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1.
Bioact Mater ; 10: 255-268, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34901544

RESUMO

Physical signals provided by the extracellular matrix (ECM) are key microenvironmental parameters for the fate decision of hematopoietic stem and progenitor cells (HSPC) in bone marrow. Insights into cell-ECM interactions are critical for advancing HSC-based tissue engineering. Herein, we employed collagen hydrogels and collagen-alginate hydrogels of defined stiffness to study the behaviors of hematopoietic progenitor cells (HPCs). Three-dimensional (3D) collagen hydrogels with a stiffness of 45 Pa were found to promote HPC maintenance and colony formation of monocyte/macrophage progenitors. Using single-cell RNA sequencing (scRNA-seq), we also characterized the comprehensive transcriptional profiles of cells randomly selected from two-dimensional (2D) and 3D hydrogels. A distinct maturation trajectory from HPCs into macrophages within the 3D microenvironment was revealed by these results. 3D-derived macrophages expressed high levels of various cytokines and chemokines, such as Saa3, Cxcl2, Socs3 and Tnf. Furthermore, enhanced communication between 3D-macrophages and other hematopoietic clusters based on ligand-repair interactions was demonstrated through bioinformatic analyses. Our research underlines the regulatory role of matrix-dimensionality in HPC differentiation and therefore probably be applied to the generation of specialized macrophages.

2.
Infect Immun ; : IAI0045321, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724387

RESUMO

Chlamydia trachomatis is a leading infectious cause of infertility in women due to its induction of lasting pathology such as hydrosalpinx. Chlamydia muridarum induces mouse hydrosalpinx because C. muridarum can both invade tubal epithelia directly (as a 1st hit) and induce lymphocytes to promote hydrosalpinx indirectly (as a 2nd hit). In the current study, a critical role of CD8+ T cells in chlamydial induction of hydrosalpinx was validated in both wild type C57BL/6J and OT1 transgenic mice. OT1 mice failed to develop hydrosalpinx partially due to the failure of their lymphocytes to recognize chlamydial antigens. CD8+ T cells from naïve C57BL/6J rescued the recipient OT1 mice to develop hydrosalpinx when naïve CD8+ T cells were transferred at the time of infection with Chlamydia. However, when the transfer was delayed for 2 weeks or longer after the chlamydial infection, naïve CD8+ T cells no longer promoted hydrosalpinx. Nevertheless, Chlamydia-immunized CD8+ T cells still promoted significant hydrosalpinx in the recipient OT1 mice even when the transfer was delayed for 3 weeks. Thus, CD8+ T cells must be primed within 2 weeks after chlamydial infection to be pathogenic but once primed, they can promote hydrosalpinx for >3 weeks. However, Chlamydia-primed CD4+ T cells failed to promote chlamydial induction of pathology in OT1 mice. This study has optimized an OT1 mouse-based model for revealing the pathogenic mechanisms of Chlamydia-specific CD8+ T cells.

3.
Front Surg ; 8: 734757, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631784

RESUMO

Background: GLI-Kruppel family member 3 (GLI3), a zinc finger transcription factor of the sonic hedgehog pathway, is essential for organ development. Mutations in GLI3 cause several congenital conditions, including Pallister-Hall syndrome (PHS), which is characterized by polydactyly and hypothalamic hamartoma. Most patients are diagnosed soon after birth, and surgical removal of hypothalamic hamartoma in the very young is rarely performed because of associated risks. Case presentation: A 7-month-old boy with PHS features, including a suprasellar lesion, bifid epiglottis, tracheal diverticulum, laryngomalacia, left-handed polydactyly and syndactyly, and omental hernia was referred to our service. His suprasellar lesion was partially removed, and whole-exome sequencing was applied to the resected tumor, his peripheral blood, and blood from his parents. Histopathology confirmed the diagnosis of hypothalamic hamartoma, and molecular profiling revealed a likely pathogenic de novo variant, c.2331C>G (p. H777Q), in GLI3. Magnetic resonance imaging follow-up 1 year later showed some residual tumor, and the patient experienced normal development post operation. Conclusions: We presented a case of PHS that carries a novel GLI3 variant. Hypothalamic hamartoma showed a distinct genetic landscape from germline DNA. These data offer insights into the underlying etiology of hypothalamic hamartoma development in patients with PHS.

