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CD47 is a widely expressed cell-surface protein that regulates phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, signal regulatory protein (SIRP)-α, which in turn inhibits phagocytosis. Several targeted CD47 therapeutic antibodies have been investigated clinically; however, how to improve its therapeutic efficacy remains unclear. Herein, we developed a CD47 blocking antibody, named IBI188, that could specifically block the CD47-SIRP-α axis, which transduces the "don't eat me" signal to macrophages. In vitro phagocytosis assays demonstrated the pro-phagocytosis ability of IBI188. Furthermore, several in vivo models were chosen to evaluate the anti-tumor efficacy of IBI188. IBI188 treatment upregulated cell movement- and inflammation-related genes in macrophages. Synergism was observed when combined with an anti-CD20 therapeutic antibody, whose function depends on antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). CD47 expression was evaluated following azacytidine (AZA) treatment, a standard-of-care for patients with multiple myeloma; enhanced anti-tumor efficacy was observed in the combination group in AML xenograft models. Notably, IBI188 treatment increased vascular endothelial growth factor-A (VEGF-A) levels in a solid tumor model, and combined treatment with an anti-VEGF-A antibody and IBI188 resulted in an enhanced anti-tumor effect. These data indicate that IBI188 is a therapeutic anti-CD47 antibody with anti-tumor potency, which can be enhanced when used in combination with standard-of-care drugs for cancer treatment.
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Anticorpos Monoclonais/farmacologia , Antígeno CD47/antagonistas & inibidores , Imunoterapia/métodos , Linfoma de Células B/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Apoptose , Antígeno CD47/imunologia , Proliferação de Células , Feminino , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/imunologia , Neoplasias/patologia , Fagocitose , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Joint stiffness is a common complication after articular-related trauma in the elbow, resulting in significant limb disability, psychological stress, and a negative impact on daily life. No previous study has reported the impact of post-traumatic elbow stiffness (PTES) on psychological health. This study aims to (1) investigate the depression and anxiety levels and (2) identify factors independently associated with depression and anxiety symptoms in patients with PTES. METHODS: A total of 108 patients with PTES presenting to 4 collaborative municipal hospitals were consecutively enrolled from September to December 2020. Sociodemographic and clinical characteristics were collected through questionnaires and medical records. The Depression Anxiety Stress Scale-21 was used to assess depression and anxiety status. Ordinal logistic regression analysis was performed to identify factors independently associated with depression and anxiety symptoms. RESULTS: The detection rates of mild-to-moderate depression and anxiety are 40.7% and 27.8%, and severe-to-extremely severe levels are 23.1% and 25.9%, respectively. Regression results show that factors independently associated with depression include elbow flexion (odds ratio [OR]per 1° loss = 1.021, 95% confidence interval [CI]: 1.001-1.041, P = .035), elbow pain on movement (ORper 1 point increase = 1.236, 95% CI: 1.029-1.484, P = .023), family relationship (ORless close/very close = 10.059, 95% CI: 2.170-46.633, P = .003), and self-care ability (ORunable/able = 3.858, 95% CI: 1.244-11.961, P = .019). Factors independently associated with anxiety are elbow flexion (ORper 1° loss = 1.031, 95% CI: 1.009-1.052, P = .005), elbow pain on movement (ORper 1 point increase = 1.212, 95% CI: 1.003-1.465, P = .047), and clinically significant heterotopic ossification around elbow (ORyes/no = 2.344, 95% CI: 1.048-5.243, P = .038). CONCLUSION: Patients with PTES exhibit significant depression and anxiety symptoms. Several sociodemographic and clinical characteristics are independently associated with depression and anxiety levels. Identifying and addressing these factors may be of particular benefit during PTES management. Future research might address whether depression and anxiety affect the outcome after stiff elbow surgery.
