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The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice. The present analysis investigated two potential mechanisms by which animals can re-establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage-gated sodium channel, a sub-type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.

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OBJECTIVE: To explore the effects of Qingshen Granules (QSG) on adenine-induced renal fibrosis in mice and in uric acid (UA)-stimulated NRK-49F cells and its mechanism for regulating exosomes, miR-330-3p and CREBBP. METHODS: A mouse model of adenine-induced renal fibrosis were treated daily with QSG at 8.0 g·kg-1·d-1 via gavage for 12 weeks. An adenoassociated virus vector was injected into the tail vein, and renal tissues of the mice were collected for analyzing exosomal marker proteins CD9, Hsp70, and TSG101 and expressions of Col-III, α-SMA, FN, and E-cad using Western blotting and immunofluorescence and for observing pathological changes using HE and Masson staining. In the cell experiment, NRK-49F cells were stimulated with uric acid (400 µmol/L) followed by treatment with QSG-medicated serum from SD rats, and the changes in expressions of the exosomal markers and Col-III, α-SMA, FN, and E-cad were analyzed. Dual luciferase reporter assay was employed to examine the targeting relationship between miR-330-3p and CREBBP, whose expressions were detected by RT-qPCR and Western blotting in treated NRK-49F cells. RESULTS: The mouse models of adenine-induced renal fibrosis showed significantly increased levels of CD9, Hsp70, and TSG101, which were decreased by treatment with QSG. The expressions of Col-III, α-SMA, and FN increased and Ecad decreased in the mouse models but these changes were reversed by QSG treatment. QSG treatment obviously alleviated renal fibrosis in the mouse models. Intravenous injection of adeno-associated viral vector obviously inhibited miR-330-3p, increased CREBBP levels, and reduced fibrosis in the mouse models. Dual luciferase assay confirmed CREBBP as a target of miR-330-3p, which was consistent with the results of the cell experiments. CONCLUSION: QSG inhibits renal fibrosis in mice by regulating the exosomes, reducing miR-330-3p levels, and increasing CREBBP expression.

Asunto(s)

Exosomas , Fibrosis , Riñón , MicroARNs , Animales , Exosomas/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Riñón/patología , Riñón/metabolismo , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/inducido químicamente , Medicamentos Herbarios Chinos/farmacología , Adenina , Ratas , Masculino , Ácido Úrico , Línea Celular

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OBJECTIVE: To elucidate the therapeutic mechanism of Qingxin Jieyu Granule (QXJYG) against atherosclerosis (AS) based on network pharmacology. METHODS: The major targets and pathways of QXJYG against AS were analyzed using network pharmacology. Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline, atorvastatin (13.15 mg/kg), or QXJYG at 0.99, 1.98, and 3.96 g/kg for 8 weeks (n=6). Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta. Blood lipids and serum levels of Ang Ⅱ, ET-1, TXA2, PGI2, and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA. The expressions of LOX-1, PPARγ, RXRα, p-P65, VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry. RESULTS: The rat models of AS showed obvious abdominal aorta wall thickening, increased pulse wave velocity and pulse index, decreased inner diameter of the abdominal aorta, elevated levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and lowered levels of HDL-C and PGI2. QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta, decreased serum levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and increased the levels of HDL-C and PGI2. Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism, PPAR and NF-κB pathways. Consistently, treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1, P-P65, VCAM-1 and ICAM-1 protein expressions while increasing PPARγ and RXRα expressions in the aorta of AS rats. CONCLUSION: QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level, reducing LOX-1 expression, activating PPARγ and RXRα, and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.

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Aterosclerosis , Medicamentos Herbarios Chinos , Metabolismo de los Lípidos , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratas , Metabolismo de los Lípidos/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aorta Abdominal/metabolismo , Aorta Abdominal/efectos de los fármacos , Farmacología en Red , Lipoproteínas LDL/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , PPAR gamma/metabolismo , Masculino , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Molécula 1 de Adhesión Celular Vascular/metabolismo , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Lípidos/sangre , Tromboxano A2/metabolismo , Epoprostenol/análogos & derivados , Receptores Depuradores de Clase E

