RESUMEN
BACKGROUND/AIM: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. MATERIALS AND METHODS: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. RESULTS: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. CONCLUSION: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.
Asunto(s)
Anoicis , Neoplasias Colorrectales , Metástasis de la Neoplasia , Complejo Represivo Polycomb 1 , Anoicis/efectos de los fármacos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/antagonistas & inhibidores , Humanos , Animales , Ratones , Pez Cebra , Femenino , Masculino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.
Asunto(s)
Neoplasias Colorrectales , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes , Resistencia a Antineoplásicos , Irinotecán , Irinotecán/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Células HT29 , Quinasas Ciclina-Dependientes/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Femenino , Proliferación Celular/efectos de los fármacosRESUMEN
Alveolar and interstitial macrophages play crucial roles in eradicating pathogens and transformed cells in the lungs. The immune checkpoint CD47, found on normal and malignant cells, interacts with the SIRPα ligand on macrophages, inhibiting phagocytosis, antigen presentation, and promoting immune evasion. In this study, we demonstrated that CD47 is not only a transmembrane protein, but that it is also highly concentrated in extracellular vesicles from lung cancer cell lines and patient plasma. Abundant CD47 was observed in the cytoplasm of lung cancer cells, aligning with our finding that it was packed into extracellular vesicles for physiological and pathological functions. In our clinical cohort, extracellular vesicle CD47 was significantly higher in the patients with early-stage lung cancer, emphasizing innate immunity inactivation in early tumor progression. To validate our hypothesis, we established an orthotopic xenograft model mimicking lung cancer development, which showed increased serum soluble CD47 and elevated IL-10/TNF-α ratio, indicating an immune-suppressive tumor microenvironment. CD47 expression led to reduced tumor-infiltrating macrophages during progression, while there was a post-xenograft increase in tumor-associated macrophages. In conclusion, CD47 is pivotal in early lung cancer progression, with soluble CD47 emerging as a key pathological effector.
Asunto(s)
Antígeno CD47 , Progresión de la Enfermedad , Neoplasias Pulmonares , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Humanos , Animales , Línea Celular Tumoral , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Ratones , Escape del Tumor , Evasión Inmune , Microambiente Tumoral/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Estadificación de NeoplasiasRESUMEN
The treatment of head and neck squamous cell carcinomas (HNSCCs) is multimodal, and chemoradiotherapy (CRT) is a critical component. However, the availability of predictive or prognostic markers in patients with HNSCC is limited. Inflammation is a well-documented factor in cancer, and several parameters have been studied, with the neutrophil-to-lymphocyte ratio (NLR) being the most promising. The NLR is the most extensively researched clinical biomarker in various solid tumors, including HNSCC. In our study, we collected clinical and next-generation sequencing (NGS) data with targeted sequencing information from 107 patients with HNSCC who underwent CRT. The difference in the NLR between the good response group and the poor response group was significant, with more patients having a high NLR in the poor response group. We also examined the genetic alterations linked to the NLR and found a total of 41 associated genes across eight common pathways searched from the KEGG database. The overall mutation rate was low, and there was no significant mutation difference between the low- and high-NLR groups. Using a multivariate binomial generalized linear model, we identified three candidate genes (MAP2K2, MAP2K4, and ABL1) that showed significant results and were used to create a gene mutation score (GMS). Using the NLR-GMS category, we noticed that the high-NLR-GMS group had significantly shorter relapse-free survival compared to the intermediate- or low-NLR-GMS groups.
RESUMEN
BACKGROUND: Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the "AhR-Nrf2 gene battery", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood. METHODS: Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors. RESULTS: Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells. CONCLUSIONS: Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.
RESUMEN
Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I-IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial-mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC.