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Depressão , Articulação do Cotovelo , Ansiedade/epidemiologia , Ansiedade/etiologia , Estudos Transversais , Depressão/epidemiologia , Depressão/etiologia , Cotovelo , Articulação do Cotovelo/cirurgia , Humanos , Prevalência , Estudos RetrospectivosRESUMO
CD47, an immune checkpoint receptor frequently unregulated in various blood and solid tumors, interacts with ligand SIPRα on innate immune cells, and conveys a "do not eat me" signal to inhibit macrophage-mediated tumor phagocytosis. This makes CD47 a valuable target for cancer immunotherapy. However, the therapeutic utility of CD47-SIRPα blockade monoclonal antibodies is largely compromised due to significant red blood cell (RBCs) toxicities and fast target-mediated clearance as a result of extensive expression of CD47 on normal cells. To overcome these limitations and further improve therapeutic efficacy, we designed IBI322, a CD47/PD-L1 bispecific antibody which attenuated CD47 activity in monovalent binding and blocked PD-L1 activity in bivalent binding. IBI322 selectively bound to CD47+PD-L1+ tumor cells, effectively inhibited CD47-SIRPα signal and triggered strong tumor cell phagocytosis in vitro, but only with minimal impact on CD47 single positive cells such as human RBCs. In addition, as a dual blocker of innate and adaptive immune checkpoints, IBI322 effectively accumulated in PD-L1-positive tumors and demonstrated synergistic activity in inducing complete tumor regression in vivo. Furthermore, IBI322 showed only marginal RBCs depletion and was well tolerated in non-human primates (NHP) after repeated weekly injections, suggesting a sufficient therapeutic window in future clinical development of IBI322 for cancer treatment.
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Anticorpos Biespecíficos/uso terapêutico , Antígeno B7-H1/uso terapêutico , Antígeno CD47/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Anticorpos Biespecíficos/farmacologia , Antígeno B7-H1/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/patologiaRESUMO
Due to excellent performance properties such as strong activity and high selectivity, single-atom catalysts have been widely used in various catalytic reactions. Exploring the application of single-atom catalysts and elucidating their reaction mechanism has become a hot area of research. This article first introduces the structure and characteristics of single-atom catalysts, and then reviews recent preparation methods, characterization techniques, and applications of single-atom catalysts, including their application potential in electrochemistry and photocatalytic reactions. Finally, application prospects and future development directions of single-atom catalysts are outlined.
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With the great success of anti-CTLA-4 and anti-PD-1 therapeutics in cancer immunotherapy, tumor necrosis factor receptor superfamily members have been recognized as ideal targets to provide co-stimulatory signals in combination with immune checkpoint blocking antibodies. Among these is OX40 (CD134), a co-stimulatory molecule expressed by activated immune cells. Recently, several anti-OX40 agonistic monoclonal antibodies, pogalizumab as the most advanced, have entered early phase clinical trials. Using a yeast platform and multiple screening methods, we identified a fully human anti-OX40 antibody (IBI101) with distinct modes of action. Unlike pogalizumab, IBI101 partially blocks the binding of OX40 to its ligand OX40L and exhibits both FcγR-dependent and independent agonistic activities in NF-κB luciferase reporter assays. IBI101 also promotes T cell activation and proliferation in vitro. These unique properties partially explain the more potent anti-tumor activity of IBI101 than that of pogalizumab in humanized NOG mice bearing LoVo tumors. In addition, IBI101 shows efficacious anti-tumor activity in mice when administrated alone or in combination with anti-PD-1 antibodies. In human OX40 knock-in mice bearing MC38 colon carcinoma, IBI101 treatment induces tumor antigen-specific CD8+ T-cell responses, decreases immunosuppressive regulatory T cells in tumor, and enhances the immune response to PD-1 inhibition. Preclinical studies of IBI101 in non-human primates demonstrate typical pharmacokinetic characteristics of an IgG antibody and no drug-related toxicity. Collectively, IBI101 has desirable preclinical attributes which support its clinical development for cancer treatment.
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Imunoterapia/métodos , Receptores OX40/imunologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
The Fujian Tanka people are officially classified as a southern Han ethnic group, whereas they have customs similar to Daic and Austronesion people. Whether they originated in Han or Daic people, there is no consensus. Three hypotheses have been proposed to explain the origin of this group: (1) the Han Chinese origin, (2) the ancient Daic origin, (3) and the admixture between Daic and Han. This study addressed this issue by analyzing the paternal Y chromosome and maternal mtDNA variation of 62 Fujian Tanka and 25 neighboring Han in Fujian. The southern East Asian predominant haplogroups (e.g., Y-chromosome O1a1a-P203 and O1b1a1a-M95, and mtDNA F2a, M7c1, and F1a1) had relatively high frequencies in Tanka. The interpopulation comparison revealed that the Tanka have a closer affinity with Daic populations than with Han Chinese in paternal lineages but are closely clustered with southern Han populations such as Hakka and Chaoshanese in maternal lineages. Network and haplotype-sharing analyses also support the admixture hypothesis. The Fujian Tanka mainly originate from the ancient indigenous Daic people and have only limited gene flows from Han Chinese populations. Notably, the divergence time inferred by the Tanka-specific haplotypes indicates that the formation of Fujian Tanka was a least 1033.8-1050.6 years before present (the early Northern Song dynasty), indicating that they are an indigenous population, not late Daic migrants from southwestern China.
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Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Genética Populacional/métodos , Povo Asiático/genética , China/etnologia , DNA Mitocondrial/história , Etnicidade/genética , Feminino , Testes Genéticos/métodos , Haplótipos/genética , História Antiga , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: This study assessed outcomes after treatment of patients with capitellum fracture diagnosed >4 weeks after the trauma (delayed) who presented with stiff elbow. METHODS: We reviewed 7 patients with stiff elbows after delayed diagnosis of capitellum fractures between February 2007 and February 2012. They were treated with arthrolysis by twin incisions, late open reduction and internal fixation, and a hinged external fixator. According to the Bryan-Morrey-McKee classification, 3 patients had type I capitellum fractures and 4 patients had type IV. RESULTS: Mean follow-up was 28 months (range, 24-38 months). The mean delay from the initial trauma was 3.7 months. The flexion arc improved from a preoperative mean of 24° to a postoperative mean of 122°. The Mayo Elbow Performance Score increased from a mean of 56 points to 93 points. Anatomic fracture union occurred in all cases, and there was no secondary displacement. CONCLUSIONS: Arthrolysis, late internal fixation, and use of a hinged external fixator can solve problems associated with stiff elbow after delayed diagnosis of capitellum fracture. Combined use of these techniques may be a safe and effective treatment option.
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Anquilose/cirurgia , Fixadores Externos , Fixação Interna de Fraturas , Fraturas Mal-Unidas/cirurgia , Fraturas não Consolidadas/cirurgia , Fraturas do Úmero/cirurgia , Adolescente , Adulto , Anquilose/etiologia , Diagnóstico Tardio , Articulação do Cotovelo/cirurgia , Feminino , Fraturas Mal-Unidas/complicações , Fraturas não Consolidadas/complicações , Humanos , Fraturas do Úmero/complicações , Fraturas do Úmero/diagnóstico , Fraturas Intra-Articulares/complicações , Fraturas Intra-Articulares/diagnóstico , Fraturas Intra-Articulares/cirurgia , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Recuperação de Função Fisiológica , Tempo para o Tratamento , Resultado do Tratamento , Adulto Jovem , Lesões no CotoveloRESUMO
INTRODUCTION: The treatment of terrible triad injury with a poor outcome after intervention has not been successful thus far. The purpose of this study was to evaluate the efficacy of arthrolysis and reconstruction in the treatment of terrible triad injury with a poor outcome after surgical as well as conservative intervention. MATERIALS AND METHODS: Twelve patients (12 elbows) with the diagnosis of terrible triad injury were respectively reviewed. All the 12 patients had elbow dysfunction after conservative and surgical treatment of the terrible triad injury. Preoperatively, the flexion arc and forearm rotation were 36.7° ± 28.5° and 51.3° ± 43.4°, respectively, and the Mayo Elbow Performance Score was 56.3 points. The mean interval between the primary injury and our surgical treatment was 6.6 months. Our surgical intervention included elbow arthrolysis, ulnar nerve transposition, radial head replacement, coronoid process and ligament repair, and hinged external fixation. Patients were encouraged to participate in rehabilitation training 24 h after surgery. RESULTS: The mean follow-up duration was 20.1 months; the flexion arc and forearm rotation were 122° ± 18° and 140° ± 20°, respectively, and the mean Mayo Elbow Performance Score was 94.6 points (9 excellent, 3 good). Concentric stability was restored in all elbows. Complications included superficial pin tract infection (1), heterotopic ossification (3), and ulnar nerve palsy (1); the ulnar nerve symptoms had improved at the last follow-up. CONCLUSIONS: The combination of open arthrolysis and reconstruction performed at a mean interval of 6-month posttrauma can restore functional mobility in cases of terrible triad injury with a poor outcome after surgical as well as conservative intervention. Thus, it may be an effective alternative for the treatment of the poor outcome terrible triad injury. We recommend early functional rehabilitation with adherence to the guidelines for hinged external fixation.
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Artroplastia de Substituição do Cotovelo/métodos , Lesões no Cotovelo , Articulação do Cotovelo/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Adulto , Artroplastia de Substituição do Cotovelo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Amplitude de Movimento Articular , Procedimentos de Cirurgia Plástica/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
An order of addition experiment is an experiment to study how the order of addition of components affect the results, with the objective of predicting and determining the optimal order of addition of components. Order of addition experiment are also commonly used in the drug combination therapy, where experimenting with all drugs combinations is unaffordable. To solve this problem, we constructed a new design table, two-level component factorial design table (TLCF), which combine the component orthogonal array design table and the two-level partial factorial design table by matrix product. TLCF can explore the order and dosage effect of components on the results and can greatly reduce the number of experiments. We also prove that the relative D-efficiency of the TLCF can reach 100% and solve an explicit expression for the D-efficiency of the full design. In the simulation experiment, we compare the D-efficiency of the TLCF with the random design table to prove the superiority of TLCF. Finally, we give a treatment plan for the combination of three drugs for glioblastoma based on the TLCF, which provides a new perspective for the precision treatment of patients.
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Projetos de Pesquisa , Humanos , Glioblastoma/tratamento farmacológico , Simulação por ComputadorRESUMO
Super 304H has been a crucial material for ultra-supercritical boilers. However, the relationship between microstructure evolution, strengthening mechanism, and embrittling behavior during long-term aging was lacking investigation. This investigation aimed to reveal the strengthening and embrittling mechanism from precipitates in Super 304H. The results showed that the hardness increment came from the grain boundary's M23C6 (GB's M23C6) and intragranular nano Cu-rich particles. After being aged for 5000 h, the GB's M23C6 and nano Cu-rich particles provided a hardness increment of approximately 10 HV and 30 HV, respectively. The impact toughness gradually decreased from 213 J/cm2 to 161 J/cm2 with the extending aging time. For the aged Super 304H, the GB's M23C6 provided a higher cracking source. In addition, the nano Cu-rich particle restricted the twin-induced plastic deformation of austenitic grain and depressed the absorbed energy from austenitic grain deformation.
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Ferroptosis is a novel form of programmed cell death, distinguished from apoptosis, autophagy, and programmed necrosis and has received much attention since it was defined in 2012. Ferroptotic cells physiologically exhibit iron metabolism dysregulation, oxidative stress, and lipid peroxidation. Morphologically, they show plasma membrane disruption, cytoplasmic swelling, and mitochondrial condensation. Osteoporosis is taken more and more seriously as the proportion of the aging population continues to increase globally. Interestingly, ferroptosis has been demonstrated to be involved in the development and progression of osteoporosis in many extant studies. The review summarizes iron metabolism, lipid peroxidation, and the different regulatory signals in ferroptosis. Changes in signaling mechanisms within osteoblasts, osteoclasts, and osteocytes after ferroptosis occur are explained here. Studies showed ferroptosis play an important role in different osteoporosis models (diabetes osteoporosis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis). Inhibitors and EC (Exos) targeting ferroptosis could ameliorate bone loss in osteoporotic mice by protecting cells against lipid peroxidation. Shortly, we hope that more effective and appropriate clinical therapy means will be utilized in the treatment of osteoporosis.
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Peripheral nerve injuries (PNI) represent a prevalent and severe category of damage resulting from traumatic incidents. Predominantly, the deficiency in nerve regeneration can be ascribed to enduring inflammatory reactions, hence imposing substantial clinical implications for patients. Fisetin, a flavonoid derived from plants, is naturally present in an array of vegetables and fruits, including strawberries, apples, onions, and cucumbers. It exhibits immunomodulatory properties through the reduction of inflammation and oxidative stress. In the present research, a nerve defect is addressed for the first time utilizing a scaffold primed for controlled fisetin release. In this regard, fisetin-loaded chitosan hydrogels are incorporated into the lumen of polycaprolactone (PCL) nerve guide conduits (NGCs). The hydrogel maintained a steady release of an appropriate fisetin dosage. The study outcomes indicated that the fisetin/chitosan/polycaprolactone (FIS/CS/PCL) NGCs amplified Schwann cell proliferation and neural expression, curtailed oxidative stress, alleviated inflammation, and improved functions, electrophysiological properties, and morphology. This pioneering scaffold has the potential to contribute significantly to the field of neuroengineering.
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Quitosana , Flavonóis , Hidrogéis , Inflamação , Regeneração Nervosa , Estresse Oxidativo , Poliésteres , Flavonóis/farmacologia , Quitosana/química , Quitosana/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Regeneração Nervosa/efeitos dos fármacos , Poliésteres/química , Poliésteres/farmacologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Alicerces Teciduais/química , Ratos , Regeneração Tecidual Guiada/métodos , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/química , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/terapiaRESUMO
BACKGROUND: Limited forearm rotation is a frequent combined disorder in elbow stiffness. If the radial head cannot be saved during open arthrolysis, prosthetic replacement might be considered because it enhances stability and allows early motion. METHODS: In this study we retrospectively analyzed the outcome of 8 patients (7 men, 1 woman) who underwent open arthrolysis and simultaneous prosthetic replacement after resection of the radial head to restore elbow range of motion and forearm rotation. Patients were a mean age of 31.7 years (range, 22-40 years). RESULTS: Postoperatively, the mean (range) active range of motion improved from 29.4° (0°-70°) to 113.1° (80°-135°), mean (range) supination increased from 38.8° (0°-80°) to 77.5° (50°-90°), and mean (range) pronation improved from 18.8° (0°-80°) to 68.8° (50°-80°). The Mayo Elbow Performance Score improved from a mean (range) of 57.5 (50-70) to 92.5 (85-100) points. No elbow valgus instability was detected over a mean duration of 26 months of follow-up. The implant was considered stable in all patients. CONCLUSIONS: Open arthrolysis and prosthetic replacement of the radial head are effective in treating elbow stiffness with associated rotation limitation after resection of the radial head.
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Articulação do Cotovelo/cirurgia , Fraturas Ósseas/cirurgia , Rádio (Anatomia)/cirurgia , Adulto , Artroplastia de Substituição , Feminino , Antebraço , Humanos , Masculino , Rádio (Anatomia)/lesões , Amplitude de Movimento Articular , Recuperação de Função Fisiológica , Estudos Retrospectivos , Rotação , Adulto Jovem , Lesões no CotoveloRESUMO
BACKGROUND: An ankylosed elbow is defined as an elbow having a range of motion of 0°. Movement is extremely limited. This study retrospectively analyzes the results of arthrolysis and hinged external fixation performed on 15 patients suffering from ankylosed elbows. METHODS: Fifteen completely ankylosed elbows were treated by arthrolysis and hinged external fixation. Patients comprised nine men and six women, with a mean age of 37.93 years (37.93 ± 9.68) when arthrolysis was performed. Before surgery, the elbows were ankylosed at various angles ranging from 30° to 85°. Eleven patients underwent arthrolysis by medial and lateral approaches, three patients by the posterior approach, and one patient by posterior and lateral approaches. Hinged external fixators were applied to all patients. Subcutaneous anterior transposition of the ulnar nerve was performed in all patients. RESULT: All patients received satisfactory follow-up. The range of motion of the elbow improved from 0° preoperatively to a postoperative mean of 115.67° (115.67 ± 23.29). The Mayo Elbow Performance Score improved from a mean of 67.67 ± 11.00 to 86.67 ± 8.38 points, with excellent results in nine patients, good in five, and fair in one. This difference is statistically significant (t = -6.862; p < 0.001). CONCLUSION: Open arthrolysis and monolateral hinged external fixation are effective in treating posttraumatic ankylosed elbow. Arthrolysis should be performed by a combination of lateral and medial approaches. In addition, routine hinged external fixation and anterior transposition of the ulnar nerve may improve the postoperative recovery of elbow stiffness.
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Anquilose/cirurgia , Articulação do Cotovelo/cirurgia , Adulto , Fixadores Externos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos , Estudos Retrospectivos , Ferimentos e Lesões/complicações , Lesões no CotoveloRESUMO
In biomedical data mining, the gene dimension is often much larger than the sample size. To solve this problem, we need to use a feature selection algorithm to select feature gene subsets with a strong correlation with phenotype to ensure the accuracy of subsequent analysis. This paper presents a new three-stage hybrid feature gene selection method, that combines a variance filter, extremely randomized tree, and whale optimization algorithm. First, a variance filter is used to reduce the dimension of the feature gene space, and an extremely randomized tree is used to further reduce the feature gene set. Finally, the whale optimization algorithm is used to select the optimal feature gene subset. We evaluate the proposed method with three different classifiers in seven published gene expression profile datasets and compare it with other advanced feature selection algorithms. The results show that the proposed method has significant advantages in a variety of evaluation indicators.
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Algoritmos , Baleias , Animais , Mineração de Dados , Fenótipo , Tamanho da AmostraRESUMO
Background: Gene expression data are often used to classify cancer genes. In such high-dimensional datasets, however, only a few feature genes are closely related to tumors. Therefore, it is important to accurately select a subset of feature genes with high contributions to cancer classification. Methods: In this article, a new three-stage hybrid gene selection method is proposed that combines a variance filter, extremely randomized tree and Harris Hawks (VEH). In the first stage, we evaluated each gene in the dataset through the variance filter and selected the feature genes that meet the variance threshold. In the second stage, we use extremely randomized tree to further eliminate irrelevant genes. Finally, we used the Harris Hawks algorithm to select the gene subset from the previous two stages to obtain the optimal feature gene subset. Results: We evaluated the proposed method using three different classifiers on eight published microarray gene expression datasets. The results showed a 100% classification accuracy for VEH in gastric cancer, acute lymphoblastic leukemia and ovarian cancer, and an average classification accuracy of 95.33% across a variety of other cancers. Compared with other advanced feature selection algorithms, VEH has obvious advantages when measured by many evaluation criteria.
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Obstructive jaundice (OJ) is a common problem in daily clinical practice. However, completely understanding the pathophysiological changes in OJ remains a challenge for planning current and future management. The effects of OJ are widespread, affecting the biliary tree, hepatic cells, liver function, and causing systemic complications. The lack of bile in the intestine, destruction of the intestinal mucosal barrier, and increased absorption of endotoxins can lead to endotoxemia, production of proinflammatory cytokines, and induce systemic inflammatory response syndrome, ultimately leading to multiple organ dysfunction syndrome. Proper management of OJ includes adequate water supply and electrolyte replacement, nutritional support, preventive antibiotics, pain relief, and itching relief. The surgical treatment of OJ depends on the cause, location, and severity of the obstruction. Biliary drainage, surgery, and endoscopic intervention are potential treatment options depending on the patient's condition. In addition to modern medical treatments, Traditional Chinese medicine may offer therapeutic benefits for OJ. A comprehensive search was conducted on PubMed for relevant articles published up to August 1970. This review discusses in detail the pathophysiological changes associated with OJ and presents effective strategies for managing the condition.
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Although spinal cord injury (SCI) represents a primary etiology of disability, currently, there are exist limited viable therapies modalities. Acquiring comprehension of the diverse pathways that drive mitochondrial aberration may facilitate the identification of noteworthy targets for ameliorating the deleterious consequences precipitated by SCI. Our objective was to determine the efficiency of exosomes produced from Schwann cells (SCDEs) in protecting against mitochondrial dysfunction. This evaluation was conducted using a rat model of compressed SCI and in vitro experiments involving rat pheochromocytoma cells (PC12) exposed to oxygen-glucose deprivation (OGD). The conducted experiments yielded evidence that SCDEs effectively mitigated oxidative stress (OS) and inflammation subsequent to SCI, while concurrently diminishing necroptosis. Subsequent in vitro inquiry assessed the impact of SCDEs on PC12, with a specific emphasis on mitochondrial functionality, necrotic cell prevalence, and mitophagy. The study findings revealed that SCDEs enhanced mitophagy in PC12 cells, leading to a decrease in the generation of reactive oxygen species (ROS) and inflammatory cytokines (CK) provoked by OGD-induced injury. This, in turn, mitigated mitochondrial dysfunction and necroptosis. Mechanistically, SCDEs facilitated cellular mitophagy through activation of the AMPK signaling pathway. In conclusion, our data strongly support the notion that SCDEs hold considerable promise as a therapeutic approach for managing SCI. Furthermore, our investigation serves to elucidate the pivotal role of AMPK-mediated mitophagy in reducing cell damage, thereby unveiling novel prospects for enhancing neuro-pathological outcomes following SCI.
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Exossomos , Traumatismos da Medula Espinal , Ratos , Animais , Mitofagia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Exossomos/metabolismo , Necroptose , Transdução de Sinais , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Mitocôndrias/metabolismo , Oxigênio/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patologiaRESUMO
The disruption of the blood spinal cord barrier (BSCB) after spinal cord injury (SCI) can trigger secondary tissue damage. Edaravone is likely to protect the BSCB as a free radical scavenger, whereas it has been rarely reported thus far. In this study, the protective effect of edaravone was investigated with the use of compression spinal cord injured rats and human brain microvascular endothelial cells (HBMECs) injury. As indicated by the result of this study, edaravone treatment facilitated functional recovery after rats were subjected to SCI, ameliorated the vascular damage, and up-regulated the expression of BSCB-associated proteins. In vitro results, edaravone improved HBMECs viability, restored intercellular junctions, and promoted cellular angiogenic activities. It is noteworthy that autophagy was activated and RIP1/RIP3/MLKL phosphorylation was notably up-regulated. However, edaravone treatment exhibited the capability of mitigating above-mentioned tendency in vivo and in vitro. Moreover, rapamycin (Rapa) treatment deteriorated the protective effect of edaravone while aggravating the phosphorylation of RIP1/RIP3/MLKL expression. In the model of necrotic activator-induced HBMECs, autophagic expression was increased, whereas edaravone prevented autophagy and phosphorylation of RIP1/RIP3/MLKL. In general, our results suggested that edaravone is capable of reducing the destruction of BSCB and promoting functional recovery after SCI. The possible underlying mechanism is that edaravone is capable of protecting angiogenic activity and improving autophagy and the phosphorylation of RIP1/RIP3/MLKL, as well as their mutual deterioration. Accordingly, edaravone can be a favorable option for the treatment of SCI.
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Necroptose , Traumatismos da Medula Espinal , Ratos , Humanos , Animais , Edaravone/farmacologia , Ratos Sprague-Dawley , Células Endoteliais/metabolismo , Medula Espinal/metabolismo , Autofagia , Barreira Hematoencefálica/metabolismo , Proteínas Quinases/metabolismoRESUMO
Chlorogenic acid (CGA) has been confirmed as a polyphenol, and existing research has suggested the high bioactivity of CGA for therapeutic effects on a wide variety of diseases. Despite the existing reports of anti-inflammatory, antioxidant, and neuroprotective effects of CGA, the role and mechanism of CGA in facilitating the regeneration of peripheral nerve defects have been rarely investigated. Herein, a biodegradable polycaprolactone (PCL) conduit with embedded CGA-releasing GelMA microspheres (CGM/PCL) was successfully prepared and used for repairing a rate model with sciatic nerve defects. CGM and CGM/PCL conduits displayed high in vitro biocompatibility and can support the growth of cells for nerve regeneration. Furthermore, CGM/PCL conduits displayed high performance which is close to that of autologous nerve grafts in promoting in vivo PNI regeneration, compared with PCL conduits. The sciatic nerve functional index analysis, electrophysiological examination, and immunological analysis performed to evaluate the functional recovery of the injurious sciatic nerve of rats have indeed proved the favorable effects of CGM/PCL conduits. The result of this study not only aimed to explore CGA's contribution to nerve regeneration but also provided a new strategy for designing and preparing functional NGCs for PNI treatment.