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1.
Infect Genet Evol ; 116: 105533, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37995886

RESUMO

BACKGROUND: Aspiration pneumonia is a common and severe clinical condition. The microbiome present in the lower respiratory tract plays a crucial role in regulating human inflammatory response. However, the relationship between the altered lower respiratory tract microbiome and inflammation in aspiration pneumonia remains inadequately explored. PURPOSE: To investigate the alteration of the lower respiratory tract microbiome in severe aspiration pneumonia patients and explore the potential correlation between microbiome components and inflammatory response. METHOD: Patients in the severe aspiration pneumonia group and control group were enrolled from the intensive care unit of Jinshan Hospital, Fudan University between December 31, 2020 and August 19, 2021. Sputum specimens were collected from all participants and subsequently subjected to 16S rDNA high throughput sequencing technology. The concentration of inflammatory cytokines in serum was measured using enzyme-linked immunosorbent assay (ELISA) kits, and collected data including patients' demographic information, clinical data, and laboratory examination results were recorded for further analysis. RESULTS: Alteration in the lower respiratory tract microbiome was observed in severe aspiration pneumonia. Compared to the control group, a significant decrease in the relative abundance of Firmicutes was found at the phylum level (P < 0.01). At the family level, the relative abundance of Corynebacteriaceae, Enterobacteriaceae and Enterococcaceae increased significantly (P < 0.001, P < 0.05, P < 0.01). There were no significant differences in community diversity of the lower respiratory tract between the two groups. Patients in the severe aspiration pneumonia group exhibited significantly higher levels of inflammation compared to those in the control group. Correlation analysis showed that the relative abundance of Corynebacteriaceae was positively correlated with the expression level of IL-1ß and IL-18 (P = 0.002, P = 0.02); the relative abundance of Enterobacteriaceae was negatively correlated with IL-4 (P = 0.011); no other significant correlations have been identified between microbiome and inflammatory indicators thus far (P > 0.05). CONCLUSIONS: Alteration of the lower respiratory tract microbiome is critically involved in inflammation and disease progression in severe cases of aspiration pneumonia. The potential inflammation regulation properties of the microbiome hold promising value for developing novel therapeutic approaches aimed at mitigating the severity of the disease.


Assuntos
Microbiota , Pneumonia Aspirativa , Humanos , Microbiota/genética , Sistema Respiratório , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação , RNA Ribossômico 16S/genética
2.
Angew Chem Int Ed Engl ; 62(46): e202312706, 2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-37793987

RESUMO

Inspired by the metal-oxo cluster structural feature and charge separation behaviour of the oxygen evolving center (OEC) in photosystem II (PS-II) under photoirradiation, a new crystalline photochromic polyoxomolybdate, MV2 [ß-Mo8 O26 ] (1, MV=methyl viologen cation), is designed as a biomimetic oxygen evolution reaction (OER) catalyst in neutral electrolytes. After photoinduced electron transfer (PIET) with colour change from colourless to grey, it remains in an ultra-stable charge-separated state over a year under ambient conditions. The observed overpotential at 10 mA ⋅ cm-2 and Tafel slope decrease by 49 mV and 62.8 mV ⋅ dec-1 after coloration, respectively. The outstanding OER performance of the coloured state in neutral electrolytes even outperforms the commercial RuO2 benchmark. Experimental and theoretical studies show that oxygen holes within polyanions after irradiation serve as sites for enhancing direct O-O coupling, thus effectively promoting OER. This is the first successful application of electron-transfer photochromism to realize OER activity gain.

3.
Cytotherapy ; 25(10): 1037-1047, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37436338

RESUMO

BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.


Assuntos
Neoplasias Nasofaríngeas , Receptores de Antígenos Quiméricos , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Citocinas/metabolismo , Imunoterapia Adotiva , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Proto-Oncogênicas c-met/metabolismo
4.
Int Immunopharmacol ; 121: 110402, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37301125

RESUMO

Colorectal cancer is globally ranked second in both incidence and mortality rate. It usually develops during the middle or late stages of diagnosis, and is characterized by easy metastasis, poor prognosis, and a significant decline in postoperative quality of life. ROR1 is an excellent oncoembryonic antigen in numerous immunotherapy treatments for tumors. Additionally, it is overexpressed in colorectal cancer. To fill the void in CRC treatment with ROR1 as a target of CAR-T immunotherapy, we designed and prepared antiROR1-CART. This third-generation CAR-T cell can effectively inhibit the growth of colorectal cancer in vitro and in vivo.


Assuntos
Neoplasias Colorretais , Linfócitos T , Humanos , Receptores de Antígenos de Linfócitos T , Qualidade de Vida , Linhagem Celular Tumoral , Neoplasias Colorretais/terapia , Imunoterapia Adotiva , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética
5.
Front Physiol ; 14: 1064699, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36960160

RESUMO

Introduction: This study investigates risk factors underlying the prognosis of severe aspiration pneumonia (SAP) in intensive care unit (ICU) patients and attempts to provide early prognosis reference for clinical tasks. Methods: Patients diagnosed with SAP and admitted to the ICU of Jinshan Hospital, Fudan University, Shanghai, China, between January 2021 and December 2021 were recruited in this retrospective cohort study. Clinical data on a patient's general condition, underlying diseases, laboratory indicators, and 90-day outcomes (survival or death) were recorded. Results: Multivariate logistic regression analysis showed that a low platelet count was an independent risk factor affecting the prognosis of death (OR = 6.68, 95% CI:1.10-40.78, ß = 1.90, P = 0.040). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of variables; cut-off values were calculated and the area under the curve was 0.7782 [(95% CI:0.686-0.871), p < 0.001] for the prediction of death at 90 days in all patients. The Kaplan-Meier curve used for survival analysis showed that, compared with the normal platelet group, the overall survival rate of patients with low platelet levels was significantly lower, and the difference was statistically significant [HR = 2.11, (95% CI:1.47-3.03), p = 0.0001, z = 4.05, X 2 = 14.89]. Cox regression analysis, used to further verify the influence of prognostic risk factors, showed that a concurrent low platelet count was the most important independent risk factor affecting the prognosis of SAP (HR = 2.12 [95% CI:1.12-3.99], X2 = 50.95, p = 0.021). Conclusion: These findings demonstrate an association between SAP mortality and platelet levels on admission. Thus, platelet level at admission may be used as a readily available marker for assessing the prognosis of patients with SAP.

6.
Mol Ther Oncolytics ; 28: 46-58, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36654786

RESUMO

Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. Cytokine-inducible SH2-containing protein (CISH), a member of the suppressor of cytokine signaling (SOCS) family, inhibits JAK-STAT and T cell receptor (TCR) signaling in T and natural killer (NK) cells. However, its role in the regulation of immune checkpoints in T cells remains unclear. In this study, we ablated CISH in T cells with CRISPR-Cas9 and found that the sensitivity of T cells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor T cells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient T cells in vitro and in vivo. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated T cells after CISH ablation. Hence, this study reveals a mechanism by which CISH promotes PD-1 expression by suppressing the expression of FBXO38 and proposes a new strategy for augmenting the therapeutic effect of CAR-T cells by inhibiting CISH.

7.
Clin Exp Med ; 23(6): 2409-2419, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36495368

RESUMO

Colorectal cancer (CRC) currently has a poor prognosis with a 6.9-year median survival time; to relieve this malignant cancer, we proposed to establish CRC xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR)-T cells and accelerate the clinical translation of CAR-T cells for use against CRC. We first verified that CD318 had a higher expression level in primary human CRC tissues than in normal tissues based on hundreds of clinical samples. Then, we redirected CAR-T cells containing anti-CD318 single-chain variable fragment (anti-CD318 scFv), CD3ζ, CD28, and Toll-like receptor 2 (TLR2) domains. Next, we evaluated the function of these CAR-T cells in vitro in terms of surface phenotype changes, cytotoxicity and cytokine secretion when they encountered CD318+ CRC cells. Finally, we established two different xenograft mouse models to assess in vivo antitumor activity. The results showed that CAR318 T cells were significantly activated and exhibited strong cytotoxicity and cytokine-secreting abilities against CRC cells in vitro. Furthermore, CAR318 T cells induced CRC regression in different xenograft mouse models and suppressed tumors compared with CAR19 T cells. In summary, our work demonstrates that CAR318 T cells possess strong antitumor capabilities and represent a promising therapeutic approach for CRC.


Assuntos
Neoplasias Colorretais , Receptores de Antígenos Quiméricos , Humanos , Animais , Camundongos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/genética , Imunoterapia Adotiva/métodos , Linhagem Celular Tumoral , Linfócitos T , Citocinas/metabolismo , Neoplasias Colorretais/terapia , Neoplasias Colorretais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Angew Chem Int Ed Engl ; 61(22): e202201590, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35289052

RESUMO

Achieving white-light emission, especially white circularly polarized luminescence (CPL) from a single-phase material is challenging. Herein, a pair of chiral CuI coordination polymers (1-M and 1-P) have been prepared by the asymmetrical assembly of achiral ligands and Cu2 I2 clusters. The compounds display dual emission bands and can be used as single-phase white-light phosphors, achieving a "warm"-white-light-emitting diode with an ultra-high color rendering index (CRI) of 93.4 and an appropriate correlated color temperature (CCT) of 3632 K. Meanwhile, corresponding CPL signals with maximum dissymmetry factor |glum |=8×10-3 have been observed. Hence, intrinsic white-light emission and CPL have been realized simultaneously in coordination polymers for the first time. This work gains insight into the nature of chiral assembly from achiral units and offers a prospect for the development of single-phase white-CPL materials.

9.
Front Immunol ; 12: 660488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326835

RESUMO

T cell infiltration into tumors is essential for successful immunotherapy against solid tumors. Herein, we found that the expression of hyaluronic acid synthases (HAS) was negatively correlated with patient survival in multiple types of solid tumors including gastric cancer. HA impeded in vitro anti-tumor activities of anti-mesothelin (MSLN) chimeric antigen receptor T cells (CAR-T cells) against gastric cancer cells by restricting CAR-T cell mobility in vitro. We then constructed a secreted form of the human hyaluronidase PH20 (termed sPH20-IgG2) by replacing the PH20 signal peptide with a tPA signal peptide and attached with IgG2 Fc fragments. We found that overexpression of sPH20-IgG2 promoted CAR-T cell transmigration through an HA-containing matrix but did not affect the cytotoxicity or cytokine secretion of the CAR-T cells. In BGC823 and MKN28 gastric cancer cell xenografts, sPH20-IgG2 promoted anti-mesothelin CAR-T cell infiltration into tumors. Furthermore, mice infused with sPH20-IgG2 overexpressing anti-MSLN CAR-T cells had smaller tumors than mice injected with anti-MSLN CAR-T cells. Thus, we demonstrated that sPH20-IgG2 can enhance the antitumor activity of CAR-T cells against solid tumors by promoting CAR-T cell infiltration.


Assuntos
Proteínas Ligadas por GPI/imunologia , Hialuronan Sintases/genética , Hialuronan Sintases/imunologia , Neoplasias Gástricas/imunologia , Linfócitos T/classificação , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Imunoterapia Adotiva , Mesotelina , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Organismos Livres de Patógenos Específicos , Neoplasias Gástricas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncogene ; 40(8): 1476-1489, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33452453

RESUMO

Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues was associated with the progression of cancer status, and was positively correlated with the Patient-derived xenograft model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.


Assuntos
Proliferação de Células/genética , Quimiocina CCL11/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Metástase Neoplásica , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Leukemia ; 35(5): 1380-1391, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33168950

RESUMO

Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.


Assuntos
Interleucina-6/imunologia , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células HEK293 , Humanos , Ativação Linfocitária/imunologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Sci Total Environ ; 747: 141222, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795795

RESUMO

Rainfall events have profound influence on the soil carbon release in different forest ecosystems. However, seasonal variations in soil respiration (RS) response to rainfall events and associated regulatory processes are not well documented in riparian forest ecosystems to date. We continuously measured soil respiration in a riparian plantation ecosystem from 2015 to 2018 to explore the relationships between soil respiration and rainfall events. Across the 4 years, 83 individual rainfall events were identified for spring, summer and autumn. We found that mean RS rate after rain (post-RS) was significantly higher than that before rain (pre-RS) (p < 0.05) in spring, and the relative change in soil respiration (RSrc) increased against rainfall size due to the stimulation by the significant increases in soil moisture content (ΔSM). In contrast, mean post-RS was lower than pre-RS and RSrc was significantly decreased with the increasing rainfall size (p < 0.01) in summer and autumn. Reduced changes in soil temperature (ΔTS) and increased soil moisture content after rain (post-SM) contributed to the decreased RS due to frequently occurring heavy rain events in summer. Increased ΔSM following rainfall events coupled with groundwater level increase suppressed RSrc in autumn, even though increased ΔTS could offset the negative effects of SM on RS to some extent. In addition, we found that higher post-SM after large rainfall events (>10 mm day-1) changed the response of RS to soil temperature (TS) by reducing the temperature sensitivity (Q10) even in this riparian plantation ecosystem. Our study highlights the importance of integrating seasonal difference in soil respiration response to rainfall events and the impact of large rainfall events on soil C release for estimating forest soil carbon cycling at multiple scales.


Assuntos
Populus , Solo , Ecossistema , Chuva , Estações do Ano , Temperatura
13.
J Athl Train ; 55(5): 515-521, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32239963

RESUMO

CONTEXT: A variety of factors have been linked to the occurrence of anterior cruciate ligament injury (ACLI), including sex, familial factors, and genetic variations. OBJECTIVE: To find the genetic loci associated with ACLI and explore the genetic mechanism of ACLI in order to provide a genetic basis for the diagnosis, prognosis, and treatment of patients with ACLI. DESIGN: Cross-sectional study. SETTING: Hospital. PATIENTS OR OTHER PARTICIPANTS: Data from 101 Chinese Yunnan Han patients with ACLI and 110 Yunnan Han individuals without ACLI (control group) were collected. MAIN OUTCOME MEASURE(S): The single nucleotide polymorphisms of COL1A1 rs1800012, COL5A1 rs12722 and rs13946, COL12A1 rs970547 and rs240736 and the rs1800787, rs1800788, rs1800789, rs1800790, rs1800791, and rs2227389 in the ß-fibrinogen (ß-fib) promoter region were analyzed using restriction fragment length polymorphism and DNA sequencing detection, and their genetic associations with ACLI were assessed. RESULTS: Single nucleotide polymorphisms of COL1A1 rs1800012, COL5A1 rs12722 and rs13946, and the rs1800789 and rs1800791 in the ß-fib promoter region showed no difference between patients with ACLI and control participants, but the changes of COL12A1 rs970547 and rs240736 and the rs1800787, rs1800788, rs1800790, and rs2227389 genotypes in the ß-fib promoter region were associated with ACLI. Furthermore, the rs970547 allele and genotype frequencies in male ACLI patients were different from the control group (P < .05): the frequencies of the rs970547 A and G alleles in the patients were 71.9% and 28.1%, respectively, and in the control group were 58.8% and 41.2%, respectively. The frequencies of AA, AG, and GG genotypes in the patients were 49.3%, 45.2%, and 5.5%, respectively, and in the control group were 27.5%, 62.7%, and 9.8%, respectively, suggesting that male carriers of rs970547 A and rs970547 AA were at high risk of ACLI. CONCLUSIONS: Males with the rs970547 A allele and rs970547 AA genotype of COL12A1 may be at high risk for ACLI. Low rs1800787 TT and high rs1800788 CT, rs1800790 AG, and rs2227389 CT frequencies as well as high TGA* of rs1800790, rs1800791, and rs2227389 in the ß-fib promoter region may be genetic risk factors related to ACLI.


Assuntos
Lesões do Ligamento Cruzado Anterior/genética , Povo Asiático/genética , Colágeno Tipo I/genética , Colágeno Tipo V/genética , Colágeno Tipo XII/genética , Fibrinogênio/genética , Adulto , Estudos de Casos e Controles , China , Cadeia alfa 1 do Colágeno Tipo I , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Risco
14.
Biomark Res ; 8: 3, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32010446

RESUMO

BACKGROUND: Gastric cancer is a deadly malignancy and is a prognostically unfavorable entity with restricted therapeutic strategies available. Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein widely expressed in bladder, prostate, and pancreatic cancers. Existing studies have thoroughly recognized the availability of utilizing anti-PSCA CAR-T cells in the treatment of metastatic prostate cancer and non-small-cell lung cancer. However, no previous study has investigated the feasibility of using anti-PSCA CAR-T cells to treat gastric cancer, irrespective of the proven expression of PSCA on the gastric cancer cell surface. METHODS: We determined the expression of PSCA in several primary tumor tissues and constructed third-generation anti-PSCA CAR-T cells. We then incubated anti-PSCA CAR-T cells and GFP-T cells with target tumor cell lines at E:T ratios of 2:1, 1:1, 1:2, and 1:4 to evaluate the therapeutic efficacy of anti-PSCA CAR-T cells in vitro. We also assayed canonical T cell activation markers after coculturing anti-PSCA CAR-T cells with target cell lines by flow cytometry. The detection of a functional cytokine profile was carried out via enzyme-linked immunosorbent assays. We then evaluated the antitumor activity of anti-PSCA CAR-T cells in vivo by establishing two different xenograft GC mouse models. RESULTS: Anti-PSCA CAR-T cells exhibited upregulated activation markers and increased cytokine production profiles related to T cell cytotoxicity in an antigen-dependent manner. Moreover, anti-PSCA CAR-T cells exhibited robust anti-tumor cytotoxicity in vitro. Importantly, we demonstrated that anti-PSCA CAR-T cells delivered by peritumoral injection successfully stunted tumor progression in vivo. However, intravenous administration of anti-PSCA CAR-T cells failed to reveal any therapeutic improvements. CONCLUSIONS: Our findings corroborated the feasibility of anti-PSCA CAR-T cells and their efficacy against gastric cancer, implicating the potential of applying anti-PSCA CAR-T cells to treat GC patients in the clinic.

15.
Biomark Res ; 7: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31463062

RESUMO

CAR-T cell therapy targeting CD19 has achieved remarkable success in the treatment of B cell malignancies, while various solid malignancies are still refractory for lack of suitable target. In recent years, a large number of studies have sought to find suitable targets with low "on target, off tumor" concern for the treatment of solid tumors. Mesothelin (MSLN), a tumor-associated antigen broadly overexpressed on various malignant tumor cells, while its expression is generally limited to normal mesothelial cells, is an attractive candidate for targeted therapy. Strategies targeting MSLN, including antibody-based drugs, vaccines and CAR-T therapies, have been assessed in a large number of preclinical investigations and clinical trials. In particular, the development of CAR-T therapy has shown great promise as a treatment for various types of cancers. The safety, efficacy, doses, and pharmacokinetics of relevant strategies have been evaluated in many clinical trials. This review is intended to provide a brief overview of the characteristics of mesothelin and the development of strategies targeting MSLN for solid tumors. Further, we discussed the challenges and proposed potential strategies to improve the efficacy of MSLN targeted immunotherapy.

16.
J Hematol Oncol ; 12(1): 18, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777106

RESUMO

BACKGROUND: Gastric cancer (GC) is a common cancer in Asia and currently lacks a targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells. Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T cells to treat GC remains to be studied. METHODS: We verified MSLN expression in primary human GC tissues and GC cell lines and then redirected T cells with a CAR containing the MSLN scFv (single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes when they encountered MSLN+ GC cells. We also established four different xenograft GC mouse models to assess in vivo antitumor activity. RESULTS: M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting ability against GC cells in vitro. In addition, cell surface phenotyping suggested significant activation of M28z10 T cells upon target cell stimulation. M28z10 T cells induced GC regression in different xenograft mouse models and prolonged the survival of these mice compared with GFP-transduced T cells in the intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue and significantly suppress the growth of GC in a subcutaneous GC model. CONCLUSION: These results demonstrate that M28z10 T cells possess strong antitumor activity and represent a promising therapeutic approach to GC.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Proteínas Ligadas por GPI/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/genética , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/farmacologia , Modelos Animais de Doenças , Proteínas Ligadas por GPI/farmacologia , Humanos , Mesotelina , Camundongos , Transfecção
17.
Opt Lett ; 43(13): 3037-3040, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29957775

RESUMO

A volume grating-based holographic sensor in highly stretchable PVA/AA polymer for sensing its micro-deformation and, hence, the displacement has been studied. One-dimensional micro-displacement induced by tensile stress is analyzed using a diffraction spectrum in two kinds of sensor construction methods, i.e., transmission and reflection. The dependence of the peak wavelength on the displacement presents a good linear relationship which provides a quantitative sensing strategy for hydrogel micro-deformation. The available sensitivity is better than 4 µm/0.5 nm (displacement/wavelength shift) using a commercial spectrometer with a resolution of 0.5 nm. Finally, the reversible deformation response further validates the practical applicability of a holographic sensor constructed by photosensitive hydrogel. The optical measurement of micro-displacement as a novel sensing strategy can accelerate the development of the holographic optical element.

18.
Zookeys ; (592): 143-53, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27408548

RESUMO

The range of the Amur leopard (Panthera pardus orientalis) has decreased dramatically over the last 100 years. This species is still under extreme risk of extinction and conservation efforts are rigorous. Understanding the long-term dynamics of the population decline would be helpful to offer insight into the mechanism behind the decline and endangerment and improve conservation perspectives and strategies. Historical data collection has been the challenge for reconstructing the historical distribution. In China, new gazetteers having systematic compilation and considerable local ecological data can be considered as an important complementary for reconstruction. Therefore, we have set up a data set (mainly based on the new gazetteers) in order to identify the historical range of the Amur Leopard from the 1950s to 2014. The result shows that the Amur leopard was historically widely distributed with large populations in Northeastern China, but it presented a sharp decline after the 1970s. The decline appeared from the plains to the mountains and northeast to southwest since the 1950s. Long-term historical data, mainly from new gazetteers, demonstrates that such resources are capable of tracking species change through time and offers an opportunity to reduce data shortage and enhance understanding in conservation.

19.
J Am Geriatr Soc ; 64(5): 1068-72, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27131061

RESUMO

OBJECTIVES: To assess the serum of 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (iPTH) levels in postmenopausal women from northern China with hip and upper limb fractures. DESIGN: Case-control. SETTING: Affiliated Hospital of Qingdao University. PARTICIPANTS: Postmenopausal women diagnosed with hip fracture (n = 335) and matched controls without fracture (n = 335). MEASUREMENTS: Between 2011 and 2013, fasting venous samples were analyzed for 25(OH)D, iPTH, alkaline phosphatase (ALP), calcium, and phosphorus. All women completed a standardized questionnaire designed to document putative risk factors for fractures. RESULTS: Eight percent of participants had vitamin D deficiency, and 66.0% had secondary hyperparathyroidism. Serum 25(OH)D levels were significantly (P < .001) lower in women with hip fracture than in controls. Multivariate logistic regression analysis adjusted for common risk factors showed that serum 25(OH)D of 20 ng/mL or less was an independent indicator of hip fracture (odds ratio (OR) = 2.98, 95% confidence interval (CI) = 2.11-4.20) and concomitant upper limb fracture in those with existing hip fractures (OR = 4.77, 95% CI = 1.60-10.12). The area under the receiver operating characteristic curve of 25(OH)D was 0.77 (95% CI = 0.68-0.84) for hip fracture and 0.80 (95% CI = 0.72-0.89) for hip and upper limb fractures. CONCLUSION: Vitamin D insufficiency and secondary hyperparathyroidism were a common problem in postmenopausal women who presented with concomitant hip and upper limb fractures, suggesting that they might contribute to the pathophysiology of fractures in postmenopausal women.


Assuntos
Traumatismos do Braço/epidemiologia , Fraturas Ósseas/epidemiologia , Fraturas do Quadril/epidemiologia , Hormônio Paratireóideo/sangue , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Idoso , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Cálcio/sangue , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Hiperparatireoidismo/epidemiologia , Pessoa de Meia-Idade , Fósforo/sangue , Pós-Menopausa , Fatores de Risco , Inquéritos e Questionários , Vitamina D/sangue
20.
Opt Express ; 23(22): 29113-26, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26561180

RESUMO

Holographic sensing of organic vapor is characterized at transmission and reflection geometries in ZSM-5 nanozeolites dispersed acrylamide photopolymer. Nano-zeolites as absorption medium are dispersed into the polymer to enhance the absorptivity to organic vapor. Obvious enhancements of spectrum strength are observed during the sensing process. Two primary factors causing the enhancement, absorption of nanozeolites and photopolymerization induced by broadband white light, are analyzed experimentally. Significant increment provides a quick and intuitive identification strategy for holographic sensing. Accompanying with the wavelength blue-shift, the shrinkage of sample is measured quantitatively under homogeneous white light. It is further demonstrated that the significance of nanozeolites absorption. Finally a theoretical model with mutual diffusion is used to simulate the swelling process. This study provides significant foundation for the application of holographic sensor.

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