-scale phage tail-like protein complexes that can mediate antagonistic interactions between closely related bacterial species. While the capacity to produce R-type tailocin was found widely across Gammaproteobacteria, the production of F-type tailocins seems comparatively rare. In this study, we examined the freshwater isolate, Pragia fontium 24613, which can produce both R- and F-type tailocins. We investigated their inhibition spectrum, focusing on clinically relevant enterobacteria, and identified the associated tailocin gene cluster. Transmission electron microscopy confirmed that inactivation of the tape measure protein within the tailocin cluster disrupted R-tailocin production. Comparative analysis of Budviciaceae gene clusters showed high conservation of R-type tailocin genes, whereas F-type tailocin genes were found in only a few species, with little conservation. Our findings indicate a high prevalence of bacteriocin production among underexplored Enterobacteriales species. Detected tailocins showed potential as antimicrobials targeting clinically significant pathogens.
PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
- MeSH
- Algorithms MeSH
- Child MeSH
- Genetic Testing * methods MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation genetics MeSH
- Dwarfism genetics diagnosis MeSH
- Consanguinity * MeSH
- Growth Disorders genetics diagnosis MeSH
- Child, Preschool MeSH
- Pedigree MeSH
- Exome Sequencing methods MeSH
- Body Height genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Iraq MeSH
The diversity of cultivable endophytic fungi in native subshrubs of the Brazilian Cerrado is largely unknown. This study investigated the cultivable endophytic mycobiome of stems, leaves, and flowers of Peltaea polymorpha (Malvaceae). In total, 208 endophytic fungi were isolated, 95 from stems, 65 from leaves, and 48 from flowers. The isolates were classified as ascomycetes belonging to three classes, eight orders, ten families, 12 genera, and 31 species. Diaporthe, Nigrospora, and Colletotrichum were the dominant genera in the three analyzed organs. The richness estimators suggested that the number of species might be slightly higher than observed. The highest values for the Shannon and Simpson diversity indices were observed in stems. Beta diversity showed overlapping of fungal communities in different organs, with a high rate of sharing of taxa. Furthermore, the dominant primary fungal lifestyles were plant pathogens and saprobes. Our findings show that the cultivable endophytic fungal community of P. polymorpha is species-rich and that communities in different organs share genera and species.
- MeSH
- Ascomycota isolation & purification classification genetics MeSH
- Biodiversity * MeSH
- Endophytes * classification isolation & purification genetics growth & development MeSH
- Phylogeny MeSH
- Fungi * classification isolation & purification genetics growth & development MeSH
- Flowers microbiology MeSH
- Plant Leaves microbiology MeSH
- Mycobiome MeSH
- Grassland MeSH
- Plant Stems microbiology MeSH
- Tropical Climate MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Brazil MeSH
During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.
- MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit metabolism genetics MeSH
- Matrix Metalloproteinase Inhibitors pharmacology MeSH
- Hydroxamic Acids pharmacology MeSH
- Metalloproteases metabolism genetics MeSH
- Molar embryology growth & development metabolism enzymology MeSH
- Morphogenesis MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Odontogenesis * MeSH
- Cell Proliferation * MeSH
- Gene Expression Regulation, Developmental MeSH
- Tooth Germ embryology metabolism enzymology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Worldwide prevalence of multi-antibiotic resistant bacteria is rapidly increasing, and the education of undergraduates and graduates about antibiotic resistance and its associated horizontal gene transfer is critical in the general effort to confront the spread of antibiotic resistance. In this study, a deeper understanding of antibiotic resistance and horizontal gene transfer was achieved by biomedical undergraduate students through a scientific research programme. The enthusiasm of students to participate in the training programme was very high, and results revealed that each student could identify the antibiotic resistance integrative and conjugative element from the Stenotrophomonas maltophilia MER1 genome. Each student could also draw the phylogenetic relationship of the antibiotic resistance integrative and conjugative element. In addition, students proved the horizontal transfer of antibiotic resistance genes from S. maltophilia MER1 to Escherichia coli strain 25DN through conjugation and PCR assays. Each group of students was able to obtain the expected results, indicating that the outcome of the scientific research programme was highly reproducible. This programme improved the theoretical knowledge about antibiotic resistance and horizontal gene transfer and the research skills of biomedical sciences students. Through this programme, students learned that antibiotic resistance genes can be horizontally transferred among different bacteria, laying a solid foundation for students to value the importance of the appropriate use of antibiotics in their future work and life.
- MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Drug Resistance, Microbial * genetics MeSH
- Drug Resistance, Bacterial * genetics MeSH
- Biomedical Research * education MeSH
- Escherichia coli genetics drug effects MeSH
- Phylogeny MeSH
- Humans MeSH
- Gene Transfer, Horizontal * MeSH
- Students, Medical MeSH
- Students MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
