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1.
Artigo em Inglês | MEDLINE | ID: mdl-38991773

RESUMO

BACKGROUND AND PURPOSE: After repeat administration of gadolinium-based contrast agents (GBCAs), the association between gadolinium retention in the central and peripheral nervous systems and the main manifestations of myelopathy and progressive neurologic symptoms remains unclear. We investigated the effects of the repeat administration of GBCAs on gadolinium retention in the central and peripheral nervous systems and the sensory, cognitive, and athletic implications. MATERIALS AND METHODS: Forty-eight male Wistar rats (6 weeks of age) were randomly divided into 4 experimental groups (12 rats in each group): the gadodiamide group (linear and nonionic GBCAs), the gadopentetate dimeglumine group (linear and ionic GBCAs), the gadoterate meglumine group (macrocyclic and ionic GBCAs), and the control group (0.9% saline solution). The brains of the rats were scanned using 9.4T MRI. Sensory behavioral tests were performed to assess the effect of GBCAs on pain sensitivity function. Gadolinium deposition in the brain, spinal cord, and peripheral nerves was determined by inductively coupled plasma mass-spectrometry. Transmission electron microscopy was used to observe the microscopic distribution of gadolinium after deposition in the spinal cord. The histopathologic features in the spinal cord were analyzed by H&E staining, Nissl staining, glial fibrillary acidic protein staining, and neuron-specific enolase staining after administration of GBCAs. RESULTS: All GBCAs resulted in gadolinium deposition in the central and peripheral nerve tissues, with the highest deposition in the sciatic nerve tissue (mean, 62.86 [SD, 12.56] nmol/g). Decreased muscle power, impairment of spatial cognitive function power, and pain hypersensitivity to thermal and mechanical stimuli were observed after exposure to gadodiamide. At the spinal cord, transmission electron microscopy found that the region of gadolinium depositions had a spheric structure similar to "sea urchins" and was mainly located near the vascular basement membrane. CONCLUSIONS: Multiple injections of GBCAs caused gadolinium deposition in the brain, spinal cord, and peripheral nerves, especially in the spinal cords of the gadodiamide group. Gadodiamide led to pain hypersensitivity and decreased muscle power and cognitive ability. For the patients who are hypersensitive to pain and need multiple MRI examinations, we recommend using macrocyclic GBCAs and the lowest dose possible.

2.
Nat Immunol ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38942990

RESUMO

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

3.
Nat Commun ; 15(1): 3653, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38688896

RESUMO

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFß1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFß1 expression and promoting tumor progression via the TGFß/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.


Assuntos
Neoplasias do Colo , DNA Mitocondrial , Progressão da Doença , Células Epiteliais , Vesículas Extracelulares , Genoma Mitocondrial , Espécies Reativas de Oxigênio , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Espécies Reativas de Oxigênio/metabolismo , Vesículas Extracelulares/metabolismo , Animais , Masculino , Camundongos , Feminino , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Colo/metabolismo , Colo/patologia , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Pessoa de Meia-Idade , Reprogramação Metabólica
4.
bioRxiv ; 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38496556

RESUMO

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCE: Mechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk.

5.
Clin Transl Med ; 14(2): e1591, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38385857

RESUMO

BACKGROUND: Metastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour-associated macrophages (TAMs) in CRC metastasis was explored. METHODS: Immunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM-derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells. RESULTS: Our results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC-38 and CT-26 cells via EVs. According to the RNA-seq data, TAM-EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM-EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver-metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours. CONCLUSIONS: Overall, our findings suggest that DOCK7 delivered via TAM-EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.


