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1.
BMC Musculoskelet Disord ; 22(1): 178, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33583400

RESUMO

BACKGROUND: Aim of this multicenter, observational, cross-sectional study was to evaluate health-related quality of life (HRQoL) and treatment satisfaction of current medications in Chinese knee OA patients. METHODS: Brief Pain Inventory (BPI), Treatment Satisfaction Questionnaire (TSQM-1.4), and HRQoL (EQ-5D-5L) were assessed in total of 601 OA of knee patients. Impact on QoL (EQ-5D-5L) and treatment satisfaction (TSQM-1.4) by BPI-Severity score (< 4 and ≥ 4) were presented using mean standard deviations (SDs) and were compared using a t-test. For each of self-assessed health EQ-5D-5L and TSQM, a linear regression model was used to estimate the regression coefficient along with corresponding 95% confidence interval (CI) for BPI-Severity. RESULTS: Mean score of EQ-5D-5L of patients with BPI-Severity ≥4 was significantly lower than those with BPI-Severity < 4. All the scores of TSQM in 4 dimensions were lower in patients with BPI-Severity ≥4 than in those with BPI-Severity < 4. Both HRQoL scores and TSQM scores showed a statistically significant decreasing trend with increasing BPI-Severity pain score. CONCLUSION: Chronic knee OA pain has a significant impact on patients' HRQoL. More severe patients with OA were less satisfied with current treatments.

2.
Biochem Cell Biol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33481678

RESUMO

The proteolytic autophagy system is involved in a major regulatory pathway in dexamethasone (Dex)-induced muscle atrophy. Sirtuin 2 (SIRT2) is known to participate in modulating autophagy signaling, exerting effects in skeletal muscle atrophy. We aimed to determine the effects of SIRT2 on autophagy in Dex-induced myoatrophy. Mice were randomly divided into the normal, Dex, and sirtinol groups. C2C12 cells were differentiated into myotubes and transfected with short hairpin (sh)-Sirt2-green fluorescent protein (GFP) or Sirt2-GFP lentivirus. To evaluate the mass and function of skeletal muscles, we measured the myofiber cross-sectional area, myotube size, gastrocnemius muscle wet weight/body weight ratio (%), and time-to-exhaustion. The SIRT2, myosin heavy chain (MyHC), LC3, and Beclin-1 expression levels were detected by western blotting and quantitative reverse transcription-polymerase chain reaction. Inhibition of SIRT2 markedly attenuated the muscle mass and endurance capacity. The same phenotype was observed in Sirt2-shRNA-treated myotubes, as evidenced by their decreased size. Conversely, SIRT2 overexpression alleviated Dex-induced myoatrophy in vitro. Moreover, SIRT2 negatively regulated the expression of the LC3b and Beclin-1 in skeletal muscles. These findings suggested that SIRT2 activation protects myotubes against Dex-induced atrophy through the inhibition of the autophagy system; this phenomenon may potentially serve as a target for treating glucocorticoid-induced myopathy.

3.
Mol Ther ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33278564

RESUMO

Chimeric antigen receptor T-cell(CAR-T)therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B-cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in clinical patients remains unexplored. Here, we longitudinally profiled the transcriptomes of 55,488 T cells including CAR-T products, CAR-T cells and endogenous T cells at the peak and remission phases in a plasma cell leukemia (PCL) patient treated with BCMA CAR-T cells by single cell transcriptomic analysis. Our results showed distinct CAR-T and endogenous T cell subsets indicating stage-specific expression in proliferation, cytotoxicity, and intercellular signaling pathways. Furthermore, we found that CAR-T cells at peak phase gradually converting to a highly cytotoxic state from a highly proliferative state along a development trajectory. Moreover, re-analysis of a single cell study from CD8+ CD19 CAR-T confirmed our findings. These commonalities suggest conserved mechanisms for CAR-T treatment across hematological malignancies. Taken together, our current study provides insight into CAR-T cell dynamics during CAR-T therapy, and proves that both BCMA CAR-T and CD19 CAR-T have similar transcriptional characteristics, especially at the CAR-T peak phase.

4.
Cancer Manag Res ; 12: 11435-11444, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204156

RESUMO

Introduction: Baohuoside I, a novel oncotherapeutic agent, has been reported to have anti-cancer effects on a variety of cancers, but its role in glioma and its molecular mechanism are still unclear. Methods: The proliferation of U251 cells was detected by real-time cellular analysis (RTCA), CCK-8, Ki67 immunofluorescence and colony formation assay. The effect of Baohuoside I on the invasion and migration of U251 cells was measured by transwell and scratch tests. The apoptosis of U251 cells was detected by flow cytometry. The expression level of related protein was detected by western blotting. Results: Baohuoside I could inhibit the proliferation of human glioma cells and induce apoptosis. Further study showed that the migration and invasion ability of glioma was significantly decreased by Baohuoside I. Western blot revealed the expression of p-AMPKα1 protein was up-regulated, and the expression of p-mTOR and p-S6K was down-regulated after Baohuoside I treatment. Tumorigenesis in nude mice showed that Baohuoside I had an anti-glioma effect in vivo. Conclusion: We propose a natural product, which can inhibit the proliferation, invasion and migration of glioma and may be a valuable anti-tumor candidate. The inhibitory effect of Baohuoside I on the glioma is achieved by inducing the apoptosis of the tumor cells, rather than autophagy. In addition, the pathway to induce cell apoptosis of Baohuoside I is to target the mTOR signal.

5.
Front Neurol ; 11: 986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192957

RESUMO

A stroke prediction model based on the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project was developed. We compared its predictive ability with the revised Framingham Stroke Risk Score (R-FSRS) for 5-year stroke incidence in a community cohort of Chinese adults, namely the Beijing Longitudinal Study of Aging (BLSA). Calibration, discrimination, and recalibration were used to compare the predictive ability between the two prediction models. Category-less net reclassification improvement (NRI) and integrated discrimination improvement (IDI) values were also assessed. During a mean follow-up duration of 5.1 years, 106 incidents of fatal or non-fatal strokes occurred among 1,203 participants aged 55-84 years. The R-FSRS applied to our cohort underestimated the 5-year risk for stroke in men and women. China-PAR performed better than the R-FSRS in terms of calibration (men, R-FSRS: χ2-value 144.2 [P < 0.001], China-PAR: 10.4 [P = 0.238]; women, R-FSRS: 280.1 [P < 0.001], China-PAR: 12.5 [P = 0.129]). In terms of discrimination, R-FSRS and China-PAR models performed modestly in our cohort (C-statistic 0.603 [95% CI: 0.560-0.644] for men using China-PAR and 0.568 [95% CI: 0.524-0.610] using the R-FSRS; the corresponding numbers for women were 0.602 [95% CI: 0.564-0.639] and 0.575 [95% CI: 0.537-0.613). The recalibrated China-PAR model significantly improved the discrimination in C statistics and produced higher category-less NRI and IDI for stroke incidence than the R-FSRS. Although China-PAR fairly estimated stroke risk in our cohort, it did not sufficiently identify adults at high risk of stroke. Caution would be exercised by practitioners in applying the original China-PAR to Chinese older adults. Further studies are needed to develop an adequate prediction model based on the recalibrated China-PAR or to find new risk markers which could upgrade this model.

6.
Phys Rev Lett ; 125(14): 143605, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33064545

RESUMO

We propose how to achieve nonreciprocal quantum entanglement of light and motion and reveal its counterintuitive robustness against random losses. We find that by splitting the counterpropagating lights of a spinning resonator via the Sagnac effect, photons and phonons can be entangled strongly in a chosen direction but fully uncorrelated in the other. This makes it possible both to realize quantum nonreciprocity even in the absence of any classical nonreciprocity and also to achieve significant entanglement revival against backscattering losses in practical devices. Our work provides a way to protect and engineer quantum resources by utilizing diverse nonreciprocal devices, for building noise-tolerant quantum processors, realizing chiral networks, and backaction-immune quantum sensors.

8.
Opt Express ; 28(8): 11144-11155, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32403631

RESUMO

Nonlinear optical effects in integrated microcavities have been studied extensively with the advantages of strong light-matter interaction, great scalability, and stability due to the small mode volume. However, the pump lasers stimulating nonlinear effects impose obstacles for practical applications, since the material absorption causes thermal resonance drift and instability. Here we experimentally demonstrate an all-optical control of the thermal behavior in optical microcavities for tunable doubly-resonant second-harmonic (SH) generation on an integrated photonic chip. Through an auxiliary control laser, the temperature of a selected microring can be efficiently changed, thus allowing precise frequency tuning of the doubly-resonant wavelength while eliminating the distortion of the lineshape induced by the thermo-optic effect. Although the phase-matching conditions will limit the tuning range of 55GHz, the technique is still potential to achieve a larger tuning range in combination with temperature regulation. Additionally, this approach has the advantage of quick reconfiguration, showing a fast modulation rate up to about 256 kHz. The theoretical model behind our experimental scheme is universal and applicable to other microcavity-enhanced nonlinear optical processes, and our work paves the way for controlling and utilizing the thermal effect in the applications of microcavities.

9.
J Headache Pain ; 21(1): 53, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404048

RESUMO

BACKGROUND: Adult migraine remains underdiagnosed and undertreated, despite significant negative effects on physical and emotional functioning. Information on prescribing patterns and treatment costs of migraine in China is limited. METHODS: This retrospective analysis of the China Health Insurance Research Association (CHIRA) medical insurance claims database in 2016 to 2017 evaluated treatment patterns, direct medical costs, and healthcare resource utilization among adults with migraine in mainland China. RESULTS: Of 108,375 patients with headache-related outpatient visits, 10,652 were adults with migraine (mean age 51.4 years, 55.4% female). Common comorbidities were major depressive disorder (4.1%), insomnia (3.8%), and anxiety (2.3%). Migraine patients were prescribed acute medication (26.4%), preventive medication (15.0%), and Chinese patent and herbal medicines (24.5% and 11.7%, respectively). Of patients prescribed acute medication, 68.8% received non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), 7.1% received opioids, while only 3.3% received triptans. Mean annual outpatient costs per patient were 46.5 United States dollars (USD), with mean (standard deviation) 1.8 (2.0) outpatient visits per year. Medication costs for traditional Chinese medicine (22.4 USD per patient) were higher than for Western medicine (13.5 USD). CONCLUSION: Among migraine patients in China, NSAIDs were commonly prescribed as acute medication, while utilization of migraine-specific triptans and preventive medications was low.


Assuntos
Seguro Saúde , Transtornos de Enxaqueca/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , China , Bases de Dados Factuais , Feminino , Cefaleia/tratamento farmacológico , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Triptaminas/uso terapêutico , Estados Unidos
10.
J Proteome Res ; 19(6): 2471-2482, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32283030

RESUMO

Severe acute pancreatitis (SAP) is caused by complicated biological factors, and revealing its complex pathogenesis by single-target analysis is difficult. Systematic studies have developed slowly because extraction of degradable pancreatic proteins exposed to multiple proteases is challenging. We present integrated whole proteomic and phosphoproteomic profiles of SAP rats based on a modified protein extraction strategy with less protein degradation. Data-dependent acquisition (DDA) and data-independent acquisition (DIA) strategies were applied to select an appropriate method. Total 275 differentially expressed proteins and 757 differentially expressed phosphorylated proteins were identified by DIA-based quantitative proteomics. Several signal transduction pathways, including the AMPK, MAPK, and PI3K-Akt pathways, were enriched in SAP. Up-regulation of phosphorylated proteins involved in the process of TNFA signaling and inflammatory response was also detected in SAP. Our results improve the understanding of SAP development and progression.

11.
BMC Musculoskelet Disord ; 21(1): 255, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32303207

RESUMO

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) is a common and often debilitating complication of osteoporosis, leading to significant morbidity and increased mortality. Percutaneous vertebroplasty (PVP) and Percutaneous kyphoplasty (PKP) are recommendable surgical treatments for OVCF. OBJECTIVE: To evaluate PVP/PKP utilisation and their related direct medical costs for OVCF treatment in China from the payer perspective. METHODS: A population-based medical claims database of a metropolitan city in China was analysed from the payer perspective, which included all inpatient claims from 01/01/2015 to 31/12/2017. All vertebral fractures patients that met the eligibility criteria (aged ≥50 years old, having vertebral fracture diagnosis, without unrelated diseases diagnoses such as tumour and scoliosis, received PVP/PKP) were deemed as OVCF patients. Baseline characteristics, surgery rate, length of stay in hospital, time to re-surgery, and costs (including costs per hospitalisation and annual costs) were described. Survival analysis function was used to estimate the re-surgery rate. RESULTS: Of the 50,686 patients with OVCF identified, 14,527 (28.66%) received a total number of 15,599 records of PVP/PKP surgeries from 2015 to 2017. Mean age was 75 at the first surgery captured in the database analysis period; females accounted for 79.54% of all cases. The median length of surgery stay was 9 days. Cumulative re-surgery rates were 1.22% in 30 days, 2.58% in 90 days, 3.61% in 183 days, 5.42% in 1 year, and 7.95% in 2 years. There was no significant difference in re-surgery rate between PVP and PKP (p = 0.3897). The median time to the re-surgery was 139 days. Mean costs per PVP/PKP-related hospitalisation were 35,906 CNY/5122 USD (34,195 CNY/4878USD for PVP, 44,414 CNY/6336 USD for PKP, p < 0.01). The overall costs of hospitalisation averaged 186.61 million CNY (26.62 million USD) per year in this metropolitan city. CONCLUSION: From 2015 to 2017, nearly one-third of OVCF inpatients received PVP/PKP and the re-surgery rate was 7.95%. PVP/PKP procedures for OVCF place a high economic burden for both the healthcare system and patients. Early detection and treatment of patients with osteoporosis are critical in China.

12.
Waste Manag ; 106: 250-260, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240941

RESUMO

Here in this work, porous carbon is prepared from waste of a traditional Chinese medicine Salvia miltiorrhiza flowers. Structures of the porous carbons are regulated by simply regulating of activation temperatures and dosages of activator. The optimized porous carbon owns a high specific surface area of 1715.3 m2 g-1 and total pore volume of 0.6392 cm3 g-1, together with a unique hierarchical architecture and ultrahigh content of 45.97 at% self-doped O and 0.49 at% of N. When used as electrode materials for supercapacitors, the prepared porous carbon exhibited excellent specific capacitance and energy density as well as fantastic cycle stability. Under a current density of 0.5 A/g, the electrode based on this material showed high specific capacitance of 530 F/g, with fantastic rate performance of 258 F/g at 20 A/g and excellent cycle stability of 91% capacitance retention for 10,000 cycles at 10 A/g in a three-electrode system in 6 M KOH. In assembled supercapacitors, the SF-PC700-3 based electrode worked under potential of 1 V and exhibited 222 F/g of specific capacitance at a current density of 0.5 A/g, and even when the current density was increased up to 30 A/g, the specific capacitance can still as high as 168 F/g, verified the excellent performance of SF-PC700-3. Symmetric supercapacitors in Na2SO4 and TEABF4/AN electrolyte showed voltage ranges of 1.8 V and 3 V respectively, and high energy density of 22.2 Wh Kg-1 at 448. W Kg-1 and 40.6 Wh Kg-1 at 755.8 W Kg-1 are obtained.


Assuntos
Carbono , Eletrólitos , Capacitância Elétrica , Eletrodos , Porosidade
13.
Top Stroke Rehabil ; 27(7): 553-562, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32172677

RESUMO

Background/objectives: Functional disability (FD) is common after stroke and associated with the occurrence of future adverse events; however, whether FD is as strong a risk factor as comorbid vascular risk factors for cardiovascular events and death is unclear. Methods: Consecutive patients 3-6 months after index ischemic stroke were assessed at baseline and followed up for documented new cardiovascular events (recurrent stroke, acute myocardial infarction, and sudden death) and death within 5 years. Comorbidity of vascular risk factors was stratified as low or intermediate-to-high risk according to the Stroke Prognostic Instrument II. Four mutually exclusive cohorts were identified (1) intermediate-to-high risk only, n = 505, (2) FD only, n = 78, (3) both intermediate-to-high risk and FD, n = 264, and (4) low risk and no FD, n = 240. Results: The incidence of cardiovascular events was lowest in patients free of FD with low risk, followed by patients with FD alone, intermediate-to-high risk alone, and both. Compared with intermediate-to-high risk only, patients free of FD with low risk had a significantly lower adjusted hazard ratio (HR) (HR: 0.56, 95% confidence interval [CI]: 0.33-0.94), patients with FD only had a similar HR (HR: 0.47, 95% CI: 0.19 -1.18), and patients with both FD and intermediate-to-high risk had a significantly higher HR (HR: 2.13, 95% CI: 1.53-2.98) of cardiovascular events. A similar trend but a larger HR was noted for all-cause death. Conclusion: FD 3-6 months after ischemic stroke is a risk equivalent to comorbidity of conventional vascular risk factors for the incidence of cardiovascular events and mortality of all-cause death.

14.
Bone Marrow Transplant ; 55(4): 717-721, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32005917

RESUMO

Treatment of acute lymphoblastic leukemia (ALL) is still a challenge despite years of researching, especially for those of poor prognosis. Zhang and his team recently proved that FLT3 gene mutation was identified in ~5% of ALL and the mutation spectrum is different from AML. Recently, chimeric antigen receptor T cells (CART) therapy presents great efficacy in treating refractory leukemia. We report a case of a refractory ALL patient with FLT3-ITD mutations and unfavorable karyotypes, who failed to respond to chemotherapy and small molecule tyrosine kinase inhibitors, successfully treated by CART therapy. FLT3-ITD mutations were downregulated dramatically into 14.1% positive 3 days after the infusion and remained negative until now. MRD has stayed to be negative from the 10th day. This case suggests that CART-cell therapy might be effective in treating FLT3-ITD positive refractory ALL, implying the possibility to overcome the traditional prognosis scoring system for leukemia and providing a new chance for other leukemia patients with inferior prognosis factors.

15.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4116-4120, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872686

RESUMO

With digital satellite remote sensing image data of GF-1,in 2018 the object-oriented classification method was used to extract Zizyphus jujuba planting area in Jia county of Shaanxi province. The results showed that the remote sensing classification method based on rule set could extract and reckon Z. jujube planting area in the study area effectively. The planting area of Z. jujube in Jia county was about 5. 34×104 hm2 and the area of consistent accuracy was 97. 92%. The method used in this study could provide a technical reference for the area extraction of the same type of medicinal materials. And it is of great significance to provide decision support for the protection and utilization of Z. jujube resources.


Assuntos
Ziziphus , Agricultura , China , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa
16.
J Headache Pain ; 20(1): 111, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805851

RESUMO

BACKGROUND: The objective of this review was to determine the unmet needs for migraine in East Asian adults and children. METHODS: We searched MEDLINE and EMBASE (January 1, 1988 to January 14, 2019). Studies reporting the prevalence, humanistic and economic burden, and clinical management of migraine in China (including Hong Kong and Taiwan), Japan, and South Korea were included. Studies conducted before 1988 (before the International Headache Society [IHS] first edition of the International Classification of Headache Disorders) were not included. RESULTS: We retrieved 1337 publications and 41 met the inclusion criteria (28 from China, 7 from Japan, and 6 from South Korea). The 1-year prevalence of migraine (IHS criteria) among adults ranged from 6.0% to 14.3%. Peak prevalence ranged from 11% to 20% for women and 3% to 8% for men (30- to 49-year-olds). For children, prevalence of migraine increased with age. Information on the economic burden and clinical management of migraine was limited, particularly for children. When reported, migraine was significantly associated with high levels of disability and negative effects on quality of life. Studies suggested low levels of disease awareness/diagnosis within each country. Of individuals with migraine from China, 52.9% to 68.6% had consulted a physician previously, 37.2% to 52.7% diagnosed with headache had not been diagnosed with migraine previously, and 13.5% to 18% had been diagnosed with migraine previously. Of individuals with migraine from Japan, 59.4% to 71.8% had never consulted a physician previously, 1.3% to 7.3% regularly consulted physicians for their headache, and only 11.6% of individuals with migraine were aware that they had migraine. In addition, studies suggested that over-the-counter medication use was high and prescription medication use was low in each country. CONCLUSIONS: This review suggests that there are unmet needs for migraine in terms of sufficient and appropriate diagnosis, and better management and therapies for treatment of migraine in East Asia. The findings are limited by a lack of recent information and significant gaps in the literature. More recent, population-based studies assessing disease burden and clinical management of migraine are needed to confirm unmet needs for migraine across East Asia.


Assuntos
Efeitos Psicossociais da Doença , Gerenciamento Clínico , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/terapia , Adulto , Criança , China/epidemiologia , Hong Kong/epidemiologia , Humanos , Japão/epidemiologia , Transtornos de Enxaqueca/psicologia , Prevalência , Qualidade de Vida/psicologia , República da Coreia/epidemiologia , Taiwan/epidemiologia
17.
J Med Chem ; 62(20): 8973-8995, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Cristalografia por Raios X , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/uso terapêutico , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
18.
J Med Chem ; 62(20): 8953-8972, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.


Assuntos
Niacinamida/análogos & derivados , Ácidos Nicotínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Regulação Alostérica , Animais , Humanos , Ligantes , Camundongos , Niacinamida/metabolismo , Niacinamida/farmacologia , Ácidos Nicotínicos/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade
19.
Leukemia ; 33(12): 2854-2866, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31110217

RESUMO

Despite worldwide promising clinical outcome of CD19 CAR-T therapy, relapse after this therapy is associated with poor prognosis and has become an urgent problem to be solved. We conducted a CD22 CAR T-cell therapy in 34 relapsed or refractory (r/r) B-ALL pediatric and adult patients who failed from previous CD19 CAR T-cell therapy. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 24 of 30 patients (80%) that could be evaluated on day 30 after infusion, which accounted for 70.5% of all 34 enrolled patients. Most patients only experienced mild cytokine-release syndrome and neurotoxicity. Seven CR patients received no further treatment, and 3 of them remained in remission at 6, 6.6, and 14 months after infusion. Eleven CR patients were promptly bridged to transplantation, and 8 of them remained in remission at 4.6 to 13.3 months after transplantation, resulted in 1-year leukemia-free survival rate of 71.6% (95% CI, 44.2-99.0). CD22 antigen loss or mutation was not observed to be associated with relapsed patients. Our study demonstrated that our CD22 CAR T-cells was highly effective in inducing remission in r/r B-ALL patients, and also provided a precious window for subsequent transplantation to achieve durable remission.


Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adolescente , Adulto , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Biópsia , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Citocinas/metabolismo , Citotoxicidade Imunológica , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lactente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Adulto Jovem
20.
Obes Facts ; 12(1): 78-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814477

RESUMO

OBJECTIVE: Obesity-related disease risks may vary depending on whether the subject has metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO). At least 5 definitions/criteria of obesity and metabolic disorders have been documented in the literature, yielding uncertainties in a reliable international comparison of obesity phenotype prevalence. This report aims to compare differences in MHO and MUO prevalence according to the 5 most frequently used definitions. METHODS: A random sample of 4,757 adults aged 35 years and older (male 51.1%) was enrolled. Obesity was defined either according to body mass index or waist circumference, and the definitions of metabolic abnormalities were derived from 5 different criteria. RESULTS: In MHO, the highest prevalence was obtained when using the homeostasis model assessment (HOMA) criteria (13.6%), followed by the Chinese Diabetes Society (11.4%), Adult Treatment Panel III (10.3%), Wildman (5.2%), and Karelis (4.2%) criteria; however, the MUO prevalence had an opposite trend to MHO prevalence. The magnitude of differences in the age-specific prevalence of MHO and MUO varied greatly and ranked in different orders. The proportion of insulin resistance for MHO and MUO individuals differed significantly regardless of which metabolic criterion was used. CONCLUSION: The prevalence of MHO and MUO in the Chinese population varies according to different definitions of obesity and metabolic disorders.


Assuntos
Obesidade Metabolicamente Benigna/diagnóstico , Obesidade Metabolicamente Benigna/epidemiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Índice de Massa Corporal , China/epidemiologia , Diagnóstico Diferencial , Técnicas de Diagnóstico Endócrino/normas , Técnicas de Diagnóstico Endócrino/estatística & dados numéricos , Feminino , Nível de Saúde , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade Metabolicamente Benigna/metabolismo , Fenótipo , Prevalência , Circunferência da Cintura , Adulto Jovem
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