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Li–Fraumeni syndrome (LFS) is a hereditary disorder characterized by an increased risk of developing multiple early-onset cancers, primarily due to germline TP53 mutations. Women and men with this mutation face lifetime cancer risks of 90% and 70%, respectively. This report describes the first documented case of LFS with clinical information in Vietnam involving a 9-year-old child diagnosed with osteosarcoma who had multiple first- and second-degree relatives with cancer. Whole-genome sequencing (WGS) revealed a heterozygous, pathogenic, autosomal dominant TP53 variant NM_000546.6:c.733G>A (p.Gly245Ser) and a translocation in the 3’UTR of the ATMIN gene with unknown pathogenicity in both the patient and her mother. Sanger sequencing confirmed the presence of the TP53 c.733G>A mutation, which was subsequently detected in extended family members. Of the 17 family members invited for testing, only 8, none of whom currently have cancer, agreed to participate: all tested negative for the mutation. This case highlights the importance of genetic testing for the early detection and management of cancers in LFS patients. It also underscores significant barriers to genetic screening in Vietnam, including limited access and the psychosocial consequences of testing, which emphasize the need for improved genetic counseling and surveillance strategies that are tailored to local contexts.

The Codonics Safe Labeling System(™) (http://www.codonics.com/Products/SLS/flash/) is a piece of equipment that is able to barcode scan medications, read aloud the medication and the concentration and print a label of the appropriate concentration in the appropriate colour code. We decided to test this system in our facility to identify risks, benefits and usability. Our project comprised a baseline survey (25 anaesthesia cases during which 212 syringes were prepared from 223 drugs), an observational study (47 cases with 330 syringes prepared) and a user acceptability survey. The baseline compliance with all labelling requirements was 58%. In the observational study the compliance using the Codonics system was 98.6% versus 63.8% with conventional labelling. In the user acceptability survey the majority agreed the Codonics machine was easy to use, more legible and adhered with better security than the conventional preprinted label. However, most were neutral when asked about the likelihood of flexibility and customisation and were dissatisfied with the increased workload. Our findings suggest that the Codonics labelling machine is user-friendly and it improved syringe labelling compliance in our study. However, staff need to be willing to follow proper labelling workflow rather than batch label during preparation. Future syringe labelling equipment developers need to concentrate on user interface issues to reduce human factor and workflow problems. Support logistics are also an important consideration prior to implementation of any new labelling system. [ABSTRACT FROM AUTHOR]

AIMS: A phase II trial was initiated to evaluate the efficacy and toxicity of combination chemotherapy with irinotecan (CPT-11) plus capecitabine in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients received a combination of CPT-11 plus capecitabine. CPT-11 was infused intravenously on day 1 every 2 weeks and oral capecitabine was taken twice daily for 5 days every 7 days. Efficacy and toxicities were assessed. RESULTS: Between 2004 and 2005, 43 patients were enrolled. The overall response rate was 51.35%. With a median follow-up of 13 months, the median time to progression was 10 months (95% confidence interval 7.6-12.3 months); the median survival was 15 months (95% confidence interval 13.9-16.9 months). The most common grade 3 haematological and non-haematological toxicities were neutropenia (5.4%), diarrhoea (8.1%) and hand-foot syndrome (2.7%). CONCLUSIONS: CPT-11 plus capecitabine with a 14 day cycle showed a comparable response with international phase II data with a 3 weekly regimen and was well tolerated as a first-line palliative chemotherapy in patients with metastatic colorectal cancer. The data should be interpreted with caution due to the limited sample size and should be further confirmed by a phase III randomised trial. [ABSTRACT FROM AUTHOR]

Background: Pelvic arterial (PLA) stenosis is associated with arterial insufficiency of the penis and erectile dysfunction (ED), but the effect of different severities of PLA stenosis on ED remains unclear., Aim: To investigate how different severities of PLA stenosis affect erectile function., Methods: We included patients who visited our clinic for ED and underwent computed tomography angiography (CTA) and dynamic duplex sonography (DUS). The erectile hardness score (EHS), simplified International Index of Erectile Function (IIEF-5), DUS and CTA results, and flow index (FI) calculated from the peak systolic velocity (PSV) and PLA stenosis percentages were analyzed. EHS < 3 was defined as significant ED. PLA stenosis was analyzed by the mean PLA (average of the right and left PLA) and unilateral or bilateral stenoses. According to severity, stenosis was classified as mild, moderate, or severe., Outcomes: Subjective and objective parameters, including the IIEF-5 score, EHS, PSV, and FI, in relation to different severities of PLA stenosis., Results: The study included 182 patients. Vascular parameters such as the mean PSV, PLA stenosis, and FI correlated with EHS and IIEF-5 scores. Receiver operating characteristic analyses for predicting EHS ≥ 3 showed that all vascular parameters had acceptable discriminatory ability. During the analysis performed using the mean PSA stenosis, EHS decreased in patients with mild and severe mean PLA stenosis, although a PSV drop was noted only in severe cases. The proportion achieving EHS 3 significantly dropped in patients with at least mild mean PLA stenosis. Using unilateral or bilateral PLA stenosis, the EHS significantly dropped in patients with severe unilateral and bilateral PLA stenosis, with PSV decreasing on the affected side in severe unilateral stenosis. However, the mean PSV did not drop despite different unilateral stenosis severities. The proportion achieving EHS 3 significantly dropped among patients with at least moderate unilateral PLA stenosis and bilateral PLA stenosis but not in mild unilateral cases., Clinical Implications: The severity of PLA stenosis is correlated with the risk of ED., Strengths & Limitations: The strength of this study lies in its analysis of the effect of PLA stenosis on erectile function from various perspectives, including unilateral, bilateral, and mean stenosis. However, the absence of validation regarding the outcomes of endovascular therapy is a limitation., Conclusion: Mild mean PLA stenosis and moderate unilateral PLA stenosis are associated with increased risks of ED; however, mild unilateral PLA stenosis does not affect erectile function., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The close interconnection of plants with rhizosphere- and root-associated microorganisms is well recognized, and high expectations are raised for considering their symbioses in the breeding of future crop varieties. However, it is unclear how consistently plant-mediated selection, a potential target in crop breeding, influences microbiome members compared to selection imposed by the agricultural environment. Landraces may have traits shaping their microbiome, which were lost during the breeding of modern varieties, but knowledge about this is scarce. We investigated prokaryotic community composition along the radial root axis of two European maize ( Zea mays L.) landraces. A sampling gradient included bulk soil, a distal and proximal rhizosphere fraction, and the root compartment. Our study was replicated at two field locations with differing edaphic and climatic conditions. Further, we tested for differences between two plant developmental stages and two precipitation treatments. Community data were generated by metabarcoding of the V4 SSU rRNA region. While communities were generally distinct between field sites, the effects of landrace variety, developmental stage, and precipitation treatment were comparatively weak and not statistically significant. Under all conditions, patterns in community composition corresponded strongly to the distance to the root. Changes in α- and β-diversity, as well as abundance shifts of many taxa along this gradient, were similar for both landraces and field locations. Most affected taxa belonged to a core microbiome present in all investigated samples. Remarkably, we observed consistent enrichment of Actinobacteriota (particularly Streptomyces , Lechevalieria ) and Pseudomonadota (particularly Sphingobium ) toward the root. Further, we report a depletion of ammonia-oxidizers along this axis at both field sites. We identified clear enrichment and depletion patterns in microbiome composition along the radial root axis of Z. mays . Many of these were consistent across two distinct field locations, plant developmental stages, precipitation treatments, and for both landraces. This suggests a considerable influence of plant-mediated effects on the microbiome. We propose that the affected taxa have key roles in the rhizosphere and root microbiome of Z. mays . Understanding the functions of these taxa appears highly relevant for the development of methods aiming to promote microbiome services for crops., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tyborski, Koehler, Steiner, Tung, Wild, Carminati, Mueller, Vidal, Wolfrum, Pausch and Lueders.)

