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OBJECTIVE: This study aimed to assess the results of primary stereotactic body radiotherapy (SBRT) for spinal bone metastases (SBM) originating from lung adenocarcinoma (ADC). We considered the revised Tokuhashi score (rTS), Spinal Instability Neoplastic Score (SINS), and genetic characteristics. METHODS: We examined adult patients with lung ADC who underwent primary SBRT (using the CyberKnife System) for SBM between March 2012 and January 2023. RESULTS: We analyzed data from 99 patients, covering 152 SBM across 194 vertebrae. The overall local control (LC) rate was 77.6% for SBM from lung ADC, with a LC rate of 90.7% at 1 year. The median period for local progression (LP) occurrence was recorded at 10.0 (3-52) months. Additionally, Asian patients demonstrated higher LC rates than White patients. Utilizing the rTS and SINS as predictive tools, we revealed that a poor survival prognosis and an unstable spinal structure were associated with increased rates of LP. Furthermore, the presence of osteolytic bone destructions and pain complaints were significantly correlated with the occurrence of LP. In the cohort of this study, 108 SBM underwent analysis to determine the expression levels of programmed cell death ligand 1 (PD-L1). Additionally, within this group, 60 showed mutations in the epidermal growth factor receptor (EGFR) alongside PD-L1 expression. Nevertheless, these genetic differences did not result in statistically significant differences in the LC rate. CONCLUSION: The one-year LC rate for primary SBRT targeting SBM from lung ADC stood at 90.7%, particularly with the use of the CyberKnife System. Patients achieving LC exhibited significantly longer survival times compared to those with LP.
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Ocular adnexa region (OAR) primary lymphomas are uncommon, accounting for 1-2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. Extranodal marginal zone lymphoma (EMZL) originates from several epithelial tissues, including the stomach, salivary gland, lung, small intestine, thyroid gland, and ocular adnexa region. Here, we report a 66-year-old female patient who was diagnosed with EMZL of OAR. In consideration of the possible side effect of radiotherapy, such as conjunctivitis, visual acuity impairment, and even retinal complications, she received six cycles of triweekly targeted chemotherapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) without radiotherapy. Then, she remained in complete remission up to the present day.
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Linfoma de Células B de la Zona Marginal , Humanos , Femenino , Anciano , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Neoplasias Orbitales/tratamiento farmacológico , Rituximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Renal cell carcinoma (RCC) is the predominant form of malignant kidney cancer. Sunitinib, a primary treatment for advanced, inoperable, recurrent, or metastatic RCC, has shown effectiveness in some patients but is increasingly limited by drug resistance. Recently identified cuproptosis, a copper-ion-dependent form of programmed cell death, holds promise in combating cancer, particularly drug-resistant types. However, its effectiveness in treating drug resistant RCC remains to be determined. Exploring cuproptosis's regulatory mechanisms could enhance RCC treatment strategies. Our analysis of data from the GEO and TCGA databases showed that the cuproptosis-related gene DBT is markedly under expressed in RCC tissues, correlating with worse prognosis and disease progression. In our study, we investigated copper CRGs in ccRCC, noting substantial expression differences, particularly in advanced-stage tumors. We established a connection between CRG expression levels and patient survival, positioning CRGs as potential therapeutic targets for ccRCC. In drug resistant RCC cases, we found distinct expression patterns for DBT and GLS CRGs, linked to treatment resistance. Our experiments demonstrated that increasing DBT expression significantly reduces RCC cell growth and spread, underscoring its potential as a therapeutic target. This research sheds new light on the role of CRGs in ccRCC and their impact on drug resistance.
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Carcinoma de Células Renales , Neoplasias Renales , Ácido Tióctico/análogos & derivados , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Sunitinib/farmacología , Sunitinib/uso terapéutico , Cobre , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , ApoptosisRESUMEN
BACKGROUND: The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings. METHODS: Using the ULCAN portal, we noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations. RESULTS: Our study emphasized the connection between PROX1 and α-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship. CONCLUSION: PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition.
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Adenocarcinoma , Fibroblastos Asociados al Cáncer , Neoplasias del Colon , Neoplasias Colorrectales , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Actinas/metabolismo , Neoplasias del Colon/genética , Genes Homeobox , Adenocarcinoma/genética , Resistencia a Antineoplásicos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Microambiente Tumoral/genética , Fibroblastos/metabolismoRESUMEN
Growing evidence underscores the circadian rhythm's essential function in liver stability and disease. Its disruption is progressively linked with metabolic issues, oncogene triggers, and heightened cancer susceptibility. Research points to slingshot protein phosphatase 1 (SSH1), a modulator of cofilin-1 (CFL-1), as instrumental in the reformation of the actin cytoskeleton, thereby impacting the invasiveness of various cancer types. Yet, the dynamics of SSH1's influence on liver cell stemness and circadian activity remain unclear. Through in-silico, tissue analysis, and functional assays, the study reveals a significant SSH1 expression in HCC samples, compared to non-cancerous counterparts, across six HCC platforms (AUC between 0.62 and 0.77, p < 0.01). The aberrant expression of SSH1 was correlated with poor patients' survival (HR = 1.70, p = 0.0063) and progression-free (HR = 1.477, p = 0.0187) survival rates. Targeting SSH1, either via Sennoside A or CRISPR SSH1 in Huh7 cells (Huh7-SSH1-/-) significantly suppressed cell viability, migration, invasion, colony and tumorsphere formation of the Huh7-SSH1-/- cells. Mechanistically, we showed that downregulated SSH1 expression suppressed CLOCK, BMAL1, WNT3, ß-catenin, LRP5/6, BCL2, VIM and Snail, with concomitant upregulated CFL-1/2, and CRY1 expression, indicating dysregulated circadian rhythm and WNT/ß-catenin oncogenic pathway deactivation. Treatments in reflected notable tumor size reductions in the mice treated with SenAlight (1.76-fold, p < 0.01) and SenAdark (3.79-fold, p < 0.01). The expression of SSH1, CLOCK, BMAL1 and ß-catenin proteins were significantly downregulated in the SenAlight and SenAdark mice; this was more so in the SenAdark mice. This reveals a potential treatment approach for HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/genética , Proteína Fosfatasa 1 , beta Catenina , Vía de Señalización Wnt , Factores de Transcripción ARNTL , Neoplasias Hepáticas/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Fosfoproteínas FosfatasasRESUMEN
Introduction: MicroRNAs may be implicated in the acquisition of drug resistance in chronic myeloid leukemia as they regulate the expression of not only BCR-ABL1 but also genes associated with the activation of drug transfer proteins or essential signaling pathways. Methods: To understand the impact of specifically expressed miRNAs in chronic myeloid leukemia and their target genes, we collected peripheral blood mononuclear cells (PBMC) from patients diagnosed with chronic myeloid leukemia (CML) and healthy donors to determine whole miRNA expression by small RNA sequencing and screened out 31 differentially expressed microRNAs (DE-miRNAs) with high expression. With the utilization of miRNA set enrichment analysis tools, we present here a comprehensive analysis of the relevance of DE-miRNAs to disease and biological function. Furthermore, the literature-based miRNA-target gene database was used to analyze the overall target genes of the DE-miRNAs and to define their associated biological responses. We further integrated DE-miRNA target genes to identify CML miRNA targeted gene signature singscore (CMTGSS) and used gene-set enrichment analysis (GSEA) to analyze the correlation between CMTGSS and Hallmark gene-sets in PBMC samples from clinical CML patients. Finally, the association of CMTGSS stratification with multiple CML cell lineage gene sets was validated in PBMC samples from CML patients using GSEA. Results: Although individual miRNAs have been reported to have varying degrees of impact on CML, overall, our results show that abnormally upregulated miRNAs are associated with apoptosis and aberrantly downregulated miRNAs are associated with cell cycle. The clinical database shows that our defined DE-miRNAs are associated with the prognosis of CML patients. CMTGSS-based stratification analysis presented a tendency for miRNAs to affect cell differentiation in the blood microenvironment. Conclusion: Collectively, this study defined differentially expressed miRNAs by miRNA sequencing from clinical samples and comprehensively analyzed the biological functions of the differential miRNAs in association with the target genes. The analysis of the enrichment of specific myeloid differentiated cells and immune cells also suggests the magnitude and potential targets of differentially expressed miRNAs in the clinical setting. It helps us to make links between the different results obtained from the multi-faceted studies to provide more potential research directions.
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The half life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half life by the Web-Accessible Population Pharmacokinetic (PK) Service-Hemophilia during 2019-2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8-64, with a median rFVIII-Fc half life of 20.75 h (range, 8.25-41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half life for the blood groups non-O, O patients, and overall patients, respectively, including baseline VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half life (T) were respectively developed as T for non-O group patients = -0.81 + 0.63 × (BMI, kg/m2) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = -0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) - 1.17 × (BMI, kg/m2) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = -1.76 + 7.24 × (baseline VWF:Ag, IU/mL) - 3.84 × (Inhibitor history) + 2.99 × (HCV infection) - 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half life were identified. Prediction equations of rFVIII-Fc half life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8-64 without the need for PK blood sampling and clinically valuable for personalized therapy.
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AIMS: This study aims to examine the association between non-insulin-based insulin resistance indices and periodontitis severity in young males. BACKGROUND: Periodontitis has been reported with an association with insulin resistance in middle- and old-aged adults. OBJECTIVE: The association between insulin resistance and localized periodontitis in young adults is unclear. METHODS: A total of non-diabetic 1,111 military males in Taiwan were included in this study. Localized periodontitis was classified as healthy (N =665), stage I (N =130), stage II (N =161), and stage III (N =155) based on the world workshop in 2017. Insulin resistance was assessed by serum triglycerides concentrations, the triglycerides glucose (TyG) index, the product of serum triglycerides and fasting glucose, and the ratio of serum triglycerides to high-density lipoprotein cholesterol (TG/HDL-C). Multiple logistic regression analysis with adjustment for age, tobacco smoking, alcohol intake, abdominal obesity, and hypertension was used to determine the associations. RESULTS: Serum TG concentrations, TyG index, and TG/HDL-C ratio were dose-dependently associated with a greater risk of localized periodontitis severity (from stage I to stage III) [odds ratios and 95% confidence intervals: 1.001 (0.999-1.004), 1.003 (1.001-1.004) and 1.003 (1.002- 1.005) for TG; 1.45 (1.03-2.03), 1.65 (1.22-2.22) and 1.66 (1.22-2.26) for TyG index; 1.06 (0.99- 1.14), 1.09 (1.03-1.15) and 1.10 (1.04-1.16) for TG/HDL-C ratio]. However, the association was only found in obese individuals and those free of impaired fasting glucose. CONCLUSION: The present study confirmed that periodontitis may lead to insulin resistance in young male adults, particularly for those with obesity and without hyperglycemia. The TyG index is suggestive as the strongest indicator for the association between insulin resistance and periodontitis in young adults.
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Resistencia a la Insulina , Adulto Joven , Humanos , Masculino , Persona de Mediana Edad , Glucemia/análisis , Salud Bucal , Glucosa , Obesidad , Triglicéridos , HDL-Colesterol , BiomarcadoresRESUMEN
BACKGROUND: Recombinant factor VIII-Fc (rFVIIIFc) became available in Taiwan in 2018. Before this date, no people with hemophilia A (PwHA) were enrolled in a clinical trial of rFVIIIFc. We investigated changes in bleeding outcomes and product utilization in PwHA switching from rFVIII to rFVIIIFc. METHODS: Data were collected for Taiwanese PwHA (severe-type) who switched from rFVIII to rFVIIIFc, including annualized bleeding rate (ABR) and weekly dose consumption 12 months pre-switch and > 6 months post-switch. RESULTS: The 51 patients were divided into 3 groups according to their pre-switch treatment: on-demand treatment, intermittent periodic prophylaxis, and regular prophylaxis. In every group, the post-switch median ABR was significantly reduced, with no significant differences between groups. Meanwhile, the post-switch median weekly dose of each group was significantly increased. In 32 patients on pre-switch prophylaxis, switching brought a further reduction in median ABR, associated with a significant increase in median weekly dose. No adverse effects or novel inhibitor development were seen. CONCLUSION: This is the first report from Asia on real-world experience of rFVIIIFc, showing that switching to rFVIIIFc prophylaxis led to further reduction in ABR and increase in weekly dose for all patient groups, even those on pre-switch rFVIII prophylaxis.
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Hemofilia A , Humanos , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Semivida , Proteínas Recombinantes de Fusión/farmacología , Resultado del Tratamiento , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Hemorragia/prevención & control , Hemorragia/inducido químicamente , Factor VIII/efectos adversosRESUMEN
BACKGROUND: The current standard therapy for metastatic pancreatic cancer is ineffective, necessitating a new treatment approach for prognosis improvement. The urokinase-plasmin activator (uPA) is a critical factor in epithelial-mesenchymal transition (EMT) and cancer metastasis, but its underlying mechanisms in pancreatic cancer remains elusive. METHODS: We investigated uPA expression in our pancreatic cancer cohort. A bioinformatics approach was used to further determine the role of uPA in pancreatic cancer. We employed MiaPaCa-2 and PANC-1 cell lines to investigate how uPA regulates EMT and metastasis in pancreatic cancer and present a novel approach aimed at inhibiting uPA in pancreatic cancer. RESULTS: We observed that higher uPA mRNA expression was significantly associated with overall-poor survival and progression-free survival in pancreatic cancer. uPA was highly expressed in tumor tissue. Gene set enrichment analysis revealed a positive association between uPA mRNA expression and EMT and transforming growth factor ß (TGF-ß) signaling pathways. Moreover, shRNA-mediated uPA gene knockdown reduced plasmin, MMP14, and TGF-ß activation, leading to the inhibition of PANC-1 cells' EMT marker expression, migration, invasion, and cell viability. Notably, 4-acetyl-antroquinonol B (4-AAQB) treatment suppressed MiaPaCa-2 and PANC-1 cell migratory and invasive abilities by inhibiting the uPA/MMP14/TGF-ß axis through upregulation of miR-181d-5p. In the xenograft mouse model of orthotropic pancreatic cancer, 4-AAQB treatment has reduced tumor growth and metastasis rate by deactivating uPA and improving the survival of the mice model. CONCLUSION: Accordingly, to extent of our knowledge and previous studies, we demonstrated that 4-AAQB is an anti Pan-Cancer drug, and may inhibit pancreatic cancer EMT and metastasis and serve as a new therapeutic approach for patients with late-stage pancreatic cancer.
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Neoplasias Pancreáticas , Activador de Plasminógeno de Tipo Uroquinasa , Animales , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Fibrinolisina/farmacología , Humanos , Metaloproteinasa 14 de la Matriz/farmacología , Ratones , Neoplasias Pancreáticas/patología , ARN Mensajero , Factor de Crecimiento Transformador beta/metabolismo , Ubiquinona/análogos & derivados , Activador de Plasminógeno de Tipo Uroquinasa/genética , Neoplasias PancreáticasRESUMEN
BACKGROUNDS: Severe microcytic anemia has been associated with BP changes. AIMS AND OBJECTIVES: Whether the erythrocyte indices are associated with long-term BPV is unknown. This study aimed to investigate the association of hemoglobin levels and erythrocyte size with long-term blood pressure variability (BPV) in young males. METHODS: This study included 1,112 healthy military males, averaging 32 years of age, in Taiwan. All participants took a measurement of systolic and diastolic BP (SBP and DBP) every two-year from 2012 to 2018 (2012-14, 2014-15, 2015-16, 2016-18). Levels of hemoglobin and mean corpuscular volume (MCV) of erythrocytes were obtained at the first visit. Long-term BPV was assessed by the standard deviation (SD) and average real variability (ARV). Multivariate linear regression analysis with adjustment for the baseline BP levels and other covariates was used to elucidate the association. RESULTS: Hemoglobin levels were borderline positively correlated with SD DBP (ß and standard errors = 0.016 (0.009), P =0.06). In those with hemoglobin levels of 10.0-13.9 g/dL, hemoglobin was negatively correlated with SDSBP (ß= -0.039 (0.018), P =0.03). In contrast, MCV levels were borderline positively correlated with SDSBP (ß =0.085 (0.052), P =0.09). In those with MCV levels <80 fL, MCV was positively correlated with SDSBP and ARVSBP (ß= 0.445 (0.210) and 0.286 (0.149), p = 0.03 and 0.05, respectively). CONCLUSION: There were inconsistent patterns for the associations of erythrocyte indices with longterm BPV. We found a U-shaped relationship of hemoglobin levels with systolic BPV, whereas there was a positive linear relationship of hemoglobin and MCV levels with diastolic BPV, respectively.
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Índices de Eritrocitos , Hipertensión , Presión Sanguínea , Humanos , MasculinoRESUMEN
BACKGROUND: Orbital metastasis from ampullary carcinoma is rare, with no previously reported cases. CASE PRESENTATION: We report the case of a 60-year-old man who complained of a right-sided headache, blurred vision, progressive proptosis, ptosis, and right eye pain for 3 months. His past medical history included an ampullary adenocarcinoma stage IIIA treated via the Whipple procedure and adjuvant chemoradiotherapy 1 year ago. However, he was lost to follow-up. Computed tomography of the orbit showed a soft tissue lesion in the right orbital fossa measuring 3.3 × 2 × 2 cm. An orbital mass biopsy demonstrated an intestinal-type adenocarcinoma that tested positive for cytokeratins 7 and 20 and CDX2 on immunohistochemical staining. The pathologic diagnosis was metastatic adenocarcinoma from the ampulla of Vater. Despite oncological treatment, the patient's illness progressed. He received palliative treatment and died 1 month later. CONCLUSIONS: We presented a rare case of orbital metastasis from ampullary adenocarcinoma. This should be considered in the differential diagnosis of patients with a history of ampullary adenocarcinoma who present with symptoms referring to the relevant locations.
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Adenocarcinoma/secundario , Ampolla Hepatopancreática/patología , Neoplasias del Conducto Colédoco/patología , Neoplasias Orbitales/secundario , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico por imagen , Ampolla Hepatopancreática/diagnóstico por imagen , Neoplasias del Conducto Colédoco/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , PancreaticoduodenectomíaRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome, and the current standard of care is the use of tyrosine kinase inhibitors (TKI). However, some patients will not achieve a molecular response and may progress to blast crisis, and the underlying mechanisms remain to be clarified. In this study, next-generation sequencing was used to explore endogenous miRNAs in CML patients versus healthy volunteers, and miR-342-5p was identified as the primary target. We found that miR-342-5p was downregulated in CML patients and had a significant inhibitory effect on cell proliferation in CML. Through a luciferase reporter system, miR-342-5p was reported to target the 3'-UTR domain of CCND1 and downregulated its expression. Furthermore, overexpression of miR-342-5p enhanced imatinib-induced DNA double-strand breaks and apoptosis. Finally, by analyzing clinical databases, we further confirmed that miR-342-5p was associated with predicted molecular responses in CML patients. In conclusion, we found that both in vivo and in vitro experiments and database cohorts showed that miR-342-5p plays a key role in CML patients, indicating that miR-342-5p may be a potential target for future CML treatment or prognostic evaluation.
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Ciclina D1/metabolismo , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Regulación Leucémica de la Expresión Génica , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , MicroARNs/genética , Regiones no Traducidas 3'/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Ciclina D1/genética , Roturas del ADN de Doble Cadena , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Ontología de Genes , Humanos , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucocitos/patología , Ratones Endogámicos C57BL , MicroARNs/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: von Willebrand factor ristocetin cofactor activity (VWF:RCo) is the standard functional assay used for von Willebrand disease (VWD) diagnosis. However, it has some drawbacks including being time consuming and labor intensive and having high inter-laboratory variability. The HemosIL VWF activity assay has the advantages of both high speed and automation. The purpose of this study was to prospectively compare these two functional assays for type 1 VWD detection. METHODS: Plasma samples from 108 subjects were assessed in this study. HemosIL VWF activity was measured with the HemosIL latex immunoturbidimetric commercial kits by the ACL TOP coagulation analyzer. VWF:RCo was measured by platelet aggregation method. Pearson correlation analyses were performed to estimate the correlation of HemosIL VWF activity with VWF:RCo. Receiver-operator characteristic (ROC) curve analysis was used to evaluate the performance of the two diagnostic tests. RESULTS: The correlation coefficient between VWF:RCo and HemosIL VWF activity was 0.874 overall and was 0.761 and 0.811 in the cohorts of type 1 VWD and non-VWD, respectively. The sensitivity and specificity of HemosIL VWF activity assay for type 1 VWD identification were 94.7% and 80.0%, respectively, and the ROC curve of HemosIL VWF activity was larger than that of VWF:RCo (0.928 vs 0.863, p=0.0138). Finally, the positive and negative predictive values of the HemosIL VWF activity assay for type 1 VWD detection were 72.0% and 96.6%, respectively. CONCLUSION: Our results demonstrate that the HemosIL VWF activity assay was an effective method for type 1 VWD screening and diagnosis. It carried good sensitivity and specificity and had a higher ROC curve than VWF:RCo besides showing good correlation with VWF:RCo. With its advantages of greater speed and automated performance, these results suggest that the HemosIL VWF activity assay was reliable and precise in the clinical setting.
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BACKGROUND: Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. METHODS: Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). RESULTS: The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. CONCLUSION: Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.
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Neoplasias del Colon/genética , Exosomas/metabolismo , Genes Supresores de Tumor/fisiología , MicroARNs/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Transducción de Señal , TransfecciónRESUMEN
ABSTRACT: We conducted a population-based cohort study enrolling patients with Stage II and III colon cancer receiving postoperative adjuvant chemotherapy with uracil and tegafur (UFT) or fluorouracil (5-FU) from the Taiwan National Health Insurance Research Database from 2000 to 2015. The outcomes of the current study were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HRs) were calculated by multivariate Cox proportional hazard regression models. We compared our effectiveness results from the literature by meta-analysis, which provided the best evidence. Severe adverse events were compared in meta-analysis of reported clinical trials. In the nationwide cohort study, UFT (14,486 patients) showed DFS similar to postoperative adjuvant chemotherapy (adjusted HR 1.037; 95% confidence interval [CI] 0.954-1.126; P = .397) and OS (adjusted HR 0.964; 95% CI 0.891-1.041; Pâ=â.349) compared with the 5-FU (866 patients). Our meta-analysis confirmed the similarity of effectiveness and found the incidence of leucopaenia was statistically significantly reduced in UFT (risk ratio 0.12; 95% CI 0.02-0.67; I2â=â0%). Through our analysis, we have confirmed that UFT is a well-tolerated adjuvant therapy choice, and has similar treatment efficacy as 5-FU in terms of DFS and OS in patients with Stage II and III colon cancer.
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Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Colon/terapia , Fluorouracilo/administración & dosificación , Recurrencia Local de Neoplasia/epidemiología , Tegafur/administración & dosificación , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Colectomía , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Taiwán/epidemiología , Tegafur/efectos adversosRESUMEN
This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.
RESUMEN
Anemia manifested as reduced red blood cell (RBC) amounts or hemoglobin levels has been associated with lower cardiorespiratory fitness. However, the relationship of smaller RBC with physical fitness was unknown. We included 2933 non-anemic military males (hemoglobin levels: 11.1-15.9 g/dL and mean corpuscular volume (MCV) <100 fL) in Taiwan during 2014. Aerobic fitness was assessed by time for a 3000-meter run, and anaerobic fitness was evaluated by numbers of sit-ups and push-ups, each performed within 2 minutes. Multiple linear and logistic regression models adjusting for age, service specialty, lipid profiles, and hemoglobin levels were used to determine the associations. Microcytosis and normocytosis were defined as MCV ≤ 70 fL (n = 190) and MCV > 70 fL (n = 2743), respectively. The linear regression shows that as compared with microcytosis, normocytosis was associated with more numbers of sit-ups performed within 2 minutes (ß = 1.51, P-value = 0.02). The logistic regression also reveals that those males with microcytosis had higher probability as the worst 10% performers in the 2-minute push-up test (odds ratio: 1.91, 95% confidence intervals: 1.18-3.12). By contrast, there was no association of microcytosis with 3000-meter running time. Our study suggests that non-anemic microcytosis was associated with lower anaerobic fitness but not with aerobic fitness. Whether the causative factors for microcytosis such as iron deficiency status and thalassemia trait unavailable in the study might account for the relationship needs further investigations.
Asunto(s)
Tamaño de la Célula , Índices de Eritrocitos/fisiología , Eritrocitos/citología , Personal Militar , Aptitud Física/fisiología , Adulto , Factores de Edad , Umbral Anaerobio/fisiología , Análisis de Varianza , Capacidad Cardiovascular/fisiología , Recuento de Eritrocitos , Ejercicio Físico/fisiología , Hemoglobina A/análisis , Humanos , Modelos Lineales , Lípidos/sangre , Modelos Logísticos , Masculino , Oportunidad Relativa , Estudios Retrospectivos , Carrera/fisiología , Taiwán , Talasemia beta/sangreRESUMEN
BACKGROUND: Bone marrow aspiration and biopsy remain the gold standard for the diagnosis of hematological diseases despite the development of flow cytometry (FCM) and molecular and gene analyses. However, the interpretation of the results is laborious and operator dependent. Furthermore, the obtained results exhibit inter- and intravariations among specialists. Therefore, it is important to develop a more objective and automated analysis system. Several deep learning models have been developed and applied in medical image analysis but not in the field of hematological histology, especially for bone marrow smear applications. OBJECTIVE: The aim of this study was to develop a deep learning model (BMSNet) for assisting hematologists in the interpretation of bone marrow smears for faster diagnosis and disease monitoring. METHODS: From January 1, 2016, to December 31, 2018, 122 bone marrow smears were photographed and divided into a development cohort (N=42), a validation cohort (N=70), and a competition cohort (N=10). The development cohort included 17,319 annotated cells from 291 high-resolution photos. In total, 20 photos were taken for each patient in the validation cohort and the competition cohort. This study included eight annotation categories: erythroid, blasts, myeloid, lymphoid, plasma cells, monocyte, megakaryocyte, and unable to identify. BMSNet is a convolutional neural network with the YOLO v3 architecture, which detects and classifies single cells in a single model. Six visiting staff members participated in a human-machine competition, and the results from the FCM were regarded as the ground truth. RESULTS: In the development cohort, according to 6-fold cross-validation, the average precision of the bounding box prediction without consideration of the classification is 67.4%. After removing the bounding box prediction error, the precision and recall of BMSNet were similar to those of the hematologists in most categories. In detecting more than 5% of blasts in the validation cohort, the area under the curve (AUC) of BMSNet (0.948) was higher than the AUC of the hematologists (0.929) but lower than the AUC of the pathologists (0.985). In detecting more than 20% of blasts, the AUCs of the hematologists (0.981) and pathologists (0.980) were similar and were higher than the AUC of BMSNet (0.942). Further analysis showed that the performance difference could be attributed to the myelodysplastic syndrome cases. In the competition cohort, the mean value of the correlations between BMSNet and FCM was 0.960, and the mean values of the correlations between the visiting staff and FCM ranged between 0.952 and 0.990. CONCLUSIONS: Our deep learning model can assist hematologists in interpreting bone marrow smears by facilitating and accelerating the detection of hematopoietic cells. However, a detailed morphological interpretation still requires trained hematologists.
RESUMEN
The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.