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Avermectin is a highly effective insecticide that has been widely used in agriculture since the 1990s. In recent years, the safety of avermectin for non-target organisms has received much attention. The vasculature is important organs in the body and participate in the composition of other organs. However, studies on the vascular safety of avermectin are lacking. The vasculature of zebrafish larvae is characterized by ease of observation and it is a commonly used model for vascular studies. Therefore, zebrafish larvae were used to explore the potential risk of avermectin on the vasculature. The results showed that avermectin induced vascular damage throughout the body of zebrafish larvae, including the head, eyes, intestine, somite, tail and other vasculature. The main forms of damage are reduction in vascular diameter, vascular area and vascular abundance. Meanwhile, avermectin induced a decrease in the number of endothelial cells and apoptosis within the vasculature. In addition, vascular damage may be related to impairment of mitochondrial function and mitochondria-mediated apoptosis. Finally, exploration of the molecular mechanisms revealed abnormal alterations in the expression of genes related to the VEGF/Notch signaling pathway. Therefore, the VEGF/Notch signaling pathway may be an important mechanism for avermectin-induced vascular damage in zebrafish larvae. This study demonstrates the vascular toxicity of avermectin in zebrafish larvae and reveals the possible molecular mechanism, which would hopefully draw more attention to the safety of avermectin in non-target organisms.
Assuntos
Apoptose , Ivermectina , Larva , Mitocôndrias , Receptores Notch , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Peixe-Zebra , Animais , Ivermectina/análogos & derivados , Ivermectina/toxicidade , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Larva/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Receptores Notch/metabolismo , Inseticidas/toxicidade , Vasos Sanguíneos/efeitos dos fármacosRESUMO
Natural pyrethrins are widely used in agriculture because of their good insecticidal activity. Meanwhile, natural pyrethrins play an important role in the safety evaluation of pyrethroids as precursors for structural development of pyrethroid insecticides. However, there are fewer studies evaluating the neurological safety of natural pyrethrins on non-target organisms. In this study, we used SH-SY5Y cells and zebrafish embryos to explore the neurotoxicity of natural pyrethrins. Natural pyrethrins were able to induce SH-SY5Y cells damage, as evidenced by decreased viability, cycle block, apoptosis and DNA damage. The apoptotic pathway may be related to the involvement of mitochondria and the results showed that natural pyrethrins induced a rise in Capase-3 viability, Ca2+ overload, a decrease in adenosine triphosphate (ATP) and a collapse of mitochondrial membrane potential in SH-SY5Y cells. Natural pyrethrins may mediate DNA damage in SH-SY5Y cells through oxidative stress. The results showed that natural pyrethrins induced an increase in reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and catalase (CAT) activity, and induced a decrease in glutathione peroxidase (GPx) activity in SH-SY5Y cells. In vivo, natural pyrethrins induced developmental malformations in zebrafish embryos, which were mainly characterized by pericardial edema and yolk sac edema. Meanwhile, the results showed that natural pyrethrins induced damage to the Huc-GFP axis and disturbed lipid metabolism in the head of zebrafish embryos. Further results showed elevated ROS levels and apoptosis in the head of zebrafish embryos, which corroborated with the results of the cell model. Finally, the results of mRNA expression assay of neurodevelopment-related genes indicated that natural pyrethrins exposure interfered with their expression and led to neurodevelopmental damage in zebrafish embryos. Our study may raise concerns about the neurological safety of natural pyrethrins on non-target organisms.
