RESUMO
BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), monocytes infiltrate visceral adipose tissue promoting local and hepatic inflammation. However, it remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assess adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort. METHODS: Visceral adipose tissue macrophages from lean and obese patients, stratified by NAFLD phenotypes, underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on a protein level via immunohistochemistry and immunofluorescence to determine targets of interest. RESULTS: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs are replenished by a common transitional macrophage (TransMac) subtype and that, during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMacs and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. However, across the NAFLD severity spectrum, alterations occur in these subsets that parallel an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue. CONCLUSIONS: NAFLD-related macrophage dysfunction coincides with a loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. IMPACT AND IMPLICATIONS: Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease. We report unique non-alcoholic steatohepatitis-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAMs) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states coincided with the loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provides a theoretical basis for new therapeutic strategies to be directed towards reinstating the endogenous metabolic, homeostatic and cytoprotective functions of ResVAMs and MMacs, including their role in protecting vascular integrity.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Células Endoteliais/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Tecido Adiposo/metabolismo , Inflamação/metabolismoRESUMO
BACKGROUND: Peripheral artery disease (PAD) in hemodialysis (HD) patients has a significant social impact due to its prevalence, poor response to standard therapy and dismal prognosis. Rheopheresis is indicated by guidelines for PAD treatment. MATERIALS AND METHODS: Twenty-five HD patients affected by PAD stage IV Lerichè-Fontaine and ischemic ulcer 1C or 2C according to the University of Texas Wound Classification System (UTWCS), without amelioration after traditional medical therapy and/or revascularization, were selected and underwent 12 Rheopheresis sessions in 10 weeks. Improvements in pain symptoms using Numerical Rating Scale (NRS), healing ulcers and laboratory hemorheological parameters have been evaluated. RESULTS: A clinically and statistically significant mean value reduction and of relative percentage differences between estimated marginal means (Δ), calculated at each visits, of NRS was observed, with a maximum value (-48.5%) between the first and last visit. At the end of the treatment period 14.3% of ulcers were completely healed, 46.4% downgraded, 53.6% were stable. Overall, no ulcers upgraded. A statistically significant reduction of the Δ, between the first and last visit, for fibrinogen (-16%) was also observed. CONCLUSION: Rheopheresis reduced overall painful symptoms; data suggest that it could heal or improve ulcers and hemorheological laboratory parameters in HD patients with PAD and ischemic ulcers resistant to standard therapies.
Assuntos
Pé Diabético , Doença Arterial Periférica , Diálise Renal , Humanos , Doença Arterial Periférica/terapia , Diálise Renal/efeitos adversos , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Pé Diabético/terapia , Itália , Remoção de Componentes Sanguíneos/métodos , Resultado do Tratamento , Cicatrização , Idoso de 80 Anos ou maisRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut-liver axis is regulated and stabilized by a complex network encompassing a metabolic, immune, and neuroendocrine cross-talk between the gut, the microbiota, and the liver. Changes in the gut-liver axis affect the metabolism of lipids and carbohydrates in the hepatocytes, and they impact the balance of inflammatory mediators and cause metabolic deregulation, promoting NAFLD and its progression to nonalcoholic steatohepatitis. Moreover, the microbiota and its metabolites can play direct and indirect roles in gut barrier function and fibrosis development. In this review, we will highlight findings from the recent literature focusing on the gut-liver axis and its relation to NAFLD. Finally, we will discuss the impact of technical issues, design bias, and other limitations on current knowledge of the gut microbiota in the context of NAFLD.
Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Hepatócitos , Humanos , MetagenomaRESUMO
BACKGROUND & AIMS: Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS: C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1â¯week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS: We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1â¯week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/ß-catenin signaling pathway, as shown by genetic intervention driving ß-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives ß-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS: We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring ß-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY: The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH.
Assuntos
Translocação Bacteriana/efeitos dos fármacos , Permeabilidade Capilar , Ácido Quenodesoxicólico/análogos & derivados , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Ácido Quenodesoxicólico/farmacologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Disbiose/imunologia , Inflamação/metabolismo , Resistência à Insulina , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Substâncias Protetoras/farmacologiaRESUMO
The role of the cell surface CD133 as a cancer stem cell marker in glioblastoma (GBM) has been widely investigated, since it identifies cells that are able to initiate neurosphere growth and form heterogeneous tumors when transplanted in immune-compromised mice. However, evidences of CD133-negative cells exhibiting similar properties have also been reported. Moreover, the functional role of CD133 in cancer stem/progenitor cells remains poorly understood. We studied the biological effects of CD133 downregulation in GBM patient-derived neurospheres. Our results indicate that there is not a hierarchical relation between CD133-positive and CD133-negative cells composing the neurospheres. Indeed, CD133 appears in an interconvertible state, changing its subcellular localization between the cytoplasm and the plasmamembrane of neurosphere cells. Silencing of CD133 in human GBM neurospheres using lentivirus-mediated short hairpin RNA impairs the self-renewal and tumorigenic capacity of neurosphere cells. These results imply that CD133 could be used as a therapeutic target in GBMs.
Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Glicoproteínas/metabolismo , Células-Tronco Neoplásicas/patologia , Peptídeos/metabolismo , Antígeno AC133 , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Apoptose/fisiologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Glioblastoma/imunologia , Glioblastoma/metabolismo , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Peptídeos/genética , Peptídeos/imunologiaRESUMO
The invasive nature of glioblastoma (GBM) is one important reason for treatment failure. GBM stem/progenitor cells retain the migratory ability of normal neural stem/progenitor cells and infiltrate the brain parenchyma. Here, we identify Rai (ShcC/N-Shc), a member of the family of Shc-like adaptor proteins, as a new regulator of migration of normal and cancer stem/progenitor cells. Rai is expressed in neurogenic areas of the brain and its knockdown impairs progenitor migration to the olfactory bulb. Its expression is retained in GBM stem/progenitor cells where it exerts the same promigratory activity. Rai silencing in cancer stem/progenitor cells isolated from different patients causes significant decrease in cell migration and invasion, both in vitro and in vivo, providing survival benefit. Rai depletion is associated with alteration of multiple-signaling pathways, yet it always leads to reduced expression of proinvasive genes.
Assuntos
Movimento Celular , Glioblastoma/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Animais , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Knockout , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/patologia , Bulbo Olfatório , Proteínas Adaptadoras da Sinalização Shc/genética , Proteína 3 de Transformação que Contém Domínio 2 de Homologia de Src , Células Tumorais CultivadasRESUMO
The rising prevalence of obesity and metabolic disorders worldwide highlights the urgent need to find new long-term and clinically meaningful weight-loss therapies. Here, we evaluate the therapeutic potential and the mechanism of action of a biomimetic cellulose-based oral superabsorbent hydrogel (OSH). Treatment with OSH exerts effects on intestinal tissue and gut microbiota composition, functioning like a protective dynamic exoskeleton. It protects from gut barrier permeability disruption and induces rapid and consistent changes in the gut microbiota composition, specifically fostering Akkermansia muciniphila expansion. The mechanobiological, physical, and chemical structures of the gel are required for A. muciniphila growth. OSH treatment induces weight loss and reduces fat accumulation, in both preventative and therapeutic settings. OSH usage also prevents liver steatosis, immune infiltration, and fibrosis, limiting the progression of non-alcoholic fatty liver disease. Our work shows the potential of using OSH as a non-systemic mechanobiological approach to treat metabolic syndrome and its comorbidities.
Assuntos
Exoesqueleto Energizado , Hepatopatia Gordurosa não Alcoólica , Humanos , Hidrogéis/uso terapêutico , Biomimética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/prevenção & controle , Obesidade/tratamento farmacológicoRESUMO
In 40% of patients with chronic hepatitis C, standard therapy is unable to eradicate the virus. Since the response to pharmacological treatment depends on the initial viral load, there is a rationale for reducing this load by means of apheretic depletion of the C virus. The aim of this work was to administer cascade filtration (CF) to non responder patients affected by hepatitis C (pts) before resuming the pharmacological treatment. 10 pts underwent 12 sessions of CF, 3 per week (treated plasma volume/session: 3000 mL). After the first week, therapy with PEG-IFN (1.5 ug/Kg/week) plus Ribavirin (1200 mg/day) was added. The viral load was determined before and after each CF session, and at the 1st, 3rd and 6th month. The mean pre-apheresis viral load dropped from 2176275+/-3109997 U/mL at the first session to 1486726+/-2091975 U/mL by the fourth (p<0.001), and 347500+/-637428 U/mL before the last (p<0.001). The mean percentage reduction of the viral load went from a minimum of 29.5% to a maximum of 42%. Early viral response (EVR) was obtained in 70% of these patients as compared with only 10% in an age- and sex-matched control group consisting of 10 patients. Unfortunately, we did not get the same good results in terms of sustained viral response (SVR: 10% in apheretic patients vs 0% in the control group). Efficacious removal of HCV was obtained with CF. However, the successful reduction in the viral load achieved with apheresis in terms of EVR was not confirmed when we considered the SVR.
