The pyranocoumarins, (±)-3′-angeloyl-4′-acetoxy-
cis-khellactone, were isolated from Radix Peucedani, the dry root of
Peucedanum praeruptorum Dunn, through bioassay-guided fractionation. The chemical ...structure of pyranocoumarins was determined by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. X-ray crystallography showed that there are eight molecules (i.e. two each of four conformers) in each unit cell with their optical activities equally cancelled out. The four conformers are 3′(
R)-angeloyl-4′(
R)-acetoxy-khellactone in two conformational forms, and 3′(
S)-angeloyl-4′(
S)-acetoxy-khellactone in two conformational forms. Pyranocoumarins caused apoptotic cell death with IC
50 of 41.9±2.8 and 17.3±8.2 μM for drug-sensitive KB-3-1 and multidrug resistant (MDR) KB-V1, respectively. The two- to threefold sensitivity difference between the two cell lines is interesting considering that the same ratio for doxorubicin is 50–300. Strong synergistic interactions were demonstrated when pyranocoumarins were combined with common anti-tumor drugs including doxorubicin, paclitaxel, puromycin or vincristine in MDR KB-V1 cell line, but not in drug-sensitive KB-3-1 cells. Pyranocoumarins increased doxorubicin accumulation in KB-V1 cells by about 25% after 6 h of incubation. Pyranocoumarins treatment for 24 h down-regulated the expression of P-glycoprotein in KB-V1 cells at both protein and mRNA levels. Pyranocoumarins also transiently reduced the cellular ATP contents in KB-V1 cells in a dose-dependent manner. Our results suggest that pyranocoumarins could be a potential MDR reversing agent.
Background: The demand for organic composts made of animal manure and food waste, such as spent coffee grounds, is increasing as organic farming is gaining popularity. One of the potential public ...health hazards of using these organic composts is the dissemination of antibiotic-resistant bacteria and antibiotic resistance genes (ARGs). Animal manure is generally believed to be the primary source of these bacteria and genes since antibiotics are commonly used in animal farming. However, there is little concrete evidence supporting this claim. Here, we examined this argument by characterising the resistome of the raw materials, namely, chicken manure (CF), spent coffee grounds (COFFEE), and chopped grass (GRASS) commonly used in Hong Kong for preparing organic composts.
Methods: Three independent samples of the three raw materials were collected from an organic farm in Hong Kong. DNA of the samples were extracted and sequenced by metagenomic sequencing. The resistome of the samples was analysed using the resistome analysis pipeline ARGs-OAP v2.0. The abundance and the richness of the ARGs among the samples were compared using one-way ANOVA with Tukey post-hoc test.
Results: COFFEE carried the highest copy number of ARGs per cell (2.771-3.539) and was significantly higher than that of CF (1.991-2.617) and GRASS (0.491-0.537). Multi-drug resistance genes predominated the resistome of COFFEE, for which the richness of the resistome was the lowest among the three materials (150-154 ARG subtypes). It was significantly lower than that of CF (203-229 ARG subtypes) but not that of GRASS (153-203 ARG subtypes).
Conclusions: Contrary to the general belief that animal manure is the primary source of antibiotic resistance genes in organic composts, it was found that COFFEE carried the highest copy number of ARGs among the three materials, and multi-drug resistance genes predominated the resistome of COFFEE.
Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection ...of minimal residual disease.
Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines.
The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis.
We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.
During the investigation of a pet shop outbreak of severe acute respiratory coronavirus 2 (SARS-CoV-2) with probable hamster-to-human transmission, the environmental and hamster samples in ...epidemiologically linked pet shops were found positive for SARS-CoV-2 Delta variant AY.127 strains which are phylogenetically closely related to patients and reported European strains. This interspecies' spill-over has triggered transmission in 58 patients epidemiologically linked to three pet shops. Incidentally, three dwarf hamsters imported from the Netherlands and centralized in a warehouse distributing animals to pet shops were positive for SARS-CoV-2 spike variant phylogenetically related to European B.1.258 strains from March 2020. This B.1.258 strain almost disappeared in July 2021. While no hamster-to-human transmission of B.1.258-like strain was found in this outbreak, molecular docking showed that its spike receptor-binding domain (RBD) has a similar binding energy to human ACE2 compared to that of Delta variant AY.127. Therefore, the potential of this B.1.258-related spike variant for interspecies jumping cannot be ignored. The co-circulation of B.1.258-related spike variants with Delta AY.127, which originated in Europe and was not previously found in Hong Kong, suggested that hamsters in our wholesale warehouse and retail pet shops more likely have acquired these viruses in the Netherlands or stopovers during delivery by aviation than locally. The risk of human-to-hamster reverse zoonosis by multiple SARS-CoV-2 variants leading to further adaptive spike mutations with subsequent transmission back to humans cannot be underestimated as an outbreak source of COVID-19. Testing imported pet animals susceptible to SARS-CoV-2 is warranted to prevent future outbreaks.
Accumulating evidence suggests the interaction of bone metabolism and the immune system, but how bone health is associated with the risk of infections remains unknown.
This study aimed to investigate ...the relationship of bone mineral density (BMD) with the risk of common infections and sepsis in Hong Kong Osteoporosis Study (HKOS). A prospective cohort study, initiated in 1995 and followed until 31 December 2020, of 5,717 participants examined the association of BMD at three skeletal sites (lumbar spine, femoral neck, and total hip) with common infections - pneumonia, urinary tract infection (UTI), skin infection, and sepsis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).
During the median follow-up of 17 years, higher BMD T-scores at the femoral neck and total hip were significantly associated with the reduced risk of pneumonia (HRs 0.89 and 0.87; 95% CIs 0.82 to 0.98 and 0.81 to 0.95), UTI (HRs 0.85 and 0.86; 95% CIs 0.76 to 0.94 and 0.78 to 0.95), skin infection (HRs 0.85 and 0.82; 95% CIs 0.74 to 0.97 and 0.73 to 0.93), and sepsis (HRs 0.83 and 0.82; 95% CIs 0.71 to 0.97 and 0.72 to 0.94). A significant association was observed for the lumbar spine BMD T-score with the risk of skin infection (HR 0.86; 95% CI: 0.78 to 0.95) but not with other infections and sepsis. Similarly, participants with osteoporosis, but not osteopenia, were significantly associated with an increased risk of infections and sepsis compared to those with normal BMD.
BMD is a novel risk factor of infections and sepsis. People with low BMD, particularly those with osteoporosis, are at higher risk of infections and sepsis than those with normal BMD. Further studies on whether improving bone health can reduce the risk of infections and sepsis are warranted.
None.
We investigated the clinical significance of CTCs in cancer progression by detecting multiple cancer driver genes associated with epithelial-to-mesenchymal transition (EMT) at the transcript level. ...The 10-gene panel, comprising CCND1, ECT2, EpCAM, FSCN1, KRT5, KRT18, MET, TFRC, TWIST1, and VEGFC, was established for characterizing CTCs from mouse ESCC xenograft models and clinical ESCC peripheral blood (PB) samples. Correlations between gene expression in CTCs from PB samples (n = 77) and clinicopathological features in ESCC patients (n = 55) were examined. The presence of CTCs at baseline was significantly correlated with tumor size (p = 0.031). The CTC-high patients were significantly correlated with advanced cancer stages (p = 0.013) and distant metastasis (p = 0.029). High mRNA levels of TWIST1 (Hazard Ratio (HR) = 5.44, p = 0.007), VEGFC (HR = 6.67, p < 0.001), TFRC (HR = 2.63, p = 0.034), and EpCAM (HR = 2.53, p = 0.041) at baseline were significantly associated with a shorter overall survival (OS) in ESCC patients. This study also revealed that TWIST1 facilitates EMT and enhances malignant potential by promoting tumor migration, invasion, and cisplatin chemoresistance through the TWIST1-TGFBI-ZEB1 axis in ESCC, highlighting the prognostic and therapeutic potential of TWIST1 in clinical ESCC treatment.
Multiple factors, including host genetics, environmental factors, and Epstein–Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility ...genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage- stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germ-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10−12). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident-macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.
Global dissemination of SARS-CoV-2 Variants of Concern (VOCs) remains a concern. The aim of this study is to describe how mass testing and phylogenetic analysis successfully prevented local ...transmission of SARS-CoV-2 VOC in a densely populated city with low herd immunity for COVID-19.
In this descriptive study, we conducted contact tracing, quarantine, and mass testing of the potentially exposed contacts with the index case. Epidemiological investigation and phylogeographic analysis were performed.
Among 11,818 laboratory confirmed cases of COVID-19 diagnosed till 13th May 2021 in Hong Kong, SARS-CoV-2 VOCs were found in 271 (2.3%) cases. Except for 10 locally acquired secondary cases, all SARS-CoV-2 VOCs were imported or acquired in quarantine hotels. The index case of this SARS-CoV-2 VOC B.1.351 epidemic, an inbound traveler with asymptomatic infection, was diagnosed 9 days after completing 21 days of quarantine. Contact tracing of 163 contacts in household, hotel, and residential building only revealed 1 (0.6%) secondary case. A symptomatic foreign domestic helper (FDH) without apparent epidemiological link but infected by virus with identical genome sequence was subsequently confirmed. Mass testing of 0.34 million FDHs identified two more cases which were phylogenetically linked. A total of 10 secondary cases were identified that were related to two household gatherings. The clinical attack rate of household close contact was significantly higher than non-household exposure during quarantine (7/25, 28% vs 0/2051, 0%; p<0.001).
The rising epidemic of SARS-CoV-2 VOC transmission could be successfully controlled by contact tracing, quarantine, and rapid genome sequencing complemented by mass testing.
Health and Medical Research Fund Commissioned Research on Control of Infectious Disease (see acknowledgments for full list).
(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk ...stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.
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