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Embrião não Mamífero , Piretrinas , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Piretrinas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Inseticidas/toxicidade , Dano ao DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Spinetoram is an important semi-synthetic insecticide extensively applied in agriculture. It is neurotoxic to insects, primarily by acting on acetylcholine receptors (nAChRs). However, few studies have examined the neurotoxicity of spinetoram in human beings. In this study, various concentrations (5, 10, 15, and 20 µM) of spinetoram were employed to expose SH-SY5Y cells in order to study the neurotoxic effects of spinetoram. The results showed that spinetoram exposure markedly inhibited cell viability and induced oxidative stress. It also induced mitochondrial membrane potential collapse (ΔΨm), and then caused a massive opening of the mitochondrial permeability transition pore (mPTP), a decrease in ATP synthesis, and Ca2+ overloading. Furthermore, spinetoram exposure induced cellular autophagy, as evidenced by the formation of autophagosomes, the conversion of LC3-I into LC3-II, down-regulation of p62, and up-regulation of beclin-1. In addition, we observed that p-mTOR expression decreased, while p-AMPK expression increased when exposed to spinetoram, indicating spinetoram triggered AMPK/mTOR-mediated autophagy. Complementarily, the effect of spinetoram on neurobehavior was studied using the zebrafish model. After being exposed to different concentrations (5, 10, and 20 µg/mL) of spinetoram, zebrafish showed neurobehavioral irregularities, such as reduced frequency of tail swings and spontaneous movements. Similarly, autophagy was also observed in zebrafish. In conclusion, spinetoram exposure produced potential neurotoxicity through autophagy mediated by mitochondrial damage. The experimental data and results of the neurotoxicity study of spinetoram provided above are intended to serve as reference for its safety assessment.
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Macrolídeos , Neuroblastoma , Síndromes Neurotóxicas , Humanos , Animais , Proteínas Quinases Ativadas por AMP , Peixe-Zebra , Autofagia , Síndromes Neurotóxicas/etiologia , Serina-Treonina Quinases TORRESUMO
PURPOSE: Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-ß (Aß) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aß PET imaging in clinical AD cohort. METHODS: We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and Aß ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aß PET imaging. RESULTS: TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aß deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aß deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003). CONCLUSION: By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aß deposition and cognitive dysfunction.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Perfilação da Expressão Gênica , Doenças Neuroinflamatórias , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Receptores de GABA/genética , Receptores de GABA/metabolismoRESUMO
Numerous studies have described the notable impact of gut microbiota on the brain in Alzheimer's disease (AD) via the gut - brain axis. However, the molecular mechanisms underlying the involvement of gut microbiota in the development of AD are limited. This study aimed to explore the potential mechanisms of gut microbiota in AD by integrating multi-omics data. In this study, APP/PS1 and WT mice at nine months of age were used as study mouse model. Cognitive function was assessed using the Morris water maze test. The levels of Aß plaque and neuroinflammation in the brain were detected using immunofluorescence and PET/CT. In addition, we not only used 16S rRNA gene sequencing and metabolomics to explore the variation characteristics of gut microbiota and serum metabolism abundance, but also combined spatial metabolomics and transcriptomics to explore the change in the brain and identify their potential correlation. APP/PS1 mice showed significant cognitive impairment and amyloid-ß deposits in the brain. The abundance of gut microbiota was significantly changed in APP/PS1 mice, including decreased Desulfoviobrio, Enterococcus, Turicibacter, and Ruminococcus and increased Pseudomonas. The integration of serum untargeted metabolomics and brain spatial metabolomics showed that glycerophospholipid metabolism was a common alteration pathway in APP/PS1 mice. Significant proliferation and activation of astrocyte and microglia were observed in APP/PS1 mice, accompanied by alterations in immune pathways. Integration analysis and fecal microbiota transplantation (FMT) intervention revealed potential association of gut microbiota, host glycerophospholipid metabolism, and neuroinflammation levels in APP/PS1 mice.
Assuntos
Doença de Alzheimer , Microbioma Gastrointestinal , Camundongos , Animais , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos Transgênicos , Doenças Neuroinflamatórias , RNA Ribossômico 16S/genética , Multiômica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Doença de Alzheimer/complicações , Glicerofosfolipídeos , Modelos Animais de DoençasRESUMO
Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma , Células T Matadoras Naturais , Humanos , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Proteômica , Linfoma/complicações , Células T Matadoras Naturais/patologia , Microambiente Tumoral/genéticaRESUMO
We report the results of GUIDANCE-01 (NCT04025593), a randomized, phase II trial of R-CHOP alone or combined with targeted agents (R-CHOP-X) guided by genetic subtyping of newly diagnosed, intermediate-risk, or high-risk diffuse large B cell lymphoma (DLBCL). A total of 128 patients were randomized 1:1 to receive R-CHOP-X or R-CHOP. The study achieved the primary endpoint, showing significantly higher complete response rate with R-CHOP-X than R-CHOP (88% vs. 66%, p = 0.003), with overall response rate of 92% vs. 73% (p = 0.005). Two-year progression-free survival rates were 88% vs. 63% (p < 0.001), and 2-year overall survival rates were 94% vs. 77% (p = 0.001). Meanwhile, post hoc RNA-sequencing validated our simplified genetic subtyping algorithm and previously established lymphoma microenvironment subtypes. Our findings highlight the efficacy and safety of R-CHOP-X, a mechanism-based tailored therapy, which dually targeted genetic and microenvironmental alterations in patients with newly diagnosed DLBCL.
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BACKGROUND: The current standard of care for non-bulky diffuse large B-cell lymphoma (DLBCL) patients with an International Prognostic Index (IPI) of 0 is four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear. This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography (PET-CT, Deauville 1-3), irrespective of age and other IPI risk factors (IPI 0-1). METHODS: This was an open-label, randomized, phase III, non-inferiority trial. Patients aged 14-75 years with newly diagnosed low-risk DLBCL, according to IPI, achieving PET-CT confirmed complete response (CR) after four cycles of R-CHOP were randomized (1:1) between four cycles of rituximab (4R-CHOP+4R arm) or two cycles of R-CHOP plus two cycles of rituximab (6R-CHOP+2R arm). The primary endpoint was 2-year progression-free survival (PFS), conducted in the intention-to-treat population. Safety was assessed in patients with at least one cycle of assigned treatment. The non-inferiority margin was -8%. RESULTS: A total of 287 patients were included in the intention-to-treat analysis, the median follow-up was 47.3 months, and the 2-year PFS rate was 95% (95% confidence interval [CI], 92% to 99%) and 94% (95% CI, 91% to 98%) for the 4R-CHOP+4R and 6R-CHOP+2R arm. The absolute difference in 2-year PFS between the two arms was 1% (95% CI, -5% to 7%), supporting the non-inferiority of 4R-CHOP+4R. Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm (16.7% versus 76.9%), with decreased risk of febrile neutropenia (0.0% versus 8.4%) and infection (2.1% versus 14.0%). CONCLUSIONS: For newly diagnosed low-risk DLBCL patients, interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might have high-risk biological features or develop resistance. Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low-risk, non-bulky DLBCL with interim PET-CT confirmed CR.
Assuntos
Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Rituximab , Anticorpos Monoclonais Murinos/uso terapêutico , Intervalo Livre de Doença , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Vincristina/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Prednisona/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type (NKTCL). We explored the efficacy and safety of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched radiotherapy. This multicenter, randomized, phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2-4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (four cycles), combined with sandwiched radiotherapy. The primary endpoint was overall response rate (ORR). The non-inferiority margin was -10.0%. From March 16, 2016, to July 17, 2020, 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat population. The ORR was 88.8% (95% confidence interval [CI], 81.9-93.7) for ESA with sandwiched radiotherapy and 86.2% (95% CI, 78.8-91.7) for MESA with sandwiched radiotherapy, with an absolute rate difference of 2.6% (95% CI, -5.6-10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. Adverse events of grade 3 or higher occurred in 42 (33.6%) patients in the ESA arm and 81 (65.9%) in the MESA arm. ESA with sandwiched radiotherapy is an effective, low toxicity, non-intravenous regimen with an outpatient design, and can be considered as a first-line treatment option in newly diagnosed early-stage nasal NKTCL.
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Anti-CD19 chimeric antigen receptor (CAR)-T cells not only target CD19-positive malignant lymphoma cells but also normal B cells. The utility of CAR-T cell therapy has been reported in rheumatoid arthritis and systemic lupus erythematosus; however, its use in Sjögren's disease (SjD) remains unknown. In this study, we describe the case of a 76-year-old woman with active SjD for 10 years who was diagnosed with diffuse large B-cell lymphoma. After receiving anti-CD19 CAR-T cell therapy, she achieved complete remission (CR) on day 28. Since the onset of her 10-year history with SjD, she was negative for antinuclear antibodies and anti-Ro-52 for the first time on day 90 after CAR-T cell therapy. Six months after CAR-T cell therapy, the CR status was maintained, serum cytokine levels returned to their normal levels, and dry mouth symptoms improved. The EULAR Sjögren's Syndrome Disease Activity Index score decreased from 5 to 2, indicating a partial remission of SjD activity compared with that before CAR-T cell treatment. In the early stage of treatment, she presented with grade 2 cytokine release syndrome and grade 1 neurotoxicity, which were completely controlled after an active intervention. This case highlights the potential application of CAR-T cells in treating autoimmune diseases, such as SjD.
Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Síndrome de Sjogren , Humanos , Feminino , Idoso , Síndrome de Sjogren/complicações , Síndrome de Sjogren/terapia , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Antígenos CD19 , Terapia Baseada em Transplante de Células e TecidosRESUMO
BACKGROUND: As an original traditional Chinese medicinal formula, Qin Huang formula (QHF) is used as adjuvant therapy for treating lymphoma in our hospital and has proven efficacy when combined with chemotherapy. However, the underlying mechanisms of QHF have not been elucidated. METHODS: A network pharmacological-based analysis method was used to screen the active components and predict the potential mechanisms of QHF in treating B cell lymphoma. Then, a murine model was built to verify the antitumor effect of QHF combined with Adriamycin (ADM) in vivo. Finally, IHC, ELISA, 18F-FDG PET-CT scan, and western blot were processed to reveal the intriguing mechanism of QHF in treating B cell lymphoma. RESULTS: The systemic pharmacological study revealed that QHF took effect following a multiple-target and multiple-pathway pattern in the human body. In vivo study showed that combination therapy with QHF and ADM potently inhibited the growth of B cell lymphoma in a syngeneic murine model, and significantly increased the proportion of tumor infiltrating CD4+ and CD8+ T cells in the tumor microenvironment (TME). Furthermore, the level of CXCL10 and IL-6 was significantly increased in the combination group. Finally, the western blot exhibited that the level of TLR2 and p38 MAPK increased in the combination therapy group. CONCLUSION: QHF in combination of ADM enhances the antitumor effect of ADM via modulating tumor immune microenvironment and can be a combination therapeutic strategy for B cell lymphoma patients.
Assuntos
Linfoma de Células B , Neoplasias , Animais , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Humanos , Linfócitos do Interstício Tumoral , Camundongos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transdução de Sinais , Receptores Toll-Like , Microambiente TumoralRESUMO
BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies. Patients with synucleinopathies frequently display eye movement abnormalities. However, whether patients with iRBD have eye movement abnormalities remains unknown. OBJECTIVE: The aim of this study was to assess eye movement abnormalities and related gray matter alterations and explore whether such abnormalities can serve as biomarkers to indicate phenoconversion to synucleinopathies in iRBD. METHODS: Forty patients with iRBD with early disease progression and 35 healthy control subjects participated in a 15-minute ocular-tracking task that evaluated their control of eye movement abilities. They also underwent clinical assessments for olfactory function, nonmotor symptoms, and autonomic symptoms, all of which are biomarkers to predict phenoconversion to synucleinopathies in iRBD. A subgroup of the participants (20 patients with iRBD and 20 healthy control subjects) also participated in structural magnetic resonance imaging. RESULTS: The ocular-tracking ability in patients with iRBD was inferior to that of healthy control subjects in two aspects: pursuit initiation and steady-state tracking. Cortical thinning in the right visual area V4 in patients with iRBD is coupled with impaired pursuit initiation. Furthermore, prolonged pursuit initiation in patients with iRBD exhibits a trend of correlation with olfactory loss, the earliest biomarker that develops prior to other prodromal biomarkers. CONCLUSIONS: We found ocular-tracking abnormalities in patients with iRBD even early in their disease progression that have not been reported before. These abnormalities are coupled with atrophy of brain areas involved in the perception of object motion and might indicate phenoconversion to synucleinopathies in iRBD. © 2022 International Parkinson and Movement Disorder Society.
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Transtorno do Comportamento do Sono REM , Sinucleinopatias , Atrofia , Biomarcadores , Progressão da Doença , HumanosRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into diverse cell types under specific conditions. Dysfunction in the osteogenic differentiation of MSCs can result in bone metabolism-related diseases, including osteoporosis. Accumulating evidence has revealed that long non-coding RNA (lncRNAs) play critical regulatory roles during MSC differentiation. METHODS: In the present study, we identified an evolutionarily conserved lncRNA expressed during the osteogenic differentiation of MSCs, which we termed LINC01119. We first identified LINC01119 as a negative regulator of the osteogenic differentiation of MSCs. RESULTS: LINC01119 knockdown markedly induced calcium deposition in bone marrow MSCs and promoted the osteogenic differentiation of MSCs. More importantly, we demonstrated the underlying molecular basis through which LINC01119 regulates osteogenesis via the Wnt pathway by targeting FZD4. Furthermore, we observed that transcription factor EBF3 could directly bind the promoter site of LINC01119. CONCLUSIONS: We first explored the molecular regulatory mechanism of LINC01119 during the osteogenic differentiation of MSCs and revealed that LINC01119 negatively regulates osteogenesis through the Wnt pathway by targeting FZD4.
Assuntos
Células-Tronco Mesenquimais , Osteogênese , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Via de Sinalização Wnt/genéticaAssuntos
Decitabina/farmacologia , Linfoma Difuso de Grandes Células B/genética , Resultado do Tratamento , Microambiente Tumoral/fisiologia , Idoso , Biomarcadores/análise , Decitabina/metabolismo , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network-International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-ß signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase >3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.
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OBJECTIVES: The positron emission tomography (PET) could predict the prognosis of DLBCL patients, but the exact procedure on interim PET (iPET) to determine chemoresistant patients remains elusive. METHODS: We retrospectively analyzed 593 newly diagnosed DLBCL patients uniformly treated with R-CHOP regimen. Among them, 352 patients diagnosed from August 2010 to December 2016 were included in the test cohort and 241 patients diagnosed from January 2017 to December 2019 were included in the validation cohort. The iPET was evaluated with Deauville criteria and ΔSUVmax method. The reduction of maximal SUV between baseline and after 4 cycles of chemotherapy were defined as ΔSUVmax. The survival functions were depicted using the Kaplan-Meier method and compared with the log-rank test. RESULTS: Patients with iPET Deauville 4 had heterogeneous outcome and end of treatment complete response rates (eCRR). Combined Deauville with ΔSUVmax method, we proposed a modified-Deauville model: patients with Deauville 4 and ΔSUVmax > 70%, as well as those with Deauville 1-3, were reclassified into the modified-Deauville negative group, while patients with Deauville 4 and ΔSUVmax ≤ 70%, as well as those with Deauville 5, into the modified-Deauville positive group. In the test cohort, 3-year PFS, OS and eCRR of modified-Deauville negative group were 80.2%, 89.9% and 91.8%, significantly higher than those of positive group (12.5%, 27.3% and 29.2%, p ≤ .001). Similar results were found in the validation cohort, that 3-year PFS, OS and eCRR were 87.8%, 95.4%, 96.3% in modified-Deauville negative group, and 27.4%, 32.5%, 13.5% in positive group. Through modified-Deauville model, patients in iPET positive group had very low eCRR and were resistant to conventional chemotherapy. CONCLUSIONS: The modified-Deauville model could better distinguish DLBCL patients with poor response to chemotherapy. Accordingly, these patients could be recognized early and provided with alternative therapeutic agents, which might improve the clinical outcome of refractory DLBCL patients.
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Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Fluordesoxiglucose F18 , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2). RESULTS: Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52-79) and 83% (95% CI 68-91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3-4 neutropenia was reported in 171, grade 3-4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported. CONCLUSION: CR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Piridinas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Biomarcadores/análise , Proteína de Ligação a CREB/efeitos dos fármacos , Proteína de Ligação a CREB/metabolismo , Estudos de Casos e Controles , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Proteína p300 Associada a E1A/efeitos dos fármacos , Proteína p300 Associada a E1A/metabolismo , Epigenômica , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
Cancer stem cells play an important role on tumor progression. Biomarkers of stem cell property and their relationship to extranodal involvement of malignant lymphocytes are undefined in diffuse large B-cell lymphoma (DLBCL). Here we showed that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintained B-lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo. As mechanism of action, JAM-A overexpression selectively activated transforming growth factor-ß (TGF-ß)/NODAL signaling, thereby enhanced B-lymphoma cell aggressiveness and induced extranodal involvement to mesoendoderm-derived organs in DLBCL. Lenalidomide downregulated JAM-A and downstream NODAL expression, resulting in inhibition of B-lymphoma cell invasion and epithelial-to-mesenchymal transition. In a murine xenograft model established with subcutaneous injection of JAM-A-overexpressing B-lymphoma cells, lenalidomide retarded tumor growth and prevented cell invasion to mesoendoderm-derived organs, consistent with the downregulation of JAM-A and NODAL expression. Collectively, these findings indicated that JAM-A was related to extranodal involvement in DLBCL through modulating TGF-ß/NODAL signaling. Identified as a biomarker of stem cell property, JAM-A indicated the sensitivity of B-lymphoma cells to lenalidomide. Therapeutic targeting of JAM-A/NODAL axis could thus be a promising clinical strategy to impede tumor progression in DLBCL.
Assuntos
Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lenalidomida/farmacologia , Metástase Linfática , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Camundongos , Invasividade Neoplásica , Proteína Nodal/metabolismo , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
BACKGROUND: In recent years, the application of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for voluntary cancer screening of asymptomatic individuals is becoming more and more popular in China. However, the utility of such screening is still controversial. METHODS: This study enrolled a total of 1,572 asymptomatic individuals who underwent FDG PET/CT as a part of cancer screening program in Shanghai Ruijin Hospital, between January 2010 and December 2014. Whole set of clinical data of each case was retrospectively collected. The cancer detection rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG PET/CT were calculated, according to the cancer data obtained from histopathological examinations or at least 12-month clinical follow-up. RESULTS: Among the 1,572 subjects, malignant tumors were found in 27 cases (1.72%). The cancer detection rate was 2.74% among subjects who were older than 50 years, 4.72% among those who had a family history of malignant tumors, and 2.77% among those whose tumor markers were positive. These rates were higher than those among other subjects (p<0.05). The detection rate of FDG PET/CT in asymptomatic cancer screening was 1.44%, and the sensitivity, specificity, PPV, and NPV were estimated to be 85.19%, 99.68%, 82.14%, and 99.75%, respectively. CONCLUSION: Considering its less cost-efficient performance, we do not recommend using FDG PET/CT for cancer screening in asymptomatic population. Nevertheless, FDG PET/CT might be a powerful cancer screening modality with the selection of high-risk group, and an optimal combination of the modalities should be provided in order to maximize diagnostic performance with lower costs.