Assuntos
Antivirais/uso terapêutico , Filtração , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Plasmaferese/métodos , Ribavirina/uso terapêutico , Carga Viral/efeitos dos fármacos , Quimioterapia Combinada , Filtração/métodos , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Proteínas Recombinantes/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
The intestinal barrier protects our body from external insults through specialized cells organized in a multilayered structure that evolved in symbiosis with the resident microbiota. A breach in the outer mucus and epithelium can be transmitted to the inner gut vascular barrier (GVB), leading to systemic dissemination of microbes or microbe-derived molecules. Several extraintestinal pathologies have been linked to gut microbiota dysbiosis that causes GVB leakage in their early phases. The consequent spreading of inflammatory stimuli to distant organs could be driven by later vascular barrier disruption at different sites, suggesting an interplay between anatomical barriers across the body. Thus, targeting the intestinal barrier holds promise for the prevention and/or therapy of several intestinal, metabolic, and neurological disorders.
Assuntos
Disbiose , Microbioma Gastrointestinal , Encéfalo , Humanos , Mucosa Intestinal , FígadoRESUMO
Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.
Assuntos
Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/patologia , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Bactérias/isolamento & purificação , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/patologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/secundárioRESUMO
BACKGROUND: Long-term treatment with low-density lipoprotein (LDL) apheresis (LA) has been shown to reduce the incidence of cardiovascular events in patients affected by familial hypercholesterolemia (FH). Data from experimental studies suggest that circulating endothelial progenitor cells (EPCs) can repair the vascular lesions caused by atherosclerosis. Since a reduction of these cells has been demonstrated to predict atherosclerosis progression, the aim of this study was to verify whether LA can increase the percentage of EPCs. METHODS: In 15 patients affected by FH periodically treated with LA, the percentage of EPCs was determined before and after performing LA, and compared with the values of 15 control subjects and 15 hypercholesterolemic patients treated with statins. RESULTS: Significant differences were found in FH patients between the pre-apheresis percentages of CD34+/KDR+, defined as EPCs by a wide consensus of opinion, and the values found 24 h after the procedures (0.00868 +/- 0.003 vs. 0.01009 +/- 0.002%, p < 0.005). Instead, the percentages of CD34+/KDR+/CD133+, considered as an immature subset of EPCs, remained substantially unchanged. However, a significant reduction in the percentage of EPCs was observed in both patient groups as compared to the controls, at all the assessment times. CONCLUSION: In the short-term LA seems to stimulate mobilization of CD34+/KDR+ cells. Hypercholesterolemic patients show a lower percentage of EPCs than controls. There were no differences in the EPCs percentages between the 2 patients groups, despite the fact that LDL cholesterol levels were higher in the group undergoing LA.
Assuntos
Remoção de Componentes Sanguíneos/métodos , Células Endoteliais , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL/isolamento & purificação , Células-Tronco , Adulto , Estudos de Casos e Controles , Contagem de Células , LDL-Colesterol/sangue , Feminino , Mobilização de Células-Tronco Hematopoéticas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
The aim of this study was to report the frequency of kidney diseases related to gender, age, clinical presentation and renal function at the time of kidney biopsy in the population of Mantua province (400,000 residents). We collected the results of 132 real-time ultrasound-guided fine-needle (18 G) kidney biopsies by optical and immunofluorescence microscopy. The clinical presentation at the time of biopsy was nephrotic syndrome in 57%, nephritic syndrome in 22%, and urinary abnormalities in 21% of cases. Serum creatinine was >-1.5 mg/dL in 48% of patients. Membranous nephropathy was the most frequent histological finding (21.4%), followed by IgA nephropathy (14.5%), focal glomerulosclerosis (11.5%), diabetic nephropathy (8.4%), and chronic interstitial nephritis (6.9%). Primary glomerulonephritis including membranous glomerulonephritis and IgA nephropathy showed a male predominance. The pathological correlations in native biopsy-proven renal disease provided useful information for clinical practice. The histological findings in our patient series are similar to those recorded in Italian and European registries. A less invasive policy in the case of isolated urinary abnormalities and a normal eGFR resulted in a lower incidence of IgA nephropathy in our series than was recorded in the national Italian registry.
Assuntos
Nefropatias/patologia , Adulto , Biópsia por Agulha Fina , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
In Drosophila melanogaster, Cup acts as a translational regulator during oocyte maturation and early embryogenesis. In this report, we show that Cup associates with Miranda, an adaptor protein involved in localization of specific mRNA complexes in both neuroblasts and oocytes. miranda and cup also interact genetically, since reducing miranda activity worsens the oogenesis defects associated with different cup mutant alleles. miranda mRNA is first detected within the cytoplasm of egg chambers during early oogenesis, coincidentally with very low levels of Miranda protein. We furthermore show that Cup interacts with Staufen, a protein involved in mRNA localization during oogenesis and nervous system development, and the two proteins co-localize within the posterior cytoplasm of late oocytes. Our results substantiate the idea that Cup is a multi-functional protein cooperating with different protein partners to direct egg chamber development at multiple time-points.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Oogênese/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Cruzamentos Genéticos , Citoplasma/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Feminino , Imunofluorescência , Imunoprecipitação , Hibridização In Situ , Oócitos/citologia , Oócitos/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Técnicas do Sistema de Duplo-HíbridoRESUMO
BACKGROUND/AIMS: An endothelial dysfunction has been described in autosomal dominant polycystic kidney disease (ADPKD) before the development of hypertension and renal impairment. The aim of this work was to verify the existence of a microvascular reactivity in the early stages of ADPKD. METHODS: Fifteen ADPKD normotensive patients with normal renal function underwent laser Doppler examination of the cutaneous microcirculation in basal conditions and after the warm test, as well as evaluation of plasma concentrations of some endothelial activation parameters [total cholesterol and fractions, fibrinogen, von Willebrand factor, Lp(a)]. The results were compared with those in 15 healthy subjects, 15 essential hypertensive patients and 15 hypertensive ADPKD patients with normal renal function. RESULTS: Both basal and post-warm-test values were significantly lower in normotensive ADPKD subjects than controls (3.2 +/- 1 vs. 5.8 +/- 1.3 AU, p = 0.0001; 35.2 +/- 10.9 vs. 50.5 +/- 10.8 AU, p = 0.005, respectively). All evaluated parameters were within normal limits and comparable between normotensive ADPKD subjects and controls, except for LDL cholesterol (125 +/- 18 vs. 101 +/- 22 mg/dl, p = 0.01) and Lp(a), which was significantly higher in the ADPKD subjects (52.2 +/- 36 vs. 6.0 +/-4 mg/dl, p = 0.0006). CONCLUSION: Our study confirms the existence of a systemic microcirculation defect in ADPKD. The presence of high levels of Lp(a) could contribute to causing the high incidence of cardiovascular events in ADPKD.
Assuntos
Microvasos/diagnóstico por imagem , Doenças Vasculares Periféricas/diagnóstico por imagem , Doenças Vasculares Periféricas/etiologia , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Pele/irrigação sanguínea , Pele/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Microcirculação , UltrassonografiaRESUMO
HYPOTHESIS: The aim of the present study was to evaluate the concentration of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in patients affected by sudden sensorineural hearing loss (SSHL). STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Patients affected by SSHL were evaluated. Inclusion criteria for this study were hearing loss of more than 30 dB hearing level affecting at least 3 contiguous frequencies, normal hearing on the contralateral ear, negative history of hearing loss or ear surgery in the affected ear, and magnetic resonance with gadolinium negative for VIII cranial nerve pathologic findings. INTERVENTION: Circulating levels of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule (VCAM) 1 were evaluated by means of enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The levels of adhesion molecules in SSHL patients were compared with those of a control group. RESULTS: Intercellular adhesion molecule 1 and VCAM-1 levels in sera of patients with SSHL were significantly higher than those of the matched control subjects (p < 0.001). Statistical analysis did not show significant differences between the 2 groups in terms of the known vascular risk factors such as total and fractionated cholesterol, triglycerides, fibrinogen, erythrocyte sedimentation rate smoking, and diabetes. CONCLUSION: The results of this study show that in SSHL patients, there is an increased expression of circulating adhesion molecules confirming the existence of an endothelial dysfunction and supporting the vascular involvement in the pathogenesis of the disease. The identification of high levels of adhesion molecules and of the endothelial dysfunction open the way to selective pharmacologic treatments able to correct the activation of endothelial cells.
