Background and Aims
Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to ...implement salvage therapies appropriately. This study examined the feasibility of virus‐host chimera DNA (vh‐DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting.
Approach and Results
HBV integration in 50 patients with HBV‐related HCC was determined by the Hybridization capture‐based next‐generation sequencing (NGS) platform. For individual HCC, the vh‐DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV‐related HCC. Tumor‐specific ddPCR was developed to measure the corresponding vh‐DNA copy number in baseline plasma from each patient immediately before surgery. vh‐DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh‐DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh‐DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh‐DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh‐DNA, whereas 18.2% were from de novo HCC.
Conclusions
vh‐DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV‐related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation ...signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B
:89A3B
:27A3B
), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory ...activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.
Increasing evidence suggests a link between persistent human cytomegalovirus (HCMV) infection and cancer. Although the role of HCMV in cancer is still elusive, recent studies revealed the presence of ...HCMV nucleic acids and proteins in different cancer types such as glioblastoma, colorectal, breast, and prostate cancers, and neuroblastoma. Although HCMV may not be directly associated with the neoplastic transformation, the presence of HCMV DNA in the tumorous tissue has been associated with altered clinical outcomes in cancer patients. However, the mechanisms involved in the association between colorectal cancer (CRC) and HCMV are unclear. In this study, we investigated the influence of HCMV infection on CRC or their derived cells. Proliferation and migration assays revealed a high infection efficiency in CRC-derived HT29 and SW480 'stem-like' cells. After 24, 48 and 72 h of HCMV infection, both HT29 and SW480 parental and stem-like cells showed a significant increase in cell proliferation and viability (p<0.0001). Moreover, HCMV infection promoted cell migration. These results demonstrate a significant phenotypic alteration in the CRC cell line upon HCMV infection. Using epithelial to mesenchymal transition (EMT) assays, we demonstrated that the EMT markers and driver genes were upregulated during the virus infection. The WNT signaling pathway, which is associated with the proliferation and migration of CRC cells, was upregulated (6-fold) in HCMV-infected cells as compared to the non-infected cells at day 7 from infection.
Background
Experience with application of a robotic surgery platform in the management of breast cancer is limited. The preliminary results of the robotic nipple-sparing mastectomy (R-NSM) and ...immediate breast reconstruction (IBR) with Gel implant procedure are reported.
Methods
The medical records of patients from a single institution who underwent an R-NSM and IBR with Gel implant procedure for breast cancer during the period March 2017 to February 2018 were assessed. Data on clinicopathologic characteristics, type of surgery, complications, and recurrence were analyzed to determine the effectiveness and oncologic safety of R-NSM. Patient-reported cosmetic outcome results were obtained.
Results
A total of 22 patients who received 23 R-NSM and IBR with Gel implant procedures were analyzed. The mean operation time for R-NSM was 118.8 ± 50.6 min, and 74.5 ± 26.6 min for Gel implant reconstruction. Docking time quickly dropped from 20 to 6–8 min, and the time needed to complete R-NSM was usually completed within 100 min after accumulation of case experience. Mean blood loss was 37 ± 38.2 mL, and the positive surgical margin rate was 0%. Three (13%) patients had transit nipple ischemia change, and no total nipple-areolar complex necrosis cases were observed. No local recurrence or mortality was found during a mean 6.9 ± 3.5 months of follow-up. All 22 patients were satisfied with the postoperative aesthetic outcome.
Conclusion
From our preliminary experience, R-NSM and IBR with Gel implant is a safe procedure, with good cosmetic results, and could be a promising new technique for breast cancer patients indicated for mastectomy.
Background
Physical distancing and facemask use are worldwide recognized as effective non‐pharmaceutical interventions (NPIs) against the coronavirus disease‐2019 (COVID‐19). Since January 2020, ...Taiwan has introduced both NPIs but their effectiveness on non‐COVID‐19 respiratory viruses (NCRVs) remain underexplored.
Methods
This retrospective observational study examined electronic records at a tertiary hospital in northern Taiwan from pre‐COVID (January–December 2019) to post‐COVID period (January–May 2020). Patients with respiratory syndromes were tested for both enveloped (eg, influenza virus and seasonal coronavirus) and non‐enveloped RVs (eg, enterovirus and rhinovirus) using multiplex reverse transcription polymerase chain reaction assays. Monthly positivity rates of NCRVs among adult and pediatric patients were analyzed with comparison between pre‐ and post‐COVID periods.
Results
A total of 9693 patients underwent 12 127 multiplex RT‐PCR tests. The average positivity rate of NCRVs reduced by 11.2% (25.6% to 14.4%) after nationwide PHIs. Despite the COVID‐19 pandemic, the most commonly identified enveloped and non‐enveloped viruses were influenza virus and enterovirus/rhinovirus, respectively. Observed reduction in NCRV incidence was predominantly contributed by enveloped NCRVs including influenza viruses. We did not observe epidemiological impacts of NPIs on non‐enveloped viruses but an increasing trend in enterovirus/rhinovirus test positivity rate among pediatric patients. Our data were validated using Taiwan's national notification database.
Conclusions
Our frontline investigation suggests that the current NPIs in Taiwan might not effectively control the transmission of non‐enveloped respiratory viruses, despite their protective effects against influenza and seasonal coronavirus. Health authorities may consider using hydrogen peroxide or chloride‐based disinfectants as additional preventative strategies against non‐enveloped respiratory viruses in the post‐COVID‐19 era.
The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, ...we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation.
To assess the outcomes of corticosteroid treatment in critically ill patients with respiratory virus–related community-acquired pneumonia (CAP).
Adult patients who were admitted to the intensive care ...unit and had a polymerase chain reaction–confirmed diagnosis of respiratory virus–related CAP were included. Patients with and without corticosteroid treatment during the hospital course were retrospectively compared using a propensity score–matched case–control analysis.
From January 2018 to December 2020, 194 adult patients were enrolled with 1:1 matching. The 14-day and 28-day mortality rates did not differ significantly between patients treated with and without corticosteroids (14-day mortality: 7% versus 14%, P = 0.11; 28-day mortality: 15% versus 20%, P = 0.35). However, multivariate analysis by using a Cox regression model revealed that corticosteroid treatment was an independent factor predicting decreased mortality (adjusted odds ratio, 0.46; 95% confidence interval, 0.22–0.97, P = 0.04). Subgroup analysis revealed lower 14-day and 28-day mortality rates in patients younger than 70 years treated with corticosteroids than in those not treated with corticosteroids (14-day mortality: 6% versus 23%; P = 0.01 and 28-day mortality: 12% versus 27%; P = 0.04).
Non-elderly patients with severe respiratory virus–related CAP are more likely to benefit from corticosteroid treatment than elderly patients.
Lower respiratory tract infection (LRTI) is one of the most fatal diseases for adults. Influenza is a well-recognized cause of severe pneumonia; however, the outcomes of LRTI caused by non-influenza ...respiratory viruses (NIRVs) have not been sufficiently investigated. This study aimed to describe the characteristics and outcomes of LRTI associated with respiratory viruses (RVs) in adults.
A retrospective review was performed using medical records of adult patients whose lower respiratory tract (LRT) specimens (endotracheal aspirate and bronchoalveolar lavage fluid) tested positive for RVs using multiplex PCR. Underlying comorbidities, laboratory data, and clinical outcomes were analyzed.
Among the 808 LRT specimens collected from 666 adult patients, RV was identified in 115 specimens (14%) from 106 patients (16%). The underlying comorbidities and laboratory data did not differ between patients with influenza- and NIRV-related LRTI. The 14-day and 30-day mortality rates were higher in the influenza group than in the NIRV group (24% versus 7%, p = 0.03 and 33% versus 13%, p = 0.02, respectively), whereas the 90-day mortality rate did not. In a multivariate Cox model to predict 90-day mortality, shock and acute kidney injury independently predicted a higher mortality rate (hazard ratio (HR): 4.28, 95% CI: 1.46–12.58, p = 0.01 and HR: 2.80, 95% CI: 1.28–6.15, p = 0.01, respectively), whereas the detection of influenza did not.
Influenza and NIRVs were associated with increased mortality due to LRTI in adults. Therefore, NIRVs are among key pathogens causing LRTI and should not be neglected by clinicians.
PDF