Assuntos
Neoplasias do Colo , Vesículas Extracelulares , Humanos , Proteínas Proto-Oncogênicas c-akt , Macrófagos Associados a Tumor , Colesterol , Proteínas rac1 de Ligação ao GTP/genética , Fatores de Troca do Nucleotídeo Guanina , Proteínas Ativadoras de GTPase , Transportador 1 de Cassete de Ligação de ATP
6.
BMC Musculoskelet Disord ; 25(1): 81, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245679

RESUMO

BACKGROUND: Symptomatic lumbar disc herniation (LDH) and lumbar isthmic spondylolisthesis (LIS) present significant challenges for military pilots, which may result in grounding if not effectively managed. Surgical treatment for LDH and LIS may offer a pathway to return to flight duty (RTFD), but recent data on this crucial topic is lacking. This study seeks to address this gap by investigating the RTFD outcomes among Chinese military pilots who have undergone lumbar spine surgery for symptomatic LDH and LIS. METHODS: A retrospective review was conducted on active-duty military pilots who underwent isolated decompressive or fusion procedures at an authorized military medical center from March 1, 2007, to March 1, 2023. The analysis utilized descriptive statistics to examine demographic, occupational, surgical, and outcome data, with a particular focus on preoperative flight status, recommended clearance by spine surgeons, and actual RTFD outcomes and time. RESULTS: Among the identified cases of active-duty military pilots with LDH or LIS treated by lumbar surgery (n = 24), 70.8% (17 of 24) consistently maintained RTFD status without encountering surgical complications or medical issues during the follow-up period. Of the seven pilots who did not RTFD, one retired within a year of surgery, two had anterior cruciate ligament injuries, three had residual radicular symptoms, and one had chronic low back pain. Excluding pilots who retired and did not RTFD for reasons unrelated to their lumbar conditions, the RTFD rate stood at 81.0% (17 of 21). The median time for recommended clearance by spine surgeons was 143.0 days (inter-quartile range, 116.5-196.0), while the median duration for actual RTFD attainment was 221.0 days (inter-quartile range, 182.0-300.0). The median follow-up post-lumbar surgery was 1.7 years (inter-quartile range, 0.4-2.9). CONCLUSION: Most military pilots diagnosed with symptomatic LDH and LIS can continue their careers and regain active-duty flight status following lumbar spine surgery, as reflected by the high RTFD rate. Lumbar spine surgery can successfully alleviate the physical constraints associated with spinal conditions, facilitating the return of military pilots to their demanding profession.


Assuntos
Deslocamento do Disco Intervertebral , Militares , Fusão Vertebral , Espondilolistese , Humanos , Deslocamento do Disco Intervertebral/epidemiologia , Deslocamento do Disco Intervertebral/cirurgia , Espondilolistese/epidemiologia , Espondilolistese/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Vértebras Lombares/cirurgia , China/epidemiologia , Fusão Vertebral/métodos
7.
J Agric Food Chem ; 72(1): 219-229, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38131297

RESUMO

In this study, we determined the sensitivity of 148 Phytophthora litchii isolates to cyazofamid, yielding a mean EC50 value of 0.0091 ± 0.0028 µg/mL. Through fungicide adaptation, resistant mutants (RMs) carrying the F220L substitution in PlCyt b were derived from wild-type isolates. Notably, these RMs exhibited a lower fitness compared with the parental isolates. Molecular docking analysis further revealed that the F220L change contributed to a decrease in the binding energy between cyazofamid and PlCyt b. The total phenol and flavonoid contents in the litchi pericarp treated with cyazofamid on day 5 were significantly higher than in other treatments. Overall, the laboratory assessment indicated a moderate risk of cyazofamid resistance in P. litchii, but the emergence of the F220L change could lead to a high level of resistance. Thus, cyazofamid represents a promising agrochemical for controlling postharvest litchi downy blight and extending the shelf life of litchi fruits.