4.
Mol Cancer ; 20(1): 138, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34696797

RESUMO

BACKGROUND: Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. METHODS: High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502-5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. RESULTS: CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502-5p and interacting with IGF2BP2. CONCLUSION: Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

5.
J Biol Phys ; 47(3): 323-335, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34533653

RESUMO

With dwindling natural resources on earth, current and future generations will need to explore space to new planets that will require travel under no or varying gravity conditions. Hence, long-term space missions and anticipated impacts on human biology such as changes in immune function are of growing research interest. Here, we reported new findings on mechanisms of immune response to microgravity with a focus on macrophage as a cellular model. We employed a superconducting magnet to generate a simulated microgravity environment and evaluated the effects of simulated microgravity on RAW 264.7 mouse macrophage cell line in three time frames: 8, 24, and 48 h. As study endpoints, we measured cell viability, phagocytosis, and used next-generation sequencing to explore its changing mechanism. Macrophage cell viability and phagocytosis both showed a marked decrease under microgravity. The differentially expressed genes (DEG) were identified in two ways: (1) gravity-dependent DEG, compared µg samples and 1 g samples at each time point; (2) time-dependent DEG, compared time-point samples within the same gravitational field. Through transcriptome analysis and confirmed by molecular biological verification, our findings firstly suggest that microgravity might affect macrophage phagocytosis by targeting Arp2/3 complex involved cytoskeleton synthesis and causing macrophage immune dysfunction. Our findings contribute to an emerging body of scholarship on biological effects of space travel.


Assuntos
Ausência de Peso , Complexo 2-3 de Proteínas Relacionadas à Actina , Animais , Citoesqueleto , Macrófagos , Fenômenos Magnéticos , Camundongos
6.
J Allergy Clin Immunol ; 148(5): 1176-1191, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34508765

RESUMO

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.


Assuntos
COVID-19/imunologia , Infecções por HIV/epidemiologia , HIV-1/fisiologia , Insuficiência Respiratória/epidemiologia , SARS-CoV-2/fisiologia , Fatores Sexuais , Linfócitos T/imunologia , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/mortalidade , Estudos de Coortes , Resistência à Doença , Feminino , Humanos , Imunocompetência , Interleucina-6/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Transcriptoma/imunologia , Estados Unidos/epidemiologia , Carga Viral
7.
Front Immunol ; 12: 708874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484208

RESUMO

Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3+CD4+ Tregs are well established, much of CD8+ Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8+ T cells have been named "CD8+ Treg" and mainly focus on CD122hiLy49+CD8+ Tregs present in naïve mice. CD122hiLy49+CD8+ Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-ß (Transforming growth factor-ß) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8+ Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8+ Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4+ TFR (follicular regulatory T cells) and CD8+ Tregs.

