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1.
Adv Protein Chem Struct Biol ; 141: 255-297, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38960477

RESUMO

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis.


Assuntos
Glioma , Gliose , Proteínas de Membrana , Humanos , Proteínas de Membrana/metabolismo , Glioma/metabolismo , Glioma/patologia , Gliose/metabolismo , Gliose/patologia , Animais , Receptores de Peptídeos
2.
Int J Mol Sci ; 25(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38612777

RESUMO

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.


Assuntos
Glioblastoma , Glioma , Doença de Parkinson , Humanos , Glioblastoma/genética , Proteínas de Membrana/genética , Células Endoteliais , Angiogênese , Glioma/genética , Neuroglia , Neovascularização Patológica/genética
3.
J Exp Clin Cancer Res ; 43(1): 49, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365745

RESUMO

BACKGROUND: SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC. METHODS: At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo. RESULTS: We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes. CONCLUSIONS: These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC.


Assuntos
Coesinas , Neoplasias Colorretais , Animais , Humanos , Camundongos , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Proteínas Cromossômicas não Histona/genética , Coesinas/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Inativação Gênica , Fator A de Crescimento do Endotélio Vascular/genética
4.
Br J Haematol ; 204(1): 292-305, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37876306

RESUMO

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.


Assuntos
Doenças da Medula Óssea , Insuficiência Pancreática Exócrina , Lipomatose , Humanos , Síndrome de Shwachman-Diamond , Proteína Supressora de Tumor p53/genética , Lipomatose/genética , Códon sem Sentido , Mielopoese , Neutrófilos/metabolismo , Quimiotaxia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Insuficiência Pancreática Exócrina/genética , Ribossomos/metabolismo
5.
Int J Mol Sci ; 24(23)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38069286

RESUMO

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.


Assuntos
Genes Homeobox , Fatores de Transcrição Otx , Fatores de Transcrição Otx/genética , Retina/metabolismo , Proteínas de Homeodomínio/genética , Regulação da Expressão Gênica no Desenvolvimento
6.
Genes (Basel) ; 14(11)2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-38003028

RESUMO

The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML.


Assuntos
Doença Granulomatosa Crônica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Masculino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores não Relacionados , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Translocação Genética
7.
Biomedicines ; 11(8)2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37626657

RESUMO

In recent years, there has been a growing interest in developing innovative anticancer therapies targeting the tumor microenvironment (TME). The TME is a complex and dynamic milieu surrounding the tumor mass, consisting of various cellular and molecular components, including those from the host organism, endowed with the ability to significantly influence cancer development and progression. Processes such as angiogenesis, immune evasion, and metastasis are crucial targets in the search for novel anticancer drugs. Thus, identifying molecules with "multi-tasking" properties that can counteract cancer cell growth at multiple levels represents a relevant but still unmet clinical need. Extensive research over the past two decades has revealed a consistent anticancer activity for several members of the T2 ribonuclease family, found in evolutionarily distant species. Initially, it was believed that T2 ribonucleases mainly acted as anticancer agents in a cell-autonomous manner. However, further investigation uncovered a complex and independent mechanism of action that operates at a non-cell-autonomous level, affecting crucial processes in TME-induced tumor growth, such as angiogenesis, evasion of immune surveillance, and immune cell polarization. Here, we review and discuss the remarkable properties of ribonucleases from the T2 family in the context of "multilevel" oncosuppression acting on the TME.

8.
Genes (Basel) ; 14(7)2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37510256

RESUMO

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1-controlled tyrosine kinase chimeric protein responsible for CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Transtornos Mieloproliferativos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Cromossomo Filadélfia , Translocação Genética , Proteínas de Fusão bcr-abl/genética , Transtornos Mieloproliferativos/genética
9.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012339