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OBJECTIVE: To explore the mechanism underlying the protective effect of Lonicerae japonicae flos (LJF) extract against doxorubicin (DOX) -induced liver injury in mice. METHODS: Network pharmacology methods were used to obtain the intersection genes between LJF targets and disease targets, based on which the protein-protein interaction (PPI) network was constructed using STRING database for screening the core targets using Cytoscape software. DAVID database was used for bioinformatics analysis, and the core components and core targets were verified using molecular docking study. In a mouse model of DOX-induced liver injury, the effect of LJF extract on liver pathologies, serum levels of ALT and AST, and hepatic expressions of HYP, ROS, TNF-α, IL-6, COL-Ⅳ and P53 proteins were evaluated using HE and Masson staining, ELISA, and Western blotting. RESULTS: We identified 12 core targets from 43 intersection genes involving cancer pathway, IL-17 signaling pathway, and TNF signaling pathways. Molecular docking study suggested that 10 core components of LJF could bind to different core targets. The mice with DOX-induced liver injury showed elevated serum AST and ALT levels with obvious liver injury and fibrosis, increased ROS content, and enhanced expressions of TNF-α, IL-6, HYP, COL-Ⅳ and P53 proteins in the liver tissue. All these changes in the mouse models were significantly alleviated by treatment with LJF extract, suggesting obviously lowered levels of oxidative stress, inflammation and fibrosis in the liver tissues. CONCLUSION: LJF extract is capable of alleviating DOX-induced liver injury in mice by downregulating Trp53, TNF and IL-6 to reduce liver oxidative stress, inflammation and fibrosis.

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Enfermedad Hepática Inducida por Sustancias y Drogas , Doxorrubicina , Interleucina-6 , Lonicera , Simulación del Acoplamiento Molecular , Factor de Necrosis Tumoral alfa , Animales , Doxorrubicina/efectos adversos , Ratones , Lonicera/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Extractos Vegetales/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteína p53 Supresora de Tumor/metabolismo , Sustancias Protectoras/farmacología , Mapas de Interacción de Proteínas , Transducción de Señal/efectos de los fármacos , Farmacología en Red

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Objective: To investigate the safety and efficacy of a varicose vein sealant kit in the treatment of great saphenous vein dysfunction. Methods: It was a randomized controlled trial. A total of 180 patients with great saphenous vein dysfunction were enrolled prospectively, and scheduled for surgical treatment in 9 hospitals, including the Second Affiliated Hospital of Naval Medical University, Shanghai Oriental Hospital Affiliated to Tongji University, Xuanwu Hospital Capital Medical University, the First Hospital of Hebei Medical University, Ganzhou People's Hospital, Shanxi Bethune Hospital, the Second Affiliated Hospital of Zhejiang University School of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and Zhongshan Hospital Affiliated to Xiamen University, from June to October 2022. Using a random number table method, the subjects were divided into an experimental group and a control group, with 90 cases in each group. The patients of experimental group received treatment with varicose vein sealant kit, while the patients of control group received radiofrequency ablation. The main outcome measure was the complete closure rate of the great saphenous vein in both groups of patients 3 months after surgery. The secondary outcome measures were the complete closure rate of the great saphenous vein in both groups of patients immediately after surgery and 6 months after surgery, the operation time for closing the main trunk of the great saphenous vein, pain score, venous clinical severity score (VCSS), Aberdeen varicose veins questionnaire (AVVQ) at different times before and after surgery, and the incidence of complications in both groups of patients. The non inferiority threshold for the two treatment methods is set at "-10.00%". Results: A total of 177 patients were ultimately enrolled. There were 89 cases in the experimental group, including 38 males and 51 females, with a median age [M (Q1, Q3)] of 59.7(49.6, 66.7) years, and 88 cases in the control group, including 30 males and 58 females, with a median age of 57.2(46.9, 65.9) years. A total of 174 patients completed a 3-month follow-up, and 167 patients completed a 6-month follow-up. The closure time of the main saphenous vein in the experimental group was (22.1±11.1) min, which was longer than the control group, which was (18.7±9.8) min (P=0.031). The complete closure rate of the great saphenous vein immediately after surgery in both the experimental group and the control group was 100%. The complete closure rates of the great saphenous vein at 3 months after surgery were 98.8% (85/86) and 98.9% (87/88), respectively. The lower limit of the 95%CI for the difference between the two groups was -3.19%, which was greater than the non-inferiority threshold of -10.00% (non-inferiority P<0.001). The complete closure rates of the great saphenous vein at 6 months after surgery were 97.6% (81/83) and 100% (84/84), the lower limit of the 95%CI for the difference between the two groups was -5.71%, which was greater than the non-inferiority threshold of -10.00% (non-inferiority P<0.001). The immediate pain scores after complete anesthesia awakening of the experimental group and the control group were both 1.0 (0, 2.0), with no statistically significant difference (P=0.365). The incidence of bruising in the experimental group and the control group one week after surgery was 61.2% (52/85) and 67.1% (57/85), respectively, with no statistically significant difference (P=0.181). There was no statistically significant difference in VCSS and AVVQ scores between groups before surgery and at 1, 3, and 6 months after surgery (all P>0.05). There was no statistically significant difference in the incidence of complications such as deep vein thrombosis, phlebitis, pain, and subcutaneous hematoma in the lower limbs 3 months after surgery (all P>0.05). Conclusion: The varicose vein sealant kit is safe and effective in treating great saphenous vein dysfunction, and can achieve a complete closure rate of great saphenous vein that is not inferior to traditional radiofrequency ablation.

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Vena Safena , Várices , Insuficiencia Venosa , Humanos , Vena Safena/cirugía , Várices/cirugía , Insuficiencia Venosa/cirugía , Resultado del Tratamiento , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Ablación por Catéter/métodos

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To analyze the clinical characteristics of appendiceal orifice polyps and the effect of endoscopic super minimally invasive treatment. A retrospective analysis was conducted on the general situation (age and sex), the classification of appendiceal orifice polyps, the treatment method under endoscope, postoperative pathology and postoperative complications in patients who underwent resection of appendiceal orifice polyps at the Peking University First Hospital and the First Medical Center of the PLA General Hospital from January 1, 2022, to December 31, 2023. A total of 47 patients were included, consisting of 28 males and 19 females, with 35-86 (61±12) years. Appendiceal orifice polyps were classified into four types: type 0 (14 cases), type 1 (15 cases), type 2 (12 cases), and type 3 (6 cases). Among the endoscopic morphologies, 22 cases were granular laterally spreading tumors. Endoscopic mucosal dissection was performed in 37 cases. Postoperative appendiceal stent placement was performed in 1 case. The pathological types of polyps included adenoma in 15 cases, high-grade intraepithelial neoplasia in 10 cases, intramucosal carcinoma in 4 cases, submucosal carcinoma in 5 cases, inflammatory polyps in 1 cases, and sessile serrated lesion in 12 cases. Curative resection was performed in 44 cases. There were no postoperative complications such as bleeding, perforation, or acute appendicitis. The pathology of appendiceal polyps is mostly precancerous lesions, and the treatment scheme of endoscopic super minimally invasive resection is both safe and effective.

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Apéndice , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , Apéndice/cirugía , Anciano de 80 o más Años , Procedimientos Quirúrgicos Mínimamente Invasivos , Pólipos/cirugía , Resección Endoscópica de la Mucosa/métodos , Neoplasias del Apéndice/cirugía , Neoplasias del Apéndice/patología , Complicaciones Posoperatorias , Adenoma/cirugía , Adenoma/patología , Endoscopía/métodos

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Nitrogen (N) utilisation efficiency (NUE, milk N yield [g/d]/N intake [g/d]) is an important performance indicator in dairy farming. Determining the NUE-associated blood metabolite profile will contribute to the optimisation of nutritional strategies to further improve NUE among dairy cows. Here, 20 primiparous lactating cows with days in milk ranging from 95 to 115 days were selected from a total of 1 221 cows. Each cow's N intake and milk N yield were measured for 7 days. Subsequently, blood samples were collected before morning feeding. Based on analysis and calculations, cows were retrospectively classified into two groups based on their NUE values, namely, a low NUE group (LNUE, NUE = 24.8 ± 1.6%, n = 10, mean ± SD) and a high NUE group (HNUE, NUE = 35.2 ± 1.7%, n = 10, mean ± SD). Plasma samples were selected from six cows in each group for metabolomics and amino acid profiling. Among the 41 differential metabolites (DMs) identified in the metabolomic analysis, sucrose, MG(0:0/22:1(13Z)/0:0), 2-amino-6-hydroxyhexanoic acid, and L-glutamine exhibited significant correlations with NUE, milk yield, and BW (P < 0.05). Moreover, the five differential amino acids and amino acid metabolites (DAAs) identified in the amino acid profiling and 5 of the 6 differential amino acids and amino acid conjugates identified by plasma metabolomics were found to be less abundant in the HNUE group (P < 0.05). Specifically, there was a 39.4% decrease in L-arginine content and a 29.2% decrease in L-glutamine content (P < 0.05). Pathway analysis indicated that the DMs and DAAs were mainly involved in arginine biosynthesis, glutathione metabolism, arginine and proline metabolism, and tryptophan metabolism (pathway impact > 0.1). These results provided new insights into the new blood metabolite profile associated with NUE in dairy cows. These new insights can provide foundational information for the formulation of new strategies to further enhance NUE in dairy cows.

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INTRODUCTION: The progression of ferroptosis has been found to be associated with the onset and progression of many diseases. Disruption of iron homeostasis can lead to ferroptosis. We had previously hypothesized that vitamin D may affect serum calcium levels, which in turn regulates ferroptosis by regulating serum iron levels. However, the relationship between serum calcium level and serum iron level is unclear. The purpose of our study was to explore the relationship between serum calcium level and serum iron level among general population in Taizhou, China. METHODS: In this study, a cross-sectional study was conducted. Serum calcium levels and serum iron levels were determined in our work. Pearson's correlation analysis was used to determine the association between serum calcium level and serum iron level. RESULTS: The results showed that serum iron level was negatively correlated with serum calcium level and age. After controlling for age, sex and marital status, serum iron level was still negatively correlated with serum calcium level. CONCLUSIONS: The results suggest that improving serum calcium levels may be a potential strategy for regulating iron metabolism homeostasis. Whether calcium supplementation can reduce serum iron levels in people with low serum calcium levels needs further investigation.

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Calcio , Hierro , Humanos , Calcio/sangre , Hierro/sangre , Estudios Transversales , Femenino , Masculino , Persona de Mediana Edad , Adulto , China , Anciano

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A precise dynamical characterization of quantum impurity models with multiple interacting orbitals is challenging. In quantum Monte Carlo methods, this is embodied by sign problems. A dynamical sign problem makes it exponentially difficult to simulate long times. A multi-orbital sign problem generally results in a prohibitive computational cost for systems with multiple impurity degrees of freedom even in static equilibrium calculations. Here, we present a numerically exact inchworm method that simultaneously alleviates both sign problems, enabling simulation of multi-orbital systems directly in the equilibrium or nonequilibrium steady-state. The method combines ideas from the recently developed steady-state inchworm Monte Carlo framework [Erpenbeck et al., Phys. Rev. Lett. 130, 186301 (2023)] with other ideas from the equilibrium multi-orbital inchworm algorithm [Eidelstein et al., Phys. Rev. Lett. 124, 206405 (2020)]. We verify our method by comparison with analytical limits and numerical results from previous methods.

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There is a strong association between vitamin D levels and periodontal disease based on numerous epidemiological studies. We have previously shown that experimental deficiency of serum vitamin D in mice leads to gingival inflammation and alveolar bone loss. Treatment of cultured oral epithelial cells with the active form of vitamin D, 1,25(OH)2 vitamin D3 (1,25(OH)2D3), inhibits the extracellular growth and intracellular invasion of bacteria associated with periodontal disease. Maintenance of periodontal health may be due in part to the anti-inflammatory activities of vitamin D. Furthermore, this hormone can induce the expression of an antimicrobial peptide in cultured oral epithelial cells. We have shown that oral epithelial cells are capable of converting inactive vitamin D to the active form, suggesting that topical treatment of the oral epithelium with inactive vitamin D could prevent the development of periodontitis. We subjected mice to ligature-induced periodontitis (LIP), followed by daily treatment with inactive vitamin D or 1,25(OH)2D3. Treatment with both forms led to a reduction in ligature-induced bone loss and inflammation. Gingival tissues obtained from vitamin D-treated LIP showed production of specialized proresolving mediators (SPM) of inflammation. To examine the mechanism, we demonstrated that apical treatment of 3-dimensional cultures of primary gingival epithelial cells with vitamin D prevented lipopolysaccharide-induced secretion of proinflammatory cytokines and led to a similar production of SPM. Analysis of the oral microbiome of the mice treated with vitamin D showed significant changes in resident bacteria, which reflects a shift toward health-associated species. Together, our results show that topical treatment of oral tissues with inactive vitamin D can lead to the maintenance of periodontal health through the regulation of a healthy microbiome and the stimulation of resolution of inflammation. This strongly supports the development of a safe and effective vitamin D-based topical treatment or preventive agent for periodontal inflammation and disease.

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Administración Tópica , Pérdida de Hueso Alveolar , Modelos Animales de Enfermedad , Periodontitis , Vitamina D , Animales , Ratones , Pérdida de Hueso Alveolar/prevención & control , Vitamina D/farmacología , Vitamina D/administración & dosificación , Vitamina D/uso terapéutico , Periodontitis/prevención & control , Encía/efectos de los fármacos , Calcitriol/farmacología , Calcitriol/administración & dosificación , Calcitriol/uso terapéutico , Ratones Endogámicos C57BL , Gingivitis/prevención & control

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OBJECTIVE: A metabolism score for visceral fat (METS-VF) is an innovative method to access abdominal fat and visceral fat. So far, the relationship between the METS-VF index and chronic obstructive pulmonary disease (COPD) has remained unclear. We investigated the relationship between the METS-VF index and COPD prevalence utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. PATIENTS AND METHODS: A binary logistic regression analysis was performed using NHANES 2007-2018 data to assess the relationship between the METS-VF index and COPD prevalence. The relationship was verified by fitted smooth curves, generalized additive models, threshold effect analyses, subgroup analyses, and sensitivity analyses. RESULTS: In total, 7,680 subjects were recruited for the study, including 772 self-reported having COPD. The METS-VF index was positively related to COPD prevalence when adjusted for all covariates. The METS-VF index was classified by quartiles, and participants who scored highest on METS-VF were at a greater risk of COPD than those who scored lowest. According to a threshold effect analysis, the METS-VF index was negatively correlated with COPD prevalence with a METS-VF index <7.00, without statistical significance. Once the METS-VF index exceeded 7.00, there was a robust positive correlation between the METS-VF index and COPD prevalence. In the analysis of subgroups, the METS-VF index was positively correlated with COPD prevalence among subjects who were male, aged 40-59, and without asthma or hypertension. The results were robust in sensitivity analyses. METS-VF showed a significantly better diagnostic value for COPD than Body Mass Index (BMI). CONCLUSIONS: The METS-VF index has a non-linear and positive correlation with COPD prevalence in the middle-aged and elderly American population.

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Grasa Intraabdominal , Encuestas Nutricionales , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Persona de Mediana Edad , Masculino , Grasa Intraabdominal/metabolismo , Femenino , Anciano , Estados Unidos/epidemiología , Prevalencia , Síndrome Metabólico/epidemiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/diagnóstico

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BACKGROUND: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-ß (TGF-ß) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591). PATIENTS AND METHODS: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed. RESULTS: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease. CONCLUSIONS: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

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Neoplasias Encefálicas , Proteínas de Unión al ARN , Humanos , Masculino , Femenino , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Preescolar , Estudios Retrospectivos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Nestina/metabolismo , Nestina/genética , Lóbulo Parietal/patología , Lóbulo Parietal/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/metabolismo , Neoplasias del Tronco Encefálico/cirugía , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteína SMARCB1/metabolismo , Proteína SMARCB1/genética , Lóbulo Frontal/patología , Lóbulo Frontal/metabolismo , Formación de Roseta , Estudios de Seguimiento , Antígeno Ki-67/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética

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OBJECTIVES: Access to health services has received increasing attention, and the International Agency for Research on Cancer (IARC) includes 'availability' as one of the indicators to evaluate cancer screening. Evaluating, monitoring, and decision-making on cancer screening depends on systematic quantitative evidence on access to cancer screening, but indicators are currently inconsistently, if they are reported at all. This can be improved by developing systematic indicators for evaluating and reporting access to cancer screening. This requires a thorough understanding of current indicators of access to cancer screening. STUDY DESIGN: Scoping review. METHODS: We completed a scoping review of studies on access to cancer screening services from 2013 to 2022. The relevant indicators were extracted, quantified, and then matched to two widely used frameworks: a universal five-dimensional conceptual framework for access to healthcare ('U5D') and a cancer-specific framework/list on the availability/use of screening indicators endorsed by the IARC. RESULTS: A total of 331 studies on access to cancer screening services were included. Based on the U5D framework, publications from supply side reported approachability (number of publications = 16), acceptability (6), availability and accommodation (44), affordability (30), and appropriateness (11); among this process, 17 sub-indicators were identified. Correspondingly, publications from demand side reported ability to perceive (170), ability to seek (85), ability to reach (58), ability to pay (59), and ability to engage (2); 26 sub-indicators were identified. More macroscopically, the publications of the IARC-endorsed indicators reported availability of policies and guidelines for screening (13), type of screening provided (3), extent of population coverage and participation rates (76), and demographic/behavioural related considerations (167). By integrating the universal and cancer-specific frameworks, a new adapted framework was proposed. CONCLUSIONS: This study identified and collated indicators for evaluating access to cancer screening services, and determined the gaps in the current application of various indicators. The findings are anticipated to facilitate further development of an evaluation indicator system for access to cancer screening services.

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Detección Precoz del Cáncer , Accesibilidad a los Servicios de Salud , Humanos , Detección Precoz del Cáncer/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Neoplasias/diagnóstico

RESUMEN

Objective: To summarize the HRCT and MRI appearances of stapical footplate fistula related to inner ear malformation (SFF-Re-IEM). Methods: The HRCT and MRI materials of 48 cases (53 ears) SFF-Re-IEM were retrospectively analyzed. Among them, 25 SFF-Re-IEM ears were confirmed by surgery. Their CT and MRI findings including associated IEM type, internal auditory canal (IAC) malformation, tympanic fluid, its density and signal features, and accompanied labyrinthitis were recorded. Results: Among 48 cases (53 ears) with SFF-Re-IEM, 17 ears with incomplete partition type Ⅰ, accounting for 32.1%, 13 ears with common cavity for 24.5%, 13 ears with cochlear aplasia for 24.5%, 7 ears with cochlear dysplasia Ⅱ for 13.2%, and 3 ears with Mondini for 5.7%,were found respectively. 94.3% of them were associated with a defect or dysplasia in the found of the IAC. They were divided into 4 types according to the intact of the stapical footplate and accompanied CSF otorrhea: 22 ears were diagnosed as the stapical footplate leaking, of them, 2 ears might come from the stapical footplate bony defect, 6 ears were from the stapical footplate hernia. 1 ear belonged to the peristapical footplate leaking. 30 ears with the isolated the stapical footplate hernia were another found. The bony defect in 2 ears with the stapical footplate bony defect were not presented on CT and MRI.The focal bony defect of the affected stapical footplate of 36 ears with the stapical footplate hernia were demonstrated, which presented the hemispherical protruding into the tympana, the soft-tissue density on CT, and CSF-like signal on the MR heaved-T2WI images. Among 22 ears with the stapical footplate leaking, their imaging appearances varied from the different amount of the leaking CSF. Besides the focal bony defects of the affected stapical footplates, there were much more CSF-like density or signal in the ipsilateral tympanic cavity in 17 affected ears connecting with the vestibule through the defect area. In the CSF leaking ears with less CSF leaking in 5 ears, the CSF-like cysts like SFH were shown on the stapical footplate defect area, but their outer edges were irregular, and the CSF-like signal scattering in the tympanic cavity did not connect with the protruding cysts at the stapical area. Conclusion: The variable appearances of the SFF-Re-IEM ears based on the different subtypes are its characteristic HRCT and MRI appearances. This is helpful for the SFF-Re-IEM diagnosing to grasp its imaging features.

Asunto(s)

Oído Interno , Fístula , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Estudios Retrospectivos , Oído Interno/diagnóstico por imagen , Oído Interno/anomalías , Niño , Adolescente , Adulto , Fístula/diagnóstico por imagen , Fístula/etiología , Preescolar , Lactante , Adulto Joven , Persona de Mediana Edad , Estribo/anomalías , Estribo/diagnóstico por imagen , Cóclea/diagnóstico por imagen , Cóclea/anomalías

RESUMEN

Objective: To demonstrate the type of CEBPA gene mutations among patients with acute myeloid leukemia (AML), clinical characteristics, and prognostic effect on patient outcomes. Methods: Demographic data, clinical features, laboratory characteristics, and data about treatment and follow-up of 57 patients with CEBPA mutated AML diagnosed at Peking Union Medical College Hospital between April 2016 and November 2022 were collected and analyzed. Results: In total, 57 patients with CEBPA mutation accounted for 16.1% of all the 353 patients with AML, among which 28 patients had CEBPA-bZIPinf and 29 had CEBPA-other. Compared with the CEBPA-other group, the CEBPA-bZIPinf group was younger (54 vs 64 years, P=0.010), de novo AML was more common (P=0.001), and the level of bone marrow blast was higher (68.0% vs 36.3%, P=0.001). Moreover, 24 patients from the CEBPA-bZIPinf group and 19 from the CEBPA-other group received chemotherapy. The one-course complete remission (CR) rate of the CEBPA-bZIPinf group was significantly higher than that of the CEBPA-other (87.5% vs 47.4%, P=0.010) and CEBPA-wt (87.5% vs 50.3%, P=0.002) groups. After a median follow-up of 11 months, the median OS of the CEBPA-bZIPinf group was significantly longer than that of the CEBPA-wt group (not reached vs 22.1 months, P=0.012) . Conclusion: CEBPA-bZIPinf mutated AML is a unique clinical entity, with a younger age of diagnosis, better response to chemotherapy, and better prognosis.

Asunto(s)

Proteínas Potenciadoras de Unión a CCAAT , Leucemia Mieloide Aguda , Mutación , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Proteínas Potenciadoras de Unión a CCAAT/genética , Pronóstico , Persona de Mediana Edad , Masculino , Femenino

RESUMEN

Early weaning-induced stress precipitates diarrhoea, significantly curtailing the growth performance of piglets. A pivotal contributor to this postweaning affliction is the emergence of gut bacterial dysbiosis. Enterococcus hirae, a promising probiotic, has indicated unclear effects and mechanisms on intestinal health. In this study, we investigated the effects and underlying mechanisms of oral supplementation with Ningxiang pig-derived Enterococcus hirae HNAU0516 orally supplementation on the gut bacterial community, immune response and gut barrier function in piglets. 21 d age Duroc × (Landrace × Yorkshire) piglets with a similar BW were randomly allocated to two groups. The Enterococcus hirae HNAU0516 administration group was inoculated orally with Ningxiang pig-derived Enterococcus hirae HNAU0516 throughout the trial period. Conversely, the control group received the same volume of physiological saline. Our findings revealed that Enterococcus hirae HNAU0516 supplementation effectively reduced diarrhoea rates of piglets (P = 0.010). Notably, this probiotic promoted intestinal development and enhanced intestinal barrier function. It also showed potential anti-inflammatory properties. Furthermore, Enterococcus hirae HNAU0516 supplementation significantly remodelled the colonic microbiota and increased the production of acetate (P = 0.007). In conclusion, our study highlights that Ningxiang pig-derived Enterococcus hirae HNAU0516 improves postweaning diarrhoea by promoting intestinal development, enhancing intestinal barrier function, decreasing intestinal permeability, modulating intestinal microbiota, and increasing short-chain fatty acids production.

RESUMEN

Objective: To analyze the incidence of cytokine release syndrome (CRS) and its impact on the prognosis of patients with relapsed and refractory multiple myeloma (RRMM) following treatment with chimeric antigen receptor T-cell (CAR-T) therapy. Methods: A retrospective collection was conducted of the clinical data of 91 patients with RRMM who underwent CAR-T therapy at the Affiliated Hospital of Xuzhou Medical University from January 2020 to October 2022. Before CAR-T cell infusion, the patient underwent pretreatment with the fludarabine plus cyclophosphamide (FC) regimen. On day 0 (d0), the patient received a dose of 1×106 cells/kg of CAR-T. The occurrence of CRS was recorded post-treatment and graded accordingly, with grades 1 to 2 indicating mild CRS and grade≥3 indicating severe CRS. The follow-up cut-off date was February 14, 2023, with a median follow-up time [M (Q1, Q3)] of 14.1 (3.1, 37.7) months. Kaplan-Meier survival curve analysis assessed the progression-free survival (PFS) and overall survival (OS) of Grade 1 and Grade 2 CRS patients. Furthermore, univariate logistic regression analysis was conducted to identify factors associated with the development of severe CRS. Results: In a cohort of 91 patients diagnosed with RRMM, there were 51 male and 40 female individuals, with a median age [M (Q1,Q3)] of 57 (31, 73) years. All 91 cases (100%) experienced CRS, with 82 cases (90%) classified as mild (grades 1-2) CRS and 9 cases (10%) classified as severe (grades 3-5) CRS. In a study involving 9 patients with severe CRS, 8 cases resulted in mortality. The Kaplan-Meier survival curve analysis revealed that among grade 1 CRS patients, neither the median PFS nor the median OS was achieved. For grade 2 CRS patients, the median PFS was 12 months (95%CI: 4-not achieved), and the median OS was 21 months (95%CI: 4-not achieved). The progression-free survival and overall survival rates of grade 2 CRS patients were both lower than those of grade 1 CRS patients (both P<0.05). Single-factor logistic regression analysis revealed that a high tumor burden (OR=1.025, 95%CI: 1.002-1.049, P=0.031), a prolonged duration of CRS onset (OR=0.809, 95%CI: 0.646-0.971, P=0.037) and persistence (OR=1.758, 95%CI: 1.349-2.481, P=0.001) were identified as significant factors associated with severe CRS in patients with RRMM. Conclusions: Patients with RRMM who undergoes CAR-T therapy have a high incidence of CRS, with a higher mortality rate among those experiencing severe CRS. Furthermore, patients with grade 2 CRS exhibit lower rates of progression-free survival and overall survival compared to those with grade 1 CRS. Factors associated with the development of severe CRS in RRMM patients include high tumor burden and prolonged duration and onset of CRS.

Asunto(s)

Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Pronóstico , Síndrome de Liberación de Citoquinas/etiología , Estudios Retrospectivos , Femenino , Masculino , Receptores Quiméricos de Antígenos , Persona de Mediana Edad , Anciano , Adulto

Asunto(s)

Monitoreo del Ambiente , Polen , Rinitis Alérgica Estacional , China , Monitoreo del Ambiente/métodos , Rinitis Alérgica Estacional/diagnóstico , Alérgenos , Humanos

RESUMEN

Objective: To construct a prediction model for the clinical supply of blood components in Xi'an City from 2023 to 2025. Methods: Based on the blood supply data of the Blood Management Information System of Shaanxi Provincial Blood Center from January 2013 to December 2022, a gray prediction model and an exponential curve fitting model were used to construct the prediction model, and the optimal prediction model was determined according to the error parameters of the relevant indicators of the model. The supply of blood components in Xi'an from 2023 to 2025 was predicted. Results: The fitting equations of the exponential curve fitting model to predict the supply of suspended red blood cells, platelets and cryoprecipitate in Xi'an were, x（1）（t+1）=1.16e0.04t，x（1）（t+1）=1.04e0.12t and x（1）（t+1）=1.01e1.10t, respectively. The mean absolute errors (mean relative errors) of the exponential curve fitting model in predicting the supply of suspended red blood cells, platelets and cryoprecipitate in Xi'an were 10 488.7 (0.05%), 2 114.9 (0.08%) and 3 089.6 (0.07%), respectively, which were lower than those of the gray prediction model, about 10 488.7 (3.44%), 2 152.78 (8.20%) and 3 441.35 (7.92%), respectively. The exponential curve fitting model predicted that the clinical supply of blood components in Xi'an would increase year by year from 2023 to 2025, and the clinical supply of suspended red blood cells, platelets, and cryoprecipitate in Xi'an would increase to 409 467 U, 69 818 therapeutic volume and 94 724 U, respectively by 2025. Conclusion: The exponential curve fitting model can make a good prediction of the clinical supply of blood components in Xi'an City.

Asunto(s)

Bancos de Sangre , Humanos , China , Transfusión de Componentes Sanguíneos , Plaquetas , Eritrocitos , Modelos Teóricos , Predicción