RESUMO
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Hibridização in Situ Fluorescente , Translocação Genética , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/genética , Cadeias Pesadas de Imunoglobulinas/genética , Cromossomos Humanos Par 14/genéticaRESUMO
While some follicular lymphoma (FL) patients do not require treatment or experience prolonged responses, others relapse early, and little is known about genetic alterations specific to patients with a particular clinical behavior. We selected 56 grade 1-3A FL patients according to their need of treatment or timing of relapse: never treated (n = 7), non-relapsed (19), late relapse (14), early relapse or POD24 (11), and primary refractory (5). We analyzed 56 diagnostic and 12 paired relapse lymphoid tissue biopsies and performed copy number alteration (CNA) analysis and next generation sequencing (NGS). We identified six focal driver losses (1p36.32, 6p21.32, 6q14.1, 6q23.3, 9p21.3, 10q23.33) and 1p36.33 copy-neutral loss of heterozygosity (CN-LOH). By integrating CNA and NGS results, the most frequently altered genes/regions were KMT2D (79%), CREBBP (67%), TNFRSF14 (46%) and BCL2 (40%). Although we found that mutations in PIM1, FOXO1 and TMEM30A were associated with an adverse clinical behavior, definitive conclusions cannot be drawn, due to the small sample size. We identified common precursor cells harboring early oncogenic alterations of the KMT2D, CREBBP, TNFRSF14 and EP300 genes and 16p13.3-p13.2 CN-LOH. Finally, we established the functional consequences of mutations by means of protein modeling (CD79B, PLCG2, PIM1, MCL1 and IRF8). These data expand the knowledge on the genomics behind the heterogeneous FL population and, upon replication in larger cohorts, could contribute to risk stratification and the development of targeted therapies.
Assuntos
Linfoma Folicular , Humanos , Linfoma Folicular/patologia , Recidiva Local de Neoplasia , Mutação , Genômica , RecidivaRESUMO
Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (ß-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Encéfalo , Eletroencefalografia , Humanos , NeurôniosRESUMO
Hair cell (HC) loss by epithelial extrusion has been described to occur in the rodent vestibular system during chronic 3,3'-iminodipropionitrile (IDPN) ototoxicity. This is preceded by dismantlement of the calyceal junction in the contact between type I HC (HCI) and calyx afferent terminals. Here, we evaluated whether these phenomena have wider significance. First, we studied rats receiving seven different doses of streptomycin, ranging from 100 to 800 mg/kg/day, for 3-8 weeks. Streptomycin caused loss of vestibular function associated with partial loss of HCI and decreased expression of contactin-associated protein (CASPR1), denoting calyceal junction dismantlement, in the calyces encasing the surviving HCI. Additional molecular and ultrastructural data supported the conclusion that HC-calyx detachment precede HCI loss by extrusion. Animals allowed to survive after the treatment showed functional recuperation and rebuilding of the calyceal junction. Second, we evaluated human sensory epithelia obtained during therapeutic labyrinthectomies and trans-labyrinthine tumour excisions. Some samples showed abnormal CASPR1 label strongly suggestive of calyceal junction dismantlement. Therefore, reversible dismantlement of the vestibular calyceal junction may be a common response triggered by chronic stress, including ototoxic stress, before HCI loss. This may partly explain clinical observations of reversion in function loss after aminoglycoside exposure.
