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关键词： HLA   HLA-B*56:102   new allele   next generation sequencing  

摘要： HLA-B*56:102 differs from HLA-B*56:01:01:02 by one nucleotide substitution at codon 240 in exon 4.

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.