RESUMEN
Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.
Asunto(s)
Mielofibrosis Primaria , Humanos , Estudios de Seguimiento , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Salmonella enteritis in poultry can result in reduced immune function, decreased growth rate, and increased mortality. Many farm salmonella strains have developed severe drug resistance and are less susceptible to multiple antibiotics. In the post-antibiotic era, it is of great significance to identify the mechanism of salmonella-induced enteritis in chicks to protect their health and ensure food safety. This article will elucidate the activation mechanism of NOD-like receptor protein 3 (NLRP3) inflammasomes in Salmonella enteritis and review the research on interventions targeting NLRP3 inflammasomes.
Asunto(s)
Enteritis , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Infecciones por Salmonella , Enteritis/veterinaria , Inflamasomas/metabolismo , Mucosa Intestinal/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Infecciones por Salmonella/genética , Infecciones por Salmonella/metabolismo , Salmonella typhimurium , Animales , Pollos/metabolismo , Pollos/microbiologíaRESUMEN
Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3ß, N-cadherin, and ß-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.
Asunto(s)
Neoplasias Gástricas , Humanos , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Flavonoides/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Isocryptomerin (ISO) is a flavonoid isolated from the natural medicine Selaginellae Herba, which has various pharmacological activities. This study investigated the antitumor effect and underlying molecular mechanism of ISO on hepatocellular carcinoma (HCC) HepG2 cells. The cell viability assay revealed that ISO has a considerable killing effect on HCC cell lines. The apoptosis assay showed that ISO induced mitochondria-dependent apoptosis through the Bad/cyto-c/cleaved (cle)-caspase-3/cleaved (cle)-PARP pathway. The network pharmacological analysis found 13 key target genes, and epidermal growth factor receptor (EGFR), AKT, mitogen-activated protein kinase (MAPK), and reactive oxygen species (ROS) signaling pathways were strongly associated with ISO against HCC. Further verification of the results showed that ISO induced apoptosis by increasing p-p38 and p-JNK expression and decreasing p-EGFR, p-SRC, p-ERK, and p-STAT3 expression. Furthermore, ISO induced G0/G1 phase arrest by downregulating p-AKT, Cyclin D, and CDK 4 expression and upregulating p21 and p27 expression in HepG2 cells. Moreover, ISO inhibited HepG2 cell migration by decreasing p-GSK-3ß, ß-catenin, and N-cadherin expression and increasing E-cadherin expression. Additionally, ISO promoted ROS accumulation in HepG2 cells, and ISO-induced apoptosis, arrest cell cycle, and inhibition of migration were reversed by an ROS scavenger, N-acetyl- l-cysteine. Overall, ISO induced cell apoptosis and cell cycle arrest and inhibited cell migration by ROS-mediated EGFR, AKT, and MAPK signaling pathways in HepG2 cells.
Asunto(s)
Carcinoma Hepatocelular , Flavonas , Neoplasias Hepáticas , Humanos , Células Hep G2 , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Farmacología en Red , Receptores ErbBRESUMEN
Monkeypox is a viral zoonotic disease rarely found outside Africa. Monkeypox can be spread from person to person through close contact with an infected person, and the rate of transmission is not very high. In addition, monkeypox and variola virus are both pox viruses, and the spread of monkeypox virus was also controlled to some extent by the smallpox campaign, so monkeypox was not widely paid attention to. However, as smallpox vaccination is phased out in various countries or regions, people's resistance to orthopoxviruses is decreasing, especially among people who have not been vaccinated against smallpox. This has led to a significant increase in the frequency and geographical distribution of human monkeypox cases in recent years, and the monkeypox virus has become the orthopoxvirus that poses the greatest threat to public health. Since the last large-scale monkeypox infection was detected in 2022, the number of countries or territories affected has exceeded 100. Many confirmed and suspected cases of monkeypox have been found in individuals who have not travelled to affected areas, and the route of infection is not obvious, making this outbreak of monkeypox a cause for concern globally. The purpose of this systematic review is to further understand the pathophysiological and epidemiological characteristics of monkeypox, as well as existing prevention and treatment methods, with a view to providing evidence for the control of monkeypox.
Asunto(s)
Brotes de Enfermedades , Monkeypox virus , Mpox , Humanos , Mpox/epidemiología , Mpox/virología , Mpox/transmisión , Animales , Zoonosis/epidemiología , Zoonosis/virología , Zoonosis/transmisión , VacunaciónRESUMEN
AIMS: Peripheral immune cells infiltrating into the brain trigger neuroinflammation after an ischemic stroke. Partial immune cells reprogram their function for neural repair. Which immune cells promote ischemic brain recovery needs further identification. METHODS: We performed single-cell transcriptomic profiling of CD45high immune cells isolated from the ischemic hemisphere at subacute (5 days) and chronic (14 days) stages after ischemic stroke. RESULTS: A subset of phagocytic macrophages was associated with neuron projection regeneration and tissue remodeling. We also identified a unique type of T cells with highly expressed macrophage markers, including C1q, Apoe, Hexb, and Fcer1g, which showed high abilities in tissue remodeling, myelination regulation, wound healing, and anti-neuroinflammation. Moreover, natural killer cells decreased cytotoxicity and increased energy and metabolic function in the chronic stage after ischemic stroke. Two subgroups of neutrophils upregulated CCL signals to recruit peripheral immune cells and released CXCL2 to keep self-recruiting at the chronic stage. CONCLUSIONS: We identified subsets of peripheral immune cells that may provide potential therapeutic targets for promoting poststroke recovery.
Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Infarto de la Arteria Cerebral Media/complicaciones , Accidente Cerebrovascular/complicaciones , Macrófagos , Encéfalo , Accidente Cerebrovascular Isquémico/complicacionesRESUMEN
Achieving effective hydrogen evolution/oxidation reaction (HER/HOR) across a wide pH span is of critical importance in unlocking the full potential of hydrogen energy but remains intrinsically challenging. Here, we engineer the N-coordinated Ir-Mo dual atoms on a carbon matrix by ultrafast high-temperature sintering, creating an efficient bifunctional electrocatalyst for both HER and HOR in both acidic and alkaline electrolytes. The optimized catalyst, Ir-Mo DAC/NC, demonstrates exceptional performance, with a significantly reduced HER overpotential of 11.3 mV at 10 mA/cm2 and a HOR exchange current (i0,m) of 3972 mA/mgIr in acidic conditions, surpassing the performance of Pt/C and Ir/C catalysts. In alkaline conditions, Ir-Mo DAC/NC also outperforms Pt/C, as evidenced by its low HER overpotential of 23 mV at 10 mA/cm2 and a high i0,m of 1308 mA/mgIr. Furthermore, our catalyst exhibits remarkable stability in both acidic and alkaline environments. DFT calculations results reveal that the superior electrochemical performance of Ir-Mo DAC/NC arises from the electronic synergy between Ir and Mo pairs, which regulates the interaction between the intermediates and active sites. These findings present a promising strategy for the development of dual-atom catalysts (DACs), with potential applications in the polymer fuel cells and water electrolyzers.
RESUMEN
Background: IgA vasculitis (IgAV) is an immune-associated vasculitis, yet its exact etiology remains unclear. Here, we explore the interaction between IgAV and inflammatory factors using bidirectional Mendelian randomization (MR). Methods: We conducted a bidirectional summary-level MR analysis to delineate the causality of C-reactive protein (CRP), procalcitonin (PCT), and 41 circulating inflammatory regulators with IgAV. Data on genetic variants related to inflammation were obtained from three genome-wide association studies (GWASs) on CRP, PCT, and human cytokines, whereas data on IgAV was from large meta-analyses of GWAS among 216 569 FinnGen Biobank participants. The primary MR analysis was performed using the inverse-variance weighted (IVW) approach, and the sensitivity analyses were carried out using MR-Egger, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier. Results: This study revealed the association of CRP higher levels with increased risk of IgAV through IVW method (Estimate odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.01-1.98, P = 0.04), MR-Egger (OR = 1.87, CI: 1.15-3.02, P = 0.01), weighted median (OR = 2.00, CI: 1.21-3.30, P = 0.01) and weighted mode (OR = 1.74, CI: 1.13-2.68, P = 0.02). Furthermore, elevated IL-8 was strongly implicated with a higher risk of IgAV (IVW OR = 1.42, CI: 1.05-1.92; P = 0.02). Conversely, genetically predicted IgAV was associated with decreased levels of TNF-ß (IVW estimate ß = -0.093, CI: -0.178 - -0.007; P = 0.033). Additionally, no such significant statistical differences for other inflammatory factors were found. Conclusion: Our current study using bidirectional MR analysis provides compelling evidence for a causal effect of CRP, PCT, and circulating inflammatory regulators on IgAV. These findings contribute to a better understanding of the pathogenesis of IgAV and emphasize the potential of targeting inflammatory factors for therapeutic interventions.
Asunto(s)
Vasculitis por IgA , Vasculitis , Humanos , Vasculitis por IgA/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Inflamación/genética , Vasculitis/genética , Proteína C-Reactiva/genética , Polipéptido alfa Relacionado con CalcitoninaRESUMEN
BACKGROUND: Myocardial injury is the main manifestation of cardiovascular diseases, and previous studies have shown that propofol (PPF) regulates myocardial injury. However, the mechanism of PPF in regulating myocardial injury remains to be further explored. This work aims to analyze the effects of PPF on human cardiomyocyte injury and the underlying mechanism. METHODS: The regulatory and functional role of PPF and circAPBB2 in human cardiomyocyte injury were analyzed using an in vitro hypoxia/reoxygenation (H/R) cell model, which was established by treating human cardiomyocytes (AC16 cells) with H/R. The study evaluated AC16 cell injury by analyzing cytotoxicity, oxidative stress, inflammation and apoptosis of H/R-induced AC16 cells. Quantitative real-time polymerase chain reaction was performed to detect circAPBB2, miR-18a-5p and dual specificity phosphatase 14 (DUSP14) expression. Protein expression was analyzed by Western blot analysis assay. Dual-luciferase reporter assay, RNA pull-down assay and RNA immunoprecipitation assay were performed to identify the associations among circAPBB2, miR-18a-5p and DUSP14. Cytotoxicity was investigated by cell counting kit-8 assay and lactate dehydrogenase activity detection kit. Oxidative stress was evaluated by cellular reactive oxygen species assay kit and superoxide dismutase activity assay kit. The production of tumor necrosis factor-α and interleukin-1ß was evaluated by enzyme-linked immunosorbent assays. RESULTS: The expression of circAPBB2 and DUSP14 was significantly decreased, while miR-18a-5p was increased in H/R-induced AC16 cells when compared with controls. H/R treatment-induced cytotoxicity, oxidative stress, inflammation and cell apoptosis were attenuated after circAPBB2 overexpression or PPF treatment, whereas these effects were restored by increasing miR-18a-5p expression. PPF treatment improved the inhibitory effect of ectopic circAPBB2 expression on H/R-induced cell injury. MiR-18a-5p silencing ameliorated H/R-induced AC16 damage by interacting with DUSP14. Mechanically, circAPBB2 acted as a miR-18a-5p sponge, and miR-18a-5p targeted DUSP14 in AC16 cells. CONCLUSION: PPF synergized with circAPBB2 to protect AC16 cells against H/R-induced oxidative stress, inflammation and apoptosis through the miR-18a-5p/DUSP14 pathway.
Asunto(s)
MicroARNs , Propofol , Humanos , Miocitos Cardíacos , Propofol/farmacología , Estrés Oxidativo , Apoptosis , Inflamación , Hipoxia , MicroARNs/genéticaRESUMEN
Aging compromises the repair and regrowth of brain vasculature and white matter during stroke recovery, but the underlying mechanisms remain elusive. To understand how aging jeopardizes brain tissue repair after stroke, we performed single-cell transcriptomic profiling of young adult and aged mouse brains at acute (3 d) and chronic (14 d) stages after ischemic injury, focusing a priori on the expression of angiogenesis- and oligodendrogenesis-related genes. We identified unique subsets of endothelial cells (ECs) and oligodendrocyte (OL) progenitors in proangiogenesis and pro-oligodendrogenesis phenotypic states 3 d after stroke in young mice. However, this early prorepair transcriptomic reprogramming was negligible in aged stroke mice, consistent with the impairment of angiogenesis and oligodendrogenesis observed during the chronic injury stages after ischemia. In the stroke brain, microglia and macrophages (MG/MΦ) may drive angiogenesis and oligodendrogenesis through a paracrine mechanism. However, this reparative cell-cell cross talk between MG/MΦ and ECs or OLs is impeded in aged brains. In support of these findings, permanent depletion of MG/MΦ via antagonism of the colony-stimulating factor 1 receptor resulted in remarkably poor neurological recovery and loss of poststroke angiogenesis and oligodendrogenesis. Finally, transplantation of MG/MΦ from young, but not aged, mouse brains into the cerebral cortices of aged stroke mice partially restored angiogenesis and oligodendrogenesis and rejuvenated sensorimotor function and spatial learning and memory. Together, these data reveal fundamental mechanisms underlying the age-related decay in brain repair and highlight MG/MΦ as effective targets for promoting stroke recovery.
Asunto(s)
Células Endoteliales , Accidente Cerebrovascular , Animales , Ratones , Encéfalo , Macrófagos , Análisis de Secuencia de ARNRESUMEN
INTRODUCTION: On-demand treatment is the most common treatment strategy for haemophilia A in China. AIM: This study aims to evaluate the efficacy and safety of a human-derived B-domain-deleted recombinant factor VIII (TQG202) in the on-demand treatment of bleeding episodes in moderate/severe haemophilia A patients. METHODS: This multicentre, single-arm clinical trial enrolled moderate/severe haemophilia patients previously treated with FVIII concentrates for ≥50 exposure days (EDs) from May 2017 to October 2019. TQG202 was injected intravenously on-demand for bleeding episode management. The primary endpoints were the infusion efficiency at 15 and 60 min after the first administration and haemostatic efficacy of the first bleeding episode. Safety was also monitored. RESULTS: Fifty-six participants were enrolled with a median age of 24.5 (range: 12-64) years old. The median total dose of TQG202 was 29,250 IU per participant (range: 1750-2,02,500), and the median number of administrations was 24.5 (2-116). The median infusion efficiency at 15 and 60 min after the first administration was 155.4% and 145.2%, respectively. Among the 48 first bleeding episodes evaluated, 47 (83.9%, 95% CI: 71.7%-92.4%) had a haemostatic efficacy rating of excellent or good. Eleven (19.6%) participants had treatment-related adverse events (TRAEs), but no ≥grade 3 TRAE was observed. Inhibitor development (0.6BU) was observed in one participant (1.8%) after 22 EDs, but was undetectable after 43 EDs. CONCLUSION: TQG202 for on-demand treatment in moderate/severe haemophilia A shows effective control of the bleeding symptoms, with a low incidence of adverse events and inhibitors development.
Asunto(s)
Hemofilia A , Hemostáticos , Adolescente , Adulto , Niño , Humanos , Persona de Mediana Edad , Adulto Joven , China , Factor VIII/efectos adversos , Factor VIII/genética , Hemofilia A/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Hemostáticos/efectos adversos , Incidencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Women and girls with haemophilia (WGH) may have spontaneous/traumatic bleeding similar to that in males with haemophilia, and in addition excessive bleeding during menstruation and delivery. AIM: To characterize WGH in China and provide guidance for better management. METHODS: We retrospectively analysed the characteristics of WGH registered in the Haemophilia Treatment Center Collaborative Network of China (HTCCNC) Registry, including demographics, diagnosis and treatment, bleeding characteristics, obstetrical and gynaecological experiences, and surgical history. RESULTS: A total of 61 females had confirmed haemophilia. Diagnosis and treatment were typically delayed, longer in mild haemophilia than in severe and moderate. The most frequently reported bleeding manifestations were haemarthrosis in severe and moderate patients, and cutaneous bleeding in mild patients. Among 45 postmenarcheal WGH, 21 (46.7%) had history of heavy menstrual bleeding, but only three received treatments. Prenatal diagnosis and management of perinatal haemorrhage were inadequate. Of 34 deliveries in 30 women, nine deliveries were complicated by postpartum haemorrhage, and 22 offspring carried mutations causing haemophilia. Forty-four surgical procedures were performed in 29 patients. Those procedures receiving preoperative coagulation factors coverage were significantly less likely to have excessive bleeding than those who did not (P = .003). CONCLUSION: This is the first and largest study describing WGH in China. There are currently deficiencies in the identification, diagnosis, and management of these patients. Improving health insurance policies, establishing haemophilia centres, and multidisciplinary teams for bleeding and perinatal or perioperative management will help reduce morbidity and mortality.
Asunto(s)
Hemofilia A , Menorragia , Hemorragia Posparto , Masculino , Embarazo , Humanos , Femenino , Hemofilia A/complicaciones , Hemofilia A/epidemiología , Hemofilia A/genética , Estudios Retrospectivos , Hemorragia Posparto/etiología , Factores de Coagulación Sanguínea , Menorragia/complicacionesRESUMEN
Cyanidin-3-O-glucoside (C3G), an active ingredient in anthocyanins, mainly exists in dark cereals. C3G was investigated for its effect on human gastric cancer (GC) cells, together with its molecular mechanism. The CCK-8 assay results showed that C3G had significant antiproliferative effects on GC cells, but it had little effect on normal cells. Western blot and flow cytometry results showed that C3G regulated the reduction of mitochondrial membrane potential and arrested the cell cycle in the G2/M phase through the AKT signaling pathway, causing the cells to undergo apoptosis. Additionally, in MKN-45 cells, C3G markedly raised intracellular reactive oxygen species (ROS) levels. The wound healing assay and Transwell assay results showed that MKN-45 cell migration was significantly inhibited. Western blot results showed that the expression of E-cadherin protein was upregulated and the expressions of ß-catenin, N-cadherin, and Vimentin were downregulated. Additionally, following N-acetylcysteine treatment, the expression levels of these proteins were reduced. In conclusion, C3G caused MKN-45 cells to undergo apoptosis; arrested the cell cycle in the G2/M phase; hindered cell migration; and activated the MAPK, STAT3, and NF-κB signaling pathways, by inducing an increase in ROS levels. Thus, C3G may be a promising new medication for the treatment of GC.
Asunto(s)
Antocianinas , Neoplasias Gástricas , Humanos , Antocianinas/farmacología , Antocianinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Transducción de Señal , ApoptosisRESUMEN
BACKGROUND: Numerous studies have manifested long noncoding RNAs (lncRNAs) as biomarkers to determine the prognosis of multiple myeloma (MM) patients. Nevertheless, the prognostic role of lncRNAs in MM is still ambiguous. Herein, we performed a meta-analysis to evaluate the predictive value of aberrantly expressed lncRNAs in MM. METHODS: A systemic literature search was performed in PubMed, EMBASE, Cochrane, and Web of Science databases until October 9, 2021, and the protocol was registered in the PROSPERO database (CRD42021284364). Our study extracted the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), or event-free survival (EFS). Begg's and Egger's tests were employed to correct publication bias. RESULT: Twenty-six individual studies containing 3501 MM patients were enrolled in this study. The results showed that aberrant expression of lncRNAs was associated with poor OS and PFS of MM patients. The pooled HRs for univariate OS and PFS were 1.48 (95% CI = 1.17-1.88, p < 0.001) and 1.30 (95% CI = 1.18-1.43, p < 0.001), respectively, whereas the pooled HRs for multivariate OS and PFS were 1.50 (95% CI = 1.16-1.95, p < 0.001) and 1.59 (95% CI = 1.22-2.07, p < 0.001), respectively. Subgroup analysis suggested that MALAT1, TCF7, NEAT1, and PVT1 upregulation were associated with poor OS (p < 0.05), PVT1, and TCF7 upregulation were implicated with worse PFS (p < 0.05), while only TCF7 overexpression was correlated with reduced EFS (p < 0.05). Moreover, the contour-enhanced funnel plot demonstrated the reliability of our current conclusion, which was not affected by publication bias. CONCLUSION: Aberrantly expressed particular lncRNAs are critical prognostic indicators in long-term survival as well as promising biomarkers in progression-free status. However, different cutoff values and dissimilar methods to assess lncRNA expression among studies may lead to heterogeneity.
Asunto(s)
Mieloma Múltiple , ARN Largo no Codificante , Humanos , Pronóstico , Reproducibilidad de los Resultados , Modelos de Riesgos Proporcionales , Biomarcadores de Tumor/metabolismoRESUMEN
INTRODUCTION: The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. AIM: This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. METHODS: We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. RESULTS: Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p = .0002), while those with missense mutations had a low risk (p < .0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. CONCLUSION: This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication.
Asunto(s)
Factor IX , Hemofilia A , Hemofilia B , Adolescente , Niño , Preescolar , Humanos , China/epidemiología , Factor IX/antagonistas & inhibidores , Factor IX/genética , Hemofilia B/tratamiento farmacológico , Hemofilia B/genética , Hemofilia B/diagnóstico , Tolerancia Inmunológica , Estudios RetrospectivosRESUMEN
Isoorientin (ISO) is a flavonoid compound containing a luteolin structure, which can induce autophagy in some tumor cells. This study investigated the impact of ISO in gastric cancer AGS cells, and performed an experimental analysis on the main signaling pathways and transduction pathways it regulates. CCK-8 assay results showed that ISO reduced the survival rate of gastric cancer AGS cells, but the toxicity to normal cells was minimal. Hoechst 33342/PI double staining assay results showed that ISO induced apoptosis in gastric cancer AGS cells. Further analysis by flow cytometry and Western blot showed that ISO induced apoptosis via a mitochondria-dependent pathway. In addition, the level of reactive oxygen species (ROS) in gastric cancer AGS cells also increased with the extension of the ISO treatment time. However, cell apoptosis was inhibited by preconditioning cells with N-acetylcysteine (NAC). Moreover, ISO arrested the cell cycle at the G2/M phase by increasing intracellular ROS levels. Cell migration assay results showed that ISO inhibited cell migration by inhibiting the expression of p-AKT, p-GSK-3ß, and ß-catenin and was also related to the accumulation of ROS. These results suggest that ISO-induced cell apoptosis by ROS-mediated MAPK/STAT3/NF-κB signaling pathways inhibited cell migration by regulating the AKT/GSK-3ß/ß-catenin signaling pathway in gastric cancer AGS cells.
RESUMEN
The effect of ratio and consecutive number of hydrophobic residues in the repeating unit of protein chains was investigated by MD simulation. The modified off-lattice HNP model was applied in this study. The protein chains constituted by different HNP ratios or different numbers of consecutively hydrophobic residues with the same chain length were simulated under a broad temperature range. We concluded that the proteins with higher ratio or larger number of sequentially hydrophobic residues present more orientated and compact structure under a certain low temperature. It is attributed to the lower non-bonded potential energy between H-H residual pairs, especially more hydrophobic residues in a procession among the protein chain. Considering the microscopic structure of the protein, more residue contacts are achieved with the proteins with higher ratios and sequential H residues under the low temperature. Meanwhile, with the ratio and consecutive number of H residues increasing, the distribution of stem length showed a transition from exponential decline to unimodal and even multiple peaks, indicating the specific ordered structure formed. These results provide an insight into 3D structural properties of proteins from their residue sequences, which has a primary structure at molecular level and, ultimately, a practical possibility of applying in biotechnological applications.
Asunto(s)
Proteínas , Proteínas/química , Interacciones Hidrofóbicas e Hidrofílicas , Simulación por ComputadorRESUMEN
Peimine (PM), a natural product extracted from Fritillaria, has anti-inflammatory, drug resistance reversal, and other pharmacological effects. The purpose of this study was to investigate the antitumor effects and the molecular mechanisms of PM using gastric cancer MKN-45 cells. Cell counting kit-8 assays were used to evaluate the viability of gastric cancer cells after treatment with PM. The results showed that PM significantly reduced the activity of gastric cancer cells, and the effect was most obvious in MKN-45 cells. Annexin V-FITC/propidium iodide staining and flow cytometry were used to assess apoptosis of MKN-45 cells after PM treatment. Our results showed that PM-induced apoptosis of MKN-45 cells. Flow cytometry was also used to determine the mitochondrial membrane potential and reactive oxygen species (ROS) levels, and to assess PM-induced cell-cycle arrest. Additionally, Western blot was used to analyze the expression of signaling pathway proteins and the relationship between apoptosis and ROS accumulation. Our findings showed that PM destroyed the mitochondria by diminishing the mitochondrial membrane potential. In addition, PM regulated the mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3, and nuclear factor kappa-B signaling pathways by promoting the accumulation of ROS in MKN-45 cells. PM also caused cell-cycle arrest in the G2/M phase by increasing ROS accumulation. Furthermore, PM inhibited cell migration by regulating the Wnt/ß-catenin pathway. In conclusion, PM plays an anticancer role through endogenous apoptosis pathways and by inhibiting cell migration, and it has the potential to be a useful treatment for gastric cancers.
Asunto(s)
Factor de Transcripción STAT3 , Neoplasias Gástricas , Humanos , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/metabolismo , FN-kappa B/metabolismo , Neoplasias Gástricas/metabolismo , Vía de Señalización Wnt , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/farmacología , Línea Celular Tumoral , ApoptosisRESUMEN
Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.
Asunto(s)
Anemia , Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/diagnóstico , Inhibidores de las Cinasas Janus/efectos adversos , Pirimidinas/efectos adversos , Pirazoles/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Nitrilos/uso terapéutico , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Resultado del Tratamiento , Janus Quinasa 2RESUMEN
INTRODUCTION: Current treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma-derived FVIII is short in China. PURPOSE: To evaluate the efficacy and safety of a new B-domain deleted (BDD) recombinant FVIII (TQG202) produced by human-derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha. METHODS: This multicentre, clinical trial consisted of an open-label, randomized, two-period cross-over trial assessing single-dose pharmacokinetics (PK), and a single-arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single-dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded. RESULTS: Twenty-six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2-2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026-.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors. CONCLUSION: TQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.