ABSTRACT
Cancer invasion and metastasis require remodeling of the adjacent extracellular matrix (ECM). In this mini review, we will cover the mechanisms of proteolytic degradation and the mechanical remodeling of the ECM by cancer cells, with a focus on invadopodia. Invadopodia are membrane protrusions unique to cancer cells, characterized by an actin core and by the focal degradation of ECM via matrix metalloproteases (MMPs). While ECM can also be remodeled, at lower levels, by focal adhesions, or internal collagen digestion, invadopodia are now recognized as the major mechanism for MMP-dependent pericellular ECM degradation by cancer cells. Recent evidence suggests that the completion of epithelial-mesenchymal transition may be dispensable for invadopodia and metastasis, and that invadopodia are required not only for mesenchymal, single cell invasion, but also for collective invasion. During collective invasion, invadopodia was then shown to be located in leader cells, allowing follower cells to move via cooperation. Collectively, this suggests that invadopodia function may be a requirement not only for later steps of metastasis, but also for early invasion of epithelial cells into the stromal tissue. Over the last decade, invadopodia studies have transitioned into in 3D andin vivosettings, leading to the confirmation of their essential role in metastasis in preclinical animal models. In summary, invadopodia may hold a great potential for individual risk assessment as a prognostic marker for metastasis, as well as a therapeutic target.
Subject(s)
Neoplasms , Podosomes , Animals , Proteolysis , Extracellular Matrix , Focal AdhesionsABSTRACT
BACKGROUND: We have developed innovative base formulations that were designed to mimic the skin with respect to its components and galenic structure. Components include water, proteins, lipids, sugars and minerals. OBJECTIVES: We characterized formulations and their skin penetration using in vitro methods and evaluated their impact on skin hydration in a clinical trial. METHODS: Scanning electron microscopy (SEM) imaging and X-ray diffraction were used to analyse formulations as well as formulation impact on the stratum corneum (SC) structure. Mass spectrometry imaging (MSI) was used to compare formulation ingredients with SC components and to detect their distribution in the skin. Clinical studies were performed to confirm effects on skin hydration and investigate potential adverse skin effects (irritation and sensitization). RESULTS: SEM and X-ray diffraction of the formulations showed that lipids were organized in sheets similar to SC lipids. MSI demonstrated similarities between formulation components and skin constituents, as well as a good penetration into the skin. The formulations did not modify the lamellar organization of the SC lipids, but they increased the relative proportion of the crystallized lipids and some of the amorphous lipids. In in vivo studies, a high level of hydration was maintained over 24 h after application with an intense and 'very good hydration'. Both formulations were shown to be non-(photo)sensitizers with excellent tolerance. Sensorial evaluation indicated the formulations were not oily or sticky and maintained the skin's suppleness over time. Formulations had a 'nude skin' touch and created a natural protective film. CONCLUSIONS: The two formulations were well-tolerated and increased skin hydration in clinical subjects, an effect that could contribute to the alleviation of sensitive skin. The formulations were shown to resemble the lipid organization of the stratum corneum, as well as penetrate the skin without disrupting the lipid lamella organization.
Subject(s)
Epidermis , Skin , Humans , In Vitro Techniques , Oils/analysis , Oils/metabolism , Skin/diagnostic imaging , Skin/metabolism , Water/metabolismABSTRACT
BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).
Subject(s)
Fractures, Compression , Matrix Attachment Region Binding Proteins , Spinal Fractures , Transcription Factors , Adolescent , Adult , Biomarkers , Bone Density/genetics , Bone and Bones , Child , Child, Preschool , Cohort Studies , Female , Fractures, Compression/genetics , Fractures, Compression/metabolism , Fractures, Compression/pathology , Humans , Male , Matrix Attachment Region Binding Proteins/genetics , Matrix Attachment Region Binding Proteins/metabolism , Prospective Studies , Spinal Fractures/genetics , Spinal Fractures/metabolism , Spinal Fractures/pathology , Syndrome , Transcription Factors/genetics , Transcription Factors/metabolism , Young AdultABSTRACT
Luminescence and chemiluminescence have been experimentally investigated in hydrodynamic cavitating flows. By using dedicated microdevices inserted inside a light tight box, photons counting has been made possible. Luminescence has been investigated with deionized water as the working fluid; chemiluminescence has resulted from cavitating alkaline luminol solutions, and has been correlated to hydroxyl radicals formation. For the first time, luminescent and chemiluminescent phenomena have been considered together on the same devices submitted to similar cavitating flow regimes. Degassed solutions enhance the luminescence and also the hydroxyl radical yield. Due to the small sizes of the channels, the lifetimes of the collapsing bubbles correspond to pseudo frequencies matching the range of optimal frequencies used in sonochemistry. New perspectives for the study of hydrodynamic cavitation as an advanced oxidation process are suggested.
ABSTRACT
Controlled radical polymerization of ethylene using different commercially available, cheap, and non-toxic iodo alkyls is performed by iodine transfer polymerization (ITP) under mild conditions (≤100 °C and ≤200â bar). The formed well-defined iodo end-capped polyethylene (PE-I) species is very stable upon storage. Narrow molar-mass distributions (dispersities around 1.6) were obtained up to number average molar masses of 7300â g mol-1 . The ethylene copolymerization by ITP (ITcoP) with vinyl acetate allowed to form a broad range of poly(ethylene-co-vinyl acetate) (EVA) containing from 0 to 85â mol % of VAc unit. In addition, EVA-b-PE block copolymers or EVA-b-EVA gradient block copolymers with different content of VAc in the blocks were obtained for the first time using ITP. Finally, reactivity trends were explored by a theoretical mechanistic study. This highly versatile synthetic platform provides a straightforward access to a diverse range of well-defined PE based polymer materials.
ABSTRACT
Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD syndromes are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD syndromes have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign. Whole-exome sequencing and SNP array identified compound heterozygous variants in the INTU gene, which encodes a protein involved in the positioning of the ciliary basal body. INTU is a subunit of the CPLANE multiprotein complex essential for the assembly of IFT-A particles and intraflagellar transport. This report of a second patient with INTU-related OFD syndrome and the further delineation of its neuroimaging and skeletal phenotype now allow INTU-related OFD syndromes to be classified within the OFD syndrome type VI group. Patients display a phenotype similar to that of mice with a hypomorphic mutation of Intu, but with the addition of a heart defect.
Subject(s)
Cytoskeletal Proteins/genetics , Membrane Proteins/genetics , Orofaciodigital Syndromes/genetics , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Orofaciodigital Syndromes/diagnostic imagingSubject(s)
Arrhythmias, Cardiac/genetics , Genetic Diseases, X-Linked/genetics , Gigantism/genetics , Glypicans/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Arrhythmias, Cardiac/pathology , Comparative Genomic Hybridization , Genetic Diseases, X-Linked/pathology , Genetic Predisposition to Disease , Gigantism/pathology , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/pathologyABSTRACT
Progressive cerebellar ataxias are well-known hereditary neurological disorders. Among them, spinocerebellar ataxia type 7 (SCA7) is inherited as an autosomal dominant trait and is ascribed to the expansion of a CAG trinucleotide repeat within the ATXN7 gene. An anticipation phenomenon can occur during paternal transmission and sometimes is responsible for a severe infantile form. The specificity of SCA7 is the retinal involvement with retinitis pigmentosa and cone rod dystrophy. We describe a familial form with two siblings who died of a severe infantile form. Diagnosis was made in their father, who had a recent history of macular atrophy and presented with gait disturbance thereafter. Retrospectively, substantial triplet repeat expansion was confirmed in the two affected infants. These infantile forms are rare and difficult to diagnose in the absence of suggestive family symptoms.
Subject(s)
Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Ataxin-7/genetics , Brain/diagnostic imaging , Fatal Outcome , Humans , Infant , Magnetic Resonance Imaging , Male , Pedigree , Trinucleotide Repeat ExpansionABSTRACT
The synthesis and characterization of silica-grafted monopodal and bipodal aluminum hydrides has been achieved starting from 200 °C- and 700 °C-annealed silica and [AlH3(NMe2Et)]. The mechanism by which aluminum trishydride reacts with isolated and vicinal silanols, assisted by the amine, has been investigated computationally at the ωB97XD-DFT level.
ABSTRACT
The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
Subject(s)
Intellectual Disability/genetics , Musculoskeletal Abnormalities/genetics , Osteochondrodysplasias/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Association Studies , Humans , Infant , Infant, Newborn , Intellectual Disability/diagnosis , Intellectual Disability/diagnostic imaging , Intellectual Disability/physiopathology , Male , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/diagnostic imaging , Musculoskeletal Abnormalities/physiopathology , Osteochondrodysplasias/diagnosis , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/physiopathology , Radiography , Exome SequencingABSTRACT
Correction for 'Weak backbone CHO[double bond, length as m-dash]C and side chain tButBu London interactions help promote helix folding of achiral NtBu peptoids' by G. Angelici et al., Chem. Commun., 2016, 52, 4573-4576.
ABSTRACT
The synthesis of all-cis amide (NtBu)-glycine oligomers up to 15 residues long by a blockwise coupling approach is reported. The structure and dynamical behavior of these peptoids have been studied by X-ray crystallography, NMR and molecular modeling. Analyses reveal that the folding of these oligomers is driven by weak CH···O=C hydrogen bonding along the peptoid backbone and London interaction between tBu···tBu side-chains.
Subject(s)
Peptides/chemistry , Protein Folding , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Molecular , Proton Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.
Subject(s)
Adenocarcinoma, Clear Cell/mortality , Adenocarcinoma, Clear Cell/pathology , Antigens, CD/metabolism , Cell Adhesion Molecules/metabolism , Neoplasm Proteins/metabolism , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Adenocarcinoma, Clear Cell/metabolism , Animals , Antigens, CD/analysis , Antigens, CD/genetics , Antigens, Neoplasm , Carboplatin/pharmacology , Cell Adhesion Molecules/analysis , Cell Adhesion Molecules/genetics , Cell Line, Tumor/drug effects , Cell Movement , Drug Resistance, Neoplasm/drug effects , Female , Humans , Kaplan-Meier Estimate , Mice, Inbred NOD , Neoplasm Proteins/analysis , Neoplasm Proteins/genetics , Ovarian Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Spheroids, Cellular/metabolism , Spheroids, Cellular/pathology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The number of obese and morbidly obese patients within the developed world is dramatically increasing within the last 20 years. Apart from demographical changes, obese patients are especially prone to have oestrogen-dependent morbidities and neoplasias, of which laparoscopic treatment should be the standard of care. The increasing number of patients with BMI >40 is concerning, making it necessary to summarise considerations for safe and effective Gynaecological Laparoscopic Surgery. CONSIDERATIONS: The sequel to successful laparoscopic surgery in obese patients comprises an interdisciplinary appreciation of laparoscopy. Preoperatively, anaesthetics and medical review are suggested to optimise treatment of comorbidities (i.e. infections and blood sugar levels). Positioning of the patient should consider anti-slip options and pannus fixation to ease laparoscopic access and decrease pressure to the chest. There is no standard port placement in obese patients and landmarks have to be the bony structures of the pelvis and ribs. Retraction of the bowel is essential and mobilisation of the sigmoid with fan retractors or endoloops can accomplish adequate vision. 30° scopes can be considered for vision "around the obstacle". An experienced assistant with anticipation of surgical steps is favourable for successful surgery completion. Intra-operatively, good surgical techniques are essential. Vessel sealing systems reduce the need for instrument changes and may be helpful in following visualised tissue planes. A transvaginal vault closure may be advantageous compared to laparoscopic closure and Endostiches may be preferred to close the fascia of large trocar sites under vision.
Subject(s)
Gynecologic Surgical Procedures/methods , Laparoscopy/methods , Obesity, Morbid/physiopathology , Comorbidity , Female , Humans , Laparoscopy/adverse effects , Obesity, Morbid/complications , Surgical InstrumentsABSTRACT
Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.
Subject(s)
Antigens, CD/metabolism , Cell Adhesion Molecules/metabolism , Epidermal Growth Factor/pharmacology , ErbB Receptors/metabolism , Lipoylation , Membrane Proteins/metabolism , Neoplasm Proteins/metabolism , Animals , Antibodies, Monoclonal/immunology , Antigens, CD/immunology , Antigens, Neoplasm , Cell Adhesion Molecules/antagonists & inhibitors , Cell Adhesion Molecules/immunology , Cell Line, Tumor , Cell Membrane/metabolism , Cell Movement , Enzyme Activation , Female , Humans , Interleukin-6/pharmacology , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/immunology , Neoplasm Transplantation , Ovarian Neoplasms/pathology , Protein Transport , Transplantation, Heterologous , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression.
Subject(s)
Cell Nucleus/genetics , Centromere , Heterochromatin/chemistry , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Adolescent , Chromosome Aberrations , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 9 , DNA Methylation , DNA, Satellite , Face/abnormalities , Female , Humans , In Situ Hybridization, Fluorescence , Primary Immunodeficiency DiseasesABSTRACT
The ciliopathies are an expanding group of disorders caused by mutations in genes implicated in the biogenesis and function of primary cilia. Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by progressive retinal degeneration, obesity, polydactyly, cognitive impairment, kidney anomalies and hypogonadism. Mutations in SDCCAG8(NPHP10) were described recently in patients with nephronophthisis and retinal degeneration (Senior-Loken syndrome; SLS). Given the phenotypic and genetic overlap between known ciliopathy genes, we hypothesized that mutations in SDCCAG8 might also contribute alleles to more severe, multisystemic ciliopathies. We performed genetic and phenotypic analyses of 2 independent BBS cohorts. Subsequent to mutation screening, we made a detailed phenotypic analysis of 5 families mutated for SDCCAG8 (3 homozygous and 2 compound heterozygous mutations) and conducted statistical analyses across both cohorts to examine possible phenotype-genotype correlations with mutations at this locus. All patients with mutations in SDCCAG8 fulfilled the diagnostic criteria for BBS (retinal degeneration, obesity, cognitive defects, renal failure, hypogonadism). Interestingly, none of the patients with primary SDCCAG8 mutations had polydactyly, a frequent but not obligatory BBS feature. In contrast, the same patients displayed early-onset renal failure, obesity, as well as recurrent pulmonary and ENT infections. Comparison of the phenotypes of these families with our entire BBS cohort indicated that renal impairment and absent polydactyly correlated significantly with causal SDCCAG8 mutations. Thus, SDCCAG8 mutations are sufficient to cause BBS in 1-2% of our combined cohorts, and define this gene as the sixteenth BBS locus (BBS16). The absence of polydactyly and the concomitant, apparently fully penetrant association with early kidney failure represents the first significant genotype-phenotype correlation in BBS that potentially represents an indicator for phenotype-driven priority screening and informs specific patient management.