RESUMO

Ovarian cancer represents one of the most malignant gynecological cancers worldwide, with an overall 5-year survival rate, being locked in the 25-30% range in the last decade. Cancer immunotherapy is currently one of the most intensively investigated and promising therapeutic strategy and as such, is expected to provide in the incoming years significant benefits for ovarian cancer treatment as well. Here, we provide a detailed survey on the highly pleiotropic oncosuppressive roles played by the human RNASET2 gene, whose protein product has been consistently reported to establish a functional crosstalk between ovarian cancer cells and key cellular effectors of the innate immune system (the monocyte/macrophages lineage), which is in turn able to promote the recruitment to the cancer tissue of M1-polarized, antitumoral macrophages. This feature, coupled with the ability of T2 ribonucleases to negatively affect several cancer-related parameters in a cell-autonomous manner on a wide range of ovarian cancer experimental models, makes human RNASET2 a very promising candidate to develop a "multitasking" therapeutic approach for innovative future applications for ovarian cancer treatment.


Assuntos
Neoplasias Ovarianas , Ribonucleases , Proteínas Supressoras de Tumor , Feminino , Genes Supressores de Tumor , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ribonucleases/genética , Ribonucleases/metabolismo , Proteínas Supressoras de Tumor/genética
10.
Int J Exp Pathol ; 103(1): 13-22, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34725870

RESUMO

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the colon and small intestine, including Crohn's disease and ulcerative colitis. Since Danio rerio is a promising animal model to study gut function, we developed a soy-dependent model of intestinal inflammation in adult zebrafish. The soya bean meal diet was given for 4 weeks and induced an inflammatory process, as demonstrated by morphological changes together with an increased percentage of neutrophils infiltrating the intestinal wall, which developed between the second and fourth week of treatment. Pro-inflammatory genes such as interleukin-1beta, interleukin-8 and tumour necrosis factor alpha were upregulated in the second week and anti-inflammatory genes such as transforming growth factor beta and interleukin-10. Interestingly, an additional expression peak was found for interleukin-8 at the fourth week. Neuronal genes, OTX1 and OTX2, were significantly upregulated in the first two  weeks, compatible with the development of the changes in the gut wall. As for the genes of the p53 family such as p53, DNp63 and p73, a statistically significant increase was observed after two weeks of treatment compared with controls. Interestingly, DNp63 and p73 were shown an additional peak after four weeks. Our data demonstrate that soya bean meal diet negatively influences intestinal morphology and immunological function in adult zebrafish showing the features of acute inflammation. Data observed at the fourth week of treatment may suggest initiation of chronic inflammation. Adult zebrafish may represent a promising model to better understand the mechanisms of food-dependent intestinal inflammation.


Assuntos
Dieta , Glycine max , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestinos/metabolismo , Intestinos/patologia , Fator de Necrose Tumoral alfa/metabolismo , Peixe-Zebra
11.
Int J Mol Sci ; 22(24)2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34948128

RESUMO

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.


Assuntos
Calcificação Fisiológica , Osteoblastos/metabolismo , Síndrome de Shwachman-Diamond/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Osteoblastos/patologia , Proteínas/genética , Proteínas/metabolismo , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/patologia , Proteína Supressora de Tumor p53/genética
12.
Mol Cytogenet ; 14(1): 54, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819134

RESUMO

BACKGROUND: An isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q), are the most frequent anomalies in the bone marrow of patients with Shwachman-Diamond syndrome, which is caused in most cases by mutations of the SBDS gene. These clonal changes imply milder haematological symptoms and lower risk of myelodysplastic syndromes and acute myeloid leukaemia, thanks to already postulated rescue mechanisms. RESULTS: Bone marrow from fourteen patients exhibiting either the i(7)(q10) or the del(20)(q) and coming from two large cohorts of patients, were subjected to chromosome analyses, Fluorescent In Situ Hybridization with informative probes and array-Comparative Genomic Hybridization. One patient with the i(7)(q10) showed a subsequent clonal rearrangement of the normal chromosome 7 across years. Four patients carrying the del(20)(q) evolved further different del(20)(q) independent clones, within a single bone marrow sample, or across sequential samples. One patient with the del(20)(q), developed a parallel different clone with a duplication of chromosome 3 long arm. Eight patients bore the del(20)(q) as the sole chromosomal abnormality. An overall overview of patients with the del(20)(q), also including cases already reported, confirmed that all the deletions were interstitial. The loss of material varied from 1.7 to 26.9 Mb and resulted in the loss of the EIF6 gene in all patients. CONCLUSIONS: Although the i(7)(q) and the del(20)(q) clones are frequent and clinically benign in Shwachman Diamond-syndrome, in the present work we show that they may rearrange, may be lost and then reconstructed de novo, or may evolve with independent clones across years. These findings unravel a striking selective pressure exerted by SBDS deficiency driving to karyotype instability and to specific clonal abnormalities.