Background/aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients., Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan's cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray's cumulative incidence and Cox subdistribution hazards models to analyze HCC development., Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients., Conclusion: Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Background and Objectives: Probability discounting (PD), which refers to the process of adjusting the value of future probabilities when making decisions, is a method of measuring impulsive decision-making; however, the relationship between PD and nicotine remains unclear. The current study aimed at investigating the significance of PD in individuals who smoke., Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, PsycINFO, and Web of Science databases for articles comparing individuals who smoke and their tobacco-naïve controls using PD task as outcome measure from inception to May 2023. The main outcome was an overall difference in PD function, while subgroup analysis and meta-regression were conducted to examine the analysis methods and the moderators of PD., Results: Fourteen studies in total involving 384 individuals who smoke and 493 controls (mean age = 24.32 years, range = 15.1-38.05 years) were analyzed. The effect of smoking on PD was significant (g = 0.51, p = .02). The discounting parameter from the equation, compared to the area under the curve, was more sensitive to estimating PD function (p = .01). Regression analysis showed positive correlations of PD with female percentage, age, and the number of probability options (all p < .04), but not with the number of choices at each probability and maximum reward magnitude (all p > .07). There was no significant publication bias across the eligible studies (p = .09)., Conclusion and Scientific Significance: Our findings, which are the first to demonstrate a smaller PD (i.e., prone to risk-taking) in individuals who smoke, shed light on the appropriate analysis method, gender effect, age, and probability options on the PD function., (© 2024 The American Academy of Addiction Psychiatry (AAAP).)

A holistic understanding of plant strategies to acquire soil resources is pivotal in achieving sustainable food security. However, we lack knowledge about variety-specific root and rhizosphere traits for resource acquisition, their plasticity and adaptation to drought. We conducted a greenhouse experiment to phenotype root and rhizosphere traits (mean root diameter [Root D], specific root length [SRL], root tissue density, root nitrogen content, specific rhizosheath mass [SRM], arbuscular mycorrhizal fungi [AMF] colonization) of 16 landraces and 22 modern cultivars of temperate maize (Zea mays L.). Our results demonstrate that landraces and modern cultivars diverge in their root and rhizosphere traits. Although landraces follow a 'do-it-yourself' strategy with high SRLs, modern cultivars exhibit an 'outsourcing' strategy with increased mean Root Ds and a tendency towards increased root colonization by AMF. We further identified that SRM indicates an 'outsourcing' strategy. Additionally, landraces were more drought-responsive compared to modern cultivars based on multitrait response indices. We suggest that breeding leads to distinct resource acquisition strategies between temperate maize varieties. Future breeding efforts should increasingly target root and rhizosphere economics, with SRM serving as a valuable proxy for identifying varieties employing an outsourcing resource acquisition strategy., (© 2024 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Biophysicochemical rhizosheath properties play a vital role in plant drought adaptation. However, their integration into the framework of plant drought response is hampered by incomplete mechanistic understanding of their drought responsiveness and unknown linkage to intraspecific plant-soil drought reactions. Thirty-eight Zea mays varieties were grown under well-watered and drought conditions to assess the drought responsiveness of rhizosheath properties, such as soil aggregation, rhizosheath mass, net-rhizodeposition, and soil organic carbon distribution. Additionally, explanatory traits, including functional plant trait adaptations and changes in soil enzyme activities, were measured. Drought restricted soil structure formation in the rhizosheath and shifted plant-carbon from litter-derived organic matter in macroaggregates to microbially processed compounds in microaggregates. Variety-specific functional trait modifications determined variations in rhizosheath drought responsiveness. Drought responses of the plant-soil system ranged among varieties from maintaining plant-microbial interactions in the rhizosheath through accumulation of rhizodeposits, to preserving rhizosheath soil structure while increasing soil exploration through enhanced root elongation. Drought-induced alterations at the root-soil interface may hold crucial implications for ecosystem resilience in a changing climate. Our findings highlight that rhizosheath soil properties are an intrinsic component of plant drought response, emphasizing the need for a holistic concept of plant-soil systems in future research on plant drought adaptation., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

Hericium erinaceus , a consumable mushroom, has shown a potential to enhance the production of neuroprotective bioactive metabolites. Traumatic brain injury (TBI) often leads to cognitive, physical, and psychosocial impairments, resulting in neuroinflammation and the loss of cortical neurons. In this research, the effects of H. erinaceus mycelium, its derivative erinacine C, along with the underlying mechanisms, were examined in terms of oxidative stress modulation and neurological improvement in a rat model of mild traumatic brain injury (mTBI). Male Sprague-Dawley rats were administered diets containing H. erinaceus mycelium and erinacine C following experimental brain injury; these supplements were continued throughout the recovery phase. The binding activity of NF-E2-related factor 2 (Nrf2) near antioxidant genes in mixed glial cells was measured by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). The motor beam walking test revealed that dietary supplementation of H. erinaceus mycelium resulted in modest improvements in spatial memory while inhibiting neuron cell death and microglial activation according to brain histological examination. These findings were further corroborated by the upregulation of several antioxidant enzymes (catalase, glutathione reductase, thioredoxin reductase, and superoxide dismutase) and phospho-CAMP-response element-binding (p-CREB) levels in the mTBI model treated with H. erinaceus mycelium. Erinacine C treatment led to significantly reduced brain inflammation and normalization of mTBI-induced deficits through the modulation of the Nrf2 activation pathway and upregulated expression of numerous Nrf2-binding antioxidant genes such as catalase, thioredoxin reductase, superoxide dismutase, and brain-derived neurotrophic factor. This study demonstrates the potential of H. erinaceus mycelium and erinacine C in facilitating recovery following mTBI, including the prevention of neuronal injury and inactivation of microglia through the Nrf2-mediated antioxidant pathway in vivo.

Among kidney cancers, clear cell renal cell carcinoma (ccRCC) has the highest incidence rate in adults. The survival rate of patients diagnosed as having metastatic ccRCC drastically declines even with intensive treatment. We examined the efficacy of simvastatin, a lipid-lowering drug with reduced mevalonate synthesis, in ccRCC treatment. Simvastatin was found to reduce cell viability and increase autophagy induction and apoptosis. In addition, it reduced cell metastasis and lipid accumulation, the target proteins of which can be reversed through mevalonate supplementation. Moreover, simvastatin suppressed cholesterol synthesis and protein prenylation that is essential for RhoA activation. Simvastatin might also reduce cancer metastasis by suppressing the RhoA pathway. A gene set enrichment analysis (GSEA) of the human ccRCC GSE53757 data set revealed that the RhoA and lipogenesis pathways are activated. In simvastatin-treated ccRCC cells, although RhoA was upregulated, it was mainly restrained in the cytosolic fraction and concomitantly reduced Rho-associated protein kinase activity. RhoA upregulation might be a negative feedback effect owing to the loss of RhoA activity caused by simvastatin, which can be restored by mevalonate. RhoA inactivation by simvastatin was correlated with decreased cell metastasis in the transwell assay, which was mimicked in dominantly negative RhoA-overexpressing cells. Thus, owing to the increased RhoA activation and cell metastasis in the human ccRCC dataset analysis, simvastatin-mediated Rho inactivation might serve as a therapeutic target for ccRCC patients. Altogether, simvastatin suppressed the cell viability and metastasis of ccRCC cells; thus, it is a potentially effective ccRCC adjunct therapy after clinical validation for ccRCC treatment.

Introduction: This study aims to determine the outcomes of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery., Methods: This study included 31 consecutive patients with unresectable liver metastases who received SBRT between January 2012 and December 2017; 22 patients had primary colorectal cancer and nine patients had primary non-colorectal cancer. Treatments ranged from 24 Gy to 48 Gy in 3 to 6 fractions over 1 to 2 weeks. Survival, response rates, toxicities, clinical characteristics, and dosimetric parameters were evaluated. Multivariate analysis was performed to identify significant prognostic factors for survival., Results: Among these 31 patients, 65% had received at least one prior regimen of systemic therapy for metastatic disease, whereas 29% had received chemotherapy for disease progression or immediately after SBRT. The median follow-up interval was 18.9 months; actuarial in-field local control rates at 1, 2, and 3 years after SBRT were 94%, 55%, and 42%, respectively. The median survival duration was 32.9 months; 1-year, 2-year, and 3-year actuarial survival rates were 89.6%, 57.1%, and 46.2%, respectively. The median time to progression was 10.9 months. Stereotactic body radiotherapy was well-tolerated, with grade 1 toxicities of fatigue (19%) and nausea (10%). Patients who received post-SBRT chemotherapy had significant longer overall survival (P=0.039 for all patients and P=0.001 for patients with primary colorectal cancer)., Conclusion: Stereotactic body radiotherapy can be safely administered to patients with unresectable liver metastases, and it may delay the need for chemotherapy. This treatment should be considered for selected patients with unresectable liver metastases., Competing Interests: The authors declare no conflict of interest.