Assuntos
Perda Auditiva Súbita/genética , Perda Auditiva Súbita/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adolescente , Adulto , Idoso , Audiometria , Análise Química do Sangue , Feminino , Herpes Zoster da Orelha Externa/complicações , Humanos , Masculino , Doença de Meniere/complicações , Pessoa de Meia-Idade , Zumbido/complicaçõesRESUMO
The gene encoding the MEF2B transcription factor is mutated in germinal center (GC)-derived B cell lymphomas, but its role in GC development and lymphomagenesis is unknown. We demonstrate that Mef2b deletion reduces GC formation in mice and identify MEF2B transcriptional targets in GC, with roles in cell proliferation, apoptosis, GC confinement, and differentiation. The most common lymphoma-associated MEF2B mutant (MEF2BD83V) is hypomorphic, yet escapes binding and negative regulation by components of the HUCA complex and class IIa HDACs. Mef2bD83V expression in mice leads to GC enlargement and lymphoma development, a phenotype that becomes fully penetrant in combination with BCL2 de-regulation, an event associated with human MEF2B mutations. These results identify MEF2B as a critical GC regulator and a driver oncogene in lymphomagenesis.
Assuntos
Carcinogênese/genética , Centro Germinativo/patologia , Linfoma de Células B/genética , Animais , Apoptose/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/imunologia , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Oncogenes/genéticaRESUMO
Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed whole-exome sequencing on matched samples of breast cancer and BMs and found mutations in the coagulation pathway genes in 5 out of 10 BM samples. We then investigated the mutational status of 33 genes belonging to the coagulation cascade in a panel of 29 BMs and we identified 56 Single Nucleotide Variants (SNVs). The frequency of gene mutations of the pathway was significantly higher in BMs than in primary tumours, and SERPINI1 was the most frequently mutated gene in BMs. These findings provide direction in the development of new strategies for the treatment of BMs.
Assuntos
Fatores de Coagulação Sanguínea/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Mutação , Neoplasias da Mama/genética , Feminino , Humanos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do GenomaRESUMO
During hemodialysis, ultrafiltration (UF) seems to affect the dialytic dose because of convective removal of urea and contraction of its distribution volume. We aimed to assess whether the adoption of a decreasing UF profile could yield a different dialytic dose from that obtained with a constant UF mode. Ten patients were randomly assigned to undergo 12 sessions with a constant UF mode (phase A) followed by 12 sessions with a decreasing UF rate (phase B), or the reverse. Kt/V and urea reduction ratio (URR) were 1.77 +/- 0.26 and 70.02 +/- 8.26% in phase A vs. 1.81 +/- 0.36 and 71.02 +/- 6.48% in phase B, respectively, showing no significant difference. Measurement of the differences in volemic variations between the two phases showed a statistically significant difference at the second hour (P < 0.001, the volemic reduction being greater in phase B than A) and at the fourth hour (P < 0.001, being greater in phase A than B). In standard bicarbonate dialysis, the adoption of a decreasing UF profile rather than a constant one does not alter the efficiency of the dialytic treatment.
Assuntos
Diálise Renal , Ultrafiltração , Idoso , Pressão Sanguínea , Volume Sanguíneo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used.
Assuntos
Remoção de Componentes Sanguíneos , LDL-Colesterol/sangue , Úlcera do Pé/terapia , Hiperlipoproteinemia Tipo II/terapia , Doença Arterial Periférica/terapia , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , Úlcera do Pé/sangue , Úlcera do Pé/diagnóstico , Úlcera do Pé/etiologia , Úlcera do Pé/fisiopatologia , Hemodinâmica , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/fisiopatologia , Microcirculação , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/fisiopatologia , Recidiva , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , CicatrizaçãoRESUMO
Glioblastoma (GBM) is a devastating brain tumor with a poor survival outcome. It is generated and propagated by a small subpopulation of rare and hierarchically organized cells that share stem-like features with normal stem cells but, however, appear dysregulated in terms of self-renewal and proliferation and aberrantly differentiate into cells forming the bulk of the disorganized cancer tissues. The complexity and heterogeneity of human GBMs underlie the lack of standardized and effective treatments. This study is based on the assumption that available markers defining cancer stem cells (CSCs) in all GBMs are not conclusive and further work is required to identify the CSC. We implemented a method to isolate CSCs independently from cell surface markers: four patient-derived GBM neurospheres containing stem, progenitors, and differentiated cells were labeled with PKH-26 fluorescent dye that reliably selects for cells that divide at low rate. Through in vitro and in vivo assays, we investigated the growth and self-renewal properties of the two different compartments of high- and slow-dividing cells. Our data demonstrate that only slow-dividing cells retain the ability of a long-lasting self-renewal capacity after serial in vitro passaging, while high-dividing cells eventually exhaust. Moreover, orthotopic transplantation assay revealed that the incidence of tumors generated by the slow-dividing compartment is significantly higher in the four patient-derived GBM neurospheres analyzed. Importantly, slow-dividing cells feature a population made up of homogeneous stem cells that sustain tumor growth and therefore represent a viable target for GBM therapy development.