RESUMEN
Triple-negative breast cancer (TNBC) is characterized by the loss of expression of several biomarkers, which limits treatment strategies for the disease. In recent years, immunotherapy has shown promising results in the treatment of various tumors. Emerging evidence demonstrated that TNBC is an immune-activated cancer, suggesting that immunotherapy could be a feasible treatment option for TNBC. Cytokine-induced killer (CIK) cell therapy is considered as a potential treatment for cancer treatment. However, it is still not approved as a standard treatment in the clinical setting. Our previous study demonstrated that focal adhesion kinase (FAK) plays important role in regulating the sensitivity of TNBC cells to CIK cells. In this study, we further verify the role of FAK in regulating the immune response in vivo. Our in vitro study indicated that knockdown of FAK in TNBC cells or treat with the FAK inhibitor followed by co-culture with CIK cells induced more cell death than CIK cells treatment only. RNA-seq analysis indicated that suppression of FAK could affect several immune-related gene expressions in TNBC cells that affects the immune response in the tumor microenvironment of TNBC cells. The combination of FAK inhibitor and CIK cells significantly suppressed tumor growth than the treatment of FAK inhibitor or CIK cells alone in vivo. Our findings provide new insights into the cytotoxic effect of CIK cell therapy in TNBC treatment and indicate that the combination of CIK cell therapy with FAK inhibitors may be an alternative therapeutic strategy for patients with TNBC.
Asunto(s)
Antineoplásicos , Células Asesinas Inducidas por Citocinas , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Inmunoterapia Adoptiva , Microambiente TumoralRESUMEN
The most common metastatic sites in breast cancer include the liver, bone, the lungs, and the brain. Metastasis to the gastrointestinal system is rare and can occur years after breast cancer diagnosis. This case report features a woman who was diagnosed with infiltrating ductal carcinoma 10 years ago and was discovered to have stomach metastasis this year. Immunohistochemical staining was employed to distinguish the metastasis from primary gastric cancer. This case is presented to raise awareness of the risk of gastric metastasis from breast cancer after years of breast cancer therapy.
RESUMEN
Personalized genetic profiling has focused on improving treatment efficacy and predicting risk stratification by identifying mutated genes and selecting targeted agents according to genetic testing. Therefore, we evaluated the role of genetic profiling and tumor mutation burden (TMB) using next-generation sequencing in patients with head and neck squamous cell carcinoma (HNSC). The relapse mutation signature (RMS) and chromatin remodeling mutation signature (CRMS) were explored to predict the risk of relapse in patients with HNSC treated with concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy. Patients in the high RMS and CRMS groups showed significantly shorter relapse-free survival than those in the low RMS and CRMS groups, respectively (p < 0.001 and p = 0.006). Multivariate Cox regression analysis showed that extranodal extension, CCRT response, and three somatic mutation profiles (TMB, RMS, and CRMS) were independent risk predictors for HNSC relapse. The predictive nomogram showed satisfactory performance in predicting relapse-free survival in patients with HNSC treated with CCRT.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Quimioradioterapia , Biomarcadores de Tumor/genética , Mutación , GenómicaRESUMEN
Pineocytoma is a rare tumor. It is rare for pineocytoma to present as leptomeningeal metastasis. We present a rare case of pineocytoma with malignant transformation and leptomeningeal metastasis after subtotal tumor resection and adjuvant radiotherapy. This case was a 58-year-old male with an unsteady gait for 2 months. Enhanced brain magnetic resonance imaging revealed a heterogeneous mass involving the pineal region. The initial pathological diagnosis of pineocytoma was confirmed after subtotal tumor resection. Two years after adjuvant radiotherapy to the primary site, the magnetic resonance imaging showed C2 and T2 metastatic lesions, with the final pathological diagnosis being pineal parenchymal tumor (PPT) with intermediate differentiation after the removal of T2 intramedullary tumor. After that adjuvant radiotherapy at the cervical and thoracic spinal cord was completed. There was no recurrence of the tumor 1 year after the radiotherapy. We report a rare case of pineocytoma with malignant transformation to PPT with intermediate differentiation and leptomeningeal dissemination.
Asunto(s)
Neoplasias Encefálicas , Glándula Pineal , Pinealoma , Masculino , Humanos , Persona de Mediana Edad , Pinealoma/diagnóstico , Pinealoma/radioterapia , Pinealoma/cirugía , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Radioterapia Adyuvante , Glándula Pineal/patología , Médula Espinal/patología , Transformación Celular Neoplásica/patologíaRESUMEN
Botulinum toxin type A (BTX-A) injection using nerve stimulation or electromyography for recurrent temporomandibular joint (TMJ) dislocation has been reported for several years. However, using the available equipment like a nerve stimulator or an electromyograph is uncommon, and ultrasound guidance is convenient and requires no additional resources. In this report, we used ultrasound as a tool to achieve BTX-A injections in a patient with a traumatic brain injury to treat her TMJ dislocation. One week after the injections, she had no more dislocation. She remained symptom free during the 3 months of follow-up, and her clinical symptoms improved without significant complications. This is the first report using ultrasound guidance for BTX-A injections to treat recurrent TMJ dislocation. This treatment is an effective and safe technique that could be performed timely and locally without referral to a center with electromyography facilities.
