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摘要： Highlights•We experienced Surfer's myelopathy (SM) occurred during exercise unrelated to surfing. •Spine MRI showed T2 hyperintensity with “pencil-like” long-axis lesion, typical for SM. •Significant elevation of IL-6 levels were seen in the CSF. •The nerve conduction tests indicated motor dominant neuropathy in the lower limbs. •The flaccid paralysis and sensory loss only slightly improved after steroid pulse therapies.

关键词： Acne vulgaris   Interleukin-19   Global acne grading system (GAGS)   Case-control  

摘要： Acne vulgaris (AV) has a multifactorial pathogenesis, with inflammation being a key factor. The pro-inflammatory role of interleukin (IL)-19 has been explored in several systemic and some dermatological conditions. This study aimed to analyse serum levels of IL-19 in cases as well as healthy controls and to assess its correlation with the disease severity. A cross sectional, observational, analytical study was performed over a time period of 18 months at a tertiary care hospital. The study included 37 clinically diagnosed cases of acne aged between 16 to 30 years and 37 age and sex matched controls. Severity of the lesions was calculated using the Global Acne Grading System (GAGS). IL-19 levels of all the participants were measured with the help of quantitative Enzyme Linked Immunosorbent Assay (ELISA). The Spearman's rank correlation coefficient was used to evaluate the relationship between serum levels of IL-19 and the severity of AV, and a p-value of less than 0.05 was considered statistically significant. In this study, serum IL-19 levels showed a positive correlation with both the patients' age and the duration of their symptoms, with p values of 0.04 for each. The median serum IL-19 levels were observed to be higher in the cases (80.89 ng//L) as compared to controls (44.82 ng/L), although this difference was not statistically significant (p = 0.095). Additionally, no significant correlation was found between IL-19 levels and the severity of acne (p = 0.45). Unlike prior work, our study found no link between IL-19 and severity of AV. Thus, we conclude that IL-19 may not be a reliable marker of the disease severity as previously stated and further research, preferably in larger sample size is warranted to confirm the same.

摘要： OBJECTIVE:Cutaneous polyarteritis nodosa (cPAN) is a rare necrotizing vasculitis that primarily affects small-to-medium-sized arteries in subcutaneous tissue. cPAN is often characterized by a chronic and relapsing disease that presents with skin ulcers, livedo, and painful erythema. In this study, we evaluated the efficacy of anti-TNF-α inhibitor treatment for cPAN-associated refractory leg ulcers. METHODS:This retrospective study was conducted between 2016 and 2023 at three medical institutions in Japan and targeted patients with cPAN presenting with refractory leg ulcers who were treated with anti-TNF-α inhibitors. The diagnosis of cPAN was histologically confirmed, and patients with secondary PAN were excluded. Data on the clinical background, treatments, ulcer status, and glucocorticoid dosages were collected, and the therapeutic efficacy of the treatment was evaluated. RESULTS:Ten patients were included, with a mean age of 51 years, and nine were female. All patients presented with recurrent leg ulcers. Anti-TNF-α inhibitors included adalimumab (five cases), etanercept (four cases), and infliximab (one case). Complete epithelialization of the leg ulcers was achieved in all patients, and the average glucocorticoid dose was successfully reduced from 20 mg/day to 3.5 mg/day. Additionally, five patients achieved a glucocorticoid-free status. No serious adverse events were observed in any of the patients. CONCLUSION:Anti-TNF-α inhibitors suggested therapeutic efficacy for cPAN-associated refractory leg ulcers and enabled ulcer epithelialization and significant glucocorticoid dose reduction. These findings support the utility of anti-TNF-α inhibitors in the management of refractory leg ulcers in cPAN, highlighting the need for further large-scale studies to validate the results.

摘要： Purpose: Developing T-cell or vaccine therapies for pancreatic ductal adenocarcinoma (PDAC) has been challenging because of a lack of knowledge regarding immunodominant, cancer-specific antigens as PDAC are characterized by a scarcity of genomic mutation-associated neoepitopes, and effective approaches to discover them are *** Design: An advanced mass spectrometry approach was employed to compare the immunopeptidome of PDAC tissues and matched normal tissues from the same ***: This study identified HLA class I-binding variant peptides derived from canonical proteins, which had single amino-acid substitutions not attributed to genetic mutations or RNA editing. These amino-acid substitutions appeared to result from translational errors. The variant peptides were predominantly found in tumor tissues, with certain peptides common among multiple patients. Importantly, several of these variant peptides were more immunogenic than their wild-type ***: The shared noncanonical neoepitopes identified in this study offer promising candidates for vaccine and T-cell therapy development, potentially providing new avenues for immunotherapy in PDAC. See related commentary by Yuan et al., p. 1821Conclusions: The shared noncanonical neoepitopes identified in this study offer promising candidates for vaccine and T-cell therapy development, potentially providing new avenues for immunotherapy in PDAC. See related commentary by Yuan et al., p. 1821

关键词： Cellular immune response   Dermatology   Immunology   Infectious disease   Molecular pathology   Parasitology  

摘要： Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death–ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32–expressing CD8⁺ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32⁺ cells and IL-32⁺CD8⁺ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.

关键词： Subarachnoid hemorrhage   IL-33   ST2   AKT   Microglia  

摘要： Background and purpose: ST2, a member of the interleukin-1 (IL-1) receptor family, along with its ligand IL-33, plays critical roles in immune regulation and inflammatory responses. This study investigates the roles of endogenous IL-33/ST2 signaling in subarachnoid hemorrhage (SAH) and elucidates the underlying mechanisms. Methods: Dynamic changes in endogenous IL-33 levels were examined following SAH induction in vivo. Rats underwent the endovascular perforation model of SAH and were randomly assigned to receive either recombinant IL-33 (rIL-33) or a vehicle, administered intranasally 1 h post-SAH. ST2 siRNA or an AKT selective inhibitor was administered intraperitoneally (i.p.) 48 h prior to SAH induction to explore the potential mechanisms of IL33-mediated neuroprotection. Results: Endogenous IL-33 and ST2 levels were elevated in in vitro models of SAH. Exogenous IL-33 significantly alleviated neuronal apoptosis, reduced brain edema, and enhanced short-term neurofunction in a dosedependent manner following SAH in rats. Conclusion: Exogenous rIL-33 alleviates SAH-induced neurological deficits by promoting M2-like polarization of microglia post-SAH. These findings suggest a potential role of the microglial ST2/AKT axis in IL-33-related neuroprotection, which warrants further investigation.

关键词： Anti-TNF alpha   A1AT   drug reprofiling   neuroprotection   stroke  

摘要： Neuroprotection after ischemic stroke has been focused on targeting one pathway of the ischemic cascade. In this study, we have hypothesized that combination therapy with alpha-1 antitrypsin (A1AT) and a blocker of tumor necrosis factor (TNF alpha) could be beneficial in the acute phases after ischemia. Following a detailed safety assessment of the co-administration of both drugs, we tested their neuroprotective effect in a transient mouse model of proximal middle cerebral artery occlusion (MCAo) by evaluating infarct extension and functional outcomes. Anti-TNF alpha (20 mg/kg) and A1AT were administered at different doses (ranging from 60 mg/kg to 700 mg/kg), as a single therapy during occlusion or at different time-points following reperfusion. Results showed that the administration of A1AT (60 mg/kg) in combination with anti-TNF alpha (20 mg/kg) was safe and effective when given during occlusion by reducing infarct volume at 24 h by 27% compared with the vehicle group (p = 0.0001). In conclusion, the synergy of the anti-apoptotic and anti-inflammatory properties of both drugs can reduce infarct volume in a stroke mouse model when given in the hyperacute phase. This approach shows promise as an early intervention strategy for stroke patients and underscores the potential of drug repurposing to develop new stroke treatments.

关键词： TNF-alpha   Anti-TNF-alpha therapy   Sepsis   Treatment failure  

摘要： Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-alpha), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-alpha therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-alpha-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-alpha may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-alpha inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e. g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

关键词： Paneth cells   sepsis   TNF   treatment  

摘要： In a recent Cell Host & Microbe paper, Wallaeys et al. demonstrate that TNF signaling critically regulates Paneth cell dysfunction and bacterial sepsis pathogenesis, and highlights a critical localized mechanism in the gut, making a substantial contribution to our understanding of TNF's role in gut-derived sepsis pathogenesis.

关键词： 猪瘟病毒   E   蛋白   蛋白表达   化学发光检测方法  

摘要： 为建立一种特异性强、灵敏度高、操作高效便捷的检测猪瘟病毒（classical swine fever virus， CSFV）Erns蛋白抗体的方法，以便鉴别E2亚单位疫苗免疫和流行毒株感染的抗体。本研究将昆虫杆状病毒表达系统表达纯化的Erns蛋白，分别与偶联于固相载体-羧基磁珠和辣根过氧化物酶（horseradish peroxidase， HRP），对各反应参数进行优化，建立了基于全自动化学发光分析仪检测Erns蛋白抗体的双抗原夹心化学发光酶免疫方法（chemiluminescent enzyme immunoassay， CLEIA），并利用该方法对流行毒株感染血清以及猪瘟E2亚单位疫苗免疫攻毒猪血清进行了定量检测。结果显示，用于建立双抗原夹心化学发光酶免疫方法的最佳缓冲液pH为8.0，最佳蛋白偶联量为2.5 mg/g，最佳封闭液为10% BSA溶液，血清加样量为20 μL，酶标抗原最佳稀释度为1:500，一步反应时间为15 min；建立的检测CSFV Erns蛋白抗体的双抗原夹心化学发光酶免疫方法的阴性、阳性临界点为5.83 U/mL，诊断灵敏度为1:128，该方法与非洲猪瘟病毒、猪伪狂犬病病毒、猪圆环病毒2型、猪流行性腹泻病毒、猪繁殖与呼吸综合征病毒和猪传染性胃肠炎病毒阳性血清均无交叉反应。重复性试验的批内变异系数为0.77%～11.56%，批间变异系数为10.30%～14.55%，均＜15%。与商品化猪瘟病毒Erns蛋白抗体检测试剂盒的阳性样品符合率为95.24%，阴性样品符合率为92.71%，总符合率达到93.23%。本研究建立的CSFV Erns蛋白抗体检测的双抗原夹心化学发光方法具有较高的灵敏度和良好的重复性，可实现自动化检测，适用于猪瘟E2亚单位疫苗免疫和流行毒株感染的血清学鉴别。