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•A herb-based formula delivers positive clinical outcomes on COVID-19 patients.•The formula inhibits SARS-CoV-2 pathogenesis in anti-viral & -inflammatory assays.•Real-world-evidence ...offers insights to inform drug development.•Bed-to-bench approach shortens the time required for finding effective therapeutics.
COVID-19 is a global pandemic, with over 50 million confirmed cases and 1.2 million deaths as of November 11, 2020. No therapies or vaccines so far are recommended to treat or prevent the new coronavirus. A novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101), has been administered to patients with COVID-19 in Taiwan since April 2020. Its clinical outcomes and pharmacology have been evaluated. Among 33 patients with confirmed COVID-19 admitted in two medical centers, those (n = 12) who were older, sicker, with more co-existing conditions and showing no improvement after 21 days of hospitalization were given NRICM101. They achieved 3 consecutive negative results within a median of 9 days and reported no adverse events. Pharmacological assays demonstrated the effects of the formula in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and production of cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. This bedside-to-bench study suggests that NRICM101 may disrupt disease progression through its antiviral and anti-inflammatory properties, offering promise as a multi-target agent for the prevention and treatment of COVID-19.
Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and ...incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.
Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation ...(RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naïve patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10-year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, α-fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long-term survival data for patients with early-stage HCC who undergo RFA.
RSNA, 2017 Online supplemental material is available for this article.
The hormone melatonin has many properties, including antioxidant, anti‐inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune ...diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose‐dependently inhibits tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐1β expression through the PI3K/AKT, ERK, and NF‐κB signaling pathways. We also identified that melatonin inhibits TNF‐α and IL‐1β production by upregulating miR‐3150a‐3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast‐like synoviocytes confirmed that the MT1 receptor is needed for the anti‐inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen‐induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF‐α and IL‐1β production through downregulation of the PI3K/AKT, ERK, NF‐κB signaling pathways, as well as miR‐3150a‐3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.
Shigellosis appears to increase in certain at-risk populations in developed countries. Based on the nationwide surveillance, the annual incidence of shigellosis in Taiwan (1999-2019) was 0.38-5.77 ...cases per 100,000 people. Indigenous shigellosis has mostly affected men who have sex with men (MSM) and people living with HIV (PLWH) since 2015. In this retrospective study, compared with those diagnosed before 2015, indigenous cases diagnosed during 2015-2019 mostly occurred in male adults (96.0% vs 47.1%, P < 0.001), with a longer hospital stay (median 5.0 vs 3.5 days, P = 0.029) and different coinfections. The predominant strains in 2015 and 2016 were ciprofloxacin-resistant Shigella sonnei and azithromycin non-susceptible Shigella flexneri (S. flexneri) 3a, which had been replaced by ciprofloxacin-resistant S. flexneri 2a since 2018. Notably, six indigenous cases were caused by cefotaxime-resistant S. flexneri. Inappropriate use of empiric antibiotic treatment was common. In conclusion, there is an ongoing spread of ciprofloxacin-resistant shigellosis among PLWH and MSM and cefotaxime-resistant S. flexneri is an emerging threat in Taiwan.
Non-covalent functionalization was used to functionalize graphene nanosheets (GNSs) through π–π stacking of pyrene molecules with a functional segmented polymer chain, which results in a remarkable ...improvement in the thermal conductivity of GNS-filled polymer composites. The functional segmented poly(glycidyl methacrylate) containing localized pyrene groups (Py-PGMA) was prepared by atom transfer radical polymerization, and Py-PGMA was characterized by nuclear magnetic resonance spectroscopy. Raman spectra, X-ray photoelectron spectroscopy and thermogravimetric analysis reveal the characteristics of Py-PGMA–GNS. Differential scanning calorimetry indicated that the functional groups on Py-PGMA–GNSs can generate covalent bonds with the epoxy matrix, and further form a cross-linked structure in Py-PGMA–GNS/epoxy composites. The Py-PGMA on the GNS surface not only plays an important role to facilitate a homogeneous dispersion in the polymer matrix but also improves the GNS–polymer interaction, which results in a high contact area. Consequently, the thermal conductivity of integrated Py-PGMA–GNS/epoxy composites exhibited a remarkable improvement and is much higher than epoxy reinforced by multi-walled carbon nanotubes or GNSs. The thermal conductivity of 4
phr Py-PGMA–GNS/epoxy has about 20% (higher than that of pristine GNS/epoxy) and 267% (higher than pristine MWCNT/epoxy).
Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high-fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and ...stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex-specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step-down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open-field and hot-plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired-pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long-term potentiation (LTP) and long-term depression (LTD)) were lower at the Schaffer collateral-CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex-specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.
Lung cancer is one of the most common cancer in cancer‐related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an ...antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by ~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a β‐catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, β‐catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study.
Summary
Background
There is still controversy about whether tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have different effects on the outcomes of patients with hepatitis B virus ...(HBV)‐related hepatocellular carcinoma (HCC).
Aims
The aim of this study was to compare the prognoses between ETV and TDF treatment among patients with HBV‐related HCC after hepatectomy.
Methods
An analysis was done on data from the Taiwan Cancer Registry, which was linked to Taiwan National Health Insurance Research Database, for the years 2011–2016. We identified 7107 patients with HBV‐related HCC after curative hepatectomy, and 25.3% of them used ETV or TDF after surgery. After propensity score overlap weighting, 1797 patients treated with ETV (n = 1365) or TDF (n = 432) were included for analyses. Cox proportional hazards models were used to compare the efficacy of ETV and TDF for recurrence and overall survival (OS).
Results
After hepatectomy, the recurrence rate per 100 person‐years was 14.87 for the ETV group and 9.25 for the TDF group. The risk of recurrence was similar in the TDF group and the ETV group (HR 95% CI: 0.91 0.69–1.19; p = 0.479), as was the risk of all‐cause mortality (HR 95% CI: 0.67 0.42–1.07; p = 0.091). When considering early recurrence (<2 years) and late recurrence (≧2 years), the TDF and ETV groups showed no significant differences. Subgroup analyses and sensitivity analyses demonstrated consistent results.
Conclusion
Both TDF and ETV showed similar health benefits in terms of recurrence and OS in patients with HBV‐related HCC patients after hepatectomy.
The long‐term outcomes were not different statistically between HCC patients who received entecavir and tenofovir after hepatectomy.
Current staging methods are inadequate for predicting the outcome of treatment of non-small-cell lung cancer (NSCLC). We developed a five-gene signature that is closely associated with survival of ...patients with NSCLC.
We used computer-generated random numbers to assign 185 frozen specimens for microarray analysis, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, or both. We studied gene expression in frozen specimens of lung-cancer tissue from 125 randomly selected patients who had undergone surgical resection of NSCLC and evaluated the association between the level of expression and survival. We used risk scores and decision-tree analysis to develop a gene-expression model for the prediction of the outcome of treatment of NSCLC. For validation, we used randomly assigned specimens from 60 other patients.
Sixteen genes that correlated with survival among patients with NSCLC were identified by analyzing microarray data and risk scores. We selected five genes (DUSP6, MMD, STAT1, ERBB3, and LCK) for RT-PCR and decision-tree analysis. The five-gene signature was an independent predictor of relapse-free and overall survival. We validated the model with data from an independent cohort of 60 patients with NSCLC and with a set of published microarray data from 86 patients with NSCLC.
Our five-gene signature is closely associated with relapse-free and overall survival among patients with NSCLC.
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