Despite the adenoids are regularly removed in patients with mucopolysaccharidoses (MPS), the underlying tissue and cellular pathologies remain understudied. We characterized an (immuno)histopathologic and ultrastructural phenotype dominated by lysosomal storage changes in a specific subset of adenotonsillar paracortical cells in 8 MPS patients (3 MPS I, 3 MPS II, and 2 MPS IIIA). These abnormal cells were effectively detected by an antibody targeting the lysosomal membrane tetraspanin CD63. Important, CD63+ storage vacuoles in these cells lacked the monocytes/macrophages lysosomal marker CD68. Such a distinct patterning of CD63 and CD68 was not present in a patient with infantile neurovisceral variant of acid sphingomyelinase deficiency. The CD63+ storage pathology was absent in two MPS I patients who either received enzyme-replacement therapy or underwent hematopoietic stem cells transplantation prior the adenoidectomy. Our study demonstrates novel features of lysosomal storage patterning and suggests diagnostic utility of CD63 detection in adenotonsillar lymphoid tissue of MPS patients.

• MeSH
• Tetraspanin 30 MeSH
• Enzyme Replacement Therapy MeSH
• Humans MeSH
• Lymphoid Tissue pathology   MeSH
• Lysosomes MeSH
• Mucopolysaccharidoses * diagnosis   drug therapy   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.55, p < 0.001; SRT: r = 0.83, p < 0.001) and TRAP (ERT: r = 0.34, p < 0.001; SRT: r = 0.88, p < 0.001), irrespective of treatment method. A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups (ERT: p = 0.021; SRT: p = 0.028). The association of Lyso-Gb1 with evaluated markers was stronger in the SRT cohort. Our results indicate that ERT and SRT in combination or in a switch manner could offer the potential of individual drug effectiveness for particular GD symptoms. Combination of the key biomarker of GD, Lyso-Gb1, with other biomarkers can offer improved response assessment to long-term therapy.

• MeSH
• Biomarkers MeSH
• Enzyme Replacement Therapy MeSH
• Gaucher Disease * diagnosis   drug therapy   MeSH
• Humans MeSH
• Platelet Count MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alpha-galactosidase A (AGAL). The impact of X-chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients. XCI was assessed by two methylation-based and two allele-specific expression assays. The results correlated, although some variance among the four assays was observed. GLA transcript analyses identified crossing-over in three patients and detected mRNA instability in three out of four analyzed null alleles. AGAL activity correlated with XCI pattern and was not influenced by the mutation type or by reduced mRNA stability. Therefore, AGAL activity may help to detect crossing-over in patients with unstable GLA alleles. Tissue-specific XCI patterns in six patients, and age-related changes in two patients were observed. To avoid misinterpretation of XCI results in female FD patients we show that (i) a combination of several XCI assays generates more reliable results and minimizes possible biases; (ii) correlating XCI to GLA expression and AGAL activity facilitates identification of cross-over events; (iii) age- and tissue-related XCI specificities of XCI patterning should be considered.

• MeSH
• alpha-Galactosidase genetics   MeSH
• Chromosomes MeSH
• Fabry Disease * diagnosis   genetics   MeSH
• Phenotype MeSH
• X Chromosome Inactivation genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial-mesenchymal transition, and migration of cancer cells).

• Publication type
• Journal Article MeSH
• Review MeSH

PURPOSE: Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. METHODS: Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant. RESULTS: All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal. CONCLUSIONS: Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.

• MeSH
• Adult MeSH
• Electroretinography MeSH
• Glycogen Storage Disease Type IIb complications   diagnosis   genetics   MeSH
• Humans MeSH
• Lysosomal-Associated Membrane Protein 2 biosynthesis   genetics   MeSH
• Young Adult MeSH
• Tomography, Optical Coherence methods   MeSH
• Gene Expression Regulation * MeSH
• Retinal Pigment Epithelium pathology   MeSH
• Retinitis Pigmentosa diagnosis   etiology   genetics   MeSH
• RNA genetics   MeSH
• Pedigree MeSH
• Visual Acuity * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.

• MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Chelating Agents chemistry   pharmacology   MeSH
• Flavonoids chemistry   MeSH
• Heme chemistry   MeSH
• Ions chemistry   metabolism   MeSH
• Coordination Complexes chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Iron chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.

• MeSH
• Chromosome Deletion MeSH
• Adult MeSH
• Alu Elements genetics   MeSH
• Exons genetics   MeSH
• Glycogen Storage Disease Type IIb diagnosis   genetics   physiopathology   MeSH
• X Chromosome Inactivation genetics   MeSH
• Cardiomyopathies genetics   physiopathology   MeSH
• Cullin Proteins genetics   MeSH
• Humans MeSH
• Lysosomal-Associated Membrane Protein 2 genetics   MeSH
• X-Linked Intellectual Disability genetics   physiopathology   MeSH
• Loss of Function Mutation genetics   MeSH
• Myocardium metabolism   MeSH
• Sodium-Potassium-Exchanging ATPase genetics   MeSH
• Transcription Factors genetics   MeSH
• DNA Copy Number Variations genetics   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Mannose-binding lectin (MBL) is an important component of the innate immunity, and it is responsible not only for opsonization of micro-organisms, but also for efferocytosis. The aim of this study was to investigate whether MBL concentrations and lectin complement pathway activity are altered in non-pregnant women with previous adverse pregnancy outcomes. Patients were divided into four groups on the basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken. We found significantly higher MBL concentrations and functional activity of the lectin complement pathway in healthy controls who had previous uneventful term pregnancies (1341 ng/mL; activity 100% (IQR: 62%-100%)), compared to women with the history of IUFD (684 ng/mL, P = .008; activity 8.5% (IQR: 0%-97.8%), P = .011), recurrent miscarriage (524 ng/mL, P = .022; activity 44% (IQR: 4%-83%), P = .011) or preterm labour (799 ng/mL, P = .022; activity 62.5% (IQR: 0%-83%), P = .003). Our results suggest that inadequate function of the complement lectin pathway is associated with a higher risk of preterm labour, recurrent miscarriage and unexplained intrauterine foetal death.

• MeSH
• Adult MeSH
• Pregnancy Complications blood   epidemiology   MeSH
• Mannose-Binding Lectin blood   MeSH
• Complement Pathway, Mannose-Binding Lectin immunology   MeSH
• Humans MeSH
• Immunity, Innate immunology   MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Pregnancy MeSH
• Pregnancy Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440-1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.

• MeSH
• Dentinogenesis Imperfecta diagnosis   genetics   mortality   MeSH
• Child MeSH
• ErbB Receptors deficiency   genetics   MeSH
• Homozygote MeSH
• Ichthyosis diagnosis   genetics   mortality   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Loss of Function Mutation MeSH
• Kidney Diseases congenital   diagnosis   genetics   mortality   MeSH
• Infant, Premature MeSH
• Infant, Very Low Birth Weight MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Roma genetics   MeSH
• Exome Sequencing MeSH
• Severity of Illness Index MeSH
• Syndrome MeSH
• Heart Defects, Congenital diagnosis   genetics   mortality   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH

Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-3C, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues. Here, we investigated the cytotoxic mechanism of salt 1-3C compared to its analogue, salt 1-8C, with an extended side carbon chain. Live cell imaging demonstrated that salt 1-3C, but not 1-8C, is rapidly incorporated into mitochondria, correlating with increased cytotoxicity of salt 1-3C. The accumulation in mitochondria led to their fragmentation and loss of function, accompanied by increased autophagy/mitophagy. Salt 1-3C preferentially activated AMP-activated kinase and inhibited mammalian target of rapamycin (mTOR) signaling pathways, sensors of cellular metabolism, but did not induce apoptosis. These data indicate that salt 1-3C cytotoxicity involves mitochondrial perturbation and disintegration, and such compounds are promising candidates for targeting mitochondria as a weak spot of cancer.

• MeSH
• Quinazolines chemistry   pharmacology   MeSH
• Carbocyanines chemistry   MeSH
• Quaternary Ammonium Compounds chemistry   pharmacology   MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Mitophagy * MeSH
• Cell Line, Tumor MeSH
• Protein Kinases metabolism   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• TOR Serine-Threonine Kinases metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH