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BACKGROUND: AGTPBP1 is a cytosolic carboxypeptidase that cleaves poly-glutamic acids from the C terminus or side chains of α/ß tubulins. Although its dysregulated expression has been linked to the development of non-small cell lung cancer, the specific roles and mechanisms of AGTPBP1 in pancreatic cancer (PC) have yet to be fully understood. In this study, we examined the role of AGTPBP1 on PC in vitro and in vivo. METHODS: Immunohistochemistry was used to examine the expression of AGTPBP1 in PC and non-cancerous tissues. Additionally, we assessed the malignant behaviors of PC cells following siRNA-mediated AGTPBP1 knockdown both in vitro and in vivo. RNA sequencing and bioinformatics analysis were performed to identify the differentially expressed genes regulated by AGTPBP1. RESULTS: We determined that AGTPBP1 was overexpressed in PC tissues and the higher expression of AGTPBP1 was closely related to the location of tumors. AGTPBP1 inhibition can significantly decrease cell progression in vivo and in vitro. Moreover, the knockdown of AGTPBP1 inhibited the expression of ERK1/2, P-ERK1/2, MYLK, and TUBB4B proteins via the ERK signaling pathway. CONCLUSION: Our research indicates that AGTPBP1 may be a putative therapeutic target for PC.
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Carboxipeptidases , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Microtúbulos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carboxipeptidases/metabolismo , Carboxipeptidases/genética , Linhagem Celular Tumoral , Microtúbulos/metabolismo , Animais , Camundongos , Masculino , Feminino , Proliferação de Células , Progressão da Doença , Pessoa de Meia-Idade , Movimento Celular/genéticaRESUMO
BACKGROUND AND AIMS: The risk and pathological factors of recurrence after endoscopic resection (ER) for superficial esophageal squamous cell carcinoma (ESCC) are inconsistent across studies. We evaluated this in a systematic review and meta-analysis. METHODS: The data of recurrence in such patients was extracted from all studies. Risk ratios (RRs) were combined using random-effects meta-analysis, to assess pooled recurrence rate and pathological risk factors. Relapse-free survival was combined using the Kaplan-Meier method to estimate the relationship between various pathological factors and recurrence time. RESULTS: We identified 26 studies, with a total of 5100 patients and 321 with recurrences (pooled rate, 6.2%). The risk of recurrence was significantly higher in positive vertical margin (VM) (RR [95% CI]: 4.51 [2.16 - 9.44]), positive horizontal margin (HM) (RR [95% CI]: 2.54 [1.57 - 4.13]), lymphovascular invasion (LVI) (RR [95% CI]: 2.33 [1.75 - 3.11], P < 0.001), lymphatic invasion (LI) (RR [95% CI]: 2.24 [1.24 - 4.06]), and tumor invading submucosa ≤200 µm (SM1) (RR [95% CI]: 1.71 [1.32 - 2.21], compared to muscularis mucosa). Patients with LI (HR 2.47; 95% CI 1.24 - 4.90; P = 0.02) and LVI (HR 2.36; 95% CI 2.22 - 4.59; P = 0.0006) tended to have earlier recurrence after ER. CONCLUSION: The recurrence rate of superficial ESCC after ER is acceptable. Patients with positive margins, LVI, LI and SM1 need to pay significant attention to the risk of recurrence. LI and VI should be evaluate separately. (PROSPERO CRD42023406309).
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Objectives: To investigate risk factors for severe maternal morbidity (SMM) in pregnant women with hypertensive disorders of pregnancy (HDP) and to develop a risk prediction model. Methods: A prospective observational cohort study was conducted among pregnant women who were hospitalized for hypertensive disorders of pregnancy (HDP) between January 2016 and December 2020 in Fujian College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Province, China (a training set), and a risk predictive model was constructed. Pregnant women with HDP who were hospitalized between January 2021 and December 2021 were selected as a validation set. Concordance index (C-index) and calibration curves were used to test predictive model discrimination and calibration. Results: We included 970 pregnant women (790 in the training set and 180 in the validation set). Least absolute shrinkage and selection operator regression was used to screen for nine related variables such as intra-uterine growth retardation (IUGR), diastolic blood pressure (DBP) and systolic blood pressure (SBP) at suspected diagnosis, total bilirubin, albumin (ALB), uric acid, total cholesterol, serum magnesium, and suspected gestational age. SBP at suspected diagnosis (OR =1.22, 95%CI:1.08-1.42) and total cholesterol (OR = 1.78, 95%CI:1.17-2.80) were independent risk factors of severe maternal morbidity in pregnant women with HDP. A nomogram was constructed, and internal validation of the nomogram model was done using the bootstrap self-sampling method. C-index in the training and the validation set was 0.798 and 0.909, respectively. Conclusion: Our prediction model can be used to determine gestational hypertension severity in pregnant women.
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BACKGROUND: Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and granulomatous amoebic encephalitis. Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms. OBJECTIVES: To synthesize and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development. METHODS: A panel of 12 S-MGBs was synthesized and anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays. RESULTS AND DISCUSSION: S-MGB-241 has an IC50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM) and negligible activity against the other organisms. It was also found to have an IC50â>â100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTmâ=â1â±â0.1°C. CONCLUSIONS: Together, these data provide confidence that S-MGBs can be further optimized to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a 'hit' compound that is selectively active against A. castellanii, providing a starting point from which to begin optimization of DNA binding and potency.
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T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.
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BACKGROUND: Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance. METHODS: Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC. RESULTS: We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880-0.927) and 0.727 (95% CI 0.653-0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1-85.6), 87.3% (95% CI 79.4-92.4), 92.5% (95% CI 85.9-96.2), and 96.9% (95% CI 84.3-99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4-90.6) and specificity of 93.3% (95% CI 91.2-94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC. CONCLUSIONS: The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.
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Metilação de DNA , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/sangue , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Método Duplo-Cego , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , AdultoRESUMO
Objectives: For children with Kawasaki disease (KD) at high risk of developing coronary artery lesions and requiring retreatment with intravenous immunoglobulin (IVIG), the availability of accurate prediction models remains limited because of inconsistent variables and unsatisfactory prediction results. We aimed to construct models to predict patient's probability of IVIG retreatment combining children's individual inflammatory characteristics. Methods: Clinical manifestations and laboratory examinations of 266 children with KD were retrospectively analysed to build a development cohort data set (DC) and a validation cohort data set (VC). In the DC, binary logistic regression analyses were performed using R language. Nomograms and receiver operating curves were plotted. The concordance index (C index), net reclassification index, integrated discrimination improvement index and confusion matrix were applied to evaluate and validate the models. Results: Models_5V and _9V were established. Both contained variables including the percentages of CD8+ T cells, CD4+ T cells, CD3+ T cells, levels of interleukin (IL)-2R and CRP. Model_9V additionally included variables for IL-6, TNF-α, NT-proBNP and sex, with a C index of 0.86 (95% CI 0.79-0.92). When model_9V was compared with model_5V, the NRI and IDI were 0.15 (95% CI 0.01-0.30, P < 0.01) and 0.07 (95% CI 0.02-0.12, P < 0.01). In the VC, the sensitivity, specificity and precision of model_9V were 1, 0.875 and 0.667, while those of model_5V were 0.833, 0.875 and 0.625. Conclusion: Model_9V combined cytokine profiles and lymphocyte subsets with clinical characteristics and was superior to model_5V achieving satisfactory predictive power and providing a novel strategy early to identify patients who needed IVIG retreatment.
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BACKGROUND: Lifestyle plays an important role in preventing and managing gastroesophageal reflux disease (GERD). In response to the conflicting results in previous studies, we performed a systematic review and meta-analysis to investigate this association. METHODS: Relevant studies published until January 2023 were retrieved from 6 databases, and the prevalence of symptomatic gastroesophageal reflux (GER) or GERD was determined from the original studies. A random effects model was employed to meta-analyze the association by computing the pooled relative risk (RR) with 95% confidence intervals (95%CIs). Furthermore, subgroup and dose-response analyses were performed to explore subgroup differences and the association between cumulative physical activity (PA) time and GERD. RESULTS: This meta-analysis included 33 studies comprising 242,850 participants. A significant negative association was observed between PA and the prevalence of symptomatic GER (RRâ¯=â¯0.74, 95%CI: 0.66-0.83; p < 0.01) or GERD (RRâ¯=â¯0.80, 95%CI: 0.76-0.84; p < 0.01), suggesting that engaging in PA might confer a protective benefit against GERD. Subgroup analyses consistently indicated the presence of this association across nearly all subgroups, particularly among the older individuals (RR<40 years:RR≥40 yearsâ¯=â¯0.85:0.69, p < 0.01) and smokers (RRsmoker:RRnon-smokerâ¯=â¯0.67:0.82, pâ¯=â¯0.03). Furthermore, a dose-response analysis revealed that individuals who engaged in 150 min of PA per week had a 72.09% lower risk of developing GERD. CONCLUSION: Maintaining high levels of PA decreased the risk of GERD, particularly among older adults and smokers. Meeting the recommended PA level of 150 min per week may significantly decrease the prevalence of GERD.
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Exercício Físico , Refluxo Gastroesofágico , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/prevenção & controle , Humanos , Prevalência , Fatores de Risco , Fatores Etários , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
Immune checkpoint inhibitors (ICIs) represent a promising therapeutic approach for esophageal squamous cell carcinoma (ESCC). However, the subpopulations of ESCC patients expected to benefit from ICIs have not been clearly defined. The anti-tumor cytotoxic activity of T cells is an important pharmacological mechanism of ICIs. In this study, the prognostic value of the genes regulating tumor cells to T cell-mediated killing (referred to as GRTTKs) in ESCC was explored by using a comprehensive bioinformatics approach. Training and validation datasets were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. A prognostic risk scoring model was developed by integrating prognostic GRTTKs from TCGA and GEO datasets using a ridge regression algorithm. Patients with ESCC were divided into high- and low-risk groups based on eight GRTTKs (EIF4H, CDK2, TCEA1, SPTLC2, TMEM209, RGP1, EIF3D, and CAPZA3) to predict overall survival in the TCGA cohort. Using Kaplan-Meier curves, receiver operating characteristic curves, and C-index analysis, the high reliability of the prognostic risk-scoring model was certified. The model scores served as independent prognostic factors, and combining clinical staging with risk scoring improved the predictive value. Patients in the high-risk group exhibited abundant immune cell infiltration, including immune checkpoint expression, antigen presentation capability, immune cycle gene expression, and high tumor inflammation signature scores. The high-risk group exhibited a greater response to immunotherapy and neoadjuvant chemotherapy than the low-risk group. Drug sensitivity analysis demonstrated lower IC50 for AZD6244 and PD.0332991 in high-risk groups and lower IC50 for cisplatin, ATRA, QS11, and vinorelbine in the low-risk group. Furthermore, the differential expression of GRTTK-related signatures including CDK2, TCEA1, and TMEM209 were verified in ESCC tissues and paracancerous tissues. Overall, the novel GRTTK-based prognostic model can serve as indicators to predict the survival status and immunotherapy response of patients with ESCC, thereby providing guidance for the development of personalized treatment strategies.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Reprodutibilidade dos Testes , Linfócitos T , Genes cdc , Prognóstico , Fator de Iniciação 3 em EucariotosRESUMO
Rheumatoid arthritis (RA) is a common type of chronic inflammatory disease. Elucidating the mechanism of fibroblast-like synovial (FLS) as a pathologic factor in RA may address the urgent medical requirement for the treatment of RA. Isorhynchophylline (IRN) is a tetracyclic hydroxyindole alkaloid isolated from uncinaria, which has multiple biological activities and affects the progression of osteoarthritis. However, the role of IRN in rheumatoid arthritis remains unclear. Herein, our study aimed to elucidate the potential effect of IRN on RA and reveal its mechanism. Human FLS cell line MH7A cells were stimulated with TNF-α for 24 h to construct a cell model. CCK-8, Edu, wound healing, as well as transwell assays were conducted to detect the effects of IRN on cell proliferation and motility. ELISA and Immunoblot assays were further performed to detect the production of pro-inflammatory factors and the expression levels of MMPs. Immunoblot and Immunostaining assays were conducted to uncover the mechanism. ELISA, H&E staining, and Immunoblot assays were used to confirm the effects of IRN on RA in a CIA rat model. We revealed that IRN restrained TNF-α-stimulated MH7A cell proliferation and motility. In addition, IRN blocked the production of pro-inflammatory factors and MMPs in TNF-α-stimulated-MH7A cells. We further found that IRN restrained FOXC1/ß-catenin axis, and improved MH7A cell proliferation as well as migration via the FOXC1/ß-catenin axis. IRN restores CIA by inhibiting pro-inflammatory cytokines in synovial tissues. In summary, IRN attenuates proliferation and migration of FLS in RA via the FOXC1 mediated ß-catenin axis.
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Artrite Reumatoide , Sinoviócitos , Humanos , Ratos , Animais , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , beta Catenina/metabolismo , Membrana Sinovial/metabolismo , Artrite Reumatoide/metabolismo , Proliferação de Células , Fibroblastos/metabolismo , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismoRESUMO
Spermatogenesis is a complex process related to male infertility. Till now, the critical genes and specific mechanisms have not been elucidated clearly. Our objective was to determine the hub genes that play a crucial role in spermatogenesis by analyzing the differentially expressed genes (DEGs) present in non-obstructive azoospermia (NOA) compared to OA and normal samples using bioinformatics analysis. Four datasets, namely GSE45885, GSE45887, GSE9210 and GSE145467 were used. Functional enrichment analyses were performed on the DEGs. Hub genes were identified based on protein-protein interactions between DEGs. The expression of the hub genes was further examined in the testicular germ cell tumors from the TCGA by the GEPIA and validated by qRT-PCR in the testes of lipopolysaccharide-induced acute orchitis mice with impaired spermatogenesis. A total of 203 DEGs including 34 up-regulated and 169 down-regulated were identified. Functional enrichment analysis showed DEGs were mainly involved in microtubule motility, the process of cell growth and protein transport. PRM2, TEKT2, FSCN3, UBQLN3, SPATS1 and GTSF1L were identified and validated as hub genes for spermatogenesis. Three of them (PRM2, FSCN3 and TEKT2) were significantly down-regulated in the testicular germ cell tumors and their methylation levels were associated with the pathogenesis. In summary, the hub genes identified may be related to spermatogenesis and may act as potential therapeutic targets for NOA and testicular germ cell tumors.
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Infertilidade Masculina , Neoplasias Embrionárias de Células Germinativas , Humanos , Masculino , Animais , Camundongos , Perfilação da Expressão Gênica , Espermatogênese/genética , Testículo/metabolismo , Infertilidade Masculina/patologia , Biologia Computacional , Neoplasias Embrionárias de Células Germinativas/patologiaRESUMO
BACKGROUND: Early detection of esophageal squamous cell carcinoma (ESCC) can considerably improve the prognosis of patients. Aberrant cell-free DNA (cfDNA) methylation signatures are a promising tool for detecting ESCC. However, available markers based on cell-free DNA methylation are still inadequate. This study aimed to identify ESCC-specific cfDNA methylation markers and evaluate the diagnostic performance in the early detection of ESCC. METHODS: We performed whole-genome bisulfite sequencing (WGBS) for 24 ESCC tissues and their normal adjacent tissues. Based on the WGBS data, we identified 21,469,837 eligible CpG sites (CpGs). By integrating several methylation datasets, we identified several promising ESCC-specific cell-free DNA methylation markers. Finally, we developed a dual-marker panel based on methylated KCNA3 and OTOP2, and then, we evaluated its performance in our training and validation cohorts. RESULTS: The ESCC diagnostic model constructed based on KCNA3 and OTOP2 had an AUC of 0.91 [95% CI: 0.85-0.95], and an optimal sensitivity and specificity of 84.91% and 94.32%, respectively, in the training cohort. In the independent validation cohort, the AUC was 0.88 [95% CI: 0.83-0.92], along with an optimal sensitivity of 81.5% and specificity of 92.9%. The model sensitivity for stage I-II ESCC was 78.4%, which was slightly lower than the sensitivity of the model (85.7%) for stage III-IV ESCC. CONCLUSIONS: The dual-target panel based on cfDNA showed excellent performance for detecting ESCC and might be an alternative strategy for screening ESCC.
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Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1ß, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32), p < 0.0001), and the median (IQR) ß-CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from 3 (2-4) in the MTX group (p < 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant (p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) (p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) (p < 0.01, p = 0.004); the median (IQR) ALT in the JBQG group was 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) (p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN (p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html; identifier: ChiCTR2100046373.
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OBJECTIVE: Although total joint replacement (TJR) procedures are efficacious, perioperative high-dose factors replacement therapy (FRT) to avoid catastrophic bleeding represents a significant hurdle, particularly for patients with multiple joint affection. Double simultaneous bilateral TJRs were reported as safe and cost-effective. However, little is known about multiple TJRs. The feasibility and effects remain debatable. Surgeons need to weigh the high cost of FRT against safety. Accordingly, we aimed to evaluate the clinical outcomes and cost-effectiveness of single-anesthetic multiple-joint procedures of lower limbs in end-stage hemophilic arthropathy. METHODS: Our retrospective cohort study retrieved data from an inpatient database of patients with hemophilia who underwent total knee arthroplasty (TKA), total hip arthroplasty (THA), and/or ankle arthrodesis from January 2000 to April 2016. Complications, hospital stays, transfusion, doses of clotting factor, medical costs, range of motion (ROM), Harris hip scores (HHSs) and Hospital for special surgery knee scores (HSSs) were recorded. A P value < 0.05 was considered significant. RESULTS: A total number of 81 patients were included in this study, among which 89 TKAs and 52 THAs were performed. Compared to the single TJR group, the simultaneous multiple TJR group showed a significantly higher rate of blood transfusions (P < 0.05). But no significant differences were found in the length of hospital stays, factor consumption, hospitalization costs excluding prosthesis expenses, and total complication rates. Finally, similar postoperative ROM, HHS, and HSS were witnessed in two groups (P value > 0.05). CONCLUSION: Our data indicated that simultaneous multiple TJRs are a safe and cost-effective choice for treating hemophilic patients with multiple HA-affected lower limb joints.
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Anestésicos , Artrite , Artroplastia de Quadril , Humanos , Estudos Retrospectivos , Análise Custo-Benefício , Seguimentos , Resultado do TratamentoRESUMO
Objective To investigate the clinical symptoms experienced by patients with thoracic spinal tumors and verify the associated symptoms that are predictive of a decline in muscle strength in the lower limbs. Methods A single-center, retrospective cross-sectional study was conducted on in-patients diagnosed with epidural thoracic spinal tumors between January 2011 and May 2021. The study involved a review of electronic medical records and radiographs and the collection of clinical data. The differences in clinical manifestations between patients with constipation and those without constipation were analyzed. Binary logistic regression analyses were performed to identify risk factors associated with a decline in muscle strength in the lower limbs.Results A total of 227 patients were enrolled, including 131 patients with constipation and 96 without constipation. The constipation group had a significantly higher proportion of patients who experienced difficulty walking or paralysis compared to those without constipation prior to surgery (83.2% vs. 17.7%, χ2 = 99.035,P < 0.001). Constipation (OR = 9.522, 95%CI: 4.150-21.849, P < 0.001) and urinary retention (OR = 14.490, 95%CI: 4.543-46.213, P < 0.001) were independent risk factors for muscle strength decline in the lower limbs. Conclusions The study observed that patients with thoracic spinal tumors who experienced constipation symptoms had a higher incidence of lower limb weakness. Moreover, the analysis revealed that constipation and urinary retention were independent risk factors associated with a preoperative decline in muscle strength of lower limbs.
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Neoplasias da Coluna Vertebral , Retenção Urinária , Humanos , Constipação Intestinal/etiologia , Estudos Transversais , Extremidade Inferior , Força Muscular , Estudos RetrospectivosRESUMO
Background: Synaptic plasticity contributes to nociceptive signal transmission and modulation, with calcium/calmodulin-dependent protein kinase II (CaMK II) playing a fundamental role in neural plasticity. This research was conducted to investigate the role of CaMK II in the transmission and regulation of nociceptive information within the nucleus accumbens (NAc) of naïve and morphine-tolerant rats. Methods: Randall Selitto and hot-plate tests were utilized to measure the hindpaw withdrawal latencies (HWLs) in response to noxious mechanical and thermal stimuli. To induce chronic morphine tolerance, rats received intraperitoneal morphine injection twice per day for seven days. CaMK II expression and activity were assessed using western blotting. Results: Intra-NAc microinjection of autocamtide-2-related inhibitory peptide (AIP) induced an increase in HWLs in naïve rats in response to noxious thermal and mechanical stimuli. Moreover, the expression of the phosphorylated CaMK II (p-CaMK II) was significantly decreased as determined by western blotting. Chronic intraperitoneal injection of morphine resulted in significant morphine tolerance in rats on Day 7, and an increase of p-CaMK II expression in NAc in morphine-tolerant rats was observed. Furthermore, intra-NAc administration of AIP elicited significant antinociceptive responses in morphine-tolerant rats. In addition, compared with naïve rats, AIP induced stronger thermal antinociceptive effects of the same dose in rats exhibiting morphine tolerance. Conclusions: This study shows that CaMK II in the NAc is involved in the transmission and regulation of nociception in naïve and morphine-tolerant rats.
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The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.
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Anticorpos Biespecíficos , COVID-19 , Humanos , SARS-CoV-2 , Terapia Combinada de Anticorpos , Testes de Neutralização , Anticorpos Biespecíficos/uso terapêutico , Anticorpos NeutralizantesRESUMO
In recent years, motor imagery-based brain-computer interface (MI-BCI) has been applied to motor rehabilitation in patients with motor dysfunction. However, traditional MI-BCI is rarely used for foot motor intention recognition because the motor cortex regions of both feet are anatomically close to each other, and traditional event-related desynchronization (ERD) patterns for MI-BCI have insufficient spatial discrimination. This study introduced steady-state somatosensory evoked potentials (SSSEPs) by synchronous bilateral feet electrical stimulation at different frequencies, which were used as carrier signals modulated by unilateral foot motor intention. Fifteen subjects participated in MI and MI-SSSEP tasks. A Riemannian geometry classifier with a task-related component analysis (TRCA) spatial filter was proposed to demodulate the variation in SSSEP features and discriminate the left and right foot motor intentions. The feature outcomes indicated that the amplitude and phase synchronization of the SSSEPs could be well modulated by unilateral foot MI tasks under the MI-SSSEP paradigm. The classification results revealed that the modulated SSSEP features played an important role in the recognition of left-right foot discrimination. Moreover, the proposed TRCA-based method outperformed the other three methods and improved the foot average classification accuracy to 81.07± 13.29%, with the highest accuracy attained at 97.00%. Compared with the traditional MI paradigm, the foot motor intention recognition accuracy of the MI-SSSEP paradigm was significantly improved, from nearly 60% to more than 80%. This work provides a practical method for left-right foot motor intention recognition and expands the application of MI-BCI in the field of lower-extremity motor function rehabilitation.
Assuntos
Interfaces Cérebro-Computador , Intenção , Humanos , Eletroencefalografia/métodos , Imaginação/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Estimulação ElétricaRESUMO
The dysregulation of certain long non-coding RNAs (lncRNAs) has been considered to be involved in neuropsychiatric disorders such as depression, implying the vital role of these transcripts. We have previously identified many differentially expressed lncRNAs in chronic unpredictable mild stress (CUMS) induced mice. Among them, lncRNA Gm16638-201 was highly expressed in the hippocampus (HIP) of CUMS, but the specific role and the underlying mechanisms remain unclear. Here, we reported that lncRNA Gm16638-201 was highly expressed in the prefrontal cortex (PFC) of CUMS induced depressive mice. Bioinformatic analysis shows that Gm16638-201 is mainly located in the cytoplasm. Nine neurological-related genes (Elmo2, Satb1, Hnrnpul1, Sipa1l3, Mapt, Tada3, Sgip1, IL-16, and StarD5) were predicted to be regulated in cis or trans by Gm16638-201 and involved into the 14-3-3Æ neurotrophic signaling pathway. We further confirmed the down-regulation of 14-3-3Æ and the nine predicted target genes in the PFC of CUMS mice except for Sgip1 and IL-16. In addition, they were also down-regulated in the primary cortical cell cultures with overexpression of Gm16638-201 constructed using an adenoviral-medicated gene expression system. In conclusion, we found that overexpression of Gm16638-201 negatively regulated several target genes and inhibited the 14-3-3Æ pathway in the PFC of CUMS induced depressive mice. This promising result suggests that Gm16638-201 may be a potential novel therapeutic target for depression.