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1.
Cureus ; 16(5): e60234, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38872703

RESUMEN

Gefitinib is an epidermal growth factor tyrosine kinase inhibitor used as a targeted chemotherapeutic agent in the treatment of lung cancer and other solid malignancies. The most common adverse effects of gefitinib include dermatological side effects and gastrointestinal symptoms, with rare reports of vascular side effects such as myocardial infarction and stroke. We recently reported a case of a patient with diabetes and multiple comorbidities who developed a serious lower limb vascular adverse event after gefitinib treatment, ultimately leading to amputation surgery. This is the first reported case of lower extremity amputation following gefitinib therapy in a patient with type 2 diabetes mellitus and lung adenocarcinoma. This case highlights the potential risk of amputation in diabetic patients receiving targeted therapies like gefitinib, especially in those with vascular complications. It emphasizes the importance of exercising extra caution when dealing with these patients.

2.
Int Wound J ; 21(3): e14507, 2023 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-37990756

RESUMEN

Diabetic foot ulcers (DFUs) represent a major health concern for diabetic patients, often leading to debilitating complications. Hyperbaric oxygen therapy (HBOT) has been posited as an adjunctive therapeutic strategy to augment the healing rates of these ulcers. This systematic review and meta-analysis sought to critically evaluate the efficacy and safety of HBOT in the context of DFUs management. A rigorous search, adhering to PRISMA guidelines, was conducted across multiple electronic databases. Randomized controlled trials (RCTs) assessing the impact of HBOT on DFUs were included. Outcome measures were complete ulcer healing, major and minor amputation rates and adverse reactions. The analysis employed both fixed and random-effects models, contingent on the heterogeneity levels detected. Seven studies met the inclusion criteria. HBOT was found to significantly improve the complete healing rates of DFUs with a risk ratio (RR) of 3.59 (95% CI: 1.56-8.29, p < 0.001). However, HBOT's impact on both major and minor amputation rates did not yield statistically significant results. The sensitivity analysis underscored the robustness of the principal outcomes, and the publication bias assessment suggested the absence of any significant bias. Hyperbaric oxygen therapy stands out as a potent therapeutic tool in promoting the complete healing of diabetic foot ulcers, offering a promising adjunct to standard care protocols, while ensuring patient safety.

3.
Clinics (Sao Paulo) ; 78: 100129, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36473368

RESUMEN

OBJECTIVES: Although miR-653-5p has been validated to participate in the progression of multiple types of cancer, the functional role of exosomal miR-653-5p derived from Mesenchymal Stem Cells (MSCs) in Laryngeal Papilloma (LP) has still remained elusive. Hence, this study aimed to investigate the role of MSCs-derived exosomal miR-653-5p in LP. METHODS: LP tissues (n = 15) and adjacent normal tissues (n = 10) were collected to examine the expression level of miR-653-5p. The expression level of miR-653-5p in LP cells and normal cells was also detected. Then, miR-653-5p was overexpressed or silenced to explore its effects on the proliferation, migration, invasion, and apoptosis of LP cells. Thereafter, the effects of exosomal miR-653-5p derived from MSCs on LP cell progression and the potential regulatory mechanism of miR-653-5p were assessed. RESULTS: It was revealed that the expression level of miR-653-5p was downregulated in LP tissues and cells. In addition, miR-653-5p suppressed the proliferation, migration, invasion, and apoptosis of LP cells. Exosomes derived from MSCs played a suppressive role in LP development and mediated the transmission of miR-653-5p to LP cells. Further exploration identified Basic leucine Zipper and W2 domains 2 (BZW2) as the target of miR-653-5p. More importantly, the rescue experiments revealed that MSCs-secreted exosomal miR-653-5p efficiently inhibited the aggressive phenotypes of LP cells, which could be significantly reversed by BZW2 overexpression in LP cells. CONCLUSION: MSCs-derived exosomal miR-653-5p exerted inhibitory effects on LP progression through targeting BZW2, which provided a novel idea for the therapy of LP. CLINICAL TRIAL REGISTRATION NUMBER: chictr-ior-17011021.