Assuntos
Litchi , Phytophthora , Litchi/genética , Litchi/metabolismo , Frutas , Simulação de Acoplamento Molecular
8.
Cell Rep ; 42(12): 113477, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-37979167

RESUMO

Targeting lysine-specific histone demethylase 1A (LSD1) can improve tumor immunogenicity of poorly immunogenic tumors, such as non-small cell lung cancer (NSCLC), with elevated T cell infiltration and sensitize tumors to anti-PD-1 therapy. However, the lack of reliable biomarkers limits utilization of LSD1 inhibitors in cancer therapy. Here, we identify an E3 ligase, Trim35, as an effective biomarker for high activity of LSD1 to predict prognosis of LSD1-targeted therapy as well as immunotherapy. Mechanistically, Trim35 represses LSD1 demethylase activity by mediating K63 ubiquitination at lysine site 422 of LSD1. Suppressed LSD1 activity facilitates ERGIC1 transcription, followed by autophagy inhibition and IFNGR1 stabilization to activate IFN-γ signaling, leading to increased MHC class I expression and immune surveillance of NSCLC cells. Furthermore, combinational use of an LSD1 inhibitor and anti-PD-1 therapy can significantly eradicate poorly immunogenic lung cancer with low Trim35. These findings strongly suggest that Trim35 is a promising biomarker for prediction of immunotherapy outcome in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Ubiquitina-Proteína Ligases/metabolismo , Lisina/metabolismo , Ubiquitinação , Histona Desmetilases/metabolismo , Biomarcadores/metabolismo , Linhagem Celular Tumoral
9.
Front Public Health ; 11: 1226930, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38026361

RESUMO

Background: Neck pain (NP) is a common musculoskeletal disorder among fighter pilots and has become a rising concern due to its detrimental impact on military combat effectiveness. The occurrence of NP is influenced by a variety of factors, but less attention has been paid to the association of NP with demographic, occupational, and cervical sagittal characteristics in this group. This study aimed to investigate the prevalence and risk factors of NP in Chinese male fighter pilots using a questionnaire and cervical sagittal measurements. Methods: Demographic and flight-related data, as well as musculoskeletal pain information, were gathered from Chinese male fighter pilots via a self-report questionnaire. Cervical sagittal parameters were measured and subtypes were classified using standardized lateral cervical radiographs. Differences in various factors between the case and control groups were analyzed using t-tests or chi-square tests. Binary logistic regressions were conducted to explore potential risk factors contributing to NP. Predictors were presented as crude odds ratios (CORs) and adjusted odds ratios (AORs), along with their respective 95% confidence intervals (CIs). Results: A total of 185 male fighter pilots were included in this cross-sectional study. Among them, 96 (51.9%) reported experiencing NP within the previous 12 months. The multivariate regression analysis revealed that continuous flight training (AOR: 4.695, 95% CI: 2.226-9.901, p < 0.001), shoulder pain (AOR: 11.891, 95% CI: 4.671-30.268, p < 0.001), and low back pain (AOR: 3.452, 95% CI: 1.600-7.446, p = 0.002) were significantly associated with NP. Conclusion: The high 12-month prevalence of NP among Chinese male fighter pilots confirms the existence of this growing problem. Continuous flight training, shoulder pain, and low back pain have significant negative effects on pilots' neck health. Effective strategies are necessary to establish appropriate training schedules to reduce NP, and a more holistic perspective on musculoskeletal protection is needed. Given that spinal integrated balance and compensatory mechanisms may maintain individuals in a subclinical state, predicting the incidence of NP in fighter pilots based solely on sagittal characteristics in the cervical region may be inadequate.


Assuntos
Medicina Aeroespacial , Cervicalgia , Doenças Profissionais , Pilotos , Humanos , Masculino , Estudos Transversais , População do Leste Asiático , Dor Lombar , Cervicalgia/epidemiologia , Prevalência , Fatores de Risco , Dor de Ombro , Inquéritos e Questionários , Doenças Profissionais/epidemiologia
10.
Sci Immunol ; 8(88): eadh1306, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37862431

RESUMO

Overcoming CD8+ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8+ T cell (Tprog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8+ T cell (Tterm cell) subpopulation with potent cytotoxic functions. Tprog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control Tprog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific Tterm cell generation from Tprog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of Tprog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX+TCF1+ Tprog cells in both LNs and tumors. BCL6 expression in CD8+ T cells was up-regulated by TGF-ß-SMAD2 signaling but down-regulated by the IL-2-STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of Tterm cell-associated genes and induced those of Tprog cell-related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the Tprog cell program and greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-ß-BCL6 and IL-2-BLIMP1 antagonistic pathways in regulation of antitumor CD8+ T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Interleucina-2 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta , Proteínas Proto-Oncogênicas c-bcl-6/genética
11.
Arterioscler Thromb Vasc Biol ; 43(10): 2023-2029, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37675635

RESUMO

BACKGROUND: We hypothesized that transcriptomic profiling of muscle satellite cells in peripheral artery disease (PAD) would identify damage-related pathways contributing to skeletal muscle myopathy. We identified a potential role for ferroptosis-a form of programmed lytic cell death by iron-mediated lipid peroxidation-as one such pathway. Ferroptosis promotes myopathy in ischemic cardiac muscle but has an unknown role in PAD. METHODS: Muscle satellite cells from donors with PAD were obtained during surgery. cDNA libraries were processed for single-cell RNA sequencing using the 10X Genomics platform. Protein expression was confirmed based on pathways inferred by transcriptomic analysis. RESULTS: Unsupervised cluster analysis of over 25 000 cells aggregated from 8 donor samples yielded distinct cell populations grouped by a shared unique transcriptional fingerprint. Quiescent cells were diminished in ischemic muscle while myofibroblasts and apoptotic cells were prominent. Differential gene expression demonstrated a surprising increase in genes associated with iron transport and oxidative stress and a decrease in GPX4 (glutathione peroxidase 4) in ischemic PAD-derived cells. Release of the danger signal HMGB1 (high mobility group box-1) correlated with ferroptotic markers including surface transferrin receptor and were higher in ischemia. Furthermore, lipid peroxidation in muscle satellite cells was modulated by ferrostatin, a ferroptosis inhibitor. Histology confirmed iron deposition and lipofuscin, an inducer of ferroptosis in PAD-affected muscle. CONCLUSIONS: This report presents a novel finding that genes known to be involved in ferroptosis are differentially expressed in human skeletal muscle affected by PAD. Targeting ferroptosis may be a novel therapeutic strategy to reduce PAD myopathy.


Assuntos
Ferroptose , Doenças Musculares , Doença Arterial Periférica , Células Satélites de Músculo Esquelético , Humanos , Ferroptose/genética , Células Satélites de Músculo Esquelético/metabolismo , Transcriptoma , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/fisiologia , Ferro/metabolismo , Doença Arterial Periférica/genética , Isquemia
12.
Front Surg ; 10: 1232176, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37693639

RESUMO

Background: Surgically treated anterior cruciate ligament (ACL) injuries may be a waivable condition and allow return to full flight status, but waivers are based on expert opinion rather than recent published data. The purpose of this study was to evaluate return to flight after anterior cruciate ligament reconstruction (ACLR) in male military aircrews with ACL injuries and to identify factors that affect flight clearance. Method: A single-center retrospective review was conducted by the authors for all active-duty aircrew who underwent ACLR at an authorized military medical center from January 2010 to December 2019. Demographic characteristics, occupational information, surgical data, and flight readiness evaluation outcomes were collected. Based on the final medical evaluation, subjects were divided into a qualified group (N = 64) and a disqualified group (N = 9), and the difference in data collected between the two groups was then analyzed to identify factors affecting flight clearance. Results: A total of 73 patients underwent successful ACLR with a mean age of 31.6 ± 5.6 years. Non-contact injury was the main type of ACL injury, accounting for 84.9% of the total injuries. 55 cases (75.3%) occurred during daily sports activities and 18 (24.7%) during military training. 64 of the 73 crewmembers (87.7%) were able to return to flight at their last follow-up evaluation. The preoperative interval time (PIT) was significantly less in the qualified group than in the disqualified group (P = 0.002). Patients who underwent ACLR within three months were more likely to return to flying than those who underwent the procedure three months later (97.4% vs. 76.5%, P = 0.010). The incidence of failure to return to flight duty was significantly higher in aircrews with ACL injuries combined with meniscal injuries than in aircrews with isolated ACL injuries (21.4% vs. 0.0%, P = 0.017). Conclusion: ACLR appears to be safe for military aircrew suffering ACL injuries with or without meniscal injury, and return to flight status is the most likely outcome for the majority of postoperative pilots. Prolonged PIT, PIT > 3 months, and ACL injury combined with meniscus injury had a negative impact on postoperative flight readiness.

14.
Genes Dis ; 10(1): 7-9, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37013047

RESUMO

Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

15.
Arch Biochem Biophys ; 741: 109605, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37086961

RESUMO

Accumulating evidence have demonstrated that cytokines are enriched in tumor-derived extracellular vesicles (EVs) and widely involved in tumorigenesis of various types of carcinomas, including colorectal cancer (CRC). Nevertheless, the functions of cytokines in EVs secreted from colorectal cancer cells remain largely unknown. In the present study, we found that TNF-α was elevated in EVs from CRC patient serum samples and CRC cell lines, of which the expression was associated with aggressive features of colorectal cancer. EV TNF-α secretion is dependent on synaptosome-associated protein 23 (SNAP23). Functional experiments revealed that EV TNF-α promotes CRC cell metastasis via the NF-κB pathway by targeting SNAP23. Mechanistically, SNAP23 was transcriptionally upregulated by EV TNF-α/NF-κB axis to enhance the expression of laminin subunit beta-3 (LAMB3), thereby activating the PI3K/AKT signaling pathway and consequently facilitate CRC progression. Based on our findings, we could conclude that EV TNF-α plays an oncogenic role in CRC progression through SNAP23, which in turn promotes EV TNF-α secretion, suggesting that EV TNF-α/SNAP23 axis may serve as a diagnostic biomarker and potential therapeutic target for CRC.


Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Qb-SNARE/genética , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Calinina
16.
Artigo em Inglês | MEDLINE | ID: mdl-36776715

RESUMO

Vaccine-associated thrombosis has previously been described in patients presenting with cerebral sinus thrombosis, deep venous thrombosis/pulmonary embolism, or mesenteric venous thrombosis. Only recently has arterial thrombosis gained attention. A new entity known as vaccine-induced thrombotic thrombocytopenia (VITT) has been associated with the coronavirus disease of 2019 (COVID-19) vaccines produced by AstraZeneca and Johnson & Johnson. We describe a case series of three patients who presented with acute limb ischemia with vaccine-associated arterial occlusions, one of whom was diagnosed with VITT.

17.
J Exp Med ; 220(4)2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36651876

RESUMO

Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5 but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produces enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Finally, microbiota promote BCL6 expression in colonic CCR6+ ILC3 and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.


Assuntos
Linfócitos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Camundongos , Animais , Linfócitos/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Imunidade Inata , Linfócitos T Auxiliares-Indutores/metabolismo , Citocinas/metabolismo , Diferenciação Celular , Fatores de Transcrição/metabolismo , Linhagem da Célula , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CCR6/metabolismo
18.
J Exp Med ; 220(4)2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36688918

RESUMO

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratumor Texterm cell development by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while it suppresses those expressed by the progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at the effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits the development of more effective immunotherapies against tumors.


Assuntos
Neoplasias , Transdução de Sinais , Humanos , Diferenciação Celular , Neoplasias/patologia , Linfócitos T CD8-Positivos , Microambiente Tumoral , Fator de Transcrição STAT3/metabolismo
19.
J Vasc Surg ; 77(4): 1165-1173.e1, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36526086

