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OBJECTIVES: This study is to establish a nomination graph model for individualised early prediction of the 3-month prognosis of patients who had an acute ischaemic stroke (AIS) receiving intravenous thrombolysis with recombinant tissue plasminogen activator. DESIGN: For the period from January 2016 through August 2022, 991 patients who had an acute stroke eligible for intravenous thrombolysis were included in the retrospective analysis study. The study was based on multifactor logistic regression. PARTICIPANTS: Patients who received treatment from January 2016 to February 2021 were included in the training cohort, and those who received treatment from March 2021 to August 2022 were included in the testing cohort. INTERVENTIONS: Each patient received intravenous thrombolysis within 4.5 hours of onset, with treatment doses divided into standard doses (0.9 mg/kg). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was a 3-month adverse outcome (modified Rankin Scale 3-6). RESULTS: The National Institutes of Health Stroke Scale Score after thrombolysis (OR=1.18; 95% CI: 1.04 to 1.36; p = 0.015), door-to-needle time (OR=1.01; 95% CI: 1.00 to 1.02; p = 0.003), baseline blood glucose (OR=1.08; 95% CI: 1.00 to 1.16; p=0.042), blood homocysteine (OR=7.14; 95% CI: 4.12 to 12.71; p<0.001), monocytes (OR=0.05; 95% CI: 0.01 to 0.043; p=0.005) and monocytes/high-density lipoprotein (OR=62.93; 95% CI: 16.51 to 283.08; p<0.001) were independent predictors of adverse outcomes 3 months after intravenous thrombolysis, and the above six factors were included in the nominated DGHM2N nomogram. The area under the receiver operating characteristic curve value of the training cohort was 0.870 (95% CI: 0.841 to 0.899) and in the testing cohort was 0.822 (95% CI: 0.769 to 0.875). CONCLUSIONS: A reliable nomogram model (DGHM2N model) was developed and validated in this study. This nomogram could individually predict the adverse outcome of patients who had an AIS receiving intravenous thrombolysis with alteplase for 3 months.
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Fibrinolíticos , Accidente Cerebrovascular Isquémico , Nomogramas , Terapia Trombolítica , Activador de Tejido Plasminógeno , Humanos , Masculino , Femenino , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Terapia Trombolítica/métodos , Terapia Trombolítica/efectos adversos , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/uso terapéutico , Activador de Tejido Plasminógeno/efectos adversos , Anciano , Estudios Retrospectivos , Pronóstico , Fibrinolíticos/administración & dosificación , Fibrinolíticos/uso terapéutico , Persona de Mediana Edad , Modelos Logísticos , Administración IntravenosaRESUMEN
**Ischemic stroke remains a leading cause of morbidity and mortality globally. Despite the advances in thrombolytic therapy, notably recombinant tissue plasminogen activator (rtPA), patient outcomes are highly variable. This study aims to introduce a novel predictive model, the Acute Stroke Thrombolysis Non-Responder Prediction Model (ASTN-RPM), to identify patients unlikely to benefit from rtPA within the critical early recovery window. We conducted a retrospective cohort study at Baoding No.1 Central Hospital including 709 adult patients diagnosed with acute ischemic stroke and treated with intravenous alteplase within the therapeutic time window. The ASTN-RPM was developed using Least Absolute Shrinkage and Selection Operator (LASSO) regression technique, incorporating a wide range of biomarkers and clinical parameters. Model performance was evaluated using Receiver Operating Characteristic (ROC) curves, calibration plots, and Decision Curve Analysis (DCA). ASTN-RPM effectively identified patients at high risk of poor response to thrombolysis, with an AUC of 0.909 in the training set and 0.872 in the validation set, indicating high sensitivity and specificity. Key predictors included posterior circulation stroke, high admission NIHSS scores, extended door to needle time, and certain laboratory parameters like homocysteine levels. The ASTN-RPM stands as a potential tool for refining clinical decision-making in ischemic stroke management. By anticipating thrombolytic non-response, clinicians can personalize treatment strategies, possibly improving patient outcomes and reducing the burden of ineffective interventions. Future studies are needed for external validation and to explore the incorporation of emerging biomarkers and imaging data.
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Biomarcadores , Accidente Cerebrovascular Isquémico , Terapia Trombolítica , Activador de Tejido Plasminógeno , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/diagnóstico , Masculino , Biomarcadores/sangre , Femenino , Terapia Trombolítica/métodos , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Activador de Tejido Plasminógeno/uso terapéutico , Activador de Tejido Plasminógeno/administración & dosificación , Fibrinolíticos/uso terapéutico , Fibrinolíticos/administración & dosificación , Curva ROC , Resultado del TratamientoRESUMEN
BACKGROUND: Hereditary angioedema (HAE) is characterized by unpredictable and often severe cutaneous and mucosal swelling that affects the extremities, face, larynx, gastrointestinal tract, or genitourinary area. Introduction of novel long-term prophylactic treatment options (lanadelumab, berotralstat, and C1-esterase inhibitor SC [human]) into the treatment armamentarium has substantially reduced HAE attacks, allowing patients to be attack free for longer with improvements to their quality of life. Using data drawn from a wide-ranging survey of patients with HAE, we examined the relationship between duration of time attack free and health-related quality of life (HRQoL), exploring the possibility that there is an association between observed improvement in HRQoL and attack-free duration. METHODS: A survey among patients with HAE on long-term prophylaxis (LTP) in six countries (the US, Australia, Canada, UK, Germany, and Japan) assessed the relationship between attack-free duration and mean Angioedema Quality of Life (AE-QoL) scores, quality of life benefits, and rescue medication used. Analysis of covariance (ANCOVA) was used to assess the roles of LTP and attack-free period (< 1 month, 1- < 6 months, ≥ 6 months) on total AE-QoL scores. Results include descriptive p-values for strength of association, without control for multiplicity. Descriptive statistics were used to show the relationship between time attack free and quality of life benefits. RESULTS: Longer durations of time for which participants reported being attack free at the time of the survey correlated with better AE-QoL scores and less use of rescue medication. The mean total AE-QoL scores were 51.8, 33.2, and 19.9 for those who reported having been attack free for < 1 month, 1- < 6 months, and ≥ 6 months, respectively, with higher scores reflecting more impairment. The ANCOVA results showed a strong association between attack-free duration and AE-QoL total score. CONCLUSION: This study shows that longer attack-free duration has an influential role for better HRQoL in patients receiving LTP. Prolonging the attack-free period is an important goal of therapy and recent advances in LTP have increased attack-free duration. However, opportunities exist for new treatments to further increase attack-free duration and improve HRQoL for all patients with HAE.
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Angioedemas Hereditarios , Calidad de Vida , Humanos , Angioedemas Hereditarios/tratamiento farmacológico , Femenino , Masculino , Adulto , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven , AdolescenteRESUMEN
Background: Acute ischemic stroke (AIS) remains a leading cause of disability and mortality globally among adults. Despite Intravenous Thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) emerging as the standard treatment for AIS, approximately 6-40% of patients undergoing IVT experience Early Neurological Deterioration (END), significantly impacting treatment efficacy and patient prognosis. Objective: This study aimed to develop and validate a predictive model for END in AIS patients post rt-PA administration using the Least Absolute Shrinkage and Selection Operator (LASSO) regression approach. Methods: In this retrospective cohort study, data from 531 AIS patients treated with intravenous alteplase across two hospitals were analyzed. LASSO regression was employed to identify significant predictors of END, leading to the construction of a multivariate predictive model. Results: Six key predictors significantly associated with END were identified through LASSO regression analysis: previous stroke history, Body Mass Index (BMI), age, Onset to Treatment Time (OTT), lymphocyte count, and glucose levels. A predictive nomogram incorporating these factors was developed, effectively estimating the probability of END post-IVT. The model demonstrated robust predictive performance, with an Area Under the Curve (AUC) of 0.867 in the training set and 0.880 in the validation set. Conclusion: The LASSO regression-based predictive model accurately identifies critical risk factors leading to END in AIS patients following IVT. This model facilitates timely identification of high-risk patients by clinicians, enabling more personalized treatment strategies and optimizing patient management and outcomes.
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Previous studies showed that cal-miR2911, featuring an atypical biogenesis, could target genes of virus and in turn inhibit virus replication. Given its especial sequence motif and cross-kingdom potential, the stability of miR2911 under digestive environment and its impact on intestinal microbes in mice were examined. The results showed that miR2911 was of considerable stability during oral, gastric, and intestinal digestion. The coingested food matrix enhanced its stability in the gastric phase, contributing to the existence of miR2911 in mouse intestines. The survival miR2911 promoted the growth of Bifidobacterium in mice and maintained the overall composition and diversity of the gut microbiota. miR2911 specifically entered the cells of Bifidobacterium adolescentis and potentially modulated the gene expression as evidenced by the dual-luciferase assay. The current study provided evidence on the cross-kingdom communication between dietary miRNAs and gut microbes, suggesting that modulating target bacteria using miRNAs for nutritional and therapeutic ends is promising.
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Bifidobacterium , Microbioma Gastrointestinal , MicroARNs , Animales , Ratones , Bifidobacterium/genética , Bifidobacterium/metabolismo , Digestión , Alimentos , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
New evidence reveals that bol-miR159, an miRNA rich in fruits and vegetables, cross-kingdomly functions in mammalian bodies. However, whether the miRNA could regulate gut microbiota remains unclear. Here, the effect of miR159 on mouse intestinal microbes was comprehensively examined. The results showed that supplementation of miR159 to the chow diet significantly enhanced the diversity of mouse gut microbiota without causing pathological lesions or inflammatory responses on the intestines. At the phylum level, miR159 increased the abundance of Proteobacteria and decreased the Firmicute-to-Bacteroidetes (F/B) ratio. miR159 had prebiotic-like effects on mouse gut microbiota, as it promoted the growth of the bacteria that is beneficial for maintaining gut health. The miRNA can target bacteria genes and get into the bacteria cells. The data provide direct in vivo evidence on the crosstalk between plant miRNAs and intestinal microbes, highlighting the potential for miRNA-based strategies that modulate gut microbes to improve host health.
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Microbioma Gastrointestinal , MicroARNs , Animales , Ratones , MicroARNs/genética , Bacterias/genética , Proteobacteria , Dieta , ARN Ribosómico 16S/genética , Mamíferos/genéticaRESUMEN
Metabolic remodeling is one of the earliest events that occur during cell differentiation. Here, we define fatty acid metabolism as a key player in definitive endoderm differentiation from human embryonic stem cells. Fatty acid ß-oxidation is enhanced while lipogenesis is decreased, and this is due to the phosphorylation of lipogenic enzyme acetyl-CoA carboxylase by AMPK. More importantly, inhibition of fatty acid synthesis by either its inhibitors or AMPK agonist significantly promotes human endoderm differentiation, while blockade of fatty acid oxidation impairs differentiation. Mechanistically, reduced de novo fatty acid synthesis and enhanced fatty acid ß-oxidation both contribute to the accumulation of intracellular acetyl-CoA, which guarantees the acetylation of SMAD3 and further causes nuclear localization to promote endoderm differentiation. Thus, our current study identifies a fatty acid synthesis/oxidation shift during early differentiation and presents an instructive role for fatty acid metabolism in regulating human endoderm differentiation.
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Proteínas Quinasas Activadas por AMP , Lipogénesis , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Acetilación , Endodermo/metabolismo , Diferenciación Celular , Ácidos Grasos/metabolismo , Proteína smad3/metabolismoRESUMEN
BACKGROUND: Rheumatoid arthritis (RA), is a typical autoimmune disease affecting nearly 1% of the world's population. The dysfunctional hyperproliferation of synovial fibroblast (SF) in articular cartilage of RA patients is considered as the essential etiology. Traditional chemotherapeutic agents for RA treatment are imperfect for their high cost and unpredictable side-effects. L. ruthenicum anthocyanins (LRAC) is a natural product that of potential for therapeutic application against RA. METHODS: LRAC was characterized by UPLC-MS/MS. Bioinformatics analyses based on network pharmacology were applied to predict the potential targets of LRAC, and to select DEGs (differentially expressed genes) caused by RA pathogenesis from GSE77298. Interactions between LRAC and the predicted targets were evaluated by molecular docking. Effects of LRAC on SFs from RA patients were examined by in vitro assays, which were analyzed by flow cytometry and western blotting (WB). RESULTS: LRAC was able to inhibit the abnormal proliferation and aggressive invasion of SFs from RA patients. LRAC was mainly constituted by petunidin (82.7%), with small amount of delphinidin (12.9%) and malvidin (4.4%) in terms of anthocyanidin. Bioinformatics analyses showed that in 3738 RA-related DEGs, 58 of them were collectively targeted by delphinidin, malvidin and delphinidin. AR, CDK2, CHEK1, HIF1A, CXCR4, MMP2 and MMP9, the seven hub genes constructed a central network mediating the signal transduction. Molecular docking confirmed the high affinities between the LRAC ligands and the protein receptors encoded by the hub genes. The in vitro assays validated that LRAC repressed the growth of RASF by cell cycle arresting and cell invasion paralyzing (c-Myc/p21/CDK2), initiating cell apoptosis (HIF-1α/CXCR4/Bax/Bcl-2), and inducing pyroptosis via ROS-dependent pathway (NOX4/ROS/NLRP3/IL-1ß/Caspase-1). CONCLUSION: LRAC can selectively inhibit the proliferation of RASFs, without side-effecting immunosuppression that usually occurred for RA treatment using MTX (methotrexate). These findings demonstrate the potential application of LRAC as a phytomedicine for RA treatment, and provide a valid approach for exploring natural remedies against autoimmune diseases.
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Artritis Reumatoide , Lycium , Humanos , Membrana Sinovial/patología , Antocianinas/farmacología , Farmacología en Red , Cromatografía Liquida , Simulación del Acoplamiento Molecular , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masas en Tándem , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , FibroblastosRESUMEN
Here, a method using SplintR ligase-mediated ligation of complementary-pairing probes enhanced by RNase H (SPLICER) for miRNAs quantification was established. The strategy has two steps: (1) ligation of two DNA probes specifically hybridize to target miRNA and (2) qPCR amplifying the ligated probe. The miRNA-binding regions of the probes are stem-looped, a motif significantly reduces nonspecific ligation at high ligation temperature (65°C). The ends of the probes are designed complementary to form a paired probe, facilitating the recognition of target miRNAs with low concentrations. RNase H proved to be able to stabilize the heteroduplex formed by the probe and target miRNA, contributing to enhanced sensitivity (limit of detection = 60 copies). High specificity (discriminating homology miRNAs differing only one nucleotide), wide dynamic range (seven orders of magnitude) and ability to accurately detect plant miRNAs (immune to hindrance of 2'-O-methyl moiety) enable SPLICER comparable with the commercially available TaqMan and miRCURY assays. SYBR green I, rather than expensive hydrolysis or locked nucleic acid probes indispensable to TaqMan and miRCURY assays, is adequate for SPLICER. The method was efficient (<1 h), economical ($7 per sample), and robust (able to detect xeno-miRNAs in mammalian bodies), making it a powerful tool for molecular diagnosis and corresponding therapy.
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OBJECTIVE: The T1GER (A Study of SIMPONI to Arrest ß-Cell Loss in Type 1 Diabetes) study showed many metabolic benefits of the tumor necrosis factor-α blocker golimumab in children and young adults with type 1 diabetes (T1D). Off-therapy effects are reported. RESEARCH DESIGNS AND METHODS: T1GER was a phase 2, placebo-controlled, randomized trial in which golimumab or placebo was administered for 52 weeks to participants 6-21 years old diagnosed with T1D within 100 days of randomization. Assessments occurred during the 52-week on-therapy and 52-week off-therapy periods. RESULTS: After treatment was stopped, C-peptide area under the curve (AUC) remained greater in the treatment versus control group. At weeks 78 and 104, the golimumab group had lower reductions in the 4-h C-peptide AUC baseline than the placebo group, where specifically the golimumab group had reductions of 0.31 and 0.41 nmol/L, and the placebo group had reductions of 0.64 and 0.74 nmol/L. There were also trends in less insulin use, higher peak C-peptide levels and those in partial remission, and higher peak C-peptide levels in the golimumab group. Golimumab responders, defined as having an increase or minimal loss of C-peptide AUC and/or being in partial remission at week 52, showed even greater improvements in most metabolic parameters on and off therapy and had less hypoglycemia during the off-therapy period versus placebo. Adverse events, including infections, were similar between the groups during all time periods of the study. CONCLUSIONS: In children and young adults with new-onset T1D, golimumab preserved endogenous ß-cell function and resulted in other favorable metabolic parameters on and off therapy. A subpopulation had disease stabilization while on therapy, with improved metabolic parameters off therapy.
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Diabetes Mellitus Tipo 1 , Humanos , Niño , Adulto Joven , Adolescente , Adulto , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Estudios de Seguimiento , Péptido C/metabolismo , Anticuerpos Monoclonales/efectos adversos , Método Doble Ciego , Resultado del TratamientoRESUMEN
Background: Cerebral small vessel disease (CSVD) is a significant contributor to stroke, intracerebral hemorrhages, and vascular dementia, particularly in the elderly. Early diagnosis remains challenging. This study aimed to develop and validate a novel nomogram for the early diagnosis of cerebral small vessel disease (CSVD). We focused on integrating cerebrovascular risk factors and blood biochemical markers to identify individuals at high risk of CSVD, thus enabling early intervention. Methods: In a retrospective study conducted at the neurology department of the Affiliated Hospital of Hebei University from January 2020 to June 2022, 587 patients were enrolled. The patients were randomly divided into a training set (70%, n = 412) and a validation set (30%, n = 175). The nomogram was developed using multivariable logistic regression analysis, with variables selected through the Least Absolute Shrinkage and Selection Operator (LASSO) technique. The performance of the nomogram was evaluated based on the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analysis (DCA). Results: Out of 88 analyzed biomarkers, 32 showed significant differences between the CSVD and non-CSVD groups. The LASSO regression identified 12 significant indicators, with nine being independent clinical predictors of CSVD. The AUC-ROC values of the nomogram were 0.849 (95% CI: 0.821-0.894) in the training set and 0.863 (95% CI: 0.810-0.917) in the validation set, indicating excellent discriminative ability. Calibration plots demonstrated good agreement between predicted and observed probabilities in both sets. DCA showed that the nomogram had significant clinical utility. Conclusions: The study successfully developed a nomogram predictive model for CSVD, incorporating nine clinical predictive factors. This model offers a valuable tool for early identification and risk assessment of CSVD, potentially enhancing clinical decision-making and patient outcomes.
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OBJECTIVES: To investigate the value of dynamic monitoring of serum procalcitonin (PCT) in anti-infective therapy of patients with acute stroke. METHODS: This is a case control retrospective study of acute stroke patients conducted from July 2016 to October 2018, in the Department of Neurology, Affiliated Hospital of Hebei University, who who reached within twenty four hours. They, were selected as the study subjects who were divided into infection group and non-infection group according to the inclusion and exclusion criteria. The serum PCT and CRP levels were compared between the two groups at 24 hours, 48 hours and 72 hours. In order to judge the changes of PCT level and the infection of stroke patients, different kinds of antibiotics were used for corresponding treatment. Retrospective analysis of the cases that did not monitor PCT anti infective treatment before July 2016 were compared with the cases that monitored PCT to guide anti infective treatment after July 2016, and compared the efficacy of antibiotics. RESULTS: The serum PCT level of patients in the infection group was significantly higher than that of patients in the noninfection group (P<0.001). For the patients whose PCT<0.5 ng/ml within 72 hour, anti-infective therapy was not administered. However, for those patients whose PCT<0.5 ng/ml and CRP rose significantly, WBC, body temperature and chest CT were closely monitored. For the patients whose PCT increased slightly (0.5 ng/ml
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Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor-matched patient-derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR+ /PSA+ ) or NEPC (AR- /SYN+ /CHGA+ ) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229-fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC-3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell cytoplasm, LINC00261 binds to and sequesters miR-8485 from targeting the CBX2 mRNA, while inside the nucleus, LINC00261 functions as a transcriptional scaffold to induce SMAD-driven expression of the FOXA2 gene. For the first time, these results demonstrate hyperactivation of the LINC00261-CBX2-FOXA2 axes in NEPC to drive proliferation and metastasis, and that LINC00261 may be utilized as a therapeutic target and a biomarker for this incurable disease.
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Neoplasias de la Próstata , ARN Largo no Codificante , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile. RESULTS: A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies. CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).
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Anticuerpos Monoclonales/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Área Bajo la Curva , Péptido C/metabolismo , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/efectos adversos , Insulina/administración & dosificación , Insulina/efectos adversos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Proinsulina/metabolismo , Adulto JovenRESUMEN
Pathological or functional loss of pancreatic beta cells is the cause of diabetes. Understanding how signaling pathways regulate pancreatic lineage and searching for combinations of signal modulators to promote pancreatic differentiation will definitely facilitate the robust generation of functional beta cells for curing hyperglycemia. In this study, we first tested the effect of several potent BMP inhibitors on pancreatic differentiation using human embryonic stem cells. Next, we examined the endodermal lineage bias upon potent BMP inhibitor treatment and further checked the crosstalk between signal pathways governing endodermal lineage determination. Furthermore, we improved current pancreatic differentiation system based on the signaling pathway study. Finally, we used human-induced pluripotent stem cells to validate our finding. We found BMP inhibitors indeed not only blocked hepatic lineage but also impeded intestinal lineage from human definitive endoderm unexpectedly. Signaling pathway analysis indicated potent BMP inhibitor resulted in the decrease of WNT signal activity and inhibition of WNT could contribute to the improved pancreatic differentiation. Herein, we combined the dual inhibition of BMP and WNT signaling and greatly enhanced human pancreatic progenitor differentiation as well as beta cell generation from both embryonic stem cells and induced pluripotent stem cells. Conclusively, our present work identified the crosstalk between the BMP and WNT signal pathways during human endoderm patterning and pancreas specification, and provided an improved in vitro pancreatic directed differentiation protocol from human pluripotent stem cells.
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We hereby report the design and implementation of an Autonomous Microbial Cell Culture and Classification (AMC(3)) system for rapid detection of food pathogens. Traditional food testing methods require multistep procedures and long incubation period, and are thus prone to human error. AMC(3) introduces a "one click approach" to the detection and classification of pathogenic bacteria. Once the cultured materials are prepared, all operations are automatic. AMC(3) is an integrated sensor array platform in a microbial fuel cell system composed of a multi-potentiostat, an automated data collection system (Python program, Yocto Maxi-coupler electromechanical relay module) and a powerful classification program. The classification scheme consists of Probabilistic Neural Network (PNN), Support Vector Machines (SVM) and General Regression Neural Network (GRNN) oracle-based system. Differential Pulse Voltammetry (DPV) is performed on standard samples or unknown samples. Then, using preset feature extractions and quality control, accepted data are analyzed by the intelligent classification system. In a typical use, thirty-two extracted features were analyzed to correctly classify the following pathogens: Escherichia coli ATCC#25922, Escherichia coli ATCC#11775, and Staphylococcus epidermidis ATCC#12228. 85.4% accuracy range was recorded for unknown samples, and within a shorter time period than the industry standard of 24 hours.
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Inteligencia Artificial , Técnicas de Cultivo de Célula/métodos , Escherichia coli/citología , Escherichia coli/aislamiento & purificación , Microbiología de Alimentos , Staphylococcus epidermidis/citología , Staphylococcus epidermidis/aislamiento & purificación , Automatización , Electroquímica , Humanos , Redes Neurales de la Computación , Control de Calidad , Máquina de Vectores de SoporteRESUMEN
The complete mitochondrial sequence of the Japanese threadfin bream, Nemipterus japonicus has been determined. The circle genome is 16,995 bp in size, and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The gene order and composition of N. japonicus was similar to that of most other teleosts. The base composition of H-strand is 28.11% (A), 28.02% (T), 16.64 % (G) and 27.24 % (C), with an AT content of 56.12%. All genes are encoded on the heavy strand with the exception of ND6 and eight tRNA genes. The mitochondrial genome of N. japonicus presented will be in favor of resolving phylogenetic relationships within the family Nemipteridae and the Perciformes.
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Genoma Mitocondrial/genética , Perciformes/genética , Análisis de Secuencia de ADN , Animales , Anotación de Secuencia Molecular , Datos de Secuencia Molecular , FilogeniaRESUMEN
The complete mitochondrial sequence of the spotted scat Scatophagus argus has been determined using long amplification polymerase chain reaction (LA-PCR). The total length of sequence is 16,778 bp, and includes 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 control region. The base composition of H-strand is 27.23% (A), 27.54% (T), 16.22% (G) and 28.81% (C), with an AT content of 55.08%. The arrangement of genes in S. argus is identical to that of other fish species. All genes are encoded on the heavy strand with the exception of ND6 and eight tRNA genes. The mitochondrial genome of S. argus presented here will contribute to resolve phylogenetic relationships within the family Scatophagidae and the Perciformes.
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Peces/genética , Genoma Mitocondrial , Animales , Composición de Base , Orden Génico , Genes Mitocondriales , Sistemas de Lectura AbiertaRESUMEN
OBJECTIVE: The study goal was to determine whether clonidine treatment of neonatal abstinence syndrome (NAS) would result in a better neurobehavioral performance compared with morphine. METHODS: This pilot study prospectively enrolled infants ≥ 35 weeks' gestational age admitted for treatment of NAS. After informed consent was obtained, infants were randomized to receive morphine (0.4 mg/kg per day) or clonidine (5 µg/kg per day) divided into 8 doses. A 25% dose escalation every 24 hours was possible per protocol (maximum of 1 mg/kg per day for morphine and 12 µg/kg per day for clonidine). After control of symptoms, the dose was tapered by 10% every other day. Clinical staff monitored infants by using Finnegan scoring. Masked research staff administered the NICU Network Neurobehavioral Scale (NNNS) at 1 week and at 2 to 4 weeks after initiation of treatment and the Bayley Scales III, and Preschool Language Scale IV, at 1-year adjusted age. Analyses included descriptive statistics, repeated measures analysis of variance, and Wilcoxon tests. RESULTS: Infants treated with morphine (n = 15) versus clonidine (n = 16) did not differ in birth weight or age at treatment. Treatment duration was significantly longer for morphine (median 39 days) than for clonidine (median 28 days; P = .02). NNNS summary scores improved significantly with clonidine but not with morphine. On subsequent assessment, those receiving clonidine had lower height of arousal and excitability (P < .05). One-year motor, cognitive, and language scores did not differ between groups. CONCLUSIONS: Clonidine may be a favorable alternative to morphine as a single-drug therapy for NAS. A multicenter randomized trial is warranted.