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1.
Blood ; 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35015835

RESUMO

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

2.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948243

RESUMO

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1-3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent-offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.


Assuntos
Transtorno Autístico/genética , Loci Gênicos , Predisposição Genética para Doença , Deficiência Intelectual/genética , Sequenciamento Completo do Exoma , Adolescente , Transtorno Autístico/patologia , Criança , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino
3.
Am J Dermatopathol ; 43(12): 962-964, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34608003

RESUMO

ABSTRACT: One of the most common patterns of presentations that have been described in COVID-19 patients includes the erythematous/papular/morbilliform eruptions. However, actually, the diffuse exanthems containing macules and papules were not specific to COVID-19, and even histopathology does not show any specific signs that could help to differentiate COVID-19 skin lesions from non-COVID-19 causes such as drugs or other viral infections. We present the case of a COVID-19-positive woman with a morbilliform rash, whose skin biopsy showed the presence of some peculiar cytopathic epidermal changes that could represent a possible distinctive histopathological feature related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection The presence of viral particles in the keratinocytes with additional positivity of endothelial cells and eccrine glands by immunohistochemistry using an anti-SARS-CoV-2 Spike S1 antibodies supports a causal relation of the lesions with SARS-CoV-2 infection.


Assuntos
COVID-19/complicações , Exantema/patologia , Exantema/virologia , Adulto , Feminino , Humanos , Queratinócitos/patologia , Queratinócitos/virologia , SARS-CoV-2
4.
Infection ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499325

RESUMO

BACKGROUND: The most common Italian rickettsiosis is Mediterranean Spotted Fever (MSF). MSF is commonly associated with a symptom triad consisting of fever, cutaneous rash, and inoculation eschar. The rash is usually maculopapular but, especially in severe presentations, may be petechial. Other typical findings are arthromyalgia and headache. Herein, we describe for the first time an unusual case of Israeli spotted fever (ISF) associated with interstitial pneumonia and pleural effusion in which R. conorii subsp. israelensis was identified by molecular methods in the blood, as well as in the pleural fluid. CASE PRESENTATION: A 72-year-old male presented with a 10-day history of remittent fever. On admission, the patient's general condition appeared poor with confusion and drowsiness; the first assessment revealed a temperature of 38.7°, blood pressure of 110/70 mmHg, a blood oxygen saturation level of 80% with rapid, frequent, and superficial breathing using accessory muscles (28 breaths per minute), and an arrhythmia with a heart rate of 90 beats per minute. qSOFA score was 3/3. Chest CT revealed ground-glass pneumonia with massive pleural effusion. Petechial exanthema was present diffusely, including on the palms and soles, and a very little eschar surrounded by a violaceous halo was noted on the dorsum of the right foot. Awaiting the results of blood cultures, broad-spectrum antibiotic therapy with meropenem 1 g q8h, ciprofloxacin 400 mg q12h, and doxycycline 100 mg q12h was initiated. Doxycycline was included in the therapy because of the presence of petechial rash and fever, making us consider a diagnosis of rickettsiosis. This suspicion was confirmed by the positivity of polymerase chain reaction on whole blood for R. conorii subsp. israelensis. Thoracentesis was performed to improve alveolar ventilation. R. conorii subsp. israelensis was again identified in the pleural fluid by PCR technique. On day 4 the clinical condition worsened. Blood exams showed values suggestive of secondary hemophagocytic lymphohistiocytosis; 4 out of 8 diagnostic criteria were present and empirical treatment with prednisone was started resulting in a gradual improvement in general condition. CONCLUSIONS: Israeli spotted fever may be a severe disease. A high index of suspicion is required to promptly start life-saving therapy. Pleural effusion and interstitial pneumonia may be part of the clinical picture of severe rickettsial disease and should not lead the physician away from this diagnosis.

5.
Int J Biochem Cell Biol ; 140: 106087, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34563698

RESUMO

Growth factor receptors (GFRs) and receptor tyrosine kinases (RTK) are groups of proteins mediating a plethora of physiological processes, including cell growth, proliferation, survival, differentiation and migration. Under certain circumstances, expression of GFRs and subsequently their downstream kinase signaling are deregulated by genetic, epigenetic, and somatic changes leading to uncontrolled cell division in many human diseases, most notably cancer. Cancer cells rely on growth factors to sustain the increasing need to cell division and metabolic reprogramming through cancer-associated activating mutations of their receptors (i.e., GFRs). In this review, we highlight the recent advances of selected GFRs and their ligands (growth factors) in cancer with emphasis on structural and functional differences. We also interrogate how overexpression and/or hyperactivation of GFRs contribute to cancer initiation, development, progression, and resistance to conventional chemo- and radiotherapies. Novel approaches are being developed as anticancer agents to target growth factor receptors and their signaling pathways in different cancers. Here, we illustrate how the current knowledge of GFRs biology, and their ligands lead to development of targeted therapies to inhibit and/or block the activity of growth factors, GFRs and downstream kinases to treat diseases such as cancer.

6.
Nat Commun ; 12(1): 5450, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521827

RESUMO

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.


Assuntos
Carcinogênese/genética , Ciclina D1/genética , Ciclina D2/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Transcriptoma , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cromatina/química , Cromatina/metabolismo , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Análise de Sobrevida
8.
Clin Dermatol ; 39(2): 271-277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272021

RESUMO

New and emerging types of cutaneous vascular (capillary) proliferations have been described or better categorized in the last few years. They include reactive angioendotheliomatosis, acroangiodermatitis (pseudo-Kaposi sarcoma), diffuse dermal angiomatosis, intravascular histiocytosis, glomeruloid angioendotheliomatosis, and angiopericytomatosis (angiomatosis with cryoproteins). Clinically, they are characterized by multiple, red violaceous, and purpuric patches and plaques, sometimes evolving toward necrosis and ulceration with a wide distribution but a propensity to involve the extremities. Histologically, they are characterized by different patterns of intravascular or extravascular lobular or diffuse hyperplasia of endothelial cells, pericytes, and sometimes histiocytes. Although these angioproliferations can histologically have a pseudoangiosarcomatous pattern, they are reactive in that they originate from the (sub)occlusion of vascular lumina by different localized or systemic disorders. The vascular proliferation stops after the inducing hypoxic stimulus has been withdrawn. Among them, diffuse dermal angiomatosis of the breast is a variant of diffuse dermal angiomatosis involving middle-aged women with macromastia, obesity, smoking, and vasculopathic disorders, considered a distinct disorder in the spectrum of cutaneous reactive angiomatoses. It presents with reticulated erythematous to purple patches with sometimes a tendency to ulcerate and bleeding, appearing on large, pendulous breasts. The pathogenesis is related to tissue hypoxemia resulting from subclinical torsion, compression, and increased venous hydrostatic pressure due to the macromastia, aggravated by the associated ischemic conditions such as hypertension and diabetes. There is no evidence-based therapy, but reduction mammoplasty is a viable treatment option. This should be evaluated in all patients who fail conservative therapy.


Assuntos
Angiomatose , Dermatopatias Vasculares , Angiomatose/complicações , Mama , Células Endoteliais , Feminino , Humanos , Pessoa de Meia-Idade , Pele , Dermatopatias Vasculares/complicações , Dermatopatias Vasculares/diagnóstico
9.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209467

