Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

Rare Orbital Involvement Originating from Extranodal Marginal Zone Lymphoma.

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.

Association of red blood cell size and physical fitness in a military male cohort: The CHIEF study.

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.

Rare Orbital Metastasis Originating from Ampullary Adenocarcinoma.

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.

Necrotizing fasciitis in two patients with myelodysplastic syndrome treated with azacitidine.

Azacitidine is a novel agent for treating myelodysplastic syndromes (MDS). It has a relatively safe toxicity profile with very few reported skin toxicities. Patients with MDS were prone to get severe infections, especially via respiratory tract, urinary system, and bloodstream. However, necrotizing fasciitis (NF) is a relatively rare event in patients with MDS, and it is hard to diagnose early. Here, we report two MDS cases that developed NF in lower extremities while receiving azacitidine treatment. One of them survives after emergent fasciotomy along with the administration of broad-spectrum antibiotics and intravenous immunoglobulin.

The correlation between a chronic inflammatory marker Tartrate-resistant acid phosphatase 5a with cancer cachexia.

PURPOSE: The mechanism of cancer cachexia remains unclear and inflammatory cytokines may play a role in its development. Interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-α (TNFα) are known to be associated with cancer cachexia. Tartrate-resistant acid phosphatase 5a (TRACP5a) is proposed to be related to chronic inflammation. In this study we hypothesize that TRACP5a is a chronic inflammatory marker that is correlated with cancer cachexia. METHODS: Fifty-five cancer patients with and without cancer cachexia were enrolled from January 2009 to December 2012. Body mass index (BMI) was measured and serum total cholesterol, triglycerides and albumin were examined to evaluate the nutritional status. IL-6, CRP and TRACP5a protein activity were evaluated. RESULTS: Inflammatory markers including IL-6, and CRP were significantly elevated in patients with cancer cachexia (p=0.0075 and 0.0021, respectively). Patients with cachexia also had higher CRP/albumin ratio (p=0.0265). TRACP5a activity, TRACP5a protein and their combinations with albumin were increased in the cancer cachexia groups but without significant difference. There were good correlations between IL-6, CRP, and BMI. Patients with higher TRACP5a activity had shorter survival (p=0.004). CONCLUSION: TRACP5a may be a promising chronic inflammatory marker and may play a prognostic role in cancer cachexia. Further large-scale prospective studies are warranted to confirm its role in the cancer cachexia process.

Gefitinib as first-line treatment for patients with epidermal growth factor receptor-mutated advanced lung adenocarcinoma: a single institution experience in Taiwan.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a new treatment option for patients with advanced lung adenocarcinoma. In this article we assessed the treatment response and tried to identify prognostic factors which may provide some information different from previously published reports in groups with better performance status (PS) than our enrolled patients. METHODS: The records of 85 patients with EGFR-mutated advanced lung adenocarcinoma who received gefitinib 250 mg once daily as front-line monotherapy between October 2007 and October 2012 were analysed. Direct sequencing methods were used for detecting EGFR mutations. SPSS (version 20) software was used for all data analysis. RESULTS: The median overall survival (OS) and progression free survival (PFS) were 25.6 and 6.9 months, respectively. No statistical significance between the two groups of exon 19 and exon 21 in OS and PFS was registered (p=0.414 and p=0.519, respectively). The group of patients treated > 3 months had a better median OS survival compared with those treated < 3 months (25.6 vs 4.9 months, p<0.001). In multivariate analysis, significant benefit on OS was observed in patients with ECOG PS scores of 0-2 (p=0.002) and those treated for longer time periods (p<0.001), rather than age, sex and smoking. Among the adverse effects (AEs), skin manifestation was correlated with significantly better OS (p=0.007) but insignificant effect on PFS (p=0.131). CONCLUSIONS: Good ECOG PS, longer TKI use and skin rash were significant factors predictive for gefitinib antitumor activity.

Underlying mechanisms of novel cuproptosis-related dihydrolipoamide branched-chain transacylase E2 (DBT) signature in sunitinib-resistant clear-cell renal cell carcinoma.

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.

PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance.

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.

Primary Stereotactic Body Radiotherapy for Spinal Bone Metastases From Lung Adenocarcinoma.

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.

Acute hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency complicated by Ginkgo biloba.

We report on a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency who developed acute hemolytic anemia after having received an injection of Ginkgo biloba for dementia prophylaxis without medical advice. She suddenly developed general malaise, generalized yellowish skin color, and tea-colored urine. Intravenous fluid infusion and cessation of G. biloba quickly relieved her clinical symptoms. To the best of our knowledge, this is the first case report of G. biloba-induced acute hemolytic anemia in vivo.

Non-Insulin-Based Insulin Resistance Indices and Localized Periodontitis in Physically Active Young Male Adults: CHIEF Oral Health Study.

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.

Real-world bleeding outcomes and product utilization in people with severe-type hemophilia A before and after switching to extended half-life rFVIIIFc prophylaxis therapy.

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.

Profiling of miRNAs and their interfering targets in peripheral blood mononuclear cells from patients with chronic myeloid leukaemia.

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.

Dysregulated expression of slingshot protein phosphatase 1 (SSH1) disrupts circadian rhythm and WNT signaling associated to hepatocellular carcinoma pathogenesis.

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.

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A.

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.

Urokinase plasminogen activator induces epithelial-mesenchymal and metastasis of pancreatic cancer through plasmin/MMP14/TGF-ß axis, which is inhibited by 4-acetyl-antroquinonol B treatment.

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.

A Comparative Evaluation of an Automated Functional Assay for Von Willebrand Factor Activity in Type 1 Von Willebrand Disease.

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.

Erythrocyte Indices and Long-Term Blood Pressure Variability in Military Males.

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.

Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p.

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.