Asunto(s)
Neoplasias Laríngeas , Células Madre Mesenquimatosas , MicroARNs , Papiloma , Humanos , MicroARNs/genética , Papiloma/metabolismo , Proliferación Celular/genética , Proteínas de Unión al ADN
4.
Cardiovasc Diagn Ther ; 13(6): 917-928, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-38162099

RESUMEN

Background: Patients with acute ST-segment elevation myocardial infarction (STEMI) often have fewer identifiable traditional risk factors compared to other types of acute coronary syndrome. Therefore, it is necessary to explore more sensitive predictive models different from traditional cardiovascular scoring systems to identify high-risk populations. The retrospective case-control study aimed to investigate the predictive value of carotid intima-media thickness (CIMT) and homocysteine (Hcy) on the occurrence of STEMI. Methods: A total of 198 patients with first STEMI were continuously selected into the observation group, who received emergency coronary angiography in Hefei Hospital Affiliated to Anhui Medical University from January 2020 to January 2022, and a total of 129 patients with chest pain and chest tightness who received coronary angiography to exclude significant coronary artery disease were selected as the control group in the above hospitals during the same period. Hcy was biochemical index determined by fasting blood sampling within 48 h after admission, while CIMT and carotid plaque was measured using ultrasound. Univariate and multivariate logistic regression analysis was used to screen out independent risk factors including Hcy, CIMT and carotid plaque of STEMI. On the basis of traditional risk factors, Hcy, CIMT and carotid plaque were introduced in order to form different combined diagnosis models. The receiver operating characteristic (ROC) curve of single indicator and multi-indicator combined diagnosis were plotted to evaluate the clinical usefulness of the study factors or diagnostic models. Based on those, a Nomogram was constructed to predict STEMI. Results: Hcy (OR =1.161, 95% CI: 1.084-1.244, P<0.001), CIMT (OR =206.968, 95% CI: 22.375-1,914.468, P<0.001), carotid plaque (OR =2.499, 95% CI: 1.214-5.142, P=0.013) were independent risk factors for STEMI (P<0.01). ROC results suggested that the area under the curve (AUC) of Hcy was 0.729, the optimal cut-off value was 13.525 µmol/L. The AUC of CIMT is 0.763, and the optimal cut-off value is 0.875mm. Combined with the independent predictors including smoking, diabetes, high density lipoprotein cholesterol, low density lipoprotein cholesterol, Hcy, CIMT, carotid plaque, the AUC of the diagnosis model was 0.892 (95% CI: 0.856-0.928, P<0.001). Based on the above results, a Nomogram for predicting STEMI was constructed with a C-index of 0.892. The results of the H-L fitting test show that χ2=1.5049, df=2, P=0.4712; the calibration curve of the Nomogram is close to the ideal curve, and the internal validation C-index was 0.880. The clinical decision curve analysis (DCA) shows that the "nomogram line" of the model is far from the "All line" and the "None line". Conclusions: Hcy, CIMT, and carotid artery plaque could be independent risk factors of STEMI. The inclusion of these factors in addition to traditional risk factors can more fully and accurately predict the risk of STEMI. The Nomogram based on the results of this study is feasible and can bring clinical net benefit.

5.
Clinics ; 78: 100129, 2023. graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1421255

RESUMEN

Abstract Objectives: Although miR-653-5p has been validated to participate in the progression of multiple types of cancer, the functional role of exosomal miR-653-5p derived from Mesenchymal Stem Cells (MSCs) in Laryngeal Papilloma (LP) has still remained elusive. Hence, this study aimed to investigate the role of MSCs-derived exosomal miR-653-5p in LP. Methods: LP tissues (n = 15) and adjacent normal tissues (n = 10) were collected to examine the expression level of miR-653-5p. The expression level of miR-653-5p in LP cells and normal cells was also detected. Then, miR-653-5p was overexpressed or silenced to explore its effects on the proliferation, migration, invasion, and apoptosis of LP cells. Thereafter, the effects of exosomal miR-653-5p derived from MSCs on LP cell progression and the potential regulatory mechanism of miR-653-5p were assessed. Results: It was revealed that the expression level of miR-653-5p was downregulated in LP tissues and cells. In addition, miR-653-5p suppressed the proliferation, migration, invasion, and apoptosis of LP cells. Exosomes derived from MSCs played a suppressive role in LP development and mediated the transmission of miR-653-5p to LP cells. Further exploration identified Basic leucine Zipper and W2 domains 2 (BZW2) as the target of miR-653-5p. More importantly, the rescue experiments revealed that MSCs-secreted exosomal miR-653-5p efficiently inhibited the aggressive phenotypes of LP cells, which could be significantly reversed by BZW2 overexpression in LP cells. Conclusion: MSCs-derived exosomal miR-653-5p exerted inhibitory effects on LP progression through targeting BZW2, which provided a novel idea for the therapy of LP. Clinical Trial registration number: chictr-ior-17011021.

6.
EBioMedicine ; 86: 104357, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36371985

RESUMEN

BACKGROUND: Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC). METHODS: To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data. FINDINGS: In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55). INTERPRETATION: Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion. FUNDING: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Epigenómica , Epigenoma , Cromatina , Neoplasias Nasofaríngeas/patología , Microambiente Tumoral/genética
7.
Br J Cancer ; 127(12): 2166-2174, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36261585

RESUMEN

BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Hipofaríngeas , Humanos , Neoplasias Hipofaríngeas/genética , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/genética , Mutación , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/genética
8.
Mol Ther Methods Clin Dev ; 25: 136, 2022 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-35402631

RESUMEN

[This corrects the article DOI: 10.1016/j.omtm.2021.08.007.].

9.
Mol Ther Methods Clin Dev ; 23: 78-86, 2021 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-34631928

RESUMEN

The current methods for detecting circulating tumor cells (CTCs) suffer from several drawbacks. We report a novel method that is based on a chimeric virus probe and can detect CTCs with extremely high specificity and sensitivity. Moreover, it exclusively detects live CTCs, and its detection efficacy is not impacted by the variation of epithelial cell adhesion molecule (EpCAM) expression. The chimeric virus probe is composed of a capsid from human papillomavirus that provides the detection with high specificity and an SV40-based genome that can amplify extensively inside CTCs and, hence, endows the detection with high sensitivity. Furthermore, different marker genes can be incorporated into the probe to provide detection with versatility. These unique capabilities will likely improve the validity and utility of this CTC detection in several clinical applications, which is one of the drawbacks suffered by many of the current CTC detection methods.

10.
Mol Ther Methods Clin Dev ; 20: 350-356, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33521163

RESUMEN

Virus neutralization assay is principally conducted by measuring the ability of the antibodies in patient sera to prevent the infection of susceptible cells by the virus. As SARS-CoV-2 is classified as a risk group 3 pathogen, neutralization assay using a live virus needs to be handled in a biosafety level 3 laboratory. To overcome this limitation, pseudotyped viruses have been developed as an alternative for the live SARS-CoV-2. However, one of the issues that we and others have encountered during the production of pseudotyped virus with SARS-CoV-2 spike protein was the low virus yield. In our own experience, we were only able initially to produce a stock with a virus titer that is more than two orders of magnitude lower than what we usually get with a vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vector. We have conducted a series of improvements, including using a C-terminal truncated form of spike protein and a D614G mutated spike. Together, these have led to a significant improvement in the yield of the pseudotyped virus. Finally, our data show that using a high-affinity ACE2-expressing cell line resulted in a reduction in detection sensitivity of the neutralization assay.

11.
Commun Biol ; 3(1): 759, 2020 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-33311639

RESUMEN

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (Trs2517664 = 4.6%, P = 6.38 × 10-21) and rs117495548 (Grs117495548 = 3.0%, P = 4.53 × 10-13), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10-36). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10-21) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.


Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Antígenos HLA/genética , Carcinoma Nasofaríngeo/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Anciano , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Femenino , Heterogeneidad Genética , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Antígenos HLA/química , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Mutación INDEL , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/diagnóstico , Polimorfismo de Nucleótido Simple , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
12.
Mol Ther Oncolytics ; 19: 33-46, 2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33024817

