课程文献中心 更多>>

关键词： A*11:01:79   HLA   novel allele   sequence-based typing   Taiwanese  

摘要： One nucleotide substitution in codon 335 of HLA-A*11:01:01:01 results in the novel allele HLA-A*11:01:79.

关键词： Glutamine metabolism   IFN-gamma signaling   Non-small cell lung cancer   Autophagy   Immunotherapy   V9302  

摘要： Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-gamma (IFN-gamma) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-gamma. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-gamma-driven response in cancer cells by promoting autophagy-dependent IFN-gamma receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-gamma-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (alpha-KG) and ATP, which are involved in maintaining IFN-gamma signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-gamma-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

关键词： Obstructive sleep apnea   Lung transplantation   Serum markers   ELISA  

摘要： PurposeTo analyze the correlation between obstructive sleep apnea (OSA) and hypoxia-inducible factor (HIF)-1, interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) in patients complicated with OSA after lung transplantation. To identify serum markers of OSA after lung transplantation. MethodsWe retrospectively selected patients who planned to undergo lung transplantation between 2018 and 2020, including 25 without OSA before lung transplantation (group A), 20 with OSA after lung transplantation (group B), and 15 patients without OSA after lung transplantation (group C). Sleep monitoring was performed, general information collection and hematological samples were collected. HIF-1, IL-6 and iNOS were detected by ELISA. ResultsGroup B were older [59.2 +/- 10.1 (B) vs. 49.8 +/- 15.1 (A), 58.2 +/- 3.3 (C), yrs.], had a bigger neck circumference [38.1 +/- 4.7 (B) vs. 34.6 +/- 4.2 (A),35.7 +/- 4.2 (C), cm], and a greater abdominal circumference [88.2 +/- 12.5 (B) vs. 76.2 +/- 7.9 (A), 82.5 +/- 6.5 (C), cm] compared with Groups A and C (P < 0.05). iNOS in group B (4784.8 +/- 1365.2 (B) vs. 1925.2 +/- 1868.5 (A), 2838.7 +/- 3015.5 (C), pg/mL) was significantly increased compared to groups A and C (P < 0.05). iNOS was positively correlated with AHI. ConclusionsiNOS is significantly increased in OSA after lung transplantation, and maybe an important indicator of OSA.

关键词： Cancer drug delivery   Tumor microenvironment (TME) targeting   Tumor-associated macrophages (TAMs)   targeting   cancer immunotherapy   M2 macrophages polarization   Liposomal IFN-gamma   M2 macrophage-targeting peptide-modified   liposomes  

摘要： While liposomes enhance the safety and pharmacokinetic profile of free drugs, they have not significantly improved therapeutic efficacy. To overcome this challenge, targeted depletion of tumor-associated macrophages (TAMs) shows significant potential as an effective antitumor therapy, reducing off-target effects in comparison to non-targeted liposomes. In the context of peptide-mediated targeted cancer therapy, we evaluated the reprogramming activity of IFN-gamma liposomes on TAMs, as well as that of IFN-gamma liposomes modified with an M2 macrophage-targeting peptide, which binds preferentially to murine anti-inflammatory M2 macrophages/M2like TAMs. Flow cytometry analysis showed significantly enhanced cellular uptake of m2-peptide-targeted liposomes in J774.1 macrophage cell lines compared to non-targeted liposomes. In BALB/c mice bearing C-26 murine carcinoma, the m2-peptide-targeted liposome groups exhibited significantly higher IFN-gamma concentrations compared to non-targeted counterparts within the tumor environment. Furthermore, m2-peptide-targeted F2 liposomes at doses of 25 mu g IFN-gamma/kg resulted in superior tumor growth inhibition and greater tumor accumulation, indicating the potential of macrophage-targeted therapy in cancer growth inhibition. However, they failed to improve the overall therapeutic efficacy compared to Doxil. This study proposes a combination therapy of m2peptide-targeted IFN-gamma liposomes with successful chemotherapeutic liposomes such as Doxil.

关键词： dichotomy   IFN-gamma-producing gamma delta T cell   IL-17A-producing gamma delta T cell   Leishmania amazonensis  

摘要： gamma delta T cells play diverse roles in immune responses, producing either interleukin (IL)-17A or interferon gamma (IFN-gamma). Here, we investigated the impact of this functional dichotomy on cutaneous leishmaniasis. We demonstrate that in Sv129 mice susceptible to Leishmania amazonensis, V gamma 4+ gamma delta T cells are the main source of IL-17A. In type 1 IFN receptor-deficient (A129) mice with heightened susceptibility, there is an increased frequency of IL-17A-producing gamma delta T cells. L. amazonensis' lipophosphoglycan induces these IL-17A-producing gamma delta T cells. Notably, C57BL/6 mice deficient in gamma delta T cells or IL-17 receptor exhibit smaller lesions, indicating a pathogenic role of IL-17A-producing gamma delta T cells in cutaneous leishmaniasis. Conversely, adoptive transfer of fluorescence-activated cell sorting (FACS)-sorted gamma delta T cells lead to an accumulation of IFN-gamma-producing gamma delta T cells, associated with control of lesion development. On the other hand, adoptive transfer of FACS-sorted IFN-gamma-deficient gamma delta T cells abolished the control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing gamma delta T cells promote pathogenesis, while IFN-gamma-producing gamma delta T cells offer therapeutic potential in cutaneous leishmaniasis. Under steady-state conditions, gamma delta T cell expansion is minimal;however, upon infection with Leishmania amazonensis, there is a marked increase in interleukin-17-producing gamma delta T cells in the draining popliteal lymph node, which correlates with disease severity. In contrast, the transfer of interferon gamma-producing gamma delta T cells leads to reduced lesion development, emphasizing a functional dichotomy in which interleukin-17 is associated with disease and interferon gamma confers a protective role.

关键词： axial spondyloarthritis   anti-TNF therapy   NSAIDs   swept-source optical coherence tomography angiography   retinal microvascular changes   choroidal thickness   vascular density  

摘要： Objectives: The aim of this study was to investigate retinal and choroidal microvascular changes in patients with axial spondyloarthritis (axSpA) treated with long-term anti-TNF therapy and NSAIDs and in healthy control subjects using optical coherence tomography angiography (SS-OCT-A). Methods: A total of 162 eyes from 81 participants were included: 52 eyes from 26 axSpA patients treated with anti-TNF therapy (>= 5 years), 44 eyes from 22 axSpA patients treated with NSAIDs, and 66 eyes from 33 healthy control subjects. SS-OCT-A imaging was used to assess retinal thickness, ganglion cell layer thickness, retinal nerve fiber layer thickness, and the vessel densities of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). Disease activity was assessed with ASDAS-CRP. Results: Both axSpA subgroups showed a significant expansion of the foveal avascular zone and reduced SCP and DCP densities compared to the controls. The CC vessel density was higher in axSpA patients than in healthy subjects. The anti-TNF group had a lower CC vascular density than the NSAIDs group. The disease duration correlated with a decreased central DCP density and increased paracentral SCP and CC densities. Conclusions: SS-OCT-A revealed subclinical retinal and choroidal changes in axSpA patients, highlighting the impact of chronic inflammation on the retinal vasculature. While anti-TNF therapy effectively controls systemic inflammation, it cannot completely prevent microvascular changes. Further studies are needed to assess the clinical relevance of these results.

关键词： atopic dermatitis   interleukin 33   semaphorin  

摘要： Neuroimmune interaction is crucial to inducing pruritic sensations in atopic dermatitis (AD). In this study, we examine the neuroimmune pathways involved in children with AD. HumanMethylation450 BeadChip and GeneChip Human Transcriptome Array 2.0 from 24 children with ad and 24 healthy controls were cross-referenced with gene expression data from GSE116486. SEMA7A, which encodes for semaphorin 7a and is associated with neuron development and immune response and was identified on pathway analysis as a crucial gene in children with ad. In addition, we found that SEMA7A cytosine-phosphate-guanine sites (CpG sites) cg13557411 and cg17917837 were hypomethylated, and mRNA expression of SEMA7A was higher in children with ad. Vectors containing SEMA7A were then transfected into Jurkat T cells, which increased the protein excretion of interleukin 4 (IL-4) and the mRNA expression of interleukin 1 receptor-like 1 (IL1RL1, receptor for the cytokine IL-33). Furthermore, stimulation of HaCaT keratinocytes with SEMA7A protein resulted in increased mRNA expression of the genes interleukin 33 (IL33) and IL1RL1, but suppressed mRNA expression of the tight junction protein ZO-1(TJP1). In conclusion, in this study, we found that SEMA7A is overexpressed in patients with AD and is a central gene on pathway analysis. Results of our study suggest that overexpression of SEMA7A is associated with increased expression of IL4, IL33 and its receptor IL1RL1, which are associated with pruritic sensation in AD. SEMA7A also appears to suppress the expression of TJP1 in keratinocytes, thereby possibly increasing the permeability of the skin barrier. SEMA7A may be an alternative therapeutic target in AD, especially for neuroimmune-related pruritis.

关键词： dapagliflozin   IL-17   NLRP3   secukinumab   sunitinib  

摘要： Sunitinib (SUN) is a chemotherapeutic agent showing renal toxicity that limits its clinical applications. The present research aimed to clarify the potential ameliorative effects of secukinumab (SEC) and dapagliflozin (DAPA) against SUN-induced renal toxicity and the underpinning molecular mechanisms. For this purpose, adult Wistar albino rats were received SUN (25 mg/kg 3 times/week, po) and co-treated with SEC (3 mg/kg/every 2 weeks, subcutaneously) or DAPA (10 mg/kg/day, po) for 4 weeks and compared with age-matched control group (CON). Markers of kidney functions were assessed in serum samples. Kidneys were harvested for biochemical and histological examination. Compared to CON group, SUN-treated rats displayed signs of kidney dysfunction along with renal histological changes that were ameliorated by SEC or DAPA. Both drugs significantly lowered the renal levels of IL-17, but SEC exerted more inhibitory effect than DAPA. Additionally, SUN-subjected rats showed significant increases in the renal expression of NLRP3 inflammasome and the other inflammatory mediators including IL-1 beta, END-1, and MCP-1. This was associated with marked decline of the renal levels of beclin-1. Co-treatment with SEC or DAPA significantly suppressed NLRP3-induced inflammation while enhanced beclin-1-mediated autophagy. The modulatory effect of DAPA on NLRP3 and beclin-1 was superior to that of SEC. Moreover, both drugs significantly and similarly attenuated the enhanced cleaved caspase-3 expression and interstitial fibrosis in renal tissue of SUN-subjected rats. Collectively, these findings may repurpose SEC and DAPA as candidate therapies to alleviate the renal toxicity of SUN and to rescue the renal functionality in SUN-treated cancer cases.

关键词： HLA   HLA-DPA1*02:01:34   new allele   synonymous mutation  

摘要： HLA-DPA1*02:01:34 differs by a single synonymous mutation compared to HLA-DPA1*02:01:01:02 in codon 212 in Exon 4.

关键词： BK virus   Hemorrhagic Cystitis   Post-transplant   cyclophosphamide   Sirolimus   Mycophenolate mofetil  

摘要： BK hemorrhagic cystitis (BK-HC) is a common complication following hematopoietic (PTCy) is used as graft-versus-host disease (GVHD) prophylaxis. However, comparative studies of BK-HC incidence in matched sibling donors (MSD) and unrelated donors (MUD) often include small haploidentical (HAPLO) donor cohorts and usually lack detailed information on disease evolution, coinfections, management and impact on outcomes. This study aimed to evaluate the incidence, risk factors, and outcomes in patients with hematologic malignancies undergoing HSCT from MSD, MUD, HAPLO donors using PTCy as GVHD prophylaxis. Furthermore, we analyze risk factors for BK-HC and its impact on renal function and transplant outcomes. Retrospective analysis of BK-HC episodes in patients undergoing HSCT from 167 MSD, 129 MUD and 103 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type or conditioning intensity, and mesna was used