Asunto(s)
Toxinas Botulínicas Tipo A , Lesiones Encefálicas , Luxaciones Articulares , Trastornos de la Articulación Temporomandibular , Humanos , Femenino , Músculos Pterigoideos/diagnóstico por imagen , Músculos Pterigoideos/inervación , Trastornos de la Articulación Temporomandibular/diagnóstico por imagen , Trastornos de la Articulación Temporomandibular/tratamiento farmacológico , Trastornos de la Articulación Temporomandibular/complicaciones , Toxinas Botulínicas Tipo A/uso terapéutico , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/tratamiento farmacológico , Luxaciones Articulares/diagnóstico por imagen , Luxaciones Articulares/tratamiento farmacológico , Luxaciones Articulares/etiología , Articulación Temporomandibular , Ultrasonografía Intervencional/efectos adversos , Inyecciones Intramusculares/efectos adversosRESUMEN
AIMS: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS AND RESULTS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100â nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). CONCLUSION: Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.
Asunto(s)
Fibrilación Atrial , Calcio , Ratones , Animales , Calcio/metabolismo , Potasio/metabolismo , Apamina/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Potenciales de Acción/fisiología , Miocitos Cardíacos/metabolismoRESUMEN
AIMS: Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most dismal malignancies worldwide. Despite multidisciplinary involvement in interventions involving surgery, radiotherapy, and chemotherapy, most pancreatic cancer patients eventually develop distant metastasis. S-phase kinase-associated protein 2 (Skp2) plays an important role in cell-cycle regulation in pancreatic cancer. However, the role of Skp2 in individualized PDAC treatment is largely unknown. MAIN METHODS: Immunoblotting, quantitative reverse transcription polymerase chain reaction, cell viability test, chromatin immunoprecipitation assay, and xenograft in vivo assay were performed in parental and Skp2-depleted cells. The immunohistochemistry of Skp2 was analyzed on the tissue microarrays of 45 PDAC cases and mice tissues. KEY FINDINGS: In this study, we observed that Skp2 is a marker for poor prognosis in PDAC patients. Upregulation of the inhibitor of κB (IκB)-inducing kinase-nuclear factor kappa B (NF-κB) signal cascade mediated Skp2 expression thereby promoting epithelial-mesenchymal transition (EMT). Depletion of NF-κB-associated signaling effectively prevented Skp2-mediated pancreatic cancer cell migration. As a functional consequence, Skp2 orchestrated with Myc to induce zinc finger E-box binding homeobox 1 (Zeb1) transcription by recruiting p300 to the Zeb1 promoter independent of Skp2 E3-ligase activity. Therefore, blockade of Skp2 could significantly reduce the expression of Zeb1 and inhibit cancer cell migration. In conclusion, Skp2 regulated Zeb1 activity to control the migration and invasion abilities of pancreatic cancer cells. Skp2 expression in PDAC may affect cell vulnerability to standard chemotherapy regimens. SIGNIFICANCE: Therefore, in patients with PDAC, modulation of Skp2 expression could be a novel strategy for preventing cancer cell metastasis.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , FN-kappa B/metabolismo , Línea Celular Tumoral , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Ubiquitinación , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Neoplasias PancreáticasRESUMEN
In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Análisis por Conglomerados , Histona Acetiltransferasas/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histona Metiltransferasas/genética , Histonas/metabolismo , Humanos , Masculino , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Pronóstico , Neoplasias PancreáticasRESUMEN
Esophageal cancer has a dismal prognosis with a five-year survival rate below 20%. Recently, immunotherapy has become a new standard of care for this cancer; therefore, we aimed to examine the programmed death ligand 1 (PD-L1) expression in esophageal squamous cell carcinoma (ESCC) tissues before and after concurrent chemoradiation therapy (CCRT). In total, 64 patients with pre-CCRT ESCC specimens were examined for PD-L1 expression, with twenty-three of them having a partial response (N = 23) or stable disease (N = 1) after CCRT while post-CCRT tissue specimens were collected. All of them were tested for PD-L1 and 15 of them also had CD8 expression in the paired ESCC samples. The prevalence of PD-L1 positivity was 54.7% and we found a trend of decreased PD-L1 expression and increased CD8 positive signal after CCRT. High pre-CCRT PD-L1 H-score in tumors was related to poor prognosis (adjusted hazard ratio = 2.81; p = 0.02), although CD8 signal was not associated with overall survival either in pre- or post-CCRT treatment. In conclusion, we found that PD-L1 expression tended to decrease in CCRT responders and our result supports PD-L1 expression in tumor as a predictor of ESCC prognosis.
RESUMEN
Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman's correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.
RESUMEN
BACKGROUND: There has been a reported reduction in the incidence of amputation, but it is unclear whether the number of amputations has decreased in the elderly, a cohort that typically has the largest proportion of amputees. OBJECTIVES: To investigate the incidence proportion and time trends of amputation in patients aged ≥ 65 years in Taiwan. STUDY DESIGN: A retrospective cohort study from a large national database. METHODS: The records of patients who underwent an amputation were collected from a nationally representative sample of 1,000,000 enrollees of Taiwan's National Health Insurance program during 1996-2013. The patients were divided into four age groups: ≤64, 65-74, 75-84, and ≥85 years. Joinpoint regression was performed with adjustment for age and sex to identify changes in incidence proportion by year. RESULTS: During the 18 years, the incidence of upper and lower limb amputation decreased significantly in the total population, with the average annual percentage change (AAPC) of -6.1 and -1.8, respectively. However, in the elderly population over 65 years, the incidence did not decrease significantly for upper minor amputation, lower minor amputation, and major amputation with the AAPC of -1.1, -0.1, and -0.4, respectively. Although not significant, the incidence of major and minor lower limb amputation in the population over 85 years old showed an increasing trend, with the AAPC of 1.2 and 3.2, respectively. CONCLUSION: During the study period, although the incidence of amputation of the overall population decreased in Taiwan, this trend was not simultaneously observed in the elderly and hence, it should not be ignored.
Asunto(s)
Amputación Quirúrgica , Extremidad Inferior/cirugía , Extremidad Superior/cirugía , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica/estadística & datos numéricos , Amputación Quirúrgica/tendencias , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Dinámica Poblacional , Análisis de Regresión , Estudios Retrospectivos , Taiwán/epidemiologíaRESUMEN
In the original article [...].
RESUMEN
This study aimed to investigate whether the progression risk score (PRS) developed from cytoplasmic immunohistochemistry (IHC) biomarkers is available and applicable for assessing risk and prognosis in oral cancer patients. Participants in this retrospective case-control study were diagnosed between 2012 and 2014 and subsequently underwent surgical intervention. The specimens from surgery were stained by IHC for 16 cytoplasmic target markers. We evaluated the results of IHC staining, clinical and pathological features, progression-free survival (PFS), and overall survival (OS) of 102 oral cancer patients using a novel estimation approach with unsupervised hierarchical clustering analysis. Patients were stratified into high-risk (52) and low-risk (50) groups, according to their PRS; a metric consisting of cytoplasmic PLK1, PhosphoMet, SGK2, and SHC1 expression. Moreover, PRS could be extended for use in the Cox proportional hazard regression model to estimate survival outcomes with associated clinical parameters. Our study findings revealed that the high-risk patients had a significantly increased risk in cancer progression compared with low-risk patients (hazard ratio (HR) = 2.20, 95% confidence interval (CI) = 1.10-2.42, p = 0.026). After considering the influences of demographics, risk behaviors, and tumor characteristics, risk estimation with PRS provided distinct PFS groups for patients with oral cancer (p = 0.017, p = 0.019, and p = 0.020). Our findings support that PRS could serve as an ideal biomarker for clinical use in risk stratification and progression assessment in oral cancer.