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1.
Clin Exp Pharmacol Physiol ; 51(7): e13900, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38843865

RESUMEN

Traditional Chinese medicine, specifically the Jianpi Tiaoqi (JPTQ) decoction, has been explored for its role in treating breast cancer, particularly in inhibiting lung metastasis in affected mice. Our study evaluated the effects of JPTQ on several factors, including tumour growth, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT) and immune microenvironment regulation. We used bioluminescence imaging to observe in situ tumour growth and potential lung metastasis. Transcriptomic analysis provided insights into gene expression, whereas flow cytometry was used to examine changes in specific immune cells, such as CD4+ T cells and myeloid-derived suppressor cells. Several essential proteins and genes, including vascular endothelial growth factor (VEGF), matrix metalloprotein-9 (MMP-9) and B-cell lymphoma 2 (Bcl-2), were assessed through quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry. Our findings showed that JPTQ treatment inhibited tumour proliferation in cancer-bearing mice. Bioluminescence imaging and pathological analysis indicated a reduction in lung metastasis. Transcriptome analysis of lung and tumour tissues indicated that the genes associated with EMT, angiogenesis, proliferation and apoptosis were regulated in the JPTQ-treated group. Kyoto Encyclopedia of Genes and Genomes analysis suggested enrichment of immune-related pathways. Flow cytometry indicated that JPTQ treatment reduced the proportion of monocyte-myeloid-derived suppressor cells in the lung and increased the number of CD4+ T cells in the peripheral blood and the number of T helper 1 (Th1) cells in the spleen (P < 0.05). E-cadherin and cleaved caspase 3 were upregulated, whereas Snail, Bcl-2, Ki67 and VEGF were downregulated in the lung and tumour tissues; moreover, the expression of MMP-9 was downregulated in the lung tissue (P < 0.05). In essence, JPTQ not only inhibits tumour growth in affected mice, but also promotes positive immune responses, reduces angiogenesis, boosts tumour cell apoptosis, reverses EMT and decreases breast cancer lung metastasis.


Asunto(s)
Proliferación Celular , Medicamentos Herbarios Chinos , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Neoplasias de la Mama Triple Negativas , Animales , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratones , Proliferación Celular/efectos de los fármacos , Femenino , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología
3.
J Gene Med ; 26(6): e3694, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38847309

RESUMEN

BACKGROUND: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. METHODS: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. RESULTS: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. CONCLUSIONS: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Células Escamosas , Regulación Neoplásica de la Expresión Génica , Inmunoterapia , Neoplasias Pulmonares , Análisis de la Célula Individual , Transcriptoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Análisis de la Célula Individual/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Inmunoterapia/métodos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Perfilación de la Expresión Génica , Masculino , Femenino , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Persona de Mediana Edad , Anciano
4.
Med Oncol ; 41(7): 170, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847902

RESUMEN

Salvianolic acid B (Sal B) has demonstrated anticancer activity against various types of cancer. However, the underlying mechanism of Sal B-mediated anticancer effects remains incompletely understood. This study aims to investigate the impact of Sal B on the growth and metastasis of human A549 lung cells, as well as elucidate its potential mechanisms. In this study, different concentrations of Sal B were administered to A549 cells. The effects on migration and invasion abilities were assessed using MTT, wound healing, and transwell assays. Flow cytometry analysis was employed to evaluate Sal B-induced apoptosis in A549 cells. Western blotting and immunohistochemistry were conducted to measure the expression levels of cleaved caspase-3, cleaved PARP, and E-cadherin. Commercial kits were utilized for detecting intracellular reactive oxygen species (ROS) and NAD+. Additionally, a xenograft model with transplanted A549 tumors was employed to assess the anti-tumor effect of Sal B in vivo. The expression levels of NDRG2, p-PTEN, and p-AKT were determined through western blotting. Our findings demonstrate that Sal B effectively inhibits proliferation, migration, and invasion in A549 cells while inducing dose-dependent apoptosis. These apoptotic responses and inhibition of tumor cell metastasis are accompanied by alterations in intracellular ROS levels and NAD+/NADH ratio. Furthermore, our in vivo experiment reveals that Sal B significantly suppresses A549 tumor growth compared to an untreated control group while promoting increased cleavage of caspase-3 and PARP. Importantly, we observe that Sal B upregulates NDRG2 expression while downregulating p-PTEN and p-AKT expressions. Collectively, our results provide compelling evidence supporting the ability of Sal B to inhibit both growth and metastasis in A549 lung cancer cells through oxidative stress modulation as well as involvement of the NDRG2/PTEN/AKT pathway.