RESUMO

DRESS/DiHS is a complex and potentially fatal drug reaction. Little is known about risk factors and elements that can help to identify patients with a severe reaction early. The aim of the study was to investigate those factors favoring the disease and its severity by analyzing the clinical conditions and therapies preceding the reaction. We conducted a retrospective analysis on patients admitted to our center between 2010 and 2020 who were discharged with a diagnosis of DRESS. We used the RegiSCAR diagnostic criteria. We defined the severity of DRESS using the criteria of Mizukawa et al. We included 25 patients (15 females) with a median age of 66 years. Skin involvement, eosinophilia, and liver injury were the most important aspects. Allopurinol was found to be the most involved drug. Reaction severity was significantly associated with the number of daily medications (p=0.0067) and an age of at least 68 years (p=0.013). In addition, 75% of severe cases had at least three comorbidities in history, and most of the severe cases were female. In our study the advanced age, the high number of comorbidities and home therapies, and the inflammatory state were found to be predisposing elements to the development of the disease and its severity.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Índice de Gravidade de Doença , Dermatopatias , Idoso , Comorbidade , Síndrome de Hipersensibilidade a Medicamentos/epidemiologia , Síndrome de Hipersensibilidade a Medicamentos/terapia , Eosinofilia/epidemiologia , Eosinofilia/terapia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Dermatopatias/epidemiologia , Dermatopatias/terapia
10.
Clin Dermatol ; 39(1): 149-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33972045

RESUMO

Skin is one of target organs affected by the novel coronavirus SARS-CoV-2, and in response to the current COVID-19 pandemic, a fast body of literature has emerged on related cutaneous manifestations. Current perspective is that the skin is not only a bystander of the general cytokines storm with thrombophilic multiorgan injury, but it is directly affected by the epithelial tropism of the virus, as confirmed by the detection of SARS-CoV-2 in endothelial cells and epithelial cells of epidermis and eccrine glands. In contrast with the abundance of epidemiologic and clinical reports, histopathologic characterization of skin manifestations is limited. Without an adequate clinicopathologic correlation, nosology of clinically similar conditions is confusing, and effective association with COVID-19 remains presumptive. Several patients with different types of skin lesions, including the most specific acral chilblains-like lesions, showed negative results at SARS-CoV-2 nasopharyngeal and serologic sampling. The aim of this review is to provide an overview of what has currently been reported worldwide, with a particular emphasis on microscopic patterns of the skin manifestations in patients exposed to or affected by COVID-19. Substantial breakthroughs may occur in the near future from more skin biopsies, improvement of immunohistochemistry studies, RNA detection of SARS-CoV-2 strain by real-time polymerase chain reaction-based assay, and electron microscopic studies.


Assuntos
COVID-19/complicações , Dermatopatias/patologia , Dermatopatias/virologia , Pele/patologia , Pérnio/patologia , Pérnio/virologia , Eritema Multiforme/patologia , Eritema Multiforme/virologia , Exantema/patologia , Exantema/virologia , Humanos , Necrose/virologia , Púrpura/patologia , Púrpura/virologia , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/complicações , Urticária/patologia , Urticária/virologia
11.
Front Immunol ; 12: 651751, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868289

RESUMO

Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Recidiva Local de Neoplasia/epidemiologia , Intervalo Livre de Doença , Seleção do Doador/métodos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Resultado do Tratamento
12.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33883278

RESUMO

Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization.

13.
Haematologica ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33596642

RESUMO

Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.

14.
iScience ; 24(1): 101989, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33490899

RESUMO

Osteoclast (OC) development in response to nuclear factor kappa-Β ligand (RANKL) is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and OC-affiliated transcription factors (TFs) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early OC development entails regulation of two alternative cell fate transcriptional programmes, OC vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates OC development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TFs. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.

16.
Am J Dermatopathol ; 43(1): e13-e15, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32675467

RESUMO

ABSTRACT: We report the case of a 63-year-old white man who, 3 days after stent removal of endoscopic drainage of pancreatic cysts, developed a penile necrosis due to purpura fulminans (PF) that has been misdiagnosed as Fournier's gangrene. Penile necrosis was rapidly followed by a lethal multiorgan failure due to disseminated intravascular coagulopathy (DIC), triggered by the subsequent development of a severe acute pancreatitis. PF describes a rare syndrome involving intravascular thrombosis and hemorrhagic infarction of the skin. Although reports of penile necrosis secondary to various causes are documented in the literature, penile necrosis secondary to PF in the setting of acute pancreatitis is a rare event. Histopathologic studies of the skin showing an occlusive nonvasculitic vasculopathy are the first step to achieve an accurate diagnosis.


Assuntos
Gangrena de Fournier/patologia , Doenças do Pênis/patologia , Pênis/patologia , Púrpura Fulminante/patologia , Erros de Diagnóstico , Coagulação Intravascular Disseminada/etiologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Necrose , Doenças do Pênis/etiologia , Púrpura Fulminante/etiologia
17.
J Clin Med ; 9(11)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138211

RESUMO

Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands-HLA(Human Leukocyte Antigen) class I molecules-are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients' clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface.

18.
Front Oncol ; 10: 584607, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194728

RESUMO

Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.

19.
Vet Ital ; 56(2): 103-107, 2020 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32761581

RESUMO

Dogs are the major reservoir of Leishmania infantum, the causative agent of canine visceral and cutaneous human leishmaniasis in the Mediterranean basin. Canine and human leishmaniosis are endemic in Italy, particularly in central and southern regions, including islands. Here we show a preliminary, clinical, serological and molecular study carried out in Pantelleria island during 2017. In this study, we clinically examined 136 dogs for the presence of symptoms compatible with leishmaniasis, determined the titer of anti­Leishmania antibodies, and investigated Leishmania DNA by real time PCR in blood and/or lymph node of each dog. The prevalence of disease was equal to 27% with 95% CI [21%; 32%], lower than prevalence obtained in the other Sicily islands (Lampedusa, Lipari). We observed that enlarged lymph nodes was more positively associated with canine leishmaniasis (CanL)than other clinical signs. The results obtained showed that in an endemic area, such as Sicily, diagnosis of CanL needs to be carried out by including an immunological, molecular clinical approach.


Assuntos
Doenças do Cão/epidemiologia , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/veterinária , Animais , Estudos Transversais , Doenças do Cão/parasitologia , Cães , Feminino , Ilhas , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia , Masculino , Prevalência , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Sicília/epidemiologia
20.
PLoS Negl Trop Dis ; 14(7): e0008465, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706789

RESUMO

BACKGROUND: Leishmaniasis is one of the most important vector-borne diseases and it represents a serious world health problem affecting millions of people. High levels of Leishmania infections, affecting both humans and animals, are recognized among Italian regions. Among these, Sicily has one of the highest prevalence of Leishmania infection. METHODOLOGY/PRINCIPAL FINDINGS: Seventy-eight Leishmania strains isolated from human and animal samples across Sicily, were analyzed for the polymorphic k26-gene and genotypes were assigned according to the size of the PCR products. A multilocus microsatellite typing (MLMT) approach based on the analysis of 11 independent loci was used to investigate populations structure and genetic diversity of the isolated strains. Six L. infantum reference strains were included in the analysis for comparison. Bayesian clustering analysis of microsatellite data showed that all the isolated strains clustered in two genetically distinct populations, corresponding to human and canine isolates respectively. A further subdivision was observed between the two main groups, giving a good correlation between human strains and their geographic origin, conversely canine population showed a great genetic variability diffused in the territory. CONCLUSIONS/SIGNIFICANCE: Among the 78 Leishmania isolates, K26 analysis detected 71 samples (91%) as MON-1 zymodeme, confirming it as the predominant strain in Mediterranean area and 7 human samples (9%) as non-MON-1. MLMT gives important insights into the epidemiology of leishmaniases and allows characterization of different strains to a higher resolution than possible with zymodeme typing. Two main populations presented a strong correlation respect to the different hosts, exhibiting a co-circulation of two distinct populations of L. infantum. The population found in infected humans exhibited a correlation with geographic origin. These clusters could represent a geographically restricted population of strains with the same or related genotypes. This study can contribute to an understanding of Leishmania epidemiology, including the spread of reservoirs and sand fly vectors in the different foci of infection, characterizing parasites within the different hosts.


Assuntos
Doenças do Cão/parasitologia , Leishmania infantum/genética , Leishmaniose Visceral/veterinária , Animais , Doenças do Cão/epidemiologia , Cães , Humanos , Itália/epidemiologia , Leishmania infantum/classificação , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia
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