RESUMO

OBJECTIVE: Hypercoagulability is common in severe acute respiratory syndrome coronavirus 2 and has been associated with arterial thrombosis leading to acute limb ischemia (ALI). Our objective was to determine the outcomes of concurrent coronavirus disease 2019 (COVID-19) infection and ALI, particularly during the Delta variant surge and the impact of vaccination status. METHODS: A retrospective review was performed of patients treated at a single health care system between March 2020 and December 2021 for ALI and recent (<14 days) COVID-19 infection or who developed ALI during hospitalization for the same disease. Patients were grouped by year as well as by pre and post Delta variant emergence in 2021 based on the World Health Organization timeline (January to May vs June to December). Baseline demographics, imaging, interventions, and outcomes were evaluated. A control cohort of all patients with ALI requiring surgical intervention for a 2-year period prior to the pandemic was used for comparison. Primary outcomes were in-hospital mortality and amputation-free survival. Kaplan-Meier survival and Cox proportional hazards analysis were performed. RESULTS: Forty acutely ischemic limbs were identified in 36 patients with COVID-19, the majority during the Delta surge (52.8%) and after the wide availability of vaccines. The rate of COVID-19-associated ALI, although low overall, nearly doubled during the Delta surge (0.37% vs 0.20%; P = .09). Intervention (open or endovascular revascularization vs primary amputation) was performed on 31 limbs in 28 individuals, with the remaining eight treated with systemic anti-coagulation. Postoperative mortality was 48%, and overall mortality was 50%. Major amputation following revascularization was significantly higher with COVID-19 ALI (25% vs 3%; P = .006) compared with the pre-pandemic group. Thirty-day amputation-free survival was significantly lower (log-rank P < .001). COVID-19 infection (adjusted hazard ratio, 6.2; P < .001) and age (hazard ratio, 1.1; P = .006) were associated with 30-day amputation in multivariate analysis. Severity of COVID-19 infection, defined as vasopressor usage, was not associated with post-revascularization amputation. There was a higher incidence of re-thrombosis in the latter half of 2021 with the Delta surge, as reintervention for recurrent ischemia of the same limb was more common than our previous experience (21% vs 0%; P = .55). COVID-19-associated limb ischemia occurred almost exclusively in non-vaccinated patients (92%). CONCLUSIONS: ALI observed with Delta appears more resistant to standard therapy. Unvaccinated status correlated highly with ALI occurrence in the setting of COVID-19 infection. Information of limb loss as a COVID-19 complication among non-vaccinated patients may help to increase compliance.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Procedimentos Endovasculares , Doença Arterial Periférica , Humanos , COVID-19/complicações , Procedimentos Endovasculares/efeitos adversos , Isquemia/diagnóstico por imagem , Isquemia/etiologia , Isquemia/terapia , Salvamento de Membro , Extremidade Inferior/irrigação sanguínea , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Resultado do Tratamento , Vacinas , Vacinas contra COVID-19/efeitos adversos
20.
Animals (Basel) ; 12(22)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36428365

RESUMO

Pangolins are one of the world's most trafficked mammals. Since pangolins are highly adapted to ants and termites, they are important for controlling forest termite infestations. In addition to their ecological value, pangolins have economic and medicinal value. Currently, poaching and habitat destruction have radically reduced the number of pangolins, and Manis pentadactyla, Manis javanica, and Manis culionensis are now considered the most threatened pangolin species. In addition to the control of hunting and illegal trade, ex situ breeding is also a useful conservation method. However, many technical obstacles still limit the success of ex situ pangolin breeding. The special feeding traits of pangolins require a diet that meets nutritional and ethological needs. Based on the existing literature and practical experience, this review aims to compare the natural diet and successful diet in the human care of pangolins, to outline the key factors of successful ex situ maintenance from a dietary perspective, and the strategies to improve their conservation success in animal care centers and in the wild. The type of food used in successful pangolin protection agencies is quite variable in nutritional composition. In the diet of pangolins in the wild, the nutrient profile of different species of termites and ants and even the same species of termites and ants but different types (queens, soldiers, etc.) also displays differences. The crude protein content of some ants is higher than that of other foods, such as eggs, milk, and common cat food. The mineral and vitamin concentrations of ants also exceed many common food items, such as oil, meat, and eggs. However, not much is known about the bioavailability of minerals from ants and termites. Based on comparisons between foods, it is clear that the main difference between diets in the wild and in human care of pangolins is that the latter contains fewer insects and vitamins, such as vitamin E, vitamin A, and vitamin B2, and more carbohydrates and non-protein substances than the former. Although many successful dietary formulae have been developed, the pangolin's nutritional needs are still less well studied. A diet with the nutrient concentrations observed in the wild may add to successful ex situ conservation.

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