Assuntos
Células Ciliadas Vestibulares , Vestíbulo do Labirinto , Humanos , Ratos , Animais , Estreptomicina/toxicidade , Vestíbulo do Labirinto/patologia , Epitélio/patologia , Células Ciliadas Vestibulares/patologia , Células Ciliadas Auditivas/patologiaRESUMO
PURPOSE: The study assesses whether pre- and intraoperative factors linked to electromyography and direct electrical stimulation (DES) of facial nerve can predict facial nerve function in the short- (12 days) and long-term (1 year) after cerebellopontine angle (CPA) tumor resection. METHODS: 157 patients who underwent surgical resection of CPA tumors with facial nerve monitoring. Pre-operative factors (age, tumor size, pure tone average), surgical time and intra-operative parameters regarding facial function, minimum stimulation threshold (MST), compound muscle action potential (CMAP) and the difference between proximal and distal CMAP (DPDC) were evaluated. RESULTS: A correlation between tumor size, MST, CMAP and facial function in both short and long term was found. A higher grade of immediate facial paralysis corresponded to a higher risk of poor outcome after one year. A postoperative House-Brackmann (HB) score of V or VI was correlated with poor outcome in 88.8% and 93.8% of cases. A risk of HB 3 or more, in the long term, was correlated with a tumor size of 20.2 mm. Using an MST of 0.1 mA, for long-term predictions, sensitivity and specificity were 0.62 (95% CI 0.46-0.75) and 0.73 (95% CI 0.61-0.82), respectively. With a CMAP cut-off < 200 µV, for long-term prediction, sensitivity was 0.73 (95% CI 0.53-0.87) and specificity 0.73 (95% CI 0.55-0.85). CONCLUSION: The assessment based on the cut-offs described increases the ability to predict facial function. Improving predictive accuracy enables surgeons to address patients' expectations and to establish an intervention timeline for planning facial reanimation.
Assuntos
Paralisia Facial , Neuroma Acústico , Humanos , Nervo Facial/cirurgia , Prognóstico , Ângulo Cerebelopontino/cirurgia , Neuroma Acústico/cirurgia , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. METHODS: The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. RESULTS: Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. CONCLUSIONS: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. Video Abstract.
Assuntos
Fator 4 Ativador da Transcrição , Diabetes Mellitus Tipo 2 , Estresse do Retículo Endoplasmático , Músculo Esquelético , Serina-Treonina Quinases TOR , Fatores de Transcrição , Fator 4 Ativador da Transcrição/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Tunicamicina/metabolismo , Tunicamicina/farmacologiaRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort. METHODS: Longitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out. RESULTS: CR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out. CONCLUSIONS: These findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.
Assuntos
Esclerose Lateral Amiotrófica/psicologia , Disfunção Cognitiva/psicologia , Reserva Cognitiva/fisiologia , Função Executiva/fisiologia , Cognição Social , Idoso , Esclerose Lateral Amiotrófica/complicações , Disfunção Cognitiva/etiologia , Escolaridade , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
OBJECTIVE: To identify cortical regions engaged during the sustained attention to response task (SART) and characterize changes in their activity associated with the neurodegenerative condition amyotrophic lateral sclerosis (ALS). METHODS: High-density electroencephalography (EEG) was recorded from 33 controls and 23 ALS patients during a SART paradigm. Differences in associated event-related potential peaks were measured for Go and NoGo trials. Sources active during these peaks were localized, and ALS-associated differences were quantified. RESULTS: Go and NoGo N2 and P3 peak sources were localized to the left primary motor cortex, bilateral dorsolateral prefrontal cortex (DLPFC), and lateral posterior parietal cortex (PPC). NoGo trials evoked greater bilateral medial PPC activity during N2 and lesser left insular, PPC and DLPFC activity during P3. Widespread cortical hyperactivity was identified in ALS during P3. Changes in the inferior parietal lobule and insular activity provided very good discrimination (AUROC > 0.75) between patients and controls. Activation of the right precuneus during P3 related to greater executive function in ALS, indicative of a compensatory role. INTERPRETATION: The SART engages numerous frontal and parietal cortical structures. SART-EEG measures correlate with specific cognitive impairments that can be localized to specific structures, aiding in differential diagnosis.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Atenção/fisiologia , Encéfalo/fisiopatologia , Função Executiva/fisiologia , Rede Nervosa/fisiopatologia , Adulto , Idoso , Eletroencefalografia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE OF REVIEW: The current review provides an up to date overview of the nature and progression of the cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS). Understanding these symptoms has implications for the management of the disease and the design of clinical trials, in addition to the support of patient and caregiver regarding mental capacity and end of life decision-making. RECENT FINDINGS: Cognitive and behavioural change in ALS are best characterized as the consequence of extensive network dysfunction. 35-45% of ALS patients present with mild-moderate cognitive impairment and comorbid dementia occurs in approximately 14% of patients, the majority of these meeting diagnostic criteria for frontotemporal dementia (FTD). Cognitive change in ALS manifests most commonly as executive dysfunction and language impairment. Behavioural change in the form of apathy, disinhibition, loss of sympathy and empathy, stereotyped behaviours and dietary changes occur. SUMMARY: Cognitive and behavioural impairment is an important feature of ALS, and reflects broad network dysfunction of frontostriatal and frontotemporal systems. Cognition and behaviour should be assessed early in the diagnostic process, and data driven approaches should be developed to enable reliable quantitative outcome assessment suitable for clinical trials.
Assuntos
Esclerose Lateral Amiotrófica/psicologia , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Esclerose Lateral Amiotrófica/complicações , Apatia , Disfunção Cognitiva/etiologia , Progressão da Doença , Humanos , Testes NeuropsicológicosRESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting-state electroencephalography recordings from 74 ALS patients and 47 age-matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co-modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ- to ß-band), lateral/orbitofrontal (δ- to θ-band) and sensorimotor (ß-band) regions of the brain in patients with ALS. Furthermore, we show increased co-modulation of neural oscillations in the central and posterior (δ-, θ- and γl -band) and frontal (δ- and γl -band) regions, as well as decreased synchrony in the temporal and frontal (δ- to ß-band) and sensorimotor (ß-band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease-associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Rede Nervosa/fisiopatologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/psicologia , Ritmo beta , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Cognição , Ritmo Delta , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Testes Neuropsicológicos , Desempenho Psicomotor , Ritmo TetaRESUMO
Amyotrophic Lateral Sclerosis is a neurodegenerative disorder characterized primarily by motor network disruption. Extra-motor manifestations including executive functions, social cognition, and behavioral changes are now well recognized as important features of ALS, and are associated with frontotemporal and frontostriatal network disruption. However, the presence and characterization of language changes has received less attention. This systematic review characterizes the profile of reported language dysfunction in ALS. PRISMA guidelines were implemented to carry out and report the review. Current evidence suggests that areas of neuroanatomical disruption in ALS spread to language centers such as posterior, inferior frontal and superior temporal areas leading to deficits in word retrieval, syntactic and grammatical processing, and spelling. However, the majority of studies of language in ALS have been limited by the recruitment of small clinic-based prevalent samples and important questions remain regarding the incidence and progression of language impairment in ALS. Further studies from population-based incident cohorts will help to determine the range of language deficits in ALS, and how these relate to previously defined executive and behavioral sub-phenotypes.
Assuntos
Esclerose Lateral Amiotrófica/psicologia , Demência Frontotemporal/psicologia , Idioma , HumanosRESUMO
Research in recent years on peroxisome proliferator-activated receptor (PPAR)ß/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARß/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARß/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARß/δ as a treatment for human metabolic disorders.
Assuntos
Doenças Metabólicas/genética , PPAR delta/agonistas , PPAR beta/agonistas , Animais , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular/métodos , PPAR delta/genética , PPAR delta/metabolismo , PPAR beta/genética , PPAR beta/metabolismoRESUMO
A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on ß-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.
Assuntos
Dimerização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucosilceramidase/antagonistas & inibidores , Xilitol/síntese química , Xilitol/farmacologia , Domínio Catalítico , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Doença de Gaucher/enzimologia , Glucosilceramidase/química , Glucosilceramidase/metabolismo , Humanos , Transporte Proteico , Estereoisomerismo , Xilitol/químicaRESUMO
Correction for 'Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity' by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681-3705.
RESUMO
Injection of oncolytic vesicular stomatitis virus (VSV) into established B16ova melanomas results in tumor regression, in large part by inducing innate immune reactivity against the viral infection, mediated by MyD88- and type III interferon (IFN)-, but not TLR-4-, signaling. We show here that intratumoral (IT) treatment with lipopolysaccharide (LPS), a TLR-4 agonist, significantly enhanced the local therapy induced by VSV by combining activation of different innate immune pathways. Therapy was further enhanced by co-recruiting a potent antitumor, adaptive T-cell response by using a VSV engineered to express the ovalbumin tumor-associated antigen ova, in combination with LPS. However, the combination of IT LPS with systemically delivered VSV resulted in rapid morbidity and mortality in the majority of mice. Decreasing the intravenous (IV) dose of VSV to levels at which toxicity was ameliorated did not enhance therapy compared with IT LPS alone. Toxicity of the systemic VSV + IT LPS regimen was associated with rapidly elevated levels of serum tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, which neither systemic VSV, nor IT LPS, alone induced. These data show that therapy associated with direct IT injections of oncolytic viruses can be significantly enhanced by combination with agonists of innate immune activation pathways, which are not themselves activated by the virus alone. Importantly, they also highlight possible, unforeseen dangers of combination therapies in which an immunotherapy, even delivered locally at the tumor site, may systemically sensitize the patient to a cytokine shock-like response triggered by IV delivery of oncolytic virus.
Assuntos
Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Receptor 4 Toll-Like/agonistas , Vesiculovirus/genética , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Terapia Genética , Vetores Genéticos , Imunidade Inata , Imunoterapia , Interferon-alfa/metabolismo , Interleucina-6/sangue , Interleucina-6/imunologia , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Vírus Oncolíticos/genética , Transdução de Sinais , Linfócitos T/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Vesiculovirus/imunologiaRESUMO
Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.
Assuntos
Galectinas , Linfonodos , Linfoma Folicular , Microambiente Tumoral , Humanos , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Linfonodos/patologia , Linfonodos/imunologia , Microambiente Tumoral/imunologia , Esferoides Celulares , Imunoterapia/métodos , Transdução de Sinais , Células Tumorais CultivadasRESUMO
The diagnosis of OTB (Ocular tuberculosis) is usually difficult to make. Definitive diagnosis requires the identification of M. tuberculosis organisms in ocular tissues or fluids, but samples are often difficult to obtain, and biopsy may be hard to justify. We describe a 50-years-old Maghreb male, who presented a multifocal choroiditis associated with a choroidal tuberculoma on the left eye. Based on positive QuantiFERON-TB-Gold test and suggestive clinical and radiographic findings, a diagnosis of presumed ocular tuberculosis was made. Serial swept-source optical coherence tomography (SS-OCT) and widefield fundus retinographies during subsequent follow-up visits demonstrated the characterization of the atypical tuberculosis presentation and allowed the assessment of response to antitubercular therapy and oral steroids.
Assuntos
Corioidite , Tuberculoma , Tuberculose Ocular , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Ocular/diagnóstico , Tuberculose Ocular/tratamento farmacológico , Tuberculose Ocular/complicações , Coroidite Multifocal/complicações , Coroidite Multifocal/tratamento farmacológico , Coroidite Multifocal/patologia , Corioide/patologia , Técnicas de Diagnóstico Oftalmológico , Antituberculosos/uso terapêutico , Tuberculoma/diagnóstico , Tuberculoma/tratamento farmacológico , Tuberculoma/complicações , Corioidite/diagnóstico , Corioidite/tratamento farmacológico , Corioidite/complicações , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodosRESUMO
For the routine diagnosis of haematological neoplasms an integrative approach is used considering the morphology, and the immunophenotypic, and molecular features of the tumor sample, along with clinical information. The identification and characterization of recurrent chromosomal aberrations mainly detected by conventional and molecular cytogenetics in the tumor cells has a major impact on the classification of lymphoid neoplasms. Some of the B-cell non-Hodgkin lymphomas are characterized by particular chromosomal aberrations, highlighting the relevance of conventional and molecular cytogenetic studies in their diagnosis and prognosis. In the current genomics era, next generation sequencing provides relevant information as the mutational profiles of haematological malignancies, improving their classification and also the clinical management of the patients. In addition, other new technologies have emerged recently, such as the optical genome mapping, which can overcome some of the limitations of conventional and molecular cytogenetics and may become more widely used in the cytogenetic laboratories in the upcoming years. Moreover, epigenetic alterations may complement genetic changes for a deeper understanding of the pathogenesis underlying B-cell neoplasms and a more precise risk-based patient stratification. Overall, here we describe the current state of the genomic data integrating chromosomal rearrangements, copy number alterations, and somatic variants, as well as a succinct overview of epigenomic changes, which altogether constitute a comprehensive diagnostic approach in B-cell non-Hodgkin lymphomas.
Assuntos
Neoplasias Hematológicas , Linfoma de Células B , Linfoma , Humanos , Aberrações Cromossômicas , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Mutação , Linfoma/genéticaRESUMO
Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects.