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BACKGROUND: Gastric cancer is one of the global health concerns. A series of studies on the stomach have confirmed the role of the microbiome in shaping gastrointestinal diseases. Delineation of microbiome signatures to distinguish chronic gastritis from gastric cancer will provide a non-invasive preventative and treatment strategy. In this study, we performed whole metagenome shotgun sequencing of fecal samples to enhance the detection of rare bacterial species and increase genome sequence coverage. Additionally, we employed multiple bioinformatics approaches to investigate the potential targets of the microbiome as an indicator of differentiating gastric cancer from chronic gastritis. RESULTS: A total of 65 patients were enrolled, comprising 33 individuals with chronic gastritis and 32 with gastric cancer. Within each group, the chronic gastritis group was sub-grouped into intestinal metaplasia (n = 15) and non-intestinal metaplasia (n = 18); the gastric cancer group, early stage (stages 1 and 2, n = 13) and late stage (stages 3 and 4, n = 19) cancer. No significant differences in alpha and beta diversities were detected among the patient groups. However, in a two-group univariate comparison, higher Fusobacteria abundance was identified in phylum; Fusobacteria presented higher abundance in gastric cancer (LDA scored 4.27, q = 0.041 in LEfSe). Age and sex-adjusted MaAsLin and Random Forest variable of importance (VIMP) analysis in species provided meaningful features; Bacteria_caccae was the most contributing species toward gastric cancer and late-stage cancer (beta:2.43, se:0.891, p:0.008, VIMP score:2.543). In contrast, Bifidobacterium_longum significantly contributed to chronic gastritis (beta:-1.8, se:0.699, p:0.009, VIMP score:1.988). Age, sex, and BMI-adjusted MasAsLin on metabolic pathway analysis showed that GLCMANNANAUT-PWY degradation was higher in gastric cancer and one of the contributing species was Fusobacterium_varium. CONCLUSION: Microbiomes belonging to the pathogenic phylum Fusobacteria and species Bacteroides_caccae and Streptococcus_anginosus can be significant targets for monitoring the progression of gastric cancer. Whereas Bifidobacterium_longum and Lachnospiraceae_bacterium_5_1_63FAA might be protection biomarkers against gastric cancer.
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Bacterias , Heces , Gastritis , Metagenoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiología , Masculino , Femenino , Persona de Mediana Edad , Gastritis/microbiología , Heces/microbiología , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Anciano , Microbioma Gastrointestinal/genética , AdultoRESUMEN
Patient education and self-management are essential for patients with liver cirrhosis. Based on Fisher and Fisher's Information-Motivation-Behavior Skills model, a Cirrhosis Care App was developed to support the education and self-management of these patients. To evaluate the effectiveness of the application, a randomized controlled trial was conducted with patients having liver cirrhosis who were being followed up in the outpatient area of ââa medical center in Taiwan. The experimental group used the app for 1 month, whereas a control group continued to receive conventional patient education. A pretest and posttest questionnaire was used to evaluate the app's effectiveness in improving the knowledge and practice of self-care. In addition, a questionnaire was developed based on the Technology Acceptance Model to understand satisfaction with the app. Results showed that following the implementation of the Cirrhosis Care App, patients' self-care knowledge and ability to promote self-care practice improved. User satisfaction with the app was measured and reflected in its frequency of use. This study confirmed that the Cirrhosis Care App, based on the Information-Motivation-Behavior Skills model, can improve patient knowledge and self-care practice and be actively promoted to benefit patients with cirrhosis.
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The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be approximately about 25.24% of the population worldwide. NAFLD is a complex syndrome and is characterized by a simple benign hepatocyte steatosis to more severe steatohepatitis in the liver pathology. Phellinus linteus (PL) is traditionally used as a hepatoprotective supplement. Styrylpyrone-enriched extract (SPEE) obtained from the PL mycelia has been shown to have potential inhibition effects on high-fat- and high-fructose-diet-induced NAFLD. In the continuous study, we aimed to explore the inhibitory effects of SPEE on free fatty acid mixture O/P [oleic acid (OA): palmitic acid (PA); 2:1, molar ratio]-induced lipid accumulation in HepG2 cells. Results showed that SPEE presented the highest free radical scavenging ability on DPPH and ABTS, and reducing power on ferric ions, better than that of partitions obtained from n-hexane, n-butanol and distilled water. In free-fatty-acid-induced lipid accumulation in HepG2 cells, SPEE showed an inhibition effect on O/P-induced lipid accumulation of 27% at a dosage of 500 µg/mL. As compared to the O/P induction group, the antioxidant activities of superoxide dismutase, glutathione peroxidase and catalase were enhanced by 73%, 67% and 35%, respectively, in the SPEE group. In addition, the inflammatory factors (TNF-α, IL-6 and IL-1ß) were significantly down-regulated by the SPEE treatment. The expressions of anti-adipogenic genes involved in hepatic lipid metabolism of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were enhanced in the SPEE supplemented HepG2 cells. In the protein expression study, p-AMPK, SIRT1 and PGC1-α were significantly increased to 121, 72 and 62%, respectively, after the treatment of SPEE. Conclusively, the styrylpyrone-enriched extract SPEE can ameliorate lipid accumulation and decrease inflammation and oxidative stress through the activation of SIRT1/AMPK/PGC1-α pathways.
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Enfermedad del Hígado Graso no Alcohólico , Phellinus , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Células Hep G2/efectos de los fármacos , Células Hep G2/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Sirtuina 1/metabolismo , Productos Biológicos/química , Productos Biológicos/farmacología , Pironas/química , Pironas/farmacología , Phellinus/químicaRESUMEN
BACKGROUND: The influence of alcoholic liver disease (ALD) on the postoperative outcomes is not completely understood. Our purpose is to evaluate the complications and mortality after nonhepatic surgeries in patients with ALD. METHODS: We conducted a retrospective cohort study included adults aged 20 years and older who underwent nonhepatic elective surgeries using data of Taiwan's National Health Insurance, 2008-2013. Using a propensity-score matching procedure, we selected surgical patients with ALD (n = 26,802); or surgical patients without ALD (n = 26,802) for comparison. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of postoperative complications and in-hospital mortality associated with ALD. RESULTS: Patients with ALD had higher risks of acute renal failure (OR 2.74, 95% CI 2.28-3.28), postoperative bleeding (OR 1.64, 95% CI 1.34-2.01), stroke (OR 1.51, 95% CI 1.34-1.70) septicemia (OR 1.47, 95% CI 1.36-1.58), pneumonia (OR 1.43, 95% CI 1.29-1.58), and in-hospital mortality (OR 2.64, 95% CI 2.24-3.11) than non-ALD patients. Patients with ALD also had longer hospital stays and higher medical expenditures after nonhepatic surgical procedures than the non-ALD patients. Compared with patients without ALD, patients with ALD who had jaundice (OR 4.82, 95% CI 3.68-6.32), ascites (OR 4.57, 95% CI 3.64-5.74), hepatic coma (OR 4.41, 95% CI 3.44-5.67), gastrointestinal hemorrhage (OR 3.84, 95% CI 3.09-4.79), and alcohol dependence syndrome (OR 3.07, 95% CI 2.39-3.94) were more likely to have increased postoperative mortality. CONCLUSION: Surgical patients with ALD had more adverse events and a risk of in-hospital mortality after nonhepatic surgeries that was approximately 2.6-fold higher than that for non-ALD patients. These findings suggest the urgent need to revise the protocols for peri-operative care for this population.
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Hepatopatías Alcohólicas , Humanos , Adulto , Estudios Retrospectivos , Puntaje de Propensión , Oportunidad Relativa , Mortalidad Hospitalaria , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/cirugíaRESUMEN
The KRAS mutation is one of the leading driver mutations in colorectal cancer (CRC), and it is usually associated with poor prognosis and drug resistance. Therapies targeting the epidermal growth factor receptor (EFGR) are widely used for end-stage CRC. However, patients with KRAS mutant genes cannot benefit from this therapy because of Ras signaling activation by KRAS mutant genes. Our previous study revealed the anti-proliferative effect of 4-acetyl-antroquinonol B (4-AAQB) on CRC cells, but whether the drug is effective in KRAS-mutant CRC remains unknown. We screened CRC cell lines harboring the KRAS mutation, namely G12A, G12C, G12V and G13D, with one wild type cell line as the control; SW1463 and Caco-2 cell lines were used for further experiments. Sulforhodamine B assays, together with the clonogenicity and invasion assay, revealed that KRAS-mutant SW1463 cells were resistant to cetuximab; however, 4-AAQB treatment effectively resensitized CRC cells to cetuximab through the reduction of colony formation, invasion, and tumorsphere generation and of oncogenic KRAS signaling cascade of CRC cells. Thus, inducing cells with 4-AAQB before cetuximab therapy could resensitize KRAS-mutant, but not wild-type, cells to cetuximab. Therefore, we hypothesized that 4-AAQB can inhibit KRAS. In silico analysis of the publicly available GEO (GSE66548) dataset of KRAS-mutated versus KRAS wild-type CRC patients confirmed that miR-193a-3p was significantly downregulated in the former compared with the latter patient population. Overexpression of miR-193a-3p considerably reduced the oncogenicity of both CRC cells. Furthermore, KRAS is a key target of miR-193a-3p. In vivo treatment with the combination of 4-AAQB and cetuximab significantly reduced the tumor burden of a xenograft mice model through the reduction of the expression of oncogenic markers (EGFR) and p-MEK, p-ERK, and c-RAF/p-c-RAF signaling, with the simultaneous induction of miR-193a-3p expression in the plasma. In summary, our findings provide strong evidence regarding the therapeutic effect of 4-AAQB on KRAS-mutant CRC cells. Furthermore, 4-AAQB effectively inhibits Ras singling in CRC cells, through which KRAS-mutant CRC can be resensitized to cetuximab.
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Biomarcadores de Tumor/metabolismo , Cetuximab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Ubiquinona/análogos & derivados , Animales , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Pronóstico , Células Tumorales Cultivadas , Ubiquinona/química , Ubiquinona/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/genética , Quinasas raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
BACKGROUND AND AIM: The need for all-oral hepatitis C virus (HCV) treatments with higher response rates, improved tolerability, and lower pill burden compared with interferon-inclusive regimen has led to the development of new direct-acting antiviral agents. Ravidasvir (RDV) is a second-generation, pan-genotypic NS5A inhibitor with high barrier to resistance. The aim of this phase 2 study (EVEREST study) was to assess the efficacy and safety of interferon-free, 12-week RDV plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimen for treatment-naïve Asian HCV genotype 1 (GT1) patients without cirrhosis. METHODS: A total of 38 treatment-naïve, non-cirrhotic adult HCV GT1 patients were enrolled in this multicenter, open-label, single-arm phase 2 study (NCT03020095). All patients received a combination of RDV 200 mg once daily (q.d.) plus DNVr 100 mg/100 mg twice daily (b.i.d.) and oral RBV 1000/1200 mg/day (body weight < 75/≥ 75 kg) for 12 weeks. The primary endpoint was the rate of sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: Of 38 patients, all (100%) achieved SVR12. During the study, no treatment-related serious adverse events, no patients discontinued treatment due to adverse events, and no deaths were reported. Six of 37 (16%) patients with available sequences had HCV NS5A resistance-associated variants at baseline. All patients (6/6) with baseline NS5A resistance-associated variants achieved SVR12. CONCLUSIONS: Twelve-week RDV and DNVr in combination with RBV for 12 weeks achieves the SVR12 rate of 100% in treatment-naïve non-cirrhotic Asian patients with HCV GT1 infection. This interferon-free regimen is also safe and well tolerated.
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Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Lactamas/administración & dosificación , Ribavirina/administración & dosificación , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Administración Oftálmica , Adulto , Anciano , Anciano de 80 o más Años , Antivirales , Pueblo Asiatico , Ciclopropanos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Isoindoles , Lactamas Macrocíclicas , Cirrosis Hepática , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: The objectives of this study were to survey the frequency of engaging in a health-promoting lifestyle in patients with liver cirrhosis, and examine the mediating effects of a health-promoting lifestyle on relationships of symptoms and psychological distress with the quality of life (QOL). METHODS: A cross-sectional study was conducted to recruit 148 cirrhotic outpatients from the gastroenterology outpatient department of one medical university hospital. All study participants completed self-administered questionnaires comprising a multidimensional symptoms scale, Hospital Anxiety and Depression Scale, short-form Chinese health-promoting lifestyle profile, and the Taiwanese version of the Short-Form 36. Hierarchical linear regression and mediation models were used to evaluate the effect of a health-promoting lifestyle on the QOL. RESULTS: Results showed these cirrhotic outpatients reported low frequencies of health-promoting behaviors in their daily activities and had poor mental health but superior physical health. The hierarchical linear regression model found that depression, anxiety, and a health-promoting lifestyle were significant determinants of mental health. The mediation analysis further identified that a health-promoting lifestyle acted as a significant mediator which ameliorated the effects of depression and anxiety on the mental health aspect of the QOL. CONCLUSIONS: A health-promoting lifestyle can improve the mental health of the QOL. Healthcare professionals can develop effective health-promoting interventions to manage and improve the mental health of cirrhotic patients.
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Ansiedad/psicología , Depresión/psicología , Promoción de la Salud/métodos , Cirrosis Hepática/terapia , Salud Mental/normas , Calidad de Vida/psicología , Estudios Transversales , Femenino , Humanos , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: The assessment of symptoms distress is an important strategy for symptoms management and treatment of patients with liver cirrhosis (LC); however, appropriate instruments are limited. OBJECTIVE: The objective of this study was to validate a symptoms distress scale (SDS) by confirming the appropriateness of each item using item response theory. METHODS: A cross-sectional and convenience sampling was conducted to recruit eligible cirrhotic outpatients from the gastroenterology outpatient department of a single medical university hospital. In total, 163 patients with LC completed the 21-item SDS. A graded response model with two-parameter (discrimination and difficulty) estimation was used for data analysis. RESULTS: The item response theory model identified the validity of the SDS and found that most of the items in the SDS represented a high level of symptoms distress; moreover, three items of bruising, drowsiness, and dark urine were reported in cirrhotic patients with severe symptom distress. Four items comprising bodily pain, right upper quadrant pain, muscle cramps, and change in appearance can be appropriately represented in cirrhotic patients with mild symptoms distress. Moreover, the amount of test information in the SDS was >0.70, indicating acceptable reliability. DISCUSSION: Items of the SDS can be useful for assessing different levels of symptoms distress; however, using the scale to assess mild symptoms distress in populations with LC should be done with great caution.
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Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Evaluación de Síntomas , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND & AIMS: Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients. METHODS: The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective-prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort. RESULTS: In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development. CONCLUSIONS: Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.