8.
Oncol Lett ; 22(4): 739, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34466151

RESUMO

Abnormal expression of microfibrillar-associated protein 2 (MFAP2), a key regulator of cellular differentiation, affects the occurrence and progression of tumors. However, the underlying role of MAFP2 in hepatocellular carcinoma (HCC) remains unclear. In the present study, patterns of MFAP2 expression in HCC were analyzed using sequencing data from The Cancer Genome Atlas database. Expression profiles of MFAP2, as well as those of epithelial-mesenchymal transition (EMT)-related proteins, were compared between HCC pathological sections and fresh tissues. Thereafter, associations between patterns of MFAP2 expression and the clinicopathological characteristics of patients, and identified risk factors associated with disease-free survival (DFS) and overall survival (OS), were determined. The functions of MFAP2 in the EMT-induced proliferation and migration of MHCC97H cells were investigated using in vitro experiments, and the effects of MFAP2 on vascular endothelial growth factor A (VEGFA)-induced tumor angiogenesis were also investigated. Upregulation of MFAP2 expression was observed in HCC, and was often accompanied by the abnormal expression of EMT-related marker proteins. In addition, analysis of clinical data from 94 patients with tumor tissues revealed a significant positive correlation between MFAP2 expression and low DFS and low OS following surgery. Through in vitro experimentation, silencing MFAP2 expression was shown inhibit EMT, which thereby inhibited cellular proliferation and migration. Moreover, downregulation of MFAP2 inhibited tumor angiogenesis via the inhibition of VEGFA. Taken together, these findings indicate that MFAP2 has the potential to predict the prognosis of patients with HCC. MFAP2 also induces tumor cell proliferation and migration through EMT, and promotes tumor blood vessel formation through VEGFA, suggesting that MFAP2 may be a potential therapeutic target for HCC.

9.
J Vasc Interv Radiol ; 32(9): 1371-1374, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34462080

RESUMO

This study reported data that were collected from 11 consecutive patients undergoing treatment for acute cardioembolic extracranial carotid artery (ECCA) occlusion with extensive clot burden via the guide catheter aspiration (GCA) technique. The GCA technique was performed as a direct aspiration using 2 60-mL syringes simultaneously through an 8-F guide catheter. Successful reperfusion was achieved in all 11 patients at the end of thrombectomy, and successful reperfusion was observed in 4 patients after a single GCA procedure pass. A favorable clinical outcome was achieved in 6 (54.5%) cases after 90 days. Thus, the GCA technique is efficacious for patients with cardioembolic ECCA occlusions.


Assuntos
Acidente Vascular Cerebral , Artérias Carótidas , Cateteres , Humanos , Estudos Retrospectivos , Trombectomia , Resultado do Tratamento
10.
Cell Death Dis ; 12(7): 629, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145217

RESUMO

Detachment is the initial and critical step for cancer metastasis. Only the cells that survive from detachment can develop metastases. Following the disruption of cell-extracellular matrix (ECM) interactions, cells are exposed to a totally different chemical and mechanical environment. During which, cells inevitably suffer from multiple stresses, including loss of growth stimuli from ECM, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake, and increased reactive oxygen species generation. Here we review the impact of these stresses on the anchorage-independent survival and the underlying molecular signaling pathways. Furthermore, its implications in cancer metastasis and treatment are also discussed.


Assuntos
Adesão Celular , Movimento Celular , Junções Célula-Matriz/patologia , Mecanotransdução Celular , Neoplasias/patologia , Animais , Sobrevivência Celular , Junções Célula-Matriz/metabolismo , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/metabolismo , Estresse Mecânico , Microambiente Tumoral
11.
World Neurosurg ; 152: e302-e312, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058360

RESUMO

OBJECTIVE: To examine the impact of marital status on the mortality of patients with primary malignant brain tumors excluding bias from basic characteristics and treatment. METHODS: We used the Surveillance, Epidemiology, and End Results program to identify 81,277 patients diagnosed from 2000 through 2016 with the most common primary malignant brain tumors, including glioma, ependymoma, and medulloblastoma. To avoid bias, we used the propensity score matching method to match 44,854 patients with complete clinical and follow-up information. Then, we used Cox regression and Kaplan-Meier survival analysis to investigate the impact of marital status on cancer patient mortality. RESULTS: Married patients were more likely to receive surgery and adjuvant chemo- or radiotherapy than single and divorced, separated, and widowed (DSW) patients (all P < 0.001). Married patients with high grade glioma were more likely to survive longer and less likely to die of their malignance compared with single (adjusted odds ratio [OR] 1.120; 95% confidence interval [CI], 1.069 to 1.174; P < 0.001; OR 1.078; 95% CI, 1.025 to 1.133; P = 0.003; respectively), and DSW patients (OR 1.117; 95% CI, 1.074 to 1.161; P <0.001; OR 1.090; 95% CI, 1.046 to 1.136; P<0.001; respectively) (all adjusted to the married group). Similar results were identified in patients with low-grade glioma but not ependymoma and medulloblastoma. CONCLUSIONS: Even after adjusting for known confounders, married patients with high-grade glioma and low-grade glioma are at higher possibility to have a better outcome. This study highlights the potential significance that intimate support from spouse can improve glioma patient survival.


Assuntos
Neoplasias Encefálicas/mortalidade , Glioma/mortalidade , Estado Civil , Programa de SEER , Adulto , Idoso , Neoplasias Encefálicas/epidemiologia , Divórcio , Ependimoma/mortalidade , Feminino , Glioma/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/mortalidade , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento
12.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664496

RESUMO

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimologia , Caderinas/metabolismo , Glioblastoma/enzimologia , RNA Circular/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos CD/genética , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos Nus , Invasividade Neoplásica , RNA Circular/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
EClinicalMedicine ; 32: 100732, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33681741

RESUMO

Background: Therapeutic hypothermia may need prolonged duration for the patients with severe traumatic brain injury (sTBI). Methods: The Long-Term Hypothermia trial was a prospective, multicenter, randomized, controlled clinical trial to examine the safety and efficacy in adults with sTBI. Eligible patients were 18-65, Glasgow Coma Scale score at 4 to 8, and initial intracranial pressure (ICP) ≥ 25 mm Hg, randomly assigned to the long-term mild hypothermia group (34-35 °C for 5 days) or normothermia group at 37 °C. The primary outcome was the Glasgow outcome scale (GOS) at 6 months. Secondary outcomes included ICP control, complications and laboratory findings, the length of ICU and hospital stay, and GOS at 6 months in patients with initial ICP ≥ 30 mm Hg. This trial is registered with ClinicalTrials.gov, NCT01886222. Findings: 302 patients were enrolled from June 25, 2013, to December 31, 2018, with 6 months follow-up in 14 hospitals, 156 in hypothermia group and 146 in normothermia group. There was no difference in favorable outcome (OR 1·55, 95%CI 0·91-2·64; P = 0·105) and in mortality (P = 0·111) between groups. In patients with an initial ICP ≥ 30 mm Hg, hypothermic treatment significantly increased favorable outcome over normothermia group (60·82%, 42·71%, respectively; OR 1·861, 95%CI 1·031-3·361; P = 0·039). Long-term mild hypothermia did not increase the incidences of complications. Interpretation: Long-term mild hypothermia did not improve the neurological outcomes. However, it may be a potential option in sTBI patients with initial ICP ≥ 30 mm Hg. Funding: : Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine.

14.
Theranostics ; 11(10): 4929-4944, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754036

RESUMO

Rationale: Recently, long non-coding RNAs (lncRNAs), known to be involved in human cancer progression, have been shown to encode peptides with biological functions, but the role of lncRNA-encoded peptides in cellular senescence is largely unexplored. We previously reported the tumor-suppressive role of PINT87aa, a peptide encoded by the long intergenic non-protein coding RNA, p53 induced transcript (LINC-PINT). Here, we investigated PINT87aa's role in hepatocellular carcinoma (HCC) cellular senescence. Methods: We examined PINT87aa and truncated PINT87aa functions in vitro by monitoring cell proliferation and performed flow cytometry, senescence-associated ß-galactosidase staining, JC-1 staining indicative of mitochondrial membrane potential, the ratio of the overlapping area of light chain 3 beta (LC3B) and mitochondrial probes and the ratio of lysosomal associated membrane protein 1 (LAMP1) overlapping with cytochrome c oxidase subunit 4I1 (COXIV) denoting mitophagy. PINT87aa and truncated PINT87aa functions in vivo were verified by subcutaneously transplanted tumors in nude mice. The possible binding between PINT87aa and forkhead box M1 (FOXM1) was predicted through structural analysis and verified by co-immunoprecipitation and immunofluorescence co-localization. Rescue experiments were performed in vivo and in vitro following FOXM1 overexpression. Further, chromatin immunoprecipitation, polymerase chain reaction, and dual-luciferase reporter gene assay were conducted to validate FOXM1 binding to the prohibitin 2 (PHB2) promoter. Results: PINT87aa was significantly increased in the hydrogen peroxide-induced HCC cell senescence model. Overexpression of PINT87aa induced growth inhibition, cellular senescence, and decreased mitophagy in vitro and in vivo. In contrast, FOXM1 gain-of-function could partially reduce the proportion of senescent HCC cells and enhance mitophagy. PINT87aa overexpression did not affect the expression of FOXM1 itself but reduced that of its target genes involved in cell cycle and proliferation, especially PHB2, which was involved in mitophagy and transcribed by FOXM1. Structural analysis indicated that PINT87aa could bind to the DNA-binding domain of FOXM1, which was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Furthermore, we demonstrated that the 2 to 39 amino acid truncated form of the peptide exerted effects similarly to the full form. Conclusion: Our study established the role of PINT87aa as a novel biomarker and a key regulator of cellular senescence in HCC and identified PINT87aa as a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Senescência Celular/genética , Neoplasias Hepáticas/genética , Mitofagia/genética , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular Tumoral , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteína Forkhead Box M1/metabolismo , Células Hep G2 , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Transplante de Neoplasias , Peptídeos , RNA Longo não Codificante/genética
16.
World J Clin Cases ; 9(3): 651-658, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33553404

RESUMO

BACKGROUND: Pyogenic ventriculitis caused by extensively drug-resistant Acinetobacter baumannii (A. baumannii) is one of the most severe complications associated with craniotomy. However, limited therapeutic options exist for the treatment of A. baumannii ventriculitis due to the poor penetration rate of most antibiotics through the blood-brain barrier. CASE SUMMARY: A 68-year-old male patient with severe traumatic brain injury developed pyogenic ventriculitis on postoperative day 24 caused by extensively drug-resistant A. baumannii susceptible to tigecycline only. Successful treatment was accomplished through multi-route administration of tigecycline, including intravenous combined with continuous ventricular irrigation plus intraventricular administration. The pus was cleared on the 3rd day post-irrigation, and cerebrospinal fluid cultures were negative after 12 d. CONCLUSION: Our findings suggest that multi-route administration of tigecycline can be a therapeutic option against pyogenic ventriculitis caused by extensively drug-resistant A. baumannii.

17.
Genome Biol ; 22(1): 33, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446260

RESUMO

BACKGROUND: Aberrant activation of the Hedgehog pathway drives tumorigenesis of many cancers, including glioblastoma. However, the sensitization mechanism of the G protein-coupled-like receptor smoothened (SMO), a key component of Hedgehog signaling, remains largely unknown. RESULTS: In this study, we describe a novel protein SMO-193a.a. that is essential for Hedgehog signaling activation in glioblastoma. Encoded by circular SMO (circ-SMO), SMO-193a.a. is required for sonic hedgehog (Shh) induced SMO activation, via interacting with SMO, enhancing SMO cholesterol modification, and releasing SMO from the inhibition of patched transmembrane receptors. Deprivation of SMO-193a.a. in brain cancer stem cells attenuates Hedgehog signaling intensity and suppresses self-renewal, proliferation in vitro, and tumorigenicity in vivo. Moreover, circ-SMO/SMO-193a.a. is positively regulated by FUS, a direct transcriptional target of Gli1. Shh/Gli1/FUS/SMO-193a.a. form a positive feedback loop to sustain Hedgehog signaling activation in glioblastoma. Clinically, SMO-193a.a. is more specifically expressed in glioblastoma than SMO and is relevant to Gli1 expression. Higher expression of SMO-193a.a. predicts worse overall survival of glioblastoma patients, indicating its prognostic value. CONCLUSIONS: Our study reveals that SMO-193a.a., a novel protein encoded by circular SMO, is critical for Hedgehog signaling, drives glioblastoma tumorigenesis and is a novel target for glioblastoma treatment.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Proteínas Hedgehog/genética , RNA Circular/genética , Transdução de Sinais/genética , Receptor Smoothened/genética , Animais , Neoplasias Encefálicas/patologia , Proliferação de Células , Transformação Celular Neoplásica , Modelos Animais de Doenças , Feminino , Glioblastoma/patologia , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores Patched/metabolismo , Receptor Smoothened/metabolismo , Células-Tronco
18.
Cell Metab ; 33(1): 128-144.e9, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33406399

RESUMO

The metabolic role of micropeptides generated from untranslated regions remains unclear. Here we describe MP31, a micropeptide encoded by the upstream open reading frame (uORF) of phosphatase and tensin homolog (PTEN) acting as a "circuit breaker" that limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+). Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifesting as accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumption and production. Conditional knockout (cKO) of MP31 homolog in mouse astrocytes initiated gliomagenesis and shortened the overall survival of the animals, establishing a tumor-suppressing role for MP31. Recombinant MP31 administered intraperitoneally penetrated the blood-brain barrier and inhibited mice GBM xenografts without neurological toxicity, suggesting the clinical implication and application of this micropeptide. Our findings reveal a novel mode of MP31-orchestrated lactate metabolism reprogramming in glioblastoma.


Assuntos
Ácido Láctico/metabolismo , Peptídeos/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Tensinas/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/deficiência
19.
JCI Insight ; 6(3)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33400692

RESUMO

2'3'-cGAMP is known as a nonclassical second messenger and small immune modulator that possesses potent antitumor and antiviral activities via inducing the stimulator of IFN genes-mediated (STING-mediated) signaling pathway. However, its function in regulating type 2 immune responses remains unknown. Therefore, we sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperreactivity induced by IL-33 and a fungal allergen, Aspergillus flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING/IFN regulatory factor 3/type I IFN signaling axis to induce the production of inhibitory factors containing IFN-α, which blocked the IL-33-mediated activation of group 2 innate lymphoid (ILC2) cells in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 cells in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.


Assuntos
Asma/imunologia , Interleucina-33/metabolismo , Linfócitos/imunologia , Macrófagos Alveolares/imunologia , Proteínas de Membrana/metabolismo , Alérgenos/administração & dosagem , Animais , Aspergillus flavus/imunologia , Asma/metabolismo , Asma/patologia , Modelos Animais de Doenças , Eosinofilia/imunologia , Eosinofilia/metabolismo , Eosinofilia/patologia , Feminino , Nucleotídeos de Guanina/administração & dosagem , Nucleotídeos de Guanina/imunologia , Nucleotídeos de Guanina/metabolismo , Humanos , Imunidade Inata , Técnicas In Vitro , Interleucina-33/administração & dosagem , Interleucina-33/genética , Linfócitos/patologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais
20.
iScience ; 24(1): 101975, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33474536

RESUMO

Stepwise induction of CD69 and CD103 marks distinct differentiation stages of mucosal Trms. But the majority of non-mucosal Trm lacks CD103 expression. The expression of CD69 alone cannot faithfully define Trm cells in heavily vascularized non-mucosal tissues, such as the kidney. Here, we found that a subset of kidney Trms downregulated IL-18 receptor during differentiation. Via global transcriptional analysis and parabiosis experiments, we have discovered that the downregulation of interleukin-18 receptor (IL-18R) is associated with the establishment of tissue residency. Together with the expression of CD69, IL-18Rlo exclusively identify tissue-resident cells whereas IL-18Rhi population contains both tissue-resident and migratory ones. Local cytokines including transforming growth factor ß (TGF-ß) and interferon α (IFN-α)/ß as well as TGF-ß-dependent suppression of transcription factor Tcf-1 are essential for IL-18R downregulation during kidney Trm differentiation. Together, we identified a convenient surface marker to distinguish bona fide kidney-resident CD8+ T cells as well as underlying molecular mechanisms controlling this differentiation process.

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