Background: Complex nasal defects most often arise due to oncological resection or severe trauma. Traditional methods of two-stage nose reconstruction using a forehead flap with a skin graft have often resulted in collapse and deformity of the nose with a very compromised outcome over time. These techniques were gradually replaced by new procedures consistently reconstructing the intranasal lining, most often with flaps from the nasal septum. These methods reconstruct the cartilaginous and bony support of the nose as well, while the skin cover of the nose is, nowadays, in large defects, reconstructed in three stages. Evaluation of the topic: The options for intranasal lining reconstruction are as follows: a composite graft, a turnover flap covered with a local flap, advancement of the residual lining (bipedicle vestibular mucosa flap), a folded forehead flap, a prelaminated forehead flap, the use of another local flap (a forehead, nasolabial, facial artery myomucosal flap), a hinged turnover flap, a septal mucoperichondrial hinged flap, a composite septal chondromucosal pivot flap, a turbinate flap and microvascular free flaps (a radial forearm flap, a helix free flap, a kite flap, a dorsalis pedis free flap, a temporoparietal free flap, a postauricular free flap). Thanks to the abundant vascular supply of the face, the risk of ischemia and infection is mitigated, allowing most complex nasal defects to be reconstructed by using local flaps to restore all layers of the nose. Local tissues retain ideal quality, coloration, and texture, are reliable, and usually result in esthetically acceptable morbidity of the donor area. If the inner lining defect is extensive, it must be reconstructed by free microvascular tissue transfer. If other than intranasal flaps are used in the reconstruction of the internal lining, it is preferable to postpone the reconstruction of the supporting framework until the second stage while thinning the flaps used; otherwise, there is a high risk of obturation of the nasal airways. Conclusion: The results of modern reconstruction dramatically improved after the introduction of three-stage nasal reconstruction and emphasizing the reconstruction of all layers of the nose. Therefore, a quality inner lining is the basis for the construction of the new nose.
Boswellia resin is an exudate from the cut bark of Boswellia trees. The main constituents of pharmacological interest are boswellic acids (pentacyclic triterpenoids), namely α-boswellic acid, β-boswellic acid, 3-O-acetyl-α-boswellic acid, 3-O-acetyl-β-boswellic acid, 11-keto-β-boswellic acid, and 3-O-acetyl-11-keto-β-boswellic acid. Nowadays, dietary supplements with Boswellia serrata extract are used in the treatment of inflammatory joint diseases. Additionally, the constituents of Boswellia resin have shown potential for the treatment of other chronic inflammatory diseases and various types of cancer. Separation methods including ultra/high-performance liquid chromatography, gas chromatography, thin layer chromatography, supercritical fluid chromatography, and capillary electrochromatography coupled with UV or MS detection have been used for the determination of boswellic acids in various matrices (mostly plant material and biological samples). This review aims to provide a comprehensive summary of these separation methods, offering a critical discussion of their strengths and limitations in the analysis of boswellic acids. The knowledge of various separation methods plays a pivotal role in the quality control of herbal dietary supplements and the monitoring of the metabolism and pharmacokinetics of their constituents. The approaches based on metabolomics and network pharmacology represent new ways of fingerprinting secondary metabolites in Boswellia resin increasing the comprehensiveness of the output of these methods resulting in safer dietary supplements.
- MeSH
- Boswellia chemistry MeSH
- Humans MeSH
- Plant Extracts chemistry MeSH
- Triterpenes * analysis isolation & purification MeSH
- Chromatography, High Pressure Liquid MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Investigating prenatal hypoxia is difficult in mammals, as there are confounding factors stemming from maternal adaptations and compensatory mechanisms. We have thus established an avian model of hypoxic incubation (starting after 2 days of normoxia, 15% O2, normobaric, until the time of sampling at embryonic day 8) to study embryonic reactions to low oxygen concentration. Our previous studies have shown increased vascularization, oedema, and ventricular wall thinning preceding the lethality at mid-gestation. Analysis of the cardiac proteome after 6 days of hypoxic incubation showed strong upregulation of enzymes involved in anaerobic glycolysis as well as an increase in apoptosis-related proteins, cell adhesion proteins, and secretory activity.
- MeSH
- Apoptosis MeSH
- Glycolysis MeSH
- Hypoxia * metabolism MeSH
- Chick Embryo MeSH
- Myocardium metabolism MeSH
- Proteome metabolism MeSH
- Proteomics * methods MeSH
- Heart * embryology MeSH
- Animals MeSH
- Check Tag
- Chick Embryo MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope 161Tb, for targeted therapy in FGFR-overexpressing cancer cells. FGF1 was engineered (eFGF1) to incorporate a single cysteine at the C terminus for site-specific labeling with a DOTA chelator. eFGF1-DOTA was mixed with the radioisotope 161Tb under mild conditions, resulting in a labeling efficiency above 90%. The nonradioactive ligands were characterized by mass spectrometry, while radioligands were characterized by thin-layer chromatography. The targeting function of the radioligands was assessed through confocal microscopy, flow cytometry, and Western blot analysis, focusing on binding to cancer cells and the activation of downstream signaling pathways related to FGFR. When compared to MCF-7 and RD cell lines with low FGFR expression, eFGF1-DOTA-Tb[161Tb] radioligands demonstrated significantly higher accumulation in FGFR-overexpressing cell lines (MCF-7 FGFR1 and RMS559), leading to enhanced cytotoxicity. Besides radionuclides, eFGF1 can also deliver doxorubicin (DOX) into cancer cells. Considering these characteristics, eFGF1-DOTA-Tb[161Tb] and eFGF1-DOX emerge as promising candidates for FGFR-targeted cancer therapy, and further evaluation in vivo is warranted.
- Publication type
- Journal Article MeSH
Although the heart atria have a lesser functional importance than the ventricles, atria play an important role in the pathophysiology of heart failure and supraventricular arrhythmias, particularly atrial fibrillation. In addition, knowledge of atrial morphology recently became more relevant as cardiac electrophysiology and interventional procedures in the atria gained an increasingly significant role in the clinical management of patients with heart disease. The atrial chambers are thin-walled, and several vessels enter at the level of the atria. The left and right atrium have different structures and shape. In general, both atrial chambers have the venous part, the appendage, and the vestibule; different aspects of each part allow us to distinguish morphologically between the left and right atrium. The human atrial conduction system consists of the sinus node and the atrioventricular node with no histologically specialized conduction pathways in the atrial chamber and an interatrial connection. The data show that the propagation of the impulse depends mainly on the myocardial architecture in the atria and the orientation of the myocytes plays a significant role in conduction. To complete the picture, it is also important to know how the atria develop and what is the embryonic origin of its different structures, as this may play a role in the development of some pathological conditions such as atrial fibrillation or certain types of congenital heart defects. Functional impairment of the atria can in some situations severely compromise heart pumping function, and conversely, can support it if other areas are damaged, balancing the blood flow to the body for some time. Key words Morphology of atrial chambers, Pectinate muscles, Atrial function.
- MeSH
- Atrial Fibrillation physiopathology pathology MeSH
- Humans MeSH
- Heart Conduction System physiopathology MeSH
- Atrial Function physiology MeSH
- Heart Atria * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality.
- MeSH
- Antiphospholipid Syndrome * immunology pathology MeSH
- Killer Cells, Natural * immunology metabolism MeSH
- Disease Models, Animal * MeSH
- Mice MeSH
- Placenta * metabolism pathology MeSH
- Cell Proliferation MeSH
- Gene Expression Profiling MeSH
- Pregnancy MeSH
- Transcriptome MeSH
- Trophoblasts metabolism pathology immunology MeSH
- Uterus * pathology metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Adrenergic activation of protein kinase A (PKA) in cardiac muscle targets the sarcolemma, sarcoplasmic reticulum, and contractile apparatus to increase contractile force and heart rate. In the thin filaments of the contractile apparatus, cardiac troponin I (cTnI) Ser22 and Ser23 in the cardiac-specific N-terminal peptide (NcTnI: residues 1 to 32) are the targets for PKA phosphorylation. Phosphorylation causes a 2-3 fold decrease of affinity of cTn for Ca2+ associated with a higher rate of Ca2+ dissociation from cTnC leading to a faster relaxation rate of the cardiac muscle (lusitropy). Cardiomyopathy-linked mutations primarily affect Ca2+ regulation or the PKA-dependent modulatory system, such that Ca2+-sensitivity becomes independent of phosphorylation level (uncoupling) and this could be sufficient to induce cardiomyopathy. A drug that could restore the phosphorylation-dependent modulation of Ca2+-sensitivity could have potential for treatment of these pathologies. We have found that a number of small molecules, including silybin B, resveratrol and EGCG, can restore coupling in single filament assays. METHODS: We did molecular dynamics simulations (5x1500ns for each condition) of the unphosphorylated and phosphorylated cardiac troponin core with the G159D DCM mutation in the presence of the 5 ligands and analysed the effects on several dynamic parameters. We also studied the effect of the ligands on the contractility of cardiac muscle myocytes with ACTC E99K and TNNT2 R92Q mutations in response to dobutamine. RESULTS: Silybin B, EGCG and resveratrol restored the phosphorylation-induced change in molecular dynamics to wild-type values, whilst silybin A, an inactive isomer of silybin B, and Epicatechin gallate, an EGCG analogue that does not recouple, did not. We analysed the atomic-level changes induced by ligand binding to explain recoupling. Mutations ACTC E99K and TNNT2 R92Q blunt the increased relaxation speed response to β1 adrenergic stimulation of cardiac myocytes and we found that resveratrol, EGCG and silybin B could restore the β1 adrenergic response, whereas silybin A did not. DISCUSSION: The uncoupling phenomenon caused by cardiomyopathy-related mutations and the ability of small molecules to restore coupling in vitro and lusitropy in myocytes is observed at the cellular, molecular and atomistic levels therefore, restoring lusitropy is a suitable target for treatment. Further research on compounds that restore lusitropy is thus indicated as treatments for genetic cardiomyopathies. Further molecular dynamics simulations could define the specific properties needed for recoupling and allow for the prediction and design of potential new drugs.
- Publication type
- Journal Article MeSH
This guideline was developed in close collaboration with multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF) and the European Organization for Research and Treatment of Cancer (EORTC). Recommendations for the diagnosis and treatment of melanoma were developed on the basis of systematic literature research and consensus conferences. Cutaneous melanoma (CM) is the most dangerous form of skin tumor and accounts for 90 % of skin cancer mortality. The diagnosis of melanoma can be made clinically and must always be confirmed by dermoscopy. If melanoma is suspected, a histopathological examination is always required. Sequential digital dermoscopy and whole-body photography can be used in high-risk patients to improve the detection of early-stage melanoma. If available, confocal reflectance microscopy can also improve the clinical diagnosis in special cases. Melanoma is classified according to the 8th version of the American Joint Committee on Cancer classification. For thin melanomas up to a tumor thickness of 0.8 mm, no further diagnostic imaging is required. From stage IB, lymph node sonography is recommended, but no further imaging examinations. From stage IIB/C, whole-body examinations with computed tomography or positron emission tomography CT in combination with magnetic resonance imaging of the brain are recommended. From stage IIB/C and higher, a mutation test is recommended, especially for the BRAF V600 mutation. It is important to perform a structured follow-up to detect relapses and secondary primary melanomas as early as possible. A stage-based follow-up regimen is proposed, which in the experience of the guideline group covers the optimal requirements, although further studies may be considered. This guideline is valid until the end of 2026.
- MeSH
- Dermoscopy methods standards MeSH
- Consensus * MeSH
- Humans MeSH
- Melanoma * diagnosis therapy pathology MeSH
- Skin Neoplasms * diagnosis therapy pathology MeSH
- Neoplasm Staging MeSH
- Systematic Reviews as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Practice Guideline MeSH
- Geographicals
- Europe MeSH
Interlabiální tumor je u novorozených dívek dia gnostikován v prvních dnech, resp. týdnech života. Vyskytuje se s prevalencí 1: 500 až 1: 7 000 novorozených dívek. Tumor ve vaginálním introitu, resp. mezi velkými stydkými pysky může způsobit dia gnostické obtíže nebo vytvářet dojem genitálu nejasného pohlaví. Interlabiální útvary různé etiologie jsou si svým vzhledem podobné, což může vést k diferenciálně-dia gnostickým omylům. Nejčastější příčinou interlabiálního tumoru jsou u novorozených dívek hymenální a parauretrální cysty, které se projevují jako tenkostěnné kulovité útvary vyplněné zlatavě zbarvenou tekutinou. V případě cystického interlabiálního útvaru je nutné vyloučit zejména atrezii hymenu s hydrokolpos a prolaps ektopické ureterokély. V diferenciální dia gnostice je nutné pomyslet na prolaps uretry, rhabdomyosarkom pochvy a děložního hrdla, uretrální či vaginální polyp a u novorozence extrémně vzácný prolaps dělohy a poševních stěn nebo duplikaturu rekta. Novorozené dívky s interlabiálně lokalizovaným tumorem by měly být podle klinického nálezu vyšetřeny pediatrem, gynekologem, chirurgem nebo urologem. V závislosti na etiologii interlabiálního útvaru je možné zvolit expektační postup nebo chirurgickou léčbu. Včasná operace může zejména v případě hydrokolpos a prolapsu ektopické ureterokély zabránit obstrukci dolních močových cest a z toho plynoucímu zdraví ohrožujícímu poškození ledvin.
: An interlabial mass in newborn girls is diagnosed usually after birth or during the first days or weeks of life. According to various studies, its prevalence ranges between 1 : 500 and 1 : 7,000 newborn girls. A mass in the vaginal introitus or between the labia majora can cause a diagnostic dilemma and may be suspected even of ambiguous genitalia. Interlabial masses of different etiologies present clinically similar, and therefore, can be misdiagnosed. The most common causes of an interlabial mass in a newborn are hymenal and paraurethral cysts, both of which present as thin-walled spherical formations filled with golden fluid. When diagnosing a cystic interlabial tumor, it is necessary to particularly exclude a non-perforated hymen with hydrocolpos and prolapse of an ectopic ureterocele. In the differential diagnosis, prolapse of the urethra, rhabdomyosarcoma of the vagina or cervix, urethral or vaginal polyps, and extremely rare conditions such as genital prolapse or duplicate rectum cannot be omitted. A newborn girl with an interlabial formation should be examined by a pediatrician, gynecologist, surgeon, or urologist depending on the nature of the clinical findings. Once the etiology of an interlabial mass is identified, expectant management or surgery should be chosen. Early surgical treatment of hydrocolpos and prolapse of a ureterocele can prevent lower urinary tract obstruction and life-threatening renal damage.
- Keywords
- interlabiální tumor,
- MeSH
- Cysts diagnosis classification congenital MeSH
- Diagnosis, Differential MeSH
- Genital Diseases, Female diagnosis classification congenital MeSH
- Hydrocolpos diagnosis etiology pathology MeSH
- Humans MeSH
- Genital Diseases * diagnosis classification congenital MeSH
- Infant, Newborn MeSH
- Prolapse MeSH
- Rhabdomyosarcoma diagnosis classification MeSH
- Vagina abnormalities pathology MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Review MeSH