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Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Guanina/análogos & derivados , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/mortalidad , Neoplasias Hepáticas/epidemiología , Adulto , Várices Esofágicas y Gástricas/epidemiología , Femenino , Hemorragia Gastrointestinal/epidemiología , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Estudios Retrospectivos , Taiwán , Resultado del Tratamiento , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND AND AIM: Chronic hepatitis C (CHC) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy remains the standard of care for CHC genotype 1 in many Asian countries, and single nucleotide polymorphism or genotype of the interleukin-28B (IL28B) gene is associated with the development of sustained virologic response (SVR). The predictive value of IL28B genotype for retreatment outcomes of patients with CHC was only partly clarified and deserves further investigation. METHODS: A total of 75 CHC genotype 1 Taiwanese patients who relapsed after 24-week PEG-IFN/RBV combination therapy and received retreatment with a 48-week PEG-IFN/RBV therapy were consecutively enrolled since November 2009. The associations among IL28B rs8099917 genotype, virologic kinetics, and treatment outcomes were evaluated. RESULTS: Rapid virologic response (RVR) at week 4, end-of-treatment virologic response (EOT-VR) and SVR was 37%, 73%, and 52%, respectively. Relapse rate was 29%. None of patients had rs8099917 GG genotype. Patients with TT genotype (n = 54, 72%) had higher rates of RVR (50% vs 5%, P = 0.0002), end-of-treatment virologic response (85% vs 43%, P = 0.0001), and SVR (67% vs 14%, P = 0.0001) than those with GT genotype (n = 21, 28%). Combination of IL28Bâ TT genotype and achieving RVR had 85% positive and 90% negative predictive values of SVR. CONCLUSIONS: About half of the Taiwanese CHC relapsers to a previous 24-week combination therapy achieve SVR after retreatment for 48 weeks. IL28B genotype influences on-treatment viral kinetics and SVR rate in these retreated patients. Baseline IL28B genotype and RVR can serve as early predictors for treatment success.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferón-alfa/uso terapéutico , Interleucinas/genética , Polietilenglicoles/uso terapéutico , Polimorfismo Genético/genética , Ribavirina/uso terapéutico , Anciano , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/virología , Humanos , Interferones , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Recurrencia , Taiwán , Factores de Tiempo , Resultado del TratamientoRESUMEN
Since the 1970s, artificial intelligence (AI) has played an increasingly pivotal role in the medical field, enhancing the efficiency of disease diagnosis and treatment. Amidst an aging population and the proliferation of chronic disease, the prevalence of complex surgeries for high-risk multimorbid patients and hard-to-heal wounds has escalated. Healthcare professionals face the challenge of delivering safe and effective care to all patients concurrently. Inadequate management of skin wounds exacerbates the risk of infection and complications, which can obstruct the healing process and diminish patients' quality of life. AI shows substantial promise in revolutionizing wound care and management, thus enhancing the treatment of hospitalized patients and enabling healthcare workers to allocate their time more effectively. This review details the advancements in applying AI for skin wound assessment and the prediction of healing timelines. It emphasizes the use of diverse algorithms to automate and streamline the measurement, classification, and identification of chronic wound healing stages, and to predict wound healing times. Moreover, the review addresses existing limitations and explores future directions.
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Video 1Endoscopic full-thickness resection using double endoscope-assisted snare traction facilitates precise resection of a large exophytic gastric subepithelial lesion.
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The discovery of SARS-CoV-2 RNA in the periodontal tissues of patients who tested positive for COVID-19, 24 days post the initial symptom onset, indicates the oral cavity could serve as a viral reservoir. This research aims to investigate the antiviral capabilities of Ovatodiolide, introducing a novel periodontal ligament organoid model for the study of SARS-CoV-2. We have successfully established a reliable and expandable organoid culture from the human periodontal ligament, showcasing characteristics typical of epithelial stem cells. This organoid model enables us to delve into the lesser-known aspects of dental epithelial stem cell biology and their interactions with viruses and oral tissues. We conducted a series of in vitro and ex vivo studies to examine the inhibitory impacts of Ova on SARS-CoV-2. Our findings indicate that Ovatodiolide molecules can bind effectively to the NRP1 active domain. Our study identifies potential interaction sites for Ovatodiolide (OVA) within the b1 domain of the NRP1 receptor. We generated point mutations at this site, resulting in three variants: Y25A, T44A, and a double mutation Y25A/T44A. While these mutations did not alter the binding activity of the spike protein, they did impact the concentration of OVA required for inhibition. The inhibitory concentrations for these variants are 15 µM for Y25A, 15.2 µM for T44A, and 25 µM for the double mutant Y25A/T44A. In addition, in vitro inhibition experiments demonstrate that the EC50 of Ova against the main protease (Mpro) of the SARS-CoV-2 virus is 7.316 µM. Our in vitro studies and the use of the periodontal ligament organoid model highlight Ovatodiolide's potential as a small molecule therapeutic agent that impedes the virus's ability to bind to the Neuropilin-1 receptor on host cells. The research uncovers various pathways and biochemical strategies through which Ovatodiolide may function as an effective antiviral small molecule drug.
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Tratamiento Farmacológico de COVID-19 , Neuropilina-1 , Organoides , Ligamento Periodontal , SARS-CoV-2 , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citología , Ligamento Periodontal/virología , Humanos , Organoides/virología , Organoides/metabolismo , Organoides/efectos de los fármacos , Neuropilina-1/metabolismo , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , COVID-19/metabolismo , COVID-19/virología , Diterpenos/farmacologíaRESUMEN
OBJECTIVE: To discuss the model of reasonable dissection extent of mediastinal lymph nodes in non-small cell lung cancer of diameter less than 2 cm. METHOD: A study was carried on the clinical data of 192 patients with NSCLC of diameter less than 2 cm undergoing curative resection and mediastinal lymph nodes dissection,According to the size of tumor and the pathology quick report. RESULTS: The survival rates of patient was statistically significant difference (P < 0.01), prognostic factors included diameter of tumor, lymph node metastasis and visceral pleura invasion;51.7% mediastinal lymph node metastasis of superior lobe tumor, 28.8% transfering to subcarinal node; the mediastinal lymph node metastasis rate of adenocarcinoma was 32.2%, and squamous cell carcinoma was 15.4% (P = 0.0012) . CONCLUSION: If the patient's cardiopulmonary function permitting, regardless of the size of focus, Regional mediastinal lymph nodal and subcarinal lymph nodal dissection should be routinely performed on patients with non-small cell lung cancer of diameter less than 2 cm, and improve survival rate.
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Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Escisión del Ganglio Linfático/métodos , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To evaluate the feasibility and efficacy of salvage surgery after local failure of definitive chemoradiotherapy (dCRT) for esophageal carcinomas. METHODS: We retrospectively reviewed the esophageal cancer patients underwent salvage surgery (Group A, 26 cases) or non-surgical therapy (Group B, 11 cases) after local failure of dCRT(cT1-3N0-1M0) between July 2008 and June 2010. RESULTS: The rate of resection was 84.6% in Group A, R0 was 69.2%. There was no mortality after surgery. The rate of postoperative complications is 53.8%, especially pneumonia 30.8%, anastomosis leakage 11.5% and arrhythmia 7.7%. The median survival time is 11.1 months; the 2-year survival rate of Group A was 23.1% in Group A. The non-surgical therapy was given including second-line chemotherapy and esophagus stents; the median survival time is 8.1 months (3.1-15.1) in Group B. The survival rate of Group A was higher than Group B (Kaplan-Meier, P = 0.013). CONCLUSION: Salvage surgery provides survival benefit for esophageal cancer patients with local persistent or recurrence after primary dCRT, despite of high morbidity.Salvage surgery should be carried out for patients with good physical condition and complete resection is technically possible.
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Neoplasias Esofágicas/cirugía , Terapia Recuperativa , Anciano , Quimioradioterapia , Neoplasias Esofágicas/mortalidad , Esofagectomía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Hepatocellular carcinoma is the sixth most diagnosed malignancy and the fourth most common cause of cancer-related mortality globally. Despite progress in the treatment of liver cancer, nonsurgical treatments remain unsatisfactory, and only 15% of early-stage cases are surgically operable. Radiotherapy (RT) is a non-surgical treatment option for liver cancer when other traditional treatment methods are ineffective. However, RT has certain limitations, including eliciting poor therapeutic effects in patients with advanced and recurrent tumors. Tumor-associated macrophages (TAMs) are major inflammatory cells in the tumor microenvironment that are key to tumor development, angiogenesis, invasion, and metastasis, and they play an essential role in RT responses. METHODS: We used big data analysis to determine the potential of targeting CXCL6/CXCR2. We enrolled 50 patients with liver cancer who received RT at our hospital. Tumor tissue samples were examined for any relationship between CXCL6/CXCR2 activity and patient prognosis. Using a cell coculture system (Transwell), we cocultured Huh7 liver cancer cells and THP-1 monocytes with and without CXCL6/CXCR2 small interfering RNA for 72 h. RESULTS: The overexpression of CXCL6/CXCR2 was highly correlated with mortality. Our tissue study indicated a positive correlation between CXCL6/CXCR2 and M2-TAMs subsets. The coculture study demonstrated that THP-1 monocytes can secrete CXCL6, which acts on the CXCR2 receptor on the surface of Huh7 cells and activates IFN-g/p38 MAPK/NF-κB signals to promote the epithelial-mesenchymal transition and radio-resistance. CONCLUSIONS: Modulating the TAM/CXCL6/CXCR2 tumor immune signaling axis may be a new treatment strategy for the effective eradication of radiotherapy-resistant hepatocellular carcinoma cells.
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BACKGROUND: Hepatocellular carcinoma (HCC) remains an aggressive malignancy with a poor prognosis and a leading cause of cancer-related mortality globally. Cumulative evidence suggests critical roles for endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in chronic liver diseases. However, the role of ER stress in HCC pathogenesis, aggressiveness and therapy response remains unclear and understudied. OBJECTIVES: Against this background, the present study evaluated the therapeutic efficacy and feasibility of notopterol (NOT), a furanocoumarin and principal component of Notopterygium incisum, in the modulation of ER stress and cancer stemness, and the subsequent effect on liver oncogenicity. METHODS: An array of biomolecular methods including Western blot, drug cytotoxicity, cell motility, immunofluorescence, colony and tumorsphere formation, flow-cytometric mitochondrial function, GSH/GSSG ratio, and tumor xenograft ex vivo assays were used in the study. RESULTS: Herein, we demonstrated that NOT significantly suppresses the viability, migration, and invasion capacity of the human HCC HepJ5 and Mahlavu cell lines by disrupting ATF4 expression, inhibiting JAK2 activation, and downregulating the GPX1 and SOD1 expression in vitro. NOT also markedly suppressed the expression of vimentin (VIM), snail, b-catenin, and N-cadherin in the HCC cells, dose-dependently. Treatment with NOT significantly attenuated cancer stem cells (CSCs)-like phenotypes, namely colony and tumorsphere formation, with the concomitant downregulation of stemness markers OCT4, SOX2, CD133, and upregulated PARP-1 cleavage, dose-dependently. We also demonstrated that NOT anticancer activity was strongly associated with increased cellular reactive oxidative stress (ROS) but, conversely, reduced mitochondrial membrane potential and function in the HepJ5 and Mahlavu cells in vitro. Our tumor xenograft studies showed that compared with sorafenib, NOT elicited greater tumor growth suppression without adverse changes in mice body weights. Compared with the untreated control and sorafenib-treated mice, NOT-treated mice exhibited markedly greater apoptosis ex vivo, and this was associated with the co-suppression of stemness and drug-resistance markers OCT4, SOX2, ALDH1, and the upregulation of endoplasmic reticulum stress and oxidative stress factors PERK and CHOP. CONCLUSIONS: In summary, we demonstrated for the first time that NOT exhibits strong anticancer activity via the suppression of cancer stemness, enhanced endoplasmic reticulum stress and increased oxidative stress thus projecting NOT as a potentially effective therapeutic agent against HCC.
Asunto(s)
Carcinoma Hepatocelular , Furocumarinas , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Sorafenib/uso terapéutico , Neoplasias Hepáticas/metabolismo , Furocumarinas/farmacología , Línea Celular Tumoral , Muerte Celular , Estrés del Retículo Endoplásmico , Apoptosis , Carcinogénesis , Estrés OxidativoRESUMEN
Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p < 0.001) and tumorsphere formation (p < 0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.