Background and Aims: Stomatal regulation allows plants to promptly respond to water stress. However, our understanding of the impact of above and belowground hydraulic traits on stomatal regulation remains incomplete. The objective of this study was to investigate how key plant hydraulic traits impact transpiration of maize during soil drying. We hypothesize that the stomatal response to soil drying is related to a loss in soil hydraulic conductivity at the root-soil interface, which in turn depends on plant hydraulic traits., Methods: We investigate the response of 48 contrasting maize (Zea mays) genotypes to soil drying, utilizing a novel phenotyping facility. In this context, we measure the relationship between leaf water potential, soil water potential, soil water content and transpiration, as well as root, rhizosphere and aboveground plant traits., Key Results: Genotypes differed in their responsiveness to soil drying. The critical soil water potential at which plants started decreasing transpiration was related to a combination of above and belowground traits: genotypes with a higher maximum transpiration and plant hydraulic conductance as well as a smaller root and rhizosphere system closed stomata at less negative soil water potentials., Conclusions: Our results demonstrate the importance of belowground hydraulics for stomatal regulation and hence drought responsiveness during soil drying. Furthermore, this finding supports the hypothesis that stomata start to close when soil hydraulic conductivity drops at the root-soil interface., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy., Methods: Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases., Results: Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications., Conclusions: Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR., Impact and Implications: The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

FAM21 (family with sequence similarity 21) is a component of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) protein complex that mediates actin polymerization at endosomal membranes to facilitate sorting of cargo-containing vesicles out of endosomes. To study the function of FAM21 in vivo, we generated conditional knockout (cKO) mice in the C57BL/6 background in which FAM21 was specifically knocked out of CD11c-positive dendritic cells. BMDCs from those mice displayed enlarged early endosomes, and altered cell migration and morphology relative to WT cells. FAM21-cKO cells were less competent in phagocytosis and protein antigen presentation in vitro, though peptide antigen presentation was not affected. More importantly, we identified the TLR2/CLEC4E signaling pathway as being down-regulated in FAM21-cKO BMDCs when challenged with its specific ligand Candida albicans Moreover, FAM21-cKO mice were more susceptible to C. albicans infection than WT mice. Reconstitution of WT BMDCs in FAM21-cKO mice rescued them from lethal C. albicans infection. Thus, our study highlights the importance of FAM21 in a host immune response against a significant pathogen., (© 2023 Kulkarni et al.)

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1−30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

Co-infection of Helicobacter pylori and Fusobacterium nucleatum is a microbial biomarker for poor prognosis of gastric cancer patients. Fusobacterium nucleatum is associated with microsatellite instability and the accumulation of mutations in colorectal cancer. Here, we investigated the mutation landscape of Fusobacterium nucleatum -positive resected gastric cancer tissues using Illumina TruSight Oncology 500 comprehensive panel. Sequencing data were processed to identify the small nucleotide variants, small insertions and deletions, and unstable microsatellite sites. The bioinformatic algorithm also calculated copy number gains of preselected genes and tumor mutation burden. The recurrent genetic aberrations were identified in this study cohort. For gene amplification events, ERBB2, cell cycle regulators, and specific FGF ligands and receptors were the most frequently amplified genes. Pathogenic activation mutations of ERBB2, ERBB3, and PIK3CA, as well as loss-of-function of TP53, were identified in multiple patients. Furthermore, Fusobacterium nucleatum infection is positively correlated with a higher tumor mutation burden. Survival analysis showed that the combination of Fusobacterium nucleatum infection and high tumor mutation burden formed an extremely effective biomarker to predict poor prognosis. Our results indicated that the ERBB2-PIK3-AKT-mTOR pathway is frequently activated in gastric cancer and that Fusobacterium nucleatum and high mutation burden are strong biomarkers of poor prognosis for gastric cancer patients., Competing Interests: The authors declare no conflict of interest.

Background: Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC)., Methods: To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data., Findings: In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r 2  = 0.55)., Interpretation: Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion., Funding: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC., Competing Interests: Declaration of interests R.K.C.N. is an Advisory Board member or a Data Safety Monitoring Board member of Nuance (ShenZhen, China), received consultation fees from Pfizer, Novartis, Sanofi, AstraZeneca, Eli Lilly, Merck Sharp & Dohme, ZailLab, Roche, Eisai, and Merck, received payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, AstraZeneca, Sanofi, Pfizer, ZaiLab, Eisai, Eli Lilly, and Merck Sharp & Dohme, and received funding for travel or attending meetings from Pfizer, Astellas, Novartis, MSD, Roche, Eisai, Merck, Sanofi, Bristol-Myers Squibb, and ZaiLab. V.H.F.L. is an Advisory Board member or a Data Safety Monitoring Board member of Amgen, AstraZeneca, Merck Sharp & Dohme, Pfizer, and Takeda, received consultation fees from AQUILAB, received payment and honoraria for lectures, presentations, speakers bureaus, manuscript writing or education events from Amgen, AstraZeneca, Boston Scientific, Eli Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, and Takeda, received traveling funding from AstraZeneca and Takeda, received receipt of equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca, and received grants and contracts from AstraZeneca for his institution. The remaining authors have declared that no conflict of interest exists., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Dynamic duplex sonography (DUS) is not comprehensive in the evaluation of arteriogenic erectile dysfunction (ED). We introduced a new parameter, the flow index (FI), into the assessment of arteriogenic ED. A retrospective review of a prospective database was conducted. Patients undergoing DUS and pelvic computed tomography angiography for the evaluation of ED were included. The FI was calculated from peak systolic velocity (PSV) and the percentages of pelvic arterial (PLA) stenosis. Correlations between PSV, PLA stenosis, the FI, and erectile function were calculated. Eighty-three patients were included. Compared with PSV, the FI had better correlations with the erection hardness score (EHS) (r s  = 0.405, P < 0.001 for FI; r s  = 0.294, P = 0.007 for PSV). For EHS < 3, the areas under the ROC curve of FI and PSV were 0.759 and 0.700, respectively. In patients with normal DUS but EHS < 3, PLA stenosis was more severe (62.5% vs. 10.0%, P = 0.015), and the FI was lower (8.35 vs. 57.78, P = 0.006), while PSV was not different. The FI is better than PSV in the evaluation of arteriogenic ED. On the other hand, assessment of the pelvic arterial system should be included in the evaluation of ED., (© 2022. The Author(s).)

Background: The use of biologic agents has become the cornerstone of therapy for moderate to severe IBD. Few studies have investigated the efficacy of vedolizumab (VDZ) induction for ulcerative colitis (UC) in Asian patients in a real practice setting., Aims: To evaluate the efficacy and safety of VDZ induction therapy for moderate to severe UC in Taiwan., Methods: This was a retrospective and observational study. Selected moderate to severe UC patients received VZD 300 mg i.v. at weeks 0, 2, and 6 as induction therapy. Mayo scores were calculated to evaluate the efficacy., Results: A total of 37 patients with UC who received VDZ and completed the induction therapy at Chang Gung Memorial Hospital (2017/10-2021/5) were included. The mean age was 46.5 year-old and the male to female ratio was 1:1 (19/18). 81.8% of the patients were biologic-naive. At weeks 8-10, a clinical response, clinical remission and endoscopic remission with VDZ induction therapy were achieved in 56.8% (21/37), 32.4% (12/37) and 58.3% (7/12) of the patients, respectively. 54.1% (20/37) were able to taper off at week 8. Overall, only 10.8% (4/37) of the patients were primary non-responders during induction therapy. No obvious VDZ-related severe adverse events were noted. Overall, 58.9% (11/19) of the patients relapsed after stopping VDZ, and the relapse rate after VDZ discontinuation was 42.1% (8/19) within first 6 months and 52.6% (10/19) within the first year., Conclusion: In real-world experience, induction therapy with VDZ showed promising clinical benefits and safety profile for patients with UC., Competing Interests: Declaration of competing interest There was no any financial interests or connections, direct or indirect, or other situations that might raise the question of bias in the work reported or the conclusions, implications, or opinions stated – including pertinent commercial or other sources of funding for the individual authors or for the associated departments or organizations, personal relationships, or direct academic competition., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Real-world data on the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV infection and compensated cirrhosis is limited, especially for the 8-week regimen and in an Asian population. This retrospective study enrolled 159 consecutive patients with HCV and compensated cirrhosis who were treated with GLE/PIB at a single center in Taiwan. Sustained virological response (SVR) and adverse events (AEs) were evaluated. Among the 159 patients, 91 and 68 were treated with GLE/PIB for 8 and 12 weeks, respectively. In the per protocol analysis, both the 8- and 12-week groups achieved 100% SVR (87/87 vs. 64/64); and in the evaluable population analysis, 95.6% (87/91) of the 8-week group and 94.1% (64/68) of the 12-week group achieved SVR. The most commonly reported AEs, which included pruritus (15.4% vs. 26.5%), abdominal discomfort (9.9% vs. 5.9%), and skin rash (5.5% vs. 5.9%), were mild for the 8- and 12-week groups. Two patients in the 8-week group exhibited total bilirubin elevation over three times the upper normal limit. One of these two patients discontinued GLE/PIB treatment after 2 weeks but still achieved SVR. Both 8- and 12-week GLE/PIB treatments are safe and effective for patients of Taiwanese ethnicity with HCV and compensated cirrhosis., Competing Interests: The authors have declared that no competing interests exist.

A total of 1,589 patients who had received interferon-based treatment were enrolled and analyzed for the risk of hepatocellular carcinoma (HCC) in a real-world nationwide Taiwanese chronic hepatitis C cohort (T-COACH). We aimed to stratify HCC risk by non-invasive fibrosis index-based risk model. Of 1589 patients, 1363 (85.8%) patients achieved sustained virological response (SVR). Patients with SVR had 1, 3, 5 and 10-year cumulative HCC incidence rates of 0.55%, 1.87%, 3.48% and 8.35%, respectively. A Cox proportional hazards model revealed that non-SVR (adjusted hazard ratio [aHR]: 1.92, 95% confidence interval [CI]: 1.19-3.12, p = 0.008), diabetes mellitus (aHR: 2.11, 95% CI: 1.25-3.55, p = 0.005), and fibrosis (FIB)-4 at the end of follow-up (EOF; aHR: 5.60, 95% CI: 2.97-10.57, p < 0.0001) were independent predictors of HCC. Risk score models based on the three predictors were developed to predict HCC according to aHR. In model 1, the 10-year cumulative incidence rates of HCC were 43.35% in patients at high risk (score 9-10), 25.48% in those at intermediate risk (score 6-8), and 4.06% in those at low risk (score 3-5) of HCC. In model 2, the 10-year cumulative incidence rates of HCC were 39.64% in patients at high risk (at least two risk predictors), 19.12% in those at intermediate risk (with one risk predictor), and 2.52% in those at low risk (without any risk predictors) of HCC. The FIB-4-based prediction model at EOF could help stratify the risk of HCC in patients with chronic hepatitis C after antiviral treatment., Competing Interests: Cheng-Yuan Peng has served as an advisory committee member for AbbVie, Bristol-Myers Squibb (BMS), Gilead, and Merck, Sharp, & Dohme. Ming-Lung Yu received research support from Abbott, BMS, Gilead, and Merck and served as a consultant for AbbVie, Abbott, Ascletis, BMS, Gilead, Merck, and Roche and as a speaker for AbbVie, Abbott, BMS, Gilead, Merck, and IPSEN. No other coauthors have conflicts of interest to declare., (AJCR Copyright © 2022.)

Background/aims: A combination of fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry approach was used to search for potential markers for prognosis and intervention of colorectal cancer (CRC) at different stages of lymph node metastasis (LMN). This quantitative proteomic survey aimed to investigate the LNM-associated proteins and evaluate the clinicopathological characteristics of these target proteins in CRC from stage I to stage IV., Methods: Sixteen CRC cases were categorized into paired non-LNM and LNM groups, and two-dimensional difference gel electrophoresis and MS proteome analysis were performed. Differential protein expression between non-LNM and LNM CRC was further validated in a tissue microarray, including 40 paraffin-embedded samples by immunohistochemistry staining. Moreover, a Boyden chamber assay, flow cytometry, and shRNA were used to examine the epithelial-mesenchymal transition and mechanism invasiveness of the differentially expressed proteins in DLD-1 cells and in vivo xenograft mouse model., Results: Eighteen differentially expressed proteins were found between non-LNM and LNM CRC tissues. Among them, protein levels of Gelsolin (GSN) and peroxiredoxin 4 (PRDX4) were abundant in node-positive CRC. Downregulation of GSN and PRDX4 markedly suppressed migration and invasiveness and also induced cell cycle G1/S arrest in DLD-1. Mechanistically, the EGFR/RhoA/PKCα/ERK pathways are critical for transcriptional activation of histone modification of H3 lysine 4 trimethylation (H3K4me3) of GSN and PRDX4 promoters, resulting in upregulation of GSN, PRDX4, Twist-1/2, cyclinD1, proliferating cell-nuclear antigen, β-catenin, N-cadherin, and matrix metalloprotein-9., Conclusions: GSN and PRDX4 are novel regulators in CRC lymph node metastasis to potentially provide new insights into the mechanism of CRC progression and serve as a biomarker for CRC diagnosis at the metastatic stage.

Ailanthoidol (ATD) has been isolated from the barks of Zanthoxylum ailanthoides and displays anti-inflammatory, antioxidant, antiadipogenic, and antitumor promotion activities. Recently, we found that ATD suppressed TGF-β1-induced migration and invasion of HepG2 cells. In this report, we found that ATD exhibited more potent cytotoxicity in Huh7 hepatoma cells (mutant p53 : Y220C) than in HepG2 cells (wild-type p53 ). A trypan blue dye exclusion assay and colony assay showed ATD inhibited the growth of Huh7 cells. ATD also induced G1 arrest and reduced the expression of cyclin D1 and CDK2. Flow cytometry analysis with Annexin-V/PI staining demonstrated that ATD induced significant apoptosis in Huh7 cells. Moreover, ATD increased the expression of cleaved PARP and Bax and decreased the expression of procaspase 3/8 and Bcl-xL/Bcl-2. In addition, ATD decreased the expression of mutant p53 protein (mut p53 ), which is associated with cell proliferation with the exploration of p53 siRNA transfection. Furthermore, ATD suppressed the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and the expression of mevalonate kinase (MVK). Consistent with ATD, the administration of S3I201 (STAT 3 inhibitor) reduced the expression of Bcl-2/Bcl-xL, cyclin D1, mutp53, and MVK. These results demonstrated ATD's selectivity against mut p53 hepatoma cells involving the downregulation of mut p53 and inactivation of STAT3.

We previously reported that perfluorooctanesulfonate (PFOS) causes autophagy-induced apoptosis in renal tubular cells (RTCs) through a mechanism dependent on reactive oxygen species (ROS)/extracellular signal-regulated kinase. This study extended our findings and determined the therapeutic potency of L-Carnitine in PFOS-treated RTCs. L-Carnitine (10 mM) reversed the effects of PFOS (100 µM) on autophagy induction and impaired autophagy flux. Furthermore, it downregulated the protein level of p47Phox, which is partly related to PFOS-induced increased cytosolic ROS in RTCs. Moreover, L-Carnitine reduced ROS production in mitochondria and restored PFOS-impeded mitochondrial function, leading to sustained normal adenosine triphosphate synthesis and oxygen consumption and reduced proton leakage in a Seahorse XF stress test. The increased inositol-requiring enzyme 1α expression by PFOS, which indicated endoplasmic reticulum (ER) stress activation, was associated with PFOS-mediated autophagy activation that could be attenuated through 4-phenylbutyrate (5 mM, an ER stress inhibitor) and L-Carnitine pretreatment. Therefore, by reducing the level of IRE1α, L-Carnitine reduced the levels of Beclin and LC3BII, consequently reducing the level of apoptotic biomarkers including Bax and cleaving PARP and caspase 3. Collectively, these results indicate that through the elimination of oxidative stress, extracellular signal-regulated kinase activation, and ER stress, L-Carnitine reduced cell autophagy/apoptosis and concomitantly increased cell viability in RTCs. This study clarified the potential mechanism of PFOS-mediated RTC apoptosis and provided a new strategy for using L-Carnitine to prevent and treat PFOS-induced RTC apoptosis., (© 2022. The Author(s).)

Background: The results of long-term renal evolution in HCV-infected patients using sofosbuvir and velpatasvir (SOF/VEL), with or without ribavirin (RBV), are lacking. Aims: We evaluated the renal safety for HCV-infected patients receiving SOF/VEL. Methods: Between 1 June 2019 and 6 July 2020, we included 594 HCV-infected patients receiving SOF/VEL +/- RBV for 12 weeks in Taiwan. Viral eradication rate (defined by sustained virological response at week 12 post-treatment; SVR12) and changes to renal function were considered. Results: SVR12 was achieved in 99.3% (590/594) upon per-protocol analysis. Patients saw improved hepatobiliary function and fibrosis after the start of SOF/VEL therapy. For renal function, those with baseline estimated glomerular filtration rate (eGFR) ≥ 60 (mL/min/1.73 m 2 ) experienced transient on-treatment reduction in renal function that improved upon ending treatment, but recurrent eGFR degradation during one-year follow-up. The use of RBV (OR = 5.200, 95% CI: 1.983-13.634, p = 0.001) was a significant risk factor at SVR24, while diabetes mellitus (OR = 2.765, 95% CI: 1.104-6.922, p = 0.030) and the use of RBV (OR = 3.143, 95% CI: 1.047-9.435, p = 0.041) were identified as significant risk factors of worsening renal function at SVR48. SOF/VEL did not worsen renal function among those with stage 4-5 chronic kidney disease (CKD) who were not receiving dialysis. Conclusions: A trend of decline in eGFR at 1 year after SOF/VEL treatment was observed among diabetic patients with baseline eGFR ≥ 60 (mL/min/1.73 m 2 ) and concomitant use of RBV. The close monitoring of renal function is warranted. Further study should be conducted in order to weigh the risks and benefit of RBV.

Purpose: To investigate the determinants related to the ability to drive a motorized mobility scooter after a stroke., Method: The study was a cross-sectional study. The ability to drive a motorized mobility scooter was measured with the Power Mobility Clinical Driving Assessment. The independent variables included cognitive functions measured by the Color Trails Test and reaction time test, visual functions measured by a visual acuity test and visual field test, and motor functions measured with a dynamometer, the Box and Block Test, and the Functional Independence Measure., Results: The correlation analyses revealed that the Power Mobility Clinical Driving Assessment scores had significant correlations with reaction time ( ρ = -.65, p  < 0.01), binocular visual field ( r = .64, p < 0.01), binocular visual acuity ( r = .40, p  = 0.03), and the grip strength of the unaffected hand ( r = .47, p  = 0.01). The multiple regression analysis indicated that reaction time, binocular visual field, and the grip strength of the unaffected hand were the most significant determinants of the ability to drive a motorized mobility scooter ( R 2 = .76)., Conclusions: The reaction time, binocular visual field, and grip strength of the unaffected hand were the most significant determinants related to the ability to drive a motorized mobility scooter after a stroke. IMPLICATIONS FOR REHABILITATIONMotorized mobility scooter driving ability for stroke patients is correlated with demographics (age, mobility scooter driving experience, time since last drive) and cognitive, visual and motor functions (reaction time, binocular visual field, visual acuity, and the grip strength of unaffected hand).Primary determinants of motorized mobility scooter driving ability for stroke patients include reaction time, binocular visual field, and grip strength of the unaffected hand.Comprehensive assessments incorporating cognitive, visual and motor functions are needed to evaluate the ability to drive a motorized mobility scooter after a stroke.

Background: An increased amount of Fusobacterium nucleatum ( F. nucleatum ) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined., Aim: To identify F. nucleatum- dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer., Methods: Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival., Results: RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum , and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori ( H. pylori )., Conclusion: F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori- positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Giardia lamblia persists in a dormant state with a protective cyst wall for transmission. It is incompletely known how three cyst wall proteins (CWPs) are coordinately synthesized during encystation. Meiotic recombination is required for sexual reproduction in animals, fungi, and plants. It is initiated by formation of double-stranded breaks by a topoisomerase-like Spo11. It has been shown that exchange of genetic material in the fused nuclei occurs during Giardia encystation, suggesting parasexual recombination processes of this protozoan. Giardia possesses an evolutionarily conserved Spo11 with typical domains for cleavage reaction and an upregulated expression pattern during encystation. In this study, we asked whether Spo11 can activate encystation process, like other topoisomerases we previously characterized. We found that Spo11 was capable of binding to both single-stranded and double-stranded DNA in vitro and that it could also bind to the cwp promoters in vivo as accessed in chromatin immunoprecipitation assays. Spo11 interacted with WRKY and MYB2 (named from myeloblastosis), transcription factors that can activate cwp gene expression during encystation. Interestingly, overexpression of Spo11 resulted in increased expression of cwp1 - 3 and myb2 genes and cyst formation. Mutation of the Tyr residue for the active site or two conserved residues corresponding to key DNA-binding residues for Arabidopsis Spo11 reduced the levels of cwp1-3 and myb2 gene expression and cyst formation. Targeted disruption of spo11 gene with CRISPR/Cas9 system led to a significant decrease in cwp1-3 and myb2 gene expression and cyst number. Our results suggest that Spo11 acts as a positive regulator for Giardia differentiation into cyst.

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background and Aim: It is currently unknown how hepatitis C virus (HCV) eradication with pegylated interferon and ribavirin (PR) therapy affects the incidence of new-onset liver cirrhosis (LC) in patients without cirrhosis and the incidence of decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in patients with cirrhosis., Methods: Taiwanese chronic hepatitis C cohort (T-COACH) is a nationwide HCV registry cohort from 23 hospitals in Taiwan recruited between 2003 and 2015. This study enrolled 10 693 patients with chronic hepatitis C (CHC), linked to the Taiwan National Health Insurance Research Database, receiving PR therapy for at least 4 weeks for new-onset LC and liver-related complications (DLD or HCC)., Results: Of the 10 693 patients, 1372 (12.8%) patients had LC, and the mean age was 54.0 ± 11.4 years. The mean follow-up duration was 4.38 ± 2.79 years, with overall 46 798 person-years. The 10-year cumulative incidence rates of new-onset LC were 5.0% (95% confidence interval [CI]: 3.2-7.7) in patients without cirrhosis with a sustained virologic response (SVR) and 21.9% (95% CI: 13.4-32.4) in those without SVR (hazard ratio [HR]: 0.22, P < 0.001). The 10-year cumulative incidence rates of liver-related complications were 21.4% (95% CI: 11.1-37.2) in patients with cirrhosis with SVR and 47.0% (95% CI: 11.1-86.0) in those without SVR after adjustment for age, sex, and competing mortality (HR: 0.52, P < 0.001)., Conclusions: Hepatitis C virus eradication with PR therapy decreased the incidence of new-onset LC in noncirrhotic patients and the incidence of liver-related complications in cirrhotic patients with CHC., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Pangenotypic direct-acting antiviral agents (DAAs) glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL) are effective against all hepatitis C virus (HCV) genotype infections. However, data on pangenotypic DAA treatment for mixed genotype HCV infection are sparse., Methods: This is a retrospective, single site cohort study analyzing all patients with mixed HCV genotype infections treated with GLE/PIB or SOF/VEL from August 2018 to August 2020 in Chiayi Chang Gung Memorial Hospital, Taiwan. The primary study endpoint was sustained virologic response (SVR) 12 weeks after treatment cessation. We also reported adverse events (AEs)., Results: A total of 108 patients with mixed infections of any two or three genotypes of 1a, 1b, 2, 3, and 6 received pangenotypic DAAs during the study period. A total of 67 patients received GLE/PIB and 41 received SOF/VEL. The evaluable population analysis revealed SVR rates of 94% (63/67) and 95.1% (39/41) for GLE/PIB and SOF/VEL therapy, respectively, and the per-protocol analysis revealed an SVR of 100% for both regimens. Four patients in the GLE/PIB group and two patients in the SOF/VEL were lost to follow-up. The most common AEs for GLE/PIB versus SOF/VEL therapy included pruritus (14.9% vs 2.4%), fatigue (6.0% vs 7.3%), abdominal discomfort (4.5% vs 7.3%), and acid reflux (3.0% vs 4.9%). DAA-related significant laboratory abnormalities occurred in three patients with > 1.5 × elevated bilirubin level in the GLE/PIB group. None of the above AEs resulted in DAA discontinuation., Conclusions: Pangenotypic DAAs are well tolerated by and yield high SVR rates in patients with mixed genotype HCV infection., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The long-term outcome of hepatitis B virus (HBV) infection among patients dually infected with HBV and hepatitis C virus (HCV) remains unclear. We aimed to investigate the long-term liver outcomes of HBV/HCV-coinfected patients after antiviral therapy., Methods: A total of 11,359 chronically HCV-infected patients with interferon-based therapy were registered in a nationwide Taiwanese Chronic Hepatitis C Cohort. A propensity score matched (PSM) cohort of HCV mono-infected (n = 7020) and HBV/HCV (n = 702) co-infected patients by age, sex, and fibrosis was recruited for outcome analysis. The primary outcome was liver-related complications, including hepatocellular carcinoma (HCC) and liver decompensation during a mean follow-up period of 4.44 years., Results: Among HBV/HCV co-infected patients, patients without HCV-SVR had a significantly higher 10-year cumulative incidence of major liver-related complications than those with HCV-SVR. However, among patients with HCV-SVR in the PSM cohort, the risk of major liver-related complications, both HCC and liver decompensation, did not differ between HBV/HCV co-infected and HCV mono-infected patients. Similar results were observed among those without HCV-SVR. A substantial lower risk of major liver-related complications was found in HBV/HCV co-infected patients with HCV SVR and subsequent anti-HBV nucleot(s)ide analogues treatment. Overall, factors associated with major liver-related complications included age ≥ 65 year-old, BMI ≥ 27 kg/m 2 , FIB-4 ≥ 3.25, eGFR < 60 ml/min/1.73 m 2 , and non-HCV SVR, but not HBV co-infection., Conclusion: Interferon-based therapy reduced the long-term risk of major liver-related complications among HBV/HCV co-infected patients, as among HCV mono-infected patients. Nevertheless, post-HCV-SVR surveillance for major liver-related complications is mandatory among those high-risk groups., (© 2021. Asian Pacific Association for the Study of the Liver.)

CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino) phenyl]ethanone) is a major active agent of Camptotheca acuminata's alkaloid derivative, and its anti-tumorigenic activity, a valuable biological property of the agent, has been reported in many types of cancer. In this study, we researched the novel CIL-102-induced protein for either the induction of cell apoptosis or the inhibition of cell migration/invasiveness in colorectal cancer cells (CRC) and their molecular mechanism. Firstly, our data showed that CIL-102 treatment not only increased the cytotoxicity of cells and the production of Reactive Oxygen Species (ROS), but it also decreased cell migration and invasiveness in DLD-1 cells. In addition, many cellular death-related proteins (cleavage caspase 9, cleavage caspase 3, Bcl-2, and TNFR1 and TRAIL) and JNK MAPK/p300 pathways were increased in a time-dependent manner. Using the proteomic approach with a MALDI-TOF-TOF analysis, CIL-102-regulated differentially expressed proteins were identified, including eight downregulated and 11 upregulated proteins. Among them, upregulated Endoplasmic Reticulum resident Protein 29 (ERP29) and Fumarate Hydratase (FUMH) by CIL-102 were blocked by the inhibition of ROS production, JNK activity, and p300/CBP (CREB binding protein) signaling pathways. Importantly, the knockdown of ERP29 and FUMH expression by shRNA abolished the inhibition of cell migration and invasion by CIL-102 in DLD-1 cells. Together, our findings demonstrate that ERP29 and FUMH were upregulated by CIL102 via ROS production, JNK activity, and p300/CBP pathways, and that they were involved in the inhibition of the aggressive status of colorectal cancer cells.

Background and Aim: Chronic hepatitis C virus (HCV) infection is associated with impaired renal function. The aim of this study is to explore the risk of and factors associated with end-stage renal diseases (ESRD) under maintenance dialysis among HCV patients after anti-HCV therapy., Methods: A total of 12 696 HCV-infected patients with interferon-based therapy, including 9679 (76.2%) achieving sustained virological response (SVR), were enrolled from 23 hospitals in Taiwan., Results: During a mean follow-up period of 5.3 years (67 554 person-years), the annual incidence of 4.1/10 000 person-years, 4.0/10 000 and 4.7/10 000 person-years among SVR patients and non-SVR patients, respectively. History of diabetes and baseline estimated glomerular filtration rate < 60 mL/min/m 2 , instead of SVR, were the significant risk factors for developing ESRD with maintenance dialysis after anti-HCV therapy (adjusted hazard ratio 7.75 and 9.78)., Conclusion: Diabetes and baseline impaired renal function were strongly associated with progression to ESRD with maintenance dialysis among chronic HCV-infected patients after antiviral therapy., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Clinical trials showed pangenotypic direct-acting antivirals' (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.

Introduction: Real-world data regarding the impact of hepatic fibrosis on the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) treatment is limited in the Asian population., Methods: We analyzed data for all 823 patients with hepatitis C virus treated with SOF/VEL from June 2019 to September 2020 at Chang Gung Memorial Hospital in Chiayi, Taiwan. The degree of fibrosis was determined using the fibrosis-4 (FIB-4) index, with advanced fibrosis or cirrhosis defined as a FIB-4 score of > 3.25. The primary treatment outcome was the rate of sustained virologic response 12 weeks after treatