RESUMO
The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Nanopartículas , Humanos , Feminino , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Microambiente TumoralRESUMO
As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.
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COVID-19/terapia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , HumanosRESUMO
BACKGROUND: BI-RADS 4 breast lesions are suspicious for malignancy with a range from 2 to 95%, indicating that numerous benign lesions are unnecessarily biopsied. Thus, we aimed to investigate whether high-temporal-resolution dynamic contrast-enhanced MRI (H_DCE-MRI) would be superior to conventional low-temporal-resolution DCE-MRI (L_DCE-MRI) in the diagnosis of BI-RADS 4 breast lesions. METHODS: This single-center study was approved by the IRB. From April 2015 to June 2017, patients with breast lesions were prospectively included and randomly assigned to undergo either H_DCE-MRI, including 27 phases, or L_DCE-MRI, including 7 phases. Patients with BI-RADS 4 lesions were diagnosed by the senior radiologist in this study. Using a two-compartment extended Tofts model and a three-dimensional volume of interest, several pharmacokinetic parameters reflecting hemodynamics, including Ktrans, Kep, Ve, and Vp, were obtained from the intralesional, perilesional and background parenchymal enhancement areas, which were labeled the Lesion, Peri and BPE areas, respectively. Models were developed based on hemodynamic parameters, and the performance of these models in discriminating between benign and malignant lesions was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 140 patients were included in the study and underwent H_DCE-MRI (n = 62) or L_DCE-MRI (n = 78) scans; 56 of these 140 patients had BI-RADS 4 lesions. Some pharmacokinetic parameters from H_DCE-MRI (Lesion_Ktrans, Kep, and Vp; Peri_Ktrans, Kep, and Vp) and from L_DCE-MRI (Lesion_Kep, Peri_Vp, BPE_Ktrans and BPE_Vp) were significantly different between benign and malignant breast lesions (P < 0.01). ROC analysis showed that Lesion_Ktrans (AUC = 0.866), Lesion_Kep (AUC = 0.929), Lesion_Vp (AUC = 0.872), Peri_Ktrans (AUC = 0.733), Peri_Kep (AUC = 0.810), and Peri_Vp (AUC = 0.857) in the H_DCE-MRI group had good discrimination performance. Parameters from the BPE area showed no differentiating ability in the H_DCE-MRI group. Lesion_Kep (AUC = 0.767), Peri_Vp (AUC = 0.726), and BPE_Ktrans and BPE_Vp (AUC = 0.687 and 0.707) could differentiate between benign and malignant breast lesions in the L_DCE-MRI group. The models were compared with the senior radiologist's assessment for the identification of BI-RADS 4 breast lesions. The AUC, sensitivity and specificity of Lesion_Kep (0.963, 100.0%, and 88.9%, respectively) in the H_DCE-MRI group were significantly higher than those of the same parameter in the L_DCE-MRI group (0.663, 69.6% and 75.0%, respectively) for the assessment of BI-RADS 4 breast lesions. The DeLong test was conducted, and there was a significant difference only between Lesion_Kep in the H_DCE-MRI group and the senior radiologist (P = 0.04). CONCLUSIONS: Pharmacokinetic parameters (Ktrans, Kep and Vp) from the intralesional and perilesional regions on high-temporal-resolution DCE-MRI, especially the intralesional Kep parameter, can improve the assessment of benign and malignant BI-RADS 4 breast lesions to avoid unnecessary biopsy.
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Neoplasias da Mama , Meios de Contraste , Feminino , Humanos , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética/métodos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Omalizumab is a valuable alternative treatment for allergic bronchopulmonary aspergillosis (ABPA). The effectiveness and safety of this medication have not been confirmed. The main purpose of this study was to evaluate the effectiveness and safety of omalizumab for ABPA. METHODS: This study involved a retrospective chart review. The main indicators used were asthma control test (ACT) scores, lung function parameters, doses of corticosteroids, acute exacerbation, hospitalization rates, total serum immunoglobulin E (IgE) levels, and blood eosinophil counts. Related adverse events were also reviewed to evaluate the safety of omalizumab. RESULTS: Fourteen patients with ABPA were included, of whom 10 (71%) concurrently had allergic rhinitis (AR). There were improvements in the mean percentages of the forced vital capacity, percentages of the forced expiratory volume in 1 s, and ACT score after omalizumab administration (p < 0.05, p < 0.01, and p < 0.01, respectively). After the initiation of omalizumab administration, the median corticosteroid dose, acute exacerbation rate, hospitalization rate, and mean blood eosinophil count decreased when compared with the baseline values (p < 0.05, p < 0.05, p < 0.01, and p < 0.05, respectively). A reduction in the total serum IgE level was observed in patients with ABPA without AR compared with that in patients with AR (p < 0.05). One patient reported a concurrent skin rash, which spontaneously resolved without medication. CONCLUSION: It is safe and effective to prescribe omalizumab to patients with ABPA, irrespective of whether they have AR. Dose adjustment of omalizumab is safe after disease control. The total serum IgE level might be a predictor of the effectiveness of omalizumab in patients without AR.
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Antialérgicos , Aspergilose Broncopulmonar Alérgica , Rinite Alérgica , Humanos , Omalizumab/uso terapêutico , Antialérgicos/uso terapêutico , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Estudos Retrospectivos , Corticosteroides/uso terapêutico , Rinite Alérgica/complicações , Rinite Alérgica/tratamento farmacológico , Imunoglobulina ERESUMO
Cell-extracellular matrix (ECM) detachment is known to decrease extracellular signal-regulated kinase (ERK) signaling, an intracellular pathway that is central for control of cell behavior. How cell-ECM detachment is linked to downregulation of ERK signaling, however, is incompletely understood. We show here that focal adhesion protein Ras Suppressor 1 (RSU1) plays a critical role in cell-ECM detachment induced suppression of ERK signaling. We have identified prohibitin 2 (PHB2), a component of membrane lipid rafts, as a novel binding protein of RSU1, and mapped a major RSU1-binding site to PHB2 amino acids 150 to 206 in the C-terminal region of the PHB/SPFH (stomatin/prohibitin/flotillin/HflKC) domain. The PHB2 binding is mediated by multiple sites located in the N-terminal leucine-rich repeat region of RSU1. Depletion of PHB2 suppressed cell-ECM adhesion-induced ERK activation. Furthermore, cell-ECM detachment increased RSU1 association with membrane lipid rafts and interaction with PHB2. Finally, knockout of RSU1 or inhibition of RSU1 interaction with PHB2 by overexpression of the major RSU1-binding PHB2 fragment (amino acids 150-206) effectively suppressed the cell-ECM detachment induced downregulation of ERK signaling. Additionally, expression of venus-tagged wild-type RSU1 restored ERK signaling, while expression of venus-tagged PHB2-binding defective RSU1 mutant in which the N-terminal leucine-rich repeat region is deleted did not. Taken together, Our findings identify a novel RSU1-PHB2 signaling axis that senses cell-ECM detachment and links it to decreased ERK signaling.
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Regulação para Baixo , Matriz Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Matriz Extracelular/genética , Humanos , Proibitinas , Proteínas Repressoras/genéticaRESUMO
OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fatores de RiscoRESUMO
We report that the pincer nickel complexes display prostate cancer antitumor properties through inhibition of cell proliferation. Notably, they display better antitumor properties than cisplatin. Mechanistic studies reveal that these pincer nickel complexes trigger cell apoptosis, most likely due to cell cycle arrest. Interestingly, these complexes also inhibit androgen receptor (AR) and prostate-specific antigen (PSA) signaling, which are critical for prostate cancer survival and progression. Our study reveals a novel function of pincer nickel complexes as potential therapeutic drugs in prostate cancer.
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Antineoplásicos , Neoplasias da Próstata , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Masculino , Níquel , Pelve/patologia , Neoplasias da Próstata/patologiaRESUMO
There has been a rapid progress in developing genetically engineered T cells in recent years both in basic and clinical cancer studies. Chimeric antigen receptor (CAR)-T cells exert an immune response against various cancers, including the non-small-cell lung cancer (NSCLC). As novel agents of immunotherapy, CAR-T cells show great promise for NSCLC. However, targeting specific antigens in NSCLC with engineered CAR-T cells is complicated because of a lack of tumor-specific antigens, the immunosuppressive tumor microenvironment, low levels of infiltration of CAR-T cells into tumor tissue, and tumor antigen escape. Meanwhile, the clinical application of CAR-T cells remains limited due to the cases of on-target/off-tumor and neurological toxicity, as well as cytokine release syndrome. Hence, optimal CAR-T-cell design against NSCLC is urgently needed. In this review, we describe the basic structure and generation of CAR-T cells and summarize the common tumor-associated antigens targeted in clinical trials on CAR-T-cell therapy for NSCLC, as well as point out current challenges and novel strategies. Although many obstacles remain, the new/next generation of CARs show much promise. Taken together, research on CAR-T cells for the treatment of NSCLC is underway and has yielded promising preliminary results both in basic and pre-clinical medicine. More pre-clinical experiments and clinical trials are, therefore, warranted.
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Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia Adotiva , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Ensaios Clínicos como Assunto , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/diagnóstico , Prognóstico , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Resultado do TratamentoRESUMO
OBJECTIVE: The study was primarily used to evaluate subchronic oral toxicity of rhubarb extract. METHODS: The rhubarb extract was orally administered to rats at doses of 0.00, 0.65, 1.62 and 4.05 g/kg BW/day for 13 weeks with a recovery period of 4 weeks. The weight and the relative organ weight of the kidney in the 0.65 g/kg BW group were significantly increased but no significant changes were seen in renal histopathology. When the rats received rhubarb extract at 1.62 g/kg BW or above, the relative weight of the spleen and kidney were significantly increased; the kidney was also swollen and black with hydronephrosis. Histologic examination showed that there was an obvious increase in pigment deposition in renal tubular epithelial cells. No toxic related changes were observed in the 0.65 g/kg BW group, even though organ weight was increased and relative ratio to body weight of kidney were observed at 0.65 g/kg BW dosage, no significant renal histopathologic changes were detected at this dose. Based on the current study conditions and results, the no observed adverse effect level (NOAEL) of rhubarb extract in rats is 0.65 g/kg BW/day.
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Extratos Vegetais/toxicidade , Rheum/toxicidade , Animais , Rim , Nível de Efeito Adverso não Observado , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade SubcrônicaRESUMO
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). OBJECTIVES: We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. METHODS: We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR-/-) mast cells. The role of ox-CaMKII in mast cell activation was further investigated. RESULTS: Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR-/- mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation. CONCLUSIONS: These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Pólipos Nasais/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Glutamato/imunologia , Rinite/imunologia , Sinusite/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/imunologia , Doença Crônica , Eosinófilos/imunologia , Eosinófilos/patologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Knockout , Pólipos Nasais/genética , Pólipos Nasais/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Glutamato/genética , Rinite/genética , Rinite/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Sinusite/genética , Sinusite/patologiaRESUMO
OBJECTIVE: To observe the sub-chronic toxicity of songaria cynomorium herb aqueous extract in rat at different oral dose levels. METHODS: The study was conducted according to the protocol of sub-chronic toxicity study in rat in Procedures and Method for Toxicolohical Assessment on Food Safety(GB 15193. 13-2015). Total 80 SPF grade Wistar rats, weighing 60-80 g, were randomized into 4 groups of 10/sex/group based on their body weight. The animals from groups 1 to 4 were orally dosed once daily with songaria cynomorium herb aqueous-soluble extract at 0, 2. 83, 5. 66 and 8. 49 g/kg BW respectively for continuous 90 days. And the dose volume was 13 mL/kg. The clinical signs, body weight, food consumption, food utilization rate, hematology, serum chemistry and histopathology were monitored or tested. RESULTS: No obvious toxic signs were observed and no animals were found dead during the whole study. There were no significant differences between the control and test article groups in the body weight, food consumption, food utilization rate. Although some hematology and serum chemistry parameters in a single dose group changed significantly, their values were still in the normal ranges of our laboratory. Therefore, all the above changes were not considered as adverse effects. However, the prothrombin time(PT) at male middle and high dose group prolonged significantly(P<0. 05). In addition, Compared with that of control, significantly increased testes index was observed in the mid-dose group, while increased spleen index, testes index, epididymis index were observed in high-dose group. no obvious histopathology changes were detected in all test article groups. CONCLUSION: Under the condition of this experiment, the No-observed-adverse-effect-level(NOAEL) was 2. 83 g/kg BW and the lowest-observed-adverse-effect-level(LOAEL) was 5. 66 g/kg BW for songaria cynomorium herb aqueous-soluble extract in the rat sub-chronic toxicity study.
Assuntos
Cynomorium , Extratos Vegetais , Animais , Cynomorium/toxicidade , Relação Dose-Resposta a Droga , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão , Extratos Vegetais/toxicidade , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade SubcrônicaRESUMO
Background: Immune-related thyroid dysfunction (irTD) is a common immune-related adverse event (irAE). The potential biomarkers of irTDs and their impact on the clinical outcomes of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) remain unclear. We aimed to identify potential biomarkers of irTDs and reveal the association between irTDs and the clinical outcomes in patients with NSCLC treated with ICIs. Methods: We conducted a retrospective study on 126 patients with NSCLC, who were treated with pembrolizumab, sintilimab, atezolizumab, or camrelizumab, as first-line therapy, at the First Affiliated Hospital, College of Medicine, Zhejiang University, between July 2019 and February 2023. Anti-thyroid antibodies (ATAs), thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb), serum interleukin-6 (IL-6), thyroid ultrasonography, overall survival (OS), and progression-free survival (PFS) were the main indicators. Results: Most (92.9%) irTD cases occurred no later than one year after ICIs initiation. Patients with irTDs had higher positive rates for ATAs and TPOAb [33.3% vs. 1.3%, and 30.3% vs. 1.3%, both P<0.01, odds ratio (OR) =39.81, and OR =35.46, respectively]. Irregular echo pattern and diffuse changes were more common in patients with irTDs (70.7% vs. 47.2%, and 19.5% vs. 1.4%, P<0.05 and P<0.01, OR =2.70, and OR =17.21, respectively). OS and PFS were similar in patients with and without irTDs (P>0.05). Conclusions: The ATAs, TPOAb, and abnormal thyroid ultrasonographic findings (irregular echo patterns and diffuse changes) are potential biomarkers of irTDs. Patients with NSCLC treated with ICIs (pembrolizumab, sintilimab, atezolizumab, and camrelizumab) who developed irTDs had no advantage in terms of clinical outcomes compared to euthyroid patients.
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The role of CD161+CD127+CD8+ T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8+ T cell subsets in NSCLC with diabetes. We recruited NSCLC patients (n = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS (p = 0.0069 and p = 0.012, respectively) and significantly lower CD8+ T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161+CD127+CD8+ T cells among CD8+T cells in NSCLC with diabetes before anti-PD-1 treatment (p = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment (p = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161+CD127+CD8+ T cells to CD8+T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161+CD127+CD8+ T cell subset compared to CD161+CD127-CD8+ T cells in NSCLC with diabetes. CD161+CD127+CD8+ T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161+CD127+CD8+ T cells to CD8+T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161+CD127+CD8+ T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Feminino , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Idoso , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Diabetes Mellitus/imunologia , Diabetes Mellitus/tratamento farmacológico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Prognóstico , AdultoRESUMO
Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.
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BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear. PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC. RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis. CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Pulmonares , Células T Invariantes Associadas à Mucosa , Receptores CXCR6 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores CXCR6/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Masculino , Feminino , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-Idade , Idoso , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Liver fibrosis can cause hepatitis B virus (HBV)-associated hepatocellular carcinoma. Menstrual blood-derived mesenchymal stem cells (MenSCs) can ameliorate liver fibrosis through paracrine. Single-cell RNA sequencing (scRNA-seq) may be used to explore the roadmap of activated hepatic stellate cell (aHSC) inactivation to target liver fibrosis. This study established HBV transgenic (HBV-Tg) mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis and demonstrated that MenSCs migrated to the injured liver to improve serological indices and reduce fibrotic accumulation. RNA-bulk analysis revealed that MenSCs mediated extracellular matrix accumulation and cell adhesion. Liver parenchymal cells and nonparenchymal cells were identified by scRNA-seq in the control, CCl4, and MenSC groups, revealing the heterogeneity of fibroblasts/HSCs. A CellChat analysis revealed that diminished intercellular adhesion molecule (ICAM) signaling is vital for MenSC therapy. Specifically, Icam1 in aHSCs acted on Itgal/Itgb2 and Itgam/Itgb2 in neutrophils, causing decreased adhesion. The expression of Itgal, Itgam, and Itgb2 was higher in CCl4 group than in the control group and decreased after MenSC therapy in neutrophil clusters. The Lcn2, Pglyrp1, Wfdc21, and Mmp8 had high expression and may be potential targets in neutrophils. This study highlights interacting cells, corresponding molecules, and underlying targets for MenSCs in treating HBV-associated liver fibrosis.
RESUMO
Environmental pollution, as a byproduct of economic growth, causes negative pressure on human health. Its sustainability management performance is closely bound up with the ecological carrying capacity. Due to the limited carrying capacity of ecosystems to pollutants, the hidden costs of pollutants may increase when pollutants flow and spread. This is an external manifestation of the internal resource imbalance within the ecosystem, restricting the sustainability of economy and environment and overlooked by most studies that target sustainability performance evaluation. Thus, this study considers the internal resource imbalance during the sustainability performance evaluation for the first time in the context of the interaction among economy, environment, and human health, by constructing a production-treatment-health framework, proposing an internal resource imbalance index and developing an additive aggregation network data envelopment analysis model with the semidefinite programming technology. This study takes 30 Chinese provinces from 2012 to 2017 as the research objects and confirms the effectiveness of sustainability management in terms of water pollution purification and water ecological construction.
Assuntos
Ecossistema , Poluentes Ambientais , Humanos , Conservação dos Recursos Naturais , Poluição da Água , Desenvolvimento Econômico , ChinaRESUMO
Anthraquinone is a recently identified contaminant present in teas globally, and its potential teratogenic and genotoxic impacts have yet to be fully comprehended. Hence, this study's objective was to determine anthraquinone's genotoxicity using various studies such as the Ames test, Mammalian erythrocyte micronucleus test, and in-vitro mammalian chromosome aberration study. Additionally, the study assessed its effects on maternal gestational toxicity and the fetus's teratogenicity through prenatal developmental toxicity research in rats. Results indicated that anthraquinone did not manifest mutagenic effects on Salmonella typhimurium histidine-deficient, did not cause chromosomal aberrations in Chinese hamster ovary cell subclone CHO-K1, and did not exhibit a genotoxic effect on mouse bone marrow erythrocytes. However, in the prenatal developmental toxicity study, administering anthraquinone orally to pregnant rats from day 5 to day 19 of gestation resulted in decreased body weight and food consumption of pregnant rats, along with a higher number of visceral malformations in the fetuses in the highest dose group (217.6 mg/kg BW). Additionally, two pregnant rats died in this group. The study has established the no observed adverse effect level (NOAEL) as 21.76 mg/kg BW, while the lowest observed adverse effect level (LOAEL) was 217.6 mg/kg BW.
Assuntos
Aberrações Cromossômicas , Mutagênicos , Camundongos , Cricetinae , Gravidez , Feminino , Ratos , Animais , Células CHO , Cricetulus , Testes para Micronúcleos , Mutagênicos/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Antraquinonas/toxicidadeRESUMO
To evaluate and compare the safety of four selenium supplements, namely Se-enriched peptides (SeP), yeast selenium (SeY), L-Se-methylselenocysteine (L-SeMc) and sodium selenite (Na2SeO3), the subchronic toxicity study was designed by 90-day gavage administration in Sprague-Dawley rats. The doses of SeP, SeY, L-SeMc and Na2SeO3 were 0.15, 0.30 and 0.60 mg/kg bw/day, with additional dose of 0.45 mg/kg L-SeMc (All dose calculated as Se). Symptoms like growling, hair loss and significant weight loss were found at 0.60 mg/kg of L-SeMc, but not in other groups. At the dose of 0.60 mg/kg, females in Na2SeO3, SeY and L-SeMc groups showed significant elevations in ALT and/or ALP. Pathologic manifestations such as bile duct hyperplasia and cholestasis were predominantly found in females at 0.6 mg/kg of L-SeMc and SeY groups, and in males at same dose of L-SeMc group showed marked testicular atrophy. 0.60 mg/kg of SeY and Na2SeO3, and 0.30, 0.45, 0.60 mg/kg of L-SeMc induced significant reductions in sperm motility rates, rapid movement and amount. In conclusion, the NOAEL of SeP, SeY, L-SeMc, Na2SeO3 was all 0.30 mg/kg for female, and 0.60, 0.30, 0.15 and 0.30 mg/kg for male respectively. Liver and reproductive organs are possible toxic target organs of hyper selenium.
Assuntos
Selênio , Masculino , Feminino , Ratos , Animais , Ratos Sprague-Dawley , Selênio/toxicidade , Motilidade dos Espermatozoides , Suplementos Nutricionais/toxicidade , Selenito de Sódio/toxicidade , Saccharomyces cerevisiaeRESUMO
China's power sector has received great research attention because of its large energy consumption and CO2 emissions. This study assesses the environmental efficiency and technology inequality of China's power sector from 2008 to 2017. Methodologically, this study proposes a non-radial FDH (free disposable hull) model and a super non-radial FDH model. The non-radial FDH model relaxes the convex assumption and captures all inefficiencies of inputs, desirable output and undesirable output. The super non-radial model is capable of discriminating efficient power sectors and always has feasible solutions. We also compare their performance with the non-radial data envelopment analysis (DEA) model. The main conclusions are summarized as follows: First, the environmental efficiency of China's power sector has experienced steady growth; the power sectors in the east region outperform those in other regions. Second, the proposed FDH models are more applicable and reliable than the non-radial DEA model in efficiency measurement of China's power sector, due to the indivisibility of labor. Third, there has been growing technology inequality and the main driving factor determining technology inequality is the inter-region efficiency Gini coefficient. To improve environmental efficiency and eliminate technology inequality, the government should mainly solve the issue of excessive labor input and establish a free technology market for technology trading.