13.
Front Oncol ; 11: 662746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34026639

RESUMO

BACKGROUND: The aim of the study was to compare coronavirus disease 2019 (COVID-19) severity presentation between oncologic and non-oncologic patients and to evaluate the impact of cancer type and stage on COVID-19 course. METHODS: We performed a multicentre, retrospective study involving 13 COVID-19 Units in Campania region from February to May 2020. We defined as severe COVID-19 presentation the cases that required mechanical ventilation and/or admission to Intensive Care Units (ICU) and/or in case of death. RESULTS: We enrolled 371 COVID-19 patients, of whom 34 (9.2%) had a history or a diagnosis of cancer (24 solid, 6 onco-hematological). Oncologic patients were older (p<0.001), had more comorbidities (p<0.001) and showed a higher rate of severe COVID-19 presentation (p=0.001) and of death (p<0.001). Compared to 12 patients with non-active cancer and to 337 without cancer, the 17 patients with active cancer had more comorbidities and showed a higher rate of severe COVID-19 and of mortality (all p values <0.001). Compared to the 281 non-severe patients, the 90 subjects with a severe presentation of COVID-19 were older (p<0.01), with more comorbidities (p<0.001) and with a higher rate of cancer (p=0.001). At multivariate analysis, age (OR 1.08, 95% CI: 1.04-1.11) and suffering from cancer in an active stage (OR 5.33, 95% CI: 1.77-16.53) were independently associated with severe COVID-19. CONCLUSIONS: Since the higher risk of severe evolution of COVID-19, cancer patients, especially those with an active malignancy, should be candidates for early evaluation of symptoms and early treatment for COVID-19.

14.
PeerJ ; 8: e8442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32095330

RESUMO

BACKGROUND: Inflammatory bowel diseases are associated with remodeling of neuronal circuitries within the enteric nervous system, occurring also at sites distant from the acute site of inflammation and underlying disturbed intestinal functions. Homeoproteins orthodenticle OTX1 and OTX2 are neuronal transcription factors participating to adaptation during inflammation and underlying tumor growth both in the central nervous system and in the periphery. In this study, we evaluated OTX1 and OTX2 expression in the rat small intestine and distal colon myenteric plexus after intrarectal dinitro-benzene sulfonic (DNBS) acid-induced colitis. METHODS: OTX1 and OTX2 distribution was immunohistochemically investigated in longitudinal muscle myenteric plexus (LMMP)-whole mount preparations. mRNAs and protein levels of both OTX1 and OTX2 were evaluated by qRT-PCR and Western blotting in LMMPs. RESULTS: DNBS-treatment induced major gross morphology and histological alterations in the distal colon, while the number of myenteric neurons was significantly reduced both in the small intestine and colon. mRNA levels of the inflammatory markers, TNFα, pro-IL1ß, IL6, HIF1α and VEGFα and myeloperoxidase activity raised in both regions. In both small intestine and colon, an anti-OTX1 antibody labeled a small percentage of myenteric neurons, and prevalently enteric glial cells, as evidenced by co-staining with the glial marker S100ß. OTX2 immunoreactivity was present only in myenteric neurons and was highly co-localized with neuronal nitric oxide synthase. Both in the small intestine and distal colon, the number of OTX1- and OTX2-immunoreactive myenteric neurons significantly increased after DNBS treatment. In these conditions, OTX1 immunostaining was highly superimposable with inducible nitric oxide synthase in both regions. OTX1 and OTX2 mRNA and protein levels significantly enhanced in LMMP preparations of both regions after DNBS treatment. CONCLUSIONS: These data suggest that colitis up-regulates OTX1 and OTX2 in myenteric plexus both on site and distantly from the injury, potentially participating to inflammatory-related myenteric ganglia remodeling processes involving nitrergic transmission.

15.
Mol Cytogenet ; 13: 1, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31908654

RESUMO

BACKGROUND: Clonal chromosome changes are often found in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS). The most frequent ones include an isochromosome of the long arm of chromosome 7, i (7)(q10), and an interstitial deletion of the long arm of chromosome 20, del (20)(q). These two imbalances are mechanisms of somatic genetic rescue. The literature offers few expression studies on SDS. RESULTS: We report the expression analysis of bone marrow (BM) cells of patients with SDS in relation to normal karyotype or to the presence of clonal chromosome anomalies: del (20)(q) (five cases), i (7)(q10) (one case), and other anomalies (two cases). The study was performed using the microarray technique considering the whole transcriptome (WT) and three gene subsets selected as relevant in BM functions. The expression patterns of nine healthy controls and SDS patients with or without chromosome anomalies in the bone marrow showed clear differences. CONCLUSIONS: There is a significant difference between gene expression in the BM of SDS patients and healthy subjects, both at the WT level and in the selected gene sets. The deletion del (20)(q), with the EIF6 gene consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells led to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields a pattern similar to healthy subjects. Hence, the benign prognostic value of del (20)(q). The case of i (7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.

16.
Respirology ; 25(5): 535-542, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31373748

RESUMO

BACKGROUND AND OBJECTIVE: The aim of this study was to assess the role of lung ultrasound (LUS) in a diagnostic algorithm of respiratory diseases, and to establish the accuracy of LUS compared with chest radiography (CXR). METHODS: Over a period of 2 years, 509 consecutive patients admitted for respiratory-related symptoms to both emergency and general medicine wards were enrolled and evaluated using LUS and CXR. LUS was conducted by expert operators who were blinded to the medical history and laboratory data. Computed tomography (CT) of the chest was performed in case of discordance between the CXR and LUS, suspected lung cancer and an inconclusive diagnosis. Diagnosis made by CT was considered the gold standard. RESULTS: The difference in sensitivity and specificity between LUS and CXR as demonstrated by ROC curve analyses (LUS-AUROC: 0.853; specificity: 81.6%; sensitivity: 93.9% vs CXR-AUROC: 0.763; specificity: 57.4%; sensitivity: 96.3%) was significant (P = 0.001). Final diagnosis included 240 cases (47.2%) of pneumonia, 44 patients with cancer (8.6%), 20 patients with chronic obstructive pulmonary disease (COPD, 3.9%), 24 patients with heart failure (4.7%) and others (6.1%). In 108 patients (21.2%) with any lung pathology, a CT scan was performed with a positive diagnosis in 96 cases (88.9%); we found that CXR and LUS detected no abnormality in 24 (25%) and 5 (5.2%) cases, respectively. LUS was concordant with the final diagnosis (P < 0.0001), and in healthy patients, there was a low percentage of false positives (5.9%). CONCLUSION: The results support the routine use of LUS in the clinical context.


Assuntos
Pulmão/diagnóstico por imagem , Admissão do Paciente/estatística & dados numéricos , Radiografia Torácica/métodos , Transtornos Respiratórios , Ultrassonografia , Idoso , Algoritmos , Serviços de Diagnóstico/estatística & dados numéricos , Feminino , Humanos , Itália/epidemiologia , Masculino , Utilização de Procedimentos e Técnicas , Estudos Prospectivos , Transtornos Respiratórios/classificação , Transtornos Respiratórios/diagnóstico , Transtornos Respiratórios/epidemiologia , Sensibilidade e Especificidade , Ultrassonografia/métodos , Ultrassonografia/normas , Ultrassonografia/estatística & dados numéricos
17.
J Vis Exp ; (144)2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30882801

RESUMO

OTX homeobox (HB) genes are expressed during embryonic morphogenesis and during the development of olfactory epithelium in adult organisms. Mutations occurring in these genes are often related to tumorigenesis in human. No data are available today regarding the possible correlation between OTX genes and tumors of the nasal cavity. The aim of this work is to understand if OTX1 and OTX2 can be considered as molecular markers in the development of nasal tumors. We selected nasal and sinonasal adenocarcinomas to investigate the expression of OTX1 and OTX2 genes through immunohistochemical and real-time PCR analyses.Both OTX1 and OTX2 were absent in all the samples of sinonasal Intestinal-Type Adenocarcinomas (ITACs). OTX1 mRNA was identified only in Non-Intestinal Type Adenocarcinomas (NITACs) while OTX2 mRNA was expressed only in Olfactory Neuroblastomas (ONs). We have demonstrated that the differential gene expression for both OTX1 and OTX2 genes might be a useful molecular marker to distinguish the different types of sinonasal tumors.


Assuntos
Estesioneuroblastoma Olfatório/diagnóstico , Estesioneuroblastoma Olfatório/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Homeobox/genética , Fatores de Transcrição Otx/metabolismo , Neoplasias dos Seios Paranasais/diagnóstico , Estesioneuroblastoma Olfatório/patologia , Humanos , Neoplasias dos Seios Paranasais/genética , Neoplasias dos Seios Paranasais/patologia
18.
Cancers (Basel) ; 11(2)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813308

RESUMO

RNASET2 is an extracellular ribonuclease endowed with a marked antitumorigenic role in several carcinomas, independent from its catalytic activity. Besides its antitumorigenic role by the recruitment to the tumor mass of immune cells from the monocyte/macrophage lineage, RNASET2 is induced by cellular stress and involved in actin cytoskeleton remodeling affecting cell interactions with the extracellular matrix (ECM). Here, we aimed to investigate the effects of RNASET2 expression modulation on cell phenotype and behavior in epithelial ovarian cancer (EOC) cellular models. In silico analysis on two publicly available datasets of gene expression from EOC patients (n = 392) indicated that increased RNASET2 transcript levels are associated with longer overall survival. In EOC biopsies (n = 101), analyzed by immunohistochemistry, RNASET2 was found heterogeneously expressed among tumors with different clinical⁻pathological characteristics and, in some cases, its expression localized to tumor-associated ECM. By characterizing in vitro two models of EOC cells in which RNASET2 was silenced or overexpressed, we report that RNASET2 expression negatively affects growth capability by conferring a peculiar cell phenotype upon the interaction of EOC cells with the ECM, resulting in decreased src activation. Altogether, these data suggest that drugs targeting activated src might represent a therapeutic approach for RNASET2-expressing EOCs.

19.
Br J Haematol ; 184(6): 974-981, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30585299

RESUMO

In Shwachman-Diamond syndrome (SDS), deletion of the long arm of chromosome 20, del(20)(q), often acquired in bone marrow (BM), may imply a lower risk of developing myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), due to the loss of the EIF6 gene. The genes L3MBTL1 and SGK2, also on chromosome 20, are in a cluster of imprinted genes, and their loss implies dysregulation of BM function. We report here the results of array comparative genomic hybridization (a-CGH) performed on BM DNA of six patients which confirmed the consistent loss of EIF6 gene. Interestingly, array single nucleotide polymorphisms (SNPs) showed copy neutral loss of heterozygosity for EIF6 region in cases without del(20)(q). No preferential parental origin of the deleted chromosome 20 was detected by microsatellite analysis in six SDS patients. Our patients showed a very mild haematological condition, and none evolved into BM aplasia or MDS/AML. We extend the benign prognostic significance of del(20)(q) and loss of EIF6 to the haematological features of these patients, consistently characterized by mild hypoplastic BM, no or mild neutropenia, anaemia and thrombocytopenia. Some odd results obtained in microsatellite and SNP-array analysis demonstrate a peculiar genomic instability, in an attempt to improve BM function through the acquisition of the del(20)(q).


Assuntos
Cromossomos Humanos Par 20/genética , Instabilidade Genômica/genética , Síndrome de Shwachman-Diamond/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Prognóstico , Síndrome de Shwachman-Diamond/patologia , Adulto Jovem
20.
Cell Death Dis ; 9(3): 349, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500381

RESUMO

Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT-PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT-PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Idoso , DNA/genética , Feminino , Seguimentos , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto Jovem
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