RESUMEN

One of the major hurdles for cancer immunotherapy is the host's innate antiviral defense mechanisms. They include innate immune cells, such as natural killer (NK) cells and macrophages, which can be recruited within hours to the site of injection to clear the introduced oncolytic viruses. Here, we report a strategy to redirect these infiltrating innate immune cells to attack tumor cells instead by arming herpes simplex virus (HSV)-derived oncolytic viruses with secreted chimeric molecules that can engage these innate immune cells with tumor cells to kill the latter. These chimeric molecules have, at their N terminus, a custom-binding moiety for a tumor-associated antigen (TAA) and at their C terminus, protein L (PL) that binds to immunoglobulins (Igs). The binding of PL to Igs exposes the Fc to the Fc receptors on the surface of the innate immune cells, trigging them to attack the engaged tumor cells. In vitro and in vivo evaluation in a murine tumor model with limited permissiveness to oncolytic HSVs showed that arming the viruses with these chimeric molecules significantly boosts the killing effect and therapeutic activity. Moreover, our data also showed that the combined killing effect from the engaged innate immune cells and the oncolytic virus resulted in a more efficient stimulation of neoantigen-specific antitumor immunity than the virotherapy alone. Our data suggest that arming an oncolytic virus with this strategy represents a unique and pragmatic way of potentiating the oncolytic and immunotherapeutic effect of virotherapy.

13.
Cancers (Basel) ; 12(7)2020 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-32708712

RESUMEN

Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the nasopharynx. Cylindromatosis lysine 63 deubiquitinase (CYLD), a NF-kB inhibitor, was reported as one of the top mutated candidate genes in NPC. NF-kB is an inducible transcription factor, contributing to cancer via regulating inflammation, angiogenesis, cell proliferation, and metastasis. In this study, the impact of CYLD on regulating the NF-kB signaling pathway and its contribution to NPC development was studied using in vitro and in vivo functional assays, together with single cell RNA sequencing to understand the NPC tumor microenvironment. CYLD was downregulated in NPC clinical specimens and multiple cell lines. Functional assays revealed CYLD inhibits NPC cell proliferation and migration in vitro and suppresses NPC tumorigenicity and metastasis in vivo by negatively regulating the NF-kB signaling pathway. Additionally, CYLD was able to inhibit fibroblast and endothelial stromal cell infiltration into the NPC tumor microenvironment. These findings suggest that CYLD inhibits NPC development and provides strong evidence supporting a role for CYLD inhibiting fibroblast and endothelial stromal cell infiltration into NPC via suppressing the NF-kB pathway.

14.
Methods Mol Biol ; 2129: 149-160, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32056176

RESUMEN

Orthotopic xenograft model recapitulates the faithful organ-specific microenvironment and facilitates analyses involving tumor-stromal interactions that are crucial for developing new-generation cancer therapy. Herein, we describe the detailed rationales and protocols of a versatile orthotopic xenograft model for esophageal squamous cell carcinoma.


Asunto(s)
Carcinoma de Células Escamosas de Esófago/patología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/clasificación , Esófago/patología , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Neoplasias de la Boca/patología , Trasplante Heterólogo , Microambiente Tumoral
15.
Int J Cancer ; 146(4): 1042-1051, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31396961

RESUMEN

Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.


Asunto(s)
Proteína BRCA2/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Genes BRCA2 , Mutación de Línea Germinal , Adulto , Anciano , Pueblo Asiatico/genética , China , Estudios de Cohortes , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Penetrancia
16.
Biomed Res Int ; 2018: 2049313, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30327774

RESUMEN

Invasion and metastasis are critical pathological and mortal processes in esophageal squamous cell carcinoma (ESCC). Novel drugs, targeting the two cancer migration stages, will augment the treatment options for ESCC therapy and improve overall survival. A novel natural macrolide F806 specifically promotes apoptosis of various ESCC cells. However, whether F806 can inhibit metastasis of ESCC cells needs further evaluation. Here, our data showed that F806 inhibits dynamic F-actin assembly and then suppresses the migration of ESCC cells in vitro and their invasion and metastasis in vivo. The correlation between cancer migration and actin cytoskeleton assembly was consistent with the ability of F806 to prevent the aggregation of Paxillin, an essential protein for focal adhesion formation through binding to the ends of actin filaments. Furthermore, F806 downregulated the expression and activity of the Rho family proteins cell division cycle 42 (CDC42), RAC family small GTPase 1 (RAC1), and RAS homolog family member A (RHOA). Taken together, these results suggest that F806 can suppress cancer invasion and metastasis via interrupting the assembly of migration components involving F-actin.


Asunto(s)
Actinas/metabolismo , Antineoplásicos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Actinas/genética , Animales , Línea Celular Tumoral , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Proteínas de Unión al GTP rho/genética
17.
Oncotarget ; 9(77): 34543-34553, 2018 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-30349648

RESUMEN

Current oncolytic virotherapy is primarily administered by intratumoral injection. However, systemic delivery is desirable for treating patients, particularly for those who have developed metastatic diseases. Several components are impeding the systemic delivery efficiency of oncolytic viruses. Chief among them is the rapid clearance of viral particles by the host's mononuclear phagocyte system (MPS). We explored the possibility of genetically engrafting CD47, a "don't eat me" signal molecule, to the membrane envelop of an oncolytic herpes simplex virus (HSV) to enable it to escape from the MPS for systemic delivery. Our results show that this modification indeed allows the virus to be more efficiently delivered to local tumors by the systemic route. Moreover, this modification also prolongs the virus persistence in local tumors after it arrives there. Consequently, systemic delivery of the modified virus produced a measurable antitumor effect against a murine tumor model that is otherwise resistant to the parental virus delivered by the same route. Our data thus suggest that engrafting enveloped oncolytic viruses such as those derived from HSV with CD47 molecule represents a conceivable strategy to enhance the efficiency of systemic delivery.

18.
Transl Oncol ; 11(6): 1323-1333, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30172884

RESUMEN

The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti-PD-L1 immunotherapy to achieve better treatment outcome.

19.
Oncotarget ; 9(30): 21348-21358, 2018 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-29765544

RESUMEN

Herpes simplex virus (HSV) is one of the many viruses that have been modified or adapted for oncolytic purposes. There are two serotypes of HSV, HSV-1 and HSV-2. The majority of oncolytic HSVs, including T-VEC which has recently been approved by the US Food and Drug Administration (FDA) for clinical use in treating late stage melanoma patients, are derived from HSV-1. Recently, we and others have developed several HSV-2 based oncolytic viruses. During our in vitro characterization of oncolytic viruses developed from both serotypes (Baco-1 from HSV-1 and FusOn-H2 from HSV-2), we noticed there is a subpopulation of cancer cells in which both viruses could infect but only FusOn-H2 could spread from cell to cell on monolayers. This observation prompted us to investigate the virus receptor expression profiles in these and other tumor cells. Our data show the following: 1) This subpopulation of tumor cells only express nectin-2, not the other two major receptors (HVEM or nectin-1). 2) Baco-1 grows to a higher titer than FusOn-H2 in this subpopulation of tumor cells, but the latter kills these tumor cells more efficiently than the former. 3) FusOn-H2 is effective at treating tumors formed from these tumor cells while Baco-1 is completely ineffective. Our results suggest that this subpopulation of tumor cells may be intrinsically resistant to the therapeutic effect of a HSV-1 based oncolytic virus but they remain sensitive to a HSV-2 based virotherapy.

20.
Sci Rep ; 7(1): 12189, 2017 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-28939881

RESUMEN

Type I-interferon (IFN) is considered to exert antitumor effects through the inhibition of cancer cell proliferation and angiogenesis. Based on the species-specific biological activity of IFN, we evaluated each antitumor mechanism separately. We further examined the antitumor effects of type I-IFN combined with sorafenib. Human IFN (hIFN) significantly inhibited the proliferation of human hepatocellular carcinoma (HCC) Hep3B cells and the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Although mouse IFN (mIFN) did not inhibit the proliferation of Hep3B cells in vitro, mIFN, as well as hIFN, showed significant antitumor effects in mouse Hep3B cell-xenograft model. Furthermore, mIFN treatment amplified the antitumor effects of sorafenib in vivo with the suppression of angiogenesis. The DNA chip analysis showed that the mIFN treatment promoted the antitumor signal pathways of sorafenib, including anti-angiogenic effects. Unlike the effects observed in in vitro experiments, mIFN showed an antitumor effect in the mouse Hep3B cell-xenograft model, suggesting a role of the anti-angiogenic activity in the in vivo tumoricidal effects of type I-IFN. In addition, our findings suggested the clinical utility of combination therapy with type І-IFN and sorafenib for HCC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Interferón Tipo I/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interferón Tipo I/uso terapéutico , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/patología , Ratones , Sorafenib/farmacología , Sorafenib/uso terapéutico , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
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