RESUMO
OBJECTIVE: To investigate the effect of progression of disease within 24 months (POD24) on overall survival (OS) in patients with mantle cell lymphoma (MCL), and compare the clinical characteristics between POD24 and non-POD24 patients. METHODS: A retrospective analysis was performed on 50 MCL patients with treatment indications and regular treatment who were admitted to the Affiliated Hospital of Xuzhou Medical University from January 2010 to August 2020. According to the occurrence of POD24, the patients were grouped for prognostic evaluation and clinical characteristics comparison. RESULTS: Univariate Cox regression analysis showed that POD24, PLT, albumin, MIPI score, ECOG PS score, LDH were the factors influencing OS in newly diagnosed MCL patients (all P < 0.05). The results of multivariate Cox regression analysis showed that POD24ï¼»HR=16.797(95%CI : 3.671-76.861),P < 0.001ï¼½, albumin<40 g/Lï¼»HR=3.238(95%CI :1.095-9.572),P =0.034ï¼½ and ECOG PS score≥2ï¼»HR=4.005(95%CI :1.033-15.521),P =0.045ï¼½ were independent risk factors influencing OS in MCL patients. The incidence of PLT<100×109/L (33.3% vs 5.9%, P =0.033) and ECOG PS score ≥2 (45.5% vs 5.9%, P =0.040) were significantly higher in POD24 patients than those in non-POD24 patients. CONCLUSION: POD24 is an independent poor prognostic factor affecting the OS of MCL patients, and the patients with PLT<100×109/L and ECOG PS score≥2 at diagnosis have a higher probability of POD24.
Assuntos
Progressão da Doença , Linfoma de Célula do Manto , Humanos , Prognóstico , Estudos Retrospectivos , Masculino , Feminino , Taxa de Sobrevida , Modelos de Riscos Proporcionais , Pessoa de Meia-IdadeRESUMO
Three undescribed isosteroidal alkaloids, przewalskines A-C (1-3), as well as seven known alkaloids (4-10) were obtained from Fritillaria przewalskii bulbs. Their structures were deduced by extensive HRESIMS, 1D NMR, and 2D NMR analyses, and their bioactivities were evaluated involving the anti-inflammatory and inhibitory potencies on AChE, BChE, and Aß aggregation. Compound 4 revealed the potent effect on inhibiting Aß aggregation activity with IC50 value of 33.1â µM, AChE activity with IC50 value of 6.9â µM, and also showed NO release inhibitory acitivity with IC50 value of 32.6â µM. These findings contribute new multi-.target anti-AD agents and embody the chemical diversity of F. przewalskii.
Assuntos
Alcaloides , Fritillaria , Fritillaria/química , Alcaloides/farmacologia , Alcaloides/químicaRESUMO
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.
Assuntos
Asma , Dibenzotiepinas , Pneumonia , Piridonas , Triazinas , Animais , Camundongos , Asma/tratamento farmacológico , Asma/metabolismo , Morfolinas/farmacologia , Morfolinas/uso terapêuticoRESUMO
Four undescribed and five known isosteroidal alkaloids were isolated from the bulbs of Fritillaria taipaiensis and their structures were elucidated on the basis of HR-ESI-MS, 1D and 2D NMR spectroscopic data analyses. The undescribed compounds were designated taipainines A-D. Of these, taipainine D presented a unique structure having the D/E trans (H-13α/H-17ß) and E/F cis (ß-axial lone pair of the N atom/H-22ß) ring junctions. Possible biosynthetic pathway to taipainine D is proposed. Four compounds showed significant BChE inhibitory activities similar or better than the positive control galantamine. In addition, the preliminary structure-activity relationships (SARs) of these isosteroidal alkaloids were also investigated.
Assuntos
Alcaloides , Doença de Alzheimer , Fritillaria , Alcaloides/química , Doença de Alzheimer/tratamento farmacológico , Fritillaria/química , Raízes de Plantas/química , Relação Estrutura-AtividadeRESUMO
Tetrabromobisphenol-A (TBBPA) is an emerging organic pollutant and a commonly used brominated flame retardant that has received much attention owing to its toxicity. Although TBBPA is ubiquitously detected in atmospheric particulate matter and dust, few studies have investigated the sub-chronic inhalation exposure to TBBPA. To further understand the excretion characteristics and tissue accumulation of TBBPA after inhalation exposure, we used the rat model to conduct a sub-chronic inhalation exposure study. Male rats were administered with different doses of aerosol TBBPA (12.9, 54.6, 121.6, and 455.0 mg/m3). TBBPA was found in the excretion (feces and urine) and all the target tissues (lung, liver, heart, thymus gland, spleen, testicles, muscles, kidneys, brain and serum). Feces were the main route of excretion, which contributed 19.18% to 72.54% (urine <0.10%). TBBPA excretion through feces following inhalation administration was much higher than that following oral and dermal exposure, thereby indicating lower bioavailability of TBBPA under inhalation exposure. Liver and serum showed higher levels of TBBPA compared with those of other tissues, thereby suggesting tissue-specific accumulation of TBBPA in rats. Owing to the relative non-invasiveness of serum sampling and greatest TBBPA concentration among the tissues, serum is a suitable matrix for estimation of TBBPA bioaccumulation after inhalation exposure.
Assuntos
Líquidos Corporais/química , Retardadores de Chama , Bifenil Polibromatos/análise , Animais , Disponibilidade Biológica , Fezes/química , Exposição por Inalação , Masculino , RatosRESUMO
In sustainable development assessment of the Beijing-Tianjin-Hebei region, the ability to dynamically estimate the value of ecosystem services is of great significance. This study considers the Beijing-Tianjin-Hebei region as the research area, based on the google earth engine (GEE); the classification and decision tree (CART) classification algorithm was adopted to supervise and classify the Landsat Thematic Mapper/Operational Land Imager (TM/OLI) images in the study area in 1998, 2003, 2008, 2013, and 2018, and land use types in these five periods were obtained. Quantitative analysis of the dynamic changes of land use in the Beijing-Tianjin-Hebei region from 1998 to 2018 was carried out. Then, the ecosystem service value (ESV) equivalent estimation method was used to quantitatively estimate the ESV in the Beijing-Tianjin-Hebei region and combine it with a 15 km×15 km scale grid to detect its temporal and spatial dynamics. The main results were as follows. â From 1998 to 2018, the area of construction land (increased by 16.67%) and grassland (reduced by 13.73%) in the six land use types in the Beijing-Tianjin-Hebei region was the largest, and the change in the proportion of water bodies (0.2%) was the smallest. â¡ The total value of ESV in the Beijing-Tianjin-Hebei region experienced a short-term increase from 1998 to 2003 (an increase of 91.97×108 yuan), and continued to decrease from 2003 to 2018 (a decrease of 239.07×108 yuan), mainly related to the expansion of construction land area in the other three time periods excluding 1998 and 2003. Among the six land use types, the forest provides the highest value of ecosystem services, and the construction land and unused land provide the lowest value of ecosystem services. ⢠The ESV time-space analysis based on the 15 km×15 km scale grid showed that the ESV medium area in the Beijing-Tianjin-Hebei region gradually decreased from 1998 to 2018, the ESV lower area and the higher area gradually increased, and the ESV lower-area growth rate was higher than for the higher area. ⣠The revised value of the Beijing-Tianjin-Hebei region (sensitivity coefficient range 0-0.83) has good significance and reliability. In future economic development, the Beijing-Tianjin-Hebei region should rationally optimize the land use pattern and strengthen the protection of forest land, grassland, water bodies and cultivated land.
Assuntos
Conservação dos Recursos Naturais , Ecossistema , Florestas , Agricultura , Pequim , China , Reprodutibilidade dos TestesRESUMO
The cytotoxic T lymphocyte (CTL) response plays a key role in controlling viral infection, but only a few epitopes within the HTNV glycoprotein (GP) that are recognized by CTLs have been reported. In this study, we identified one murine HTNV GP-derived H2-Kb-restricted CTL epitope in C57BL/6 mice, which could be used to design preclinical studies of vaccines for HTNV infection. First, 15 8-mer peptides were selected from the HTNV GP amino acid sequence based on a percentile rank of <=1% by IEDB which is the most comprehensive collection of epitope prediction and analysis tool. A lower percentile rank indicates higher affinity and higher immune response. In the case of the consensus method, we also evaluated the binding score of peptide-binding affinity by the BIMAS software to confirm that all peptides were able to bind H2-Kb. Second, one novel GP-derived CTL epitope, GP6 aa456-aa463 (ITSLFSLL), was identified in the splenocytes of HTNV-infected mice using the IFN-γ ELISPOT assay. Third, a single peptide vaccine was administered to C57BL/6 mice to evaluate the immunogenic potential of the identified peptides. ELISPOT and cell-mediated cytotoxicity assays showed that this peptide vaccine induced a strong IFN-γ response and potent cytotoxicity in immunized mice. Last, we demonstrated that the peptide-vaccinated mice had partial protection from challenge with HTNV. In conclusion, we identified an H2-Kb-restricted CTL epitope with involvement in the host immune response to HTNV infection.
Assuntos
Epitopos de Linfócito T/imunologia , Antígenos H-2/isolamento & purificação , Antígenos H-2/farmacologia , Vírus Hantaan/imunologia , Febre Hemorrágica com Síndrome Renal/prevenção & controle , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Animais , Antígenos Virais/análise , Antígenos Virais/imunologia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Linhagem Celular , Citocinas/análise , Testes Imunológicos de Citotoxicidade , Modelos Animais de Doenças , ELISPOT/métodos , Feminino , Glicoproteínas/efeitos dos fármacos , Glicoproteínas/imunologia , Vírus Hantaan/genética , Vírus Hantaan/patogenicidade , Febre Hemorrágica com Síndrome Renal/virologia , Imunização , Interferon gama/análise , Camundongos , Camundongos Endogâmicos C57BL , RNA Viral/isolamento & purificação , Baço/imunologia , Baço/patologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas SintéticasRESUMO
The enantioselective environmental behaviors of the chiral insecticide fipronil and its metabolites in lab-scale aquatic ecosystems were studied and the toxicity of fipronil enantiomers and the metabolites to non-target organisms Lemna minor (L. minor) and Anodonta woodiana (A. woodiana) was also investigated in this work. Water-sediment, water-L. minor, water-A. woodiana, and water-sediment-L. minor-A. woodiana ecosystems were set up and exposed to fipronil through a 90-day period. The results showed fipronil could be degraded significantly faster (half-life of 4.6 days) in the complex water-sediment-L. minor-A. woodiana ecosystem. A. woodiana played a crucial role in the dissipation of fipronil, and the microorganisms in the sediment also made great contribution to the degradation of fipronil in aquatic ecosystems. All the three metabolites fipronil desulfinyl, fipronil sulfide and fipronil sulfone were detected in the ecosystems and were more persistent than fipronil. Enantioselective degradation of fipronil was observed with S-fipronil being preferentially degraded in sediment and L. minor, while R-fipronil was metabolized preferentially in A. woodiana. EC50 for L. minor was obtained using 7-day exposure, and for A. woodiana was obtained using 72-h exposure. S-fipronil was more toxic to A. woodiana, while R-fipronil showed higher toxicity to L. minor. Moreover, the three metabolites were found more toxic than fipronil indicating significant environment risks due to their persistence. The present study might have important implications for the risk assessment of fipronil and its metabolites in real aquatic environment.
Assuntos
Ecossistema , Inseticidas , Meia-VidaRESUMO
The enantioselective bioaccumulation and elimination of fipronil in Anodonta woodiana (A. woodiana) were studied and the main metabolites fipronil desulfinyl, fipronil sulfide and fipronil sulfone were determined. The acute toxicity of the enantiomers of fipronil and the three metabolites were also investigated. In the bioaccumulation process, fipronil in A. woodiana reached equilibrium after 11days with BCF value of 0.2, and the enantiomeric fraction (EF) values showed that the bioaccumulation was enantioselective with enantioenrichment of S-fipronil. The degradation of fipronil in A. woodiana fitted first-order kinetics model with half-lives of the enantiomers were 5.8 d for R-fipronil and 7.6 d for S-fipronil, and the EF values decreasing from 0.5 gradually indicating the R-enantiomer was preferentially degraded. The degradation of single enantiomers was also performed and the results revealed a fast conversion of R-fipronil to S-fipronil by A. woodiana. The three metabolites were all detected in A. woodiana-water system, in which fipronil sulfone and fipronil sulfide had higher concentration levels. According to the 72-h LC50 values, S-fipronil was much more toxic than the racemate and R-fipronil. Moreover, the metabolites were more toxic than the parent fipronil. The results suggested the individual enantiomers of chiral pollutants and the metabolites should be considered in the risk assessments.
Assuntos
Anodonta/metabolismo , Inseticidas/metabolismo , Pirazóis/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Cinética , Estereoisomerismo , Sulfetos/metabolismo , Sulfonas/metabolismoRESUMO
Fipronil is an effective insecticide, but it presents highly toxic effects in nontarget aquatic organisms. The present study examined the enantioselective toxicity and degradation of fipronil enantiomers in a freshwater algae Scenedesmus obliguus suspension. There was a substantial difference in the acute toxicity of the enantiomers to S. obliguus, with 72-h median effective concentrations (EC50s) of 0.29 mg L(-1) and 1.50 mg L(-1) for the R-fipronil and S-fipronil, respectively. The influences on the concentration of chlorophyll a, chlorophyll b, and carotenoids were determined, and the effects of fipronil on the concentration of chlorophyll a and chlorophyll b were also enantioselective. The degradation of fipronil in algae suspension was enantioselective, with half-lives for R-fipronil and S-fipronil of 2.9 d and 3.2 d, respectively, and the enantiomer fraction reaching 0.65 at the day 17. The enantiomeric differences should be taken into consideration for fipronil risk assessment.
Assuntos
Inseticidas/toxicidade , Pirazóis/toxicidade , Scenedesmus/efeitos dos fármacos , Bioensaio , Carotenoides/química , Clorofila/análogos & derivados , Clorofila/química , Clorofila A , Inseticidas/metabolismo , Fotossíntese , Pirazóis/metabolismo , Reprodutibilidade dos Testes , Medição de Risco , Estereoisomerismo , Suspensões , Fatores de TempoRESUMO
The enantioselective acute toxicity to earthworms of racemic fipronil and its individual enantiomers was studied. R-(-)-fipronil was approximately 1.5 times more toxic than the racemate and approximately 2 times more toxic than S-(+)-fipronil after 72 and 96 h of exposure, respectively. Assays of fipronil enantiomer bioaccumulation and degradation in earthworms were conducted. The bio-concentration factors (BCFs) were slightly different between the two enantiomers. The enantiomeric fraction (EF) values in earthworms in the bioaccumulation period were approximately 0.5, which indicated there was no enantioselective bioaccumulation. In contrast, the degradation of fipronil in earthworms was enantioselective: the t1/2 values for R- and S-fipronil were 3.3 and 2.5 days, respectively, in natural soil, and 2.1 and 1.4 days, respectively, in artificial soil. The results of soil analyses showed that the degradation of fipronil was not enantioselective, which suggested that the enantioselectivity of fipronil in earthworms results from the organism's metabolism. The study also demonstrated that the presence of earthworms could accelerate the degradation of fipronil in soil.
Assuntos
Inseticidas/toxicidade , Pirazóis/toxicidade , Poluentes do Solo/toxicidade , Animais , Bioensaio , Inseticidas/química , Dose Letal Mediana , Oligoquetos , Pirazóis/química , Solo/química , Poluentes do Solo/química , EstereoisomerismoRESUMO
The enantioselective bioaccumulation and elimination of α-hexachlorocyclohexane (α-HCH) in loaches (Misgurnus anguillicaudatus) were studied for the first time. Valid chiral residue analysis methods for α-HCH enantiomers in water and loach samples were established using gas chromatography coupled with electron capture detector and a BGB-172 chiral column. A rapid accumulation process was found during the 39-d bioaccumulation experiment. The α-HCH in loaches reached its maximum on the fourth day, after which it fluctuated slightly, reflecting a balance between elimination and reuptake. The maximum bioaccumulation factor was 728 at the 10 µg L(-1) exposure level. The enantiomeric fraction (EF) values showed that the bioaccumulation was enantioselective with enantioenrichment of (+)-α-HCH in the loaches. The elimination experiment indicated that the degradation kinetics of α-HCH fitted a typical first-order kinetics model, and the half-life was about 5 d. Significant enantioselectivity was observed during the elimination process, with the EFs declining from higher than 0.5-0.39, suggesting (+)-α-HCH is preferentially biotransformed than (-)-α-HCH in loaches. The results reveal a high capacity for α-HCH bioconcentration by loaches and that biotransformation is the main route of decontamination.
Assuntos
Cipriniformes/metabolismo , Hexaclorocicloexano/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Biotransformação , Monitoramento Ambiental , Meia-Vida , Hexaclorocicloexano/análise , Hexaclorocicloexano/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/químicaRESUMO
BACKGROUND: The order and mechanism of pathological changes in acetabular dysplasia are still unclear. This study investigated cartilage changes in rabbit acetabular dysplasia models at different ages. METHODS: Twenty-seven 1-month-old New Zealand rabbits underwent cast immobilization of the left hind limb in knee extension. Serial acetabular dysplasia models were established by assessment of the acetabular index and Sharp's angle on radiographs. The thickness of the acetabular cartilage was measured under a microscope, and fibrosis was observed. Ultrastructural changes were investigated with scanning electron microscopy and transmission electron microscopy. The messenger RNA expression of collagen I and II, ß1 integrin, and caspase-9 were measured by real-time fluorescence quantitative polymerase chain reaction. RESULTS: In an immature group of rabbits, the acetabular index of the treated hip increased with animal growth. The cartilage on the brim of the left acetabulum was significantly thicker than that on the right side. The collagen fibrils on the surface of the cartilage became gross, and the chondrocytes in the enlargement layer underwent necrosis. In a mature group of rabbits, the left Sharp's angle increased in the rabbits with 6-week casting. The cartilage on the brim of the left acetabulum underwent fibrosis. The chondrocytes were weakly stained, and the number of lysosomes was much larger than normal. The messenger RNA expression of collagen I and II, ß1 integrin, and caspase-9 in the cartilage differed significantly at different ages. CONCLUSIONS: Increasing thickness followed by fibrosis may be the order of pathological cartilage changes in acetabular dysplasia, with changes in ultrastructure and collagen expression contributing to the process.
Assuntos
Acetábulo/patologia , Cartilagem Articular/patologia , Fibrose/patologia , Acetábulo/metabolismo , Acetábulo/ultraestrutura , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/ultraestrutura , Feminino , Fibrose/metabolismo , Masculino , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase , CoelhosRESUMO
OBJECTIVE: To detect the changes of expressions of II type collagen and matrix metalloproteinases-7 (MMP-7) of acetabular cartilage in early DDH (developmental dysplasia of hip) and to investigate the relevance between II type collagen and MMP-7 and the retrogression mechanism of acetabular cartilage. METHODS: The animal model of DDH was successfully established in 8 rabbits by applying the method of knee extension in which left lower extremity as experimental group and right one as control group. And the stains of HE and toluidine blue were applied on the samples of acetabular cartilage to observe the changes of chondrocytes and extracellular matrix (ECM). The techniques of immunohistochemical staining and Western blot were employed to respectively qualify and quantitate the expression of II type collagen and MMP-7. RESULTS: Pathohistological observation indicated the signs of retrogressive changes of acetabular cartilage in experimental group, including a loss of ECM in toluidine blue stain and a cluster of chondrocytes in HE stain. The positive numbers of II type collagen and MMP-7 by immunohistochemical staining in experimental group were both higher than that of control group. The quantitative amounts of II type collagen and MMP-7 by Western blot in experimental group were both higher than that of control group. Both significant differences existed between two groups (P < 0.05). CONCLUSION: The expression of II type collagen and MMP-7 is correlated to a retrogression of acetabular cartilage and increases obviously in early DDH. The amount and intensity of II type collagen and MMP-7 are probably the rationale of differential retrogression of cartilage.
Assuntos
Doenças do Desenvolvimento Ósseo/metabolismo , Colágeno Tipo II/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Acetábulo/metabolismo , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Luxação Congênita de Quadril/metabolismo , Luxação Congênita de Quadril/patologia , CoelhosRESUMO
OBJECTIVE: To study the effect of self-setting calcium phosphate cement (CPC) on the repair of local bone defects after resection of cyst in children. METHODS: From December 1998 to May 2002, 22 patients with bone defects were repaired with CPC. Their ages ranged from 4 to 10 years with an average of 8.3 years. There were 11 cases of non-ossifying fibroma, 7 cases of osteoid osteoma, 2 cases of bone cyst and 2 cases of fibrous dysplasia. The bone defects are located as the following: femur in 14 cases, tibia in 6 cases and humerus in 2 cases. CPC spongiosa granules were filled in 11 cases, injectable CPC were filled in 2 bone cyst cases. The patients were followed up for 5-48 months, averaged 23.5 months. RESULTS: Bone matrix grew well and no recurrence was found. CONCLUSION: The method with simple CPC in repairing bone defects is safe, non-toxic, economic and convenient in children.