RESUMEN
IMPORTANCE: Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. OBJECTIVE: Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. DESIGN: We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. RESULTS: Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. CONCLUSIONS AND RELEVANCE: This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Reparación de la Incompatibilidad de ADN/genética , Inmunoterapia/métodos , Inestabilidad de Microsatélites/efectos de los fármacos , Neoplasias del Timo/tratamiento farmacológico , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Femenino , Humanos , Neoplasias del Timo/patologíaAsunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Manejo de Datos , Humanos , Homólogo 1 de la Proteína MutL/genética , Estudios ProspectivosRESUMEN
The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Cromosomas Humanos Par 15/genética , Metilación de ADN , Impresión Genómica , Síndrome de Silver-Russell/genética , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Proteínas Reguladoras de la Apoptosis , Niño , Preescolar , Femenino , Humanos , Lactante , Factores de Transcripción de Tipo Kruppel/química , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Mutación Missense , Adulto JovenRESUMEN
Aerosol composition and properties variation under the advection of different air masses were investigated, as case studies, by contemporary measurements over the atmospheric column and at the ground in a semi-rural site in South Italy. The absence of local strong sources in this area allowed to characterize background aerosol and to compare particle mixing effects under various atmospheric circulation conditions. Aerosol optical depth (AOD) and Ǻngström parameters from radiometric measurements allowed the detection and identification of polluted, dust, and volcanic atmospheric conditions. AODs were the input for a suitable model to evaluate the columnar aerosol composition, according to six main atmospheric components (water-soluble, soot, sea salt accumulation, sea salt coarse, mineral dus,t and biological). Scanning electron microscope (SEM) analysis of particulate sampled with a 13-stage impactor at the ground showed not only fingerprints typical of the different air masses but also the effects of transport and aging on atmospheric particles, suggesting processes that changed their chemical and optical properties. Background columnar aerosol was characterized by 72% of water-soluble and soot, in agreement with ground-based findings that highlighted 60% of contribution from anthropogenic carbonate particles and soot. In general, a good agreement between ground-based and columnar results was observed. Under the advection of trans-boundary air masses, water-soluble and soot were always present in columnar aerosol, whereas, in variable percentages, sea salt and mineral particles characterized both dust and volcanic conditions. At the ground, sulfates characterized the amorphous matrix produced in finer stages by the evaporation of solutions of organic and inorganic aerosols. Sulfates were also one of the key players involved in heterogeneous chemical reactions, producing complex secondary aerosol, as such clay-sulfate internally mixed particle externally mixed with soot chains.
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Contaminantes Atmosféricos/análisis , Polvo/análisis , Monitoreo del Ambiente/métodos , Modelos Teóricos , Hollín/análisis , Sulfatos/análisis , Aerosoles , Italia , Solubilidad , Propiedades de SuperficieRESUMEN
In this report, we describe two adult brothers affected by moderate non-specific intellectual disability (ID). They showed minor facial anomalies, not clearly ascribable to any specific syndromic patterns, microcephaly, brachydactyly and broad toes. Both brothers presented seizures. Karyotype, subtelomeric and FMR1 analysis were normal in both cases. We performed array-CGH analysis that revealed no copy-number variations potentially associated with ID. Subsequent exome sequence analysis allowed the identification of the ATRX c.109C>T (p.R37X) mutation in both the affected brothers. Sanger sequencing confirmed the presence of the mutation in the brothers and showed that the mother is a healthy carrier. Mutations in the ATRX gene cause the X-linked alpha thalassemia/mental retardation (ATR-X) syndrome (MIM #301040), a severe clinical condition usually associated with profound ID, facial dysmorphism and alpha thalassemia. However, the syndrome is clinically heterogeneous and some mutations, including the c.109C>T, are associated with a broad phenotypic spectrum, with patients displaying a less severe phenotype with only mild-moderate ID. In the case presented here, exome sequencing provided an effective strategy to achieve the molecular diagnosis of ATR-X syndrome, which otherwise would have been difficult to consider due to the mild non-specific phenotype and the absence of a family history with typical severe cases.
RESUMEN
Our understanding of the biochemical mechanisms that mediate chemoreception in insects has been greatly improved after the discovery of olfactory and taste receptor proteins. However, the presence of soluble polypeptides in high concentration around the dendrites of sensory neurons still poses unanswered questions. More than 2 decades after their discovery and despite the wealth of structural information available, the physiological function of odorant-binding proteins is not well understood. More recently, members of a second family of soluble polypeptides, the chemosensory proteins, were also discovered in the lymph of chemosensilla. Here we review the structural properties of both classes of soluble proteins, their affinity to small ligands, and their expression in the different parts of the insect body and subcellular localisation. Finally, we discuss current ideas and models of the role of such proteins in insect chemoreception.
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Células Quimiorreceptoras/fisiología , Proteínas de Insectos/fisiología , Insectos/fisiología , Receptores Odorantes/fisiología , Secuencia de Aminoácidos , Animales , Conducta Animal , Células Quimiorreceptoras/química , Secuencia de Consenso , Dendritas/fisiología , Femenino , Regulación de la Expresión Génica , Proteínas de Insectos/química , Proteínas de Insectos/genética , Ligandos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Familia de Multigenes , Neuronas Aferentes/fisiología , Odorantes , Especificidad de Órganos , Feromonas/fisiología , Filogenia , Unión Proteica , Conformación Proteica , Receptores Odorantes/química , Receptores Odorantes/genética , Receptores de Feromonas/química , Receptores de Feromonas/genética , Receptores de Feromonas/fisiología , Órganos de los Sentidos/fisiología , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Olfato/fisiología , Solubilidad , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
The expression of chemosensory proteins (CSPs) and odorant-binding proteins (OBPs) in individuals of different castes and ages have been monitored in three species of social hymenopterans, Polistes dominulus (Hymenoptera, Vespidae), Vespa crabro (Hymenoptera, Vespidae) and Apis mellifera (Hymenoptera, Apidae), using PCR with specific primers and polyclonal antibodies. In the paper wasp P. dominulus, OBP is equally expressed in antennae, wings and legs of all castes and ages, while CSP is often specifically present in antennae and in some cases also in legs. In the vespine species V. crabro CSP is antennal specific, while OBP is also expressed in legs and wings. The three CSPs and the five OBPs of A. mellifera show a complex pattern of expression, where both classes of proteins include members specifically expressed in antennae and others present in other parts of the body. These data indicate that at least in some hymenopteran species CSPs are specifically expressed in antennae and could perform roles in chemosensory perception so far assigned only to OBPs.
Asunto(s)
Himenópteros/genética , Receptores Odorantes/genética , Avispas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Cartilla de ADN , Femenino , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Receptores Odorantes/metabolismo , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
Members of the odorant-binding protein (OBP) and chemosensory protein (CSP) families were identified and characterised in the sensory tissues of the social wasp Polistes dominulus (Hymenoptera: Vespidae). Unlike most insects so far investigated, OBPs were detected in antennae, legs and wings, while CSPs appeared to be preferentially expressed in the antennae. The OBP is very different from the homologous proteins of other Hymenopteran species, with around 20% of identical residues, while the CSP appears to be much better conserved. Both OBP and CSP, not showing other post-translational modifications apart from disulphide bridges, were expressed with high yields in a bacterial system. Cysteine pairing in the recombinant and native proteins follows the classical arrangements described for other members of these classes of proteins. OBPs isolated from the wings were found to be associated with a number of long-chain aliphatic amides and other small organic molecules. Binding of these ligands and other related compounds was measured for both recombinant OBP and CSP.