Asunto(s)
Benzofuranos , Movimiento Celular , Proliferación Celular , Neoplasias Pulmonares , Estrés Oxidativo , Fosfohidrolasa PTEN , Transducción de Señal , Humanos , Fosfohidrolasa PTEN/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Estrés Oxidativo/efectos de los fármacos , Células A549 , Animales , Proliferación Celular/efectos de los fármacos , Benzofuranos/farmacología , Movimiento Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratones , Apoptosis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Ratones Endogámicos BALB C , Especies Reactivas de Oxígeno/metabolismo , Depsidos
5.
Clin Oral Investig ; 28(7): 360, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847917

RESUMEN

OBJECTIVES: Lung cancer (LC) is the malignant tumor with the highest mortality rate worldwide, and precise early diagnosis can improve patient prognosis. The purpose of this study was to investigate whether alterations in the glycopatterns recognized by the Hippeastrum hybrid lectin (HHL) in salivary proteins are associated with the development of LC. MATERIALS AND METHODS: First, we collected saliva samples from LC (15 lung adenocarcinoma (ADC); 15 squamous cell carcinoma (SCC); 15 small cell lung cancer (SCLC)) and 15 benign pulmonary disease (BPD) for high-throughput detection of abundance levels of HHL-recognized glycopatterns using protein microarrays, and then validated the pooled samples from each group with lectin blotting analysis. Finally, the N-glycan profiles of salivary glycoproteins isolated from the pooled samples using HHL-magnetic particle conjugates were characterized separately using MALDI-TOF/TOF-MS. RESULTS: The results showed that the abundance level of glycopatterns recognized by HHL in salivary proteins was elevated in LC compared to BPD. The proportion of mannosylated N-glycans was notably higher in ADC (31.7%), SCC (39.0%), and SCLC (46.6%) compared to BPD (23.3%). CONCLUSIONS: The altered salivary glycopatterns such as oligomannose, Manα1-3Man, or Manα1-6Man N-glycans recognized by HHL might serve as potential biomarkers for the diagnosis of LC patients. CLINICAL RELEVANCE: This study provides crucial information for studying changes in salivary to differentiate between BPD and LC and facilitate the discovery of biomarkers for LC diagnosis based on precise alterations of mannosylated N-glycans in saliva.


Asunto(s)
Neoplasias Pulmonares , Saliva , Humanos , Masculino , Saliva/química , Femenino , Persona de Mediana Edad , Anciano , Análisis por Matrices de Proteínas , Polisacáridos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Glicoproteínas , Biomarcadores de Tumor , Proteínas y Péptidos Salivales/metabolismo , Manosa , Lectinas de Plantas/química , Carcinoma de Células Escamosas
7.
Cell Commun Signal ; 22(1): 313, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844957

RESUMEN

BACKGROUND: Non-small-cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer and is the leading cause of cancer-related deaths globally. Although various treatment strategies have been introduced, the 5-year survival rate of patients with NSCLC is only 20-30%. Thus, it remains necessary to study the pathogenesis of NSCLC and develop new therapeutic drugs. Notably, PYK2 has been implicated in the progression of many tumors, including NSCLC, but its detailed mechanism remains unclear. In this study, we aimed to elucidate the mechanisms through which PYK2 promotes NSCLC progression. METHODS: The mRNA and protein levels of various molecules were measured using qRT-PCR, western blot (WB), and immunohistochemistry (IHC), respectively. We established stable PYK2 knockdown and overexpression cell lines, and CCK-8, EdU, and clonogenic assays; wound healing, transwell migration, and Matrigel invasion assays; and flow cytometry were employed to assess the phenotypes of tumor cells. Protein interactions were evaluated with co-immunoprecipitation (co-IP), immunofluorescence (IF)-based colocalization, and nucleocytoplasmic separation assays. RNA sequencing was performed to explore the transcriptional regulation mediated by PYK2. Secreted VGF levels were examined using ELISA. Dual-luciferase reporter system was used to detect transcriptional regulation site. PF4618433 (PYK2 inhibitor) and Stattic (STAT3 inhibitor) were used for rescue experiments. A public database was mined to analyze the effect of these molecules on NSCLC prognosis. To investigate the role of PYK2 in vivo, mouse xenograft models of lung carcinoma were established and examined. RESULTS: The protein level of PYK2 was higher in human NSCLC tumors than in the adjacent normal tissue, and higher PYK2 expression was associated with poorer prognosis. PYK2 knockdown inhibited the proliferation and motility of tumor cells and caused G1-S arrest and cyclinD1 downregulation in A549 and H460 cells. Meanwhile, PYK2 overexpression had the opposite effect in H1299 cells. The siRNA-induced inhibition of integrins alpha V and beta 1 led to the downregulation of p-PYK2(Tyr402). Activated PYK2 could bind to STAT3 and enhance its phosphorylation at Tyr705, regulating the nuclear accumulation of p-STAT3(Tyr705). This further promoted the expression of VGF, as confirmed by RNA sequencing in a PYK2-overexpressing H1299 cell line and validated by rescue experiments. Two sites in promoter region of VGF gene were confirmed as binding sites of STAT3 by Dual-luciferase assay. Data from the TGCA database showed that VGF was related to the poor prognosis of NSCLC. IHC revealed higher p-PYK2(Tyr402) and VGF expression in lung tumors than in adjacent normal tissues. Moreover, both proteins showed higher levels in advanced TNM stages than earlier ones. A positive linear correlation existed between the IHC score of p-PYK2(Tyr402) and VGF. Knockdown of VGF inhibited tumor progression and reversed the tumor promoting effect of PYK2 overexpression in NSCLC cells. Finally, the mouse model exhibited enhanced tumor growth when PYK2 was overexpressed, while the inhibitors PF4618433 and Stattic could attenuate this effect. CONCLUSIONS: The Integrin αVß1-PYK2-STAT3-VGF axis promotes NSCLC development, and the PYK2 inhibitor PF4618433 and STAT3 inhibitor Stattic can reverse the pro-tumorigenic effect of high PYK2 expression in mouse models. Our findings provide insights into NSCLC progression and could guide potential therapeutic strategies against NSCLC with high PYK2 expression levels.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Progresión de la Enfermedad , Quinasa 2 de Adhesión Focal , Neoplasias Pulmonares , Factor de Transcripción STAT3 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Quinasa 2 de Adhesión Focal/metabolismo , Quinasa 2 de Adhesión Focal/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Animales , Proliferación Celular/genética , Ratones , Movimiento Celular/genética , Ratones Desnudos , Línea Celular Tumoral , Transducción de Señal/genética , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB C
8.
Cancer Med ; 13(11): e7364, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38847084

RESUMEN

PURPOSE: Lung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM. METHODS: We retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan-Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively. RESULTS: The median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple-negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM. CONCLUSIONS: This single-institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.


Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Neoplasias Pulmonares , Humanos , Femenino , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/diagnóstico , Persona de Mediana Edad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Estudios Retrospectivos , Factores de Riesgo , Anciano , Masculino , Factores de Tiempo , Adulto , Estadificación de Neoplasias
9.
Medicine (Baltimore) ; 103(23): e38230, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847674

RESUMEN

The prognosis of acromelanomas (AM) is worse. The objective of this study was to investigate the clinical features of distant metastasis of AM and the factors affecting the survival and prognosis of patients. In this study, a retrospective study was conducted to select 154 AM patients admitted to Nanjing Pukou People's Hospital from January 2018 to April 2021 for clinical research. The clinical characteristics of distant metastasis were statistically analyzed, and the survival curve was drawn with 5-year follow-up outcomes. The median survival time of the patients was calculated, and the clinicopathological features and peripheral blood laboratory indexes of the surviving and dead patients were analyzed. Logistic regression model was used to analyze the risk factors affecting the prognosis of AM patients. In this study, 154 patients with AM were treated, including 88 males and 76 females, aged from 27 to 79 years old, with an average age of (59.3 ±â€…11.7) years old. Among them, 90 cases had distant metastasis. The main metastatic sites were lung (47.78%) and lymph nodes (42.22%). Among them, single site metastasis accounted for 41.11% and multiple site metastasis 58.89%. 89 cases survived and 65 cases died. The survival time was 22 months to 60 months, and the median survival time was 48.0 months. The Breslow thickness, stage at diagnosis, distant metastasis, site of metastasis and ulceration were compared between the survival group and the death group (P < .05). serum lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR) were compared between the survival group and the death group (P < .05). The results of Logistic regression model showed that LDH ≥ 281 U/L, NLR ≥ 2.96, LMR ≤ 3.57, newly diagnosed stage > stage II, distant metastasis, multiple site metastasis and tumor ulcer were independent risk factors for poor prognosis of AM patients (P < .05). Patients with AM had a higher proportion of distant metastasis, mainly lung and lymph node metastasis. Increased LDH, increased NLR, decreased LMR, higher initial stage, distant metastasis, multiple site metastasis, and combined tumor ulcer were closely related to the poor prognosis of patients after surgery.


Asunto(s)
Neoplasias Pulmonares , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Adulto , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Metástasis Linfática , Metástasis de la Neoplasia , China/epidemiología
10.
Medicine (Baltimore) ; 103(23): e38487, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847733

RESUMEN

Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with early metastasis and poor prognosis. At present, there is a lack of effective indicators to predict prognosis of SCLC patients. Delta-like 3 protein (DLL3) is selectively expressed on the surface of SCLC and is involved in proliferation and invasion. Neuron-specific enolase (NSE) is an enolase isoenzyme that is generally regarded as a biomarker for SCLC and may correlate with stage of SCLC, prognosis and chemotherapy response. NSE can be influenced by different types of factors. To explore the associations between expression levels of DLL3 in tumor tissues with platinum/etoposide chemotherapy response, and assess the prognostic values of DLL3, NSE and other potential prognostic factors in advanced SCLC patients were herein studied. Ninety-seven patients diagnosed with SCLC in Zhongda Hospital from 2014 to 2020 were enrolled in the study. Serum NSE levels were tested using ELISA methods before any treatment. The expression of DLL3 in tumor tissue was detected by Immunohistochemistry (IHC). We investigated the relationship of DLL3 expression with chemotherapy and survival. Progression free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of PFS and OS. DLL3 was detected in 84.5% (82/97) of all patients' tumor samples by IHC, mainly located on the surface of SCLC cells. Lower DLL3 expression was associated with longer PFS and better chemotherapy response. OS had no significant differences. Multivariate analysis by Cox Hazard model showed that, high DLL3 expression and maximum tumor size >5 cm were independent risk factors for PFS, where NSE < 35 ng/mL and age < 70 were independent prognostic factors for OS. Early stage was independent prognostic factors for PFS and OS (P < .05 log-rank). DLL3 was expressed in the most of SCLCs. DLL3 expression level in the tumor and NSE level in the serum may be useful biomarkers to predict the prognosis of SCLC. DLL3 may be a potential therapeutic target for SCLC in the future.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Pulmonares , Fosfopiruvato Hidratasa , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/sangre , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Masculino , Femenino , Fosfopiruvato Hidratasa/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Anciano , Proteínas de la Membrana/sangre , Proteínas de la Membrana/metabolismo , Péptidos y Proteínas de Señalización Intracelular/sangre , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Etopósido/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Valor Predictivo de las Pruebas , Estimación de Kaplan-Meier
11.
Cancer Immunol Immunother ; 73(8): 140, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833011

RESUMEN

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Femenino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Neoplasia Residual , Antígeno B7-H1/antagonistas & inhibidores , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Incidencia , Metástasis de la Neoplasia , Estudios de Seguimiento , Estudios Retrospectivos
12.
Cancer Immunol Immunother ; 73(8): 152, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833153

RESUMEN

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors. METHODS: This retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve. RESULT: In training cohort, lower baseline absolute counts of CD3+ (P < 0.001) and CD4+ (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3+ (P < 0.001), CD4+ (P < 0.001), CD8+ (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation. CONCLUSION: We constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Nomogramas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Pronóstico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Subgrupos Linfocitarios/inmunología , Adulto , Recuento de Linfocitos
13.
Cancer Immunol Immunother ; 73(8): 147, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833156

RESUMEN

BACKGROUND: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. METHODS: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. RESULTS: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. CONCLUSION: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Biomarcadores de Tumor/metabolismo , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/genética
14.
Cancer Immunol Immunother ; 73(8): 153, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833187

RESUMEN

BACKGROUND: The non-invasive biomarkers for predicting immunotherapy response are urgently needed to prevent both premature cessation of treatment and ineffective extension. This study aimed to construct a non-invasive model for predicting immunotherapy response, based on the integration of deep learning and habitat radiomics in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Independent patient cohorts from three medical centers were enrolled for training (n = 164) and test (n = 82). Habitat imaging radiomics features were derived from sub-regions clustered from individual's tumor by K-means method. The deep learning features were extracted based on 3D ResNet algorithm. Pearson correlation coefficient, T test and least absolute shrinkage and selection operator regression were used to select features. Support vector machine was applied to implement deep learning and habitat radiomics, respectively. Then, a combination model was developed integrating both sources of data. RESULTS: The combination model obtained a strong well-performance, achieving area under receiver operating characteristics curve of 0.865 (95% CI 0.772-0.931). The model significantly discerned high and low-risk patients, and exhibited a significant benefit in the clinical use. CONCLUSION: The integration of deep-leaning and habitat radiomics contributed to predicting response to immunotherapy in patients with NSCLC. The developed integration model may be used as potential tool for individual immunotherapy management.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Aprendizaje Profundo , Inmunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/inmunología , Inmunoterapia/métodos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pronóstico , Curva ROC , Radiómica
15.
BMC Cancer ; 24(1): 680, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834983

RESUMEN

BACKGROUND: Drug repurposing provides a cost-effective approach to address the need for lung cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR). METHODS: Summary-level data of gene expression quantitative trait loci (eQTLs) were sourced from the eQTLGen resource. We procured genetic associations with lung cancer and its subtypes from the TRICL, ILCCO studies (discovery) and the FinnGen study (replication). We implemented Summary-data-based Mendelian Randomization analysis to identify potential therapeutic targets for lung cancer. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. FINDINGS: In the main analysis dataset, we identified 55 genes that demonstrate a causal relationship with lung cancer and its subtypes. However, in the replication cohort, only three genes were found to have such a causal association with lung cancer and its subtypes, and of these, HYKK (also known as AGPHD1) was consistently present in both the primary analysis dataset and the replication cohort. Following HEIDI tests and colocalization analyses, it was revealed that HYKK (AGPHD1) is associated with an increased risk of squamous cell carcinoma of the lung, with an odds ratio and confidence interval of OR = 1.28,95%CI = 1.24 to 1.33. INTERPRETATION: We have found that the HYKK (AGPHD1) gene is associated with an increased risk of squamous cell carcinoma of the lung, suggesting that this gene may represent a potential therapeutic target for both the prevention and treatment of lung squamous cell carcinoma.


Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares , Análisis de la Aleatorización Mendeliana , Sitios de Carácter Cuantitativo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Reposicionamiento de Medicamentos , Terapia Molecular Dirigida/métodos
16.
Genome Med ; 16(1): 76, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38835075

RESUMEN

BACKGROUND: Accurate prediction of an individual's predisposition to diseases is vital for preventive medicine and early intervention. Various statistical and machine learning models have been developed for disease prediction using clinico-genomic data. However, the accuracy of clinico-genomic prediction of diseases may vary significantly across ancestry groups due to their unequal representation in clinical genomic datasets. METHODS: We introduced a deep transfer learning approach to improve the performance of clinico-genomic prediction models for data-disadvantaged ancestry groups. We conducted machine learning experiments on multi-ancestral genomic datasets of lung cancer, prostate cancer, and Alzheimer's disease, as well as on synthetic datasets with built-in data inequality and distribution shifts across ancestry groups. RESULTS: Deep transfer learning significantly improved disease prediction accuracy for data-disadvantaged populations in our multi-ancestral machine learning experiments. In contrast, transfer learning based on linear frameworks did not achieve comparable improvements for these data-disadvantaged populations. CONCLUSIONS: This study shows that deep transfer learning can enhance fairness in multi-ancestral machine learning by improving prediction accuracy for data-disadvantaged populations without compromising prediction accuracy for other populations, thus providing a Pareto improvement towards equitable clinico-genomic prediction of diseases.


Asunto(s)
Genómica , Aprendizaje Automático , Humanos , Genómica/métodos , Predisposición Genética a la Enfermedad , Enfermedad de Alzheimer/genética , Masculino , Neoplasias de la Próstata/genética , Neoplasias Pulmonares/genética
17.
J Cell Mol Med ; 28(11): e18408, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38837585

RESUMEN

We employed single-cell analysis techniques, specifically the inferCNV method, to dissect the complex progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) through minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IAC). This approach enabled the identification of Cluster 6, which was significantly associated with LUAD progression. Our comprehensive analysis included intercellular interaction, transcription factor regulatory networks, trajectory analysis, and gene set variation analysis (GSVA), leading to the development of the lung progression associated signature (LPAS). Interestingly, we discovered that the LPAS not only accurately predicts the prognosis of LUAD patients but also forecasts genomic alterations, distinguishes between 'cold' and 'hot' tumours, and identifies potential candidates suitable for immunotherapy. PSMB1, identified within Cluster 6, was experimentally shown to significantly enhance cancer cell invasion and migration, highlighting the clinical relevance of LPAS in predicting LUAD progression and providing a potential target for therapeutic intervention. Our findings suggest that LPAS offers a novel biomarker for LUAD patient stratification, with significant implications for improving prognostic accuracy and guiding treatment decisions.


Asunto(s)
Adenocarcinoma del Pulmón , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Genómica , Neoplasias Pulmonares , Análisis de la Célula Individual , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Pronóstico , Análisis de la Célula Individual/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Genómica/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Redes Reguladoras de Genes , Línea Celular Tumoral , Perfilación de la Expresión Génica , Invasividad Neoplásica
18.
Front Immunol ; 15: 1371831, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38840910

RESUMEN

Introduction: Lung cancer, with the highest global mortality rate among cancers, presents a grim prognosis, often diagnosed at an advanced stage in nearly 70% of cases. Recent research has unveiled a novel mechanism of cell death termed disulfidptosis, which is facilitated by glucose scarcity and the protein SLC7A11. Methods: Utilizing the least absolute shrinkage and selection operator (LASSO) regression analysis combined with Cox regression analysis, we constructed a prognostic model focusing on disulfidptosis-related genes. Nomograms, correlation analyses, and enrichment analyses were employed to assess the significance of this model. Among the genes incorporated into the model, CHRNA5 was selected for further investigation regarding its role in LUAD cells. Biological functions of CHRNA5 were assessed using EdU, transwell, and CCK-8 assays. Results: The efficacy of the model was validated through internal testing and an external validation set, with further evaluation of its robustness and clinical applicability using a nomogram. Subsequent correlation analyses revealed associations between the risk score and infiltration of various cancer types, as well as oncogene expression. Enrichment analysis also identified associations between the risk score and pivotal biological processes and KEGG pathways. Our findings underscore the significant impact of CHRNA5 on LUAD cell proliferation, migration, and disulfidptosis. Conclusion: This study successfully developed and validated a robust prognostic model centered on disulfidptosis-related genes, providing a foundation for predicting prognosis in LUAD patients.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Nomogramas , Receptores Nicotínicos , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Pronóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Receptores Nicotínicos/genética , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Proteínas del Tejido Nervioso/genética , Línea Celular Tumoral , Masculino , Proliferación Celular/genética , Femenino
19.
Front Endocrinol (Lausanne) ; 15: 1407192, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38841300

RESUMEN

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.


Asunto(s)
Diabetes Mellitus Tipo 1 , Glutamato Descarboxilasa , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Cadenas HLA-DRB1/genética , Glutamato Descarboxilasa/inmunología , Cadenas beta de HLA-DQ/genética , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Haplotipos , Japón , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Pueblos del Este de Asia
20.
Am J Case Rep ; 25: e943466, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38822519

RESUMEN

BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Receptores ErbB , Clorhidrato de Erlotinib , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Anciano , Humanos , Masculino , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Resistencia a Antineoplásicos , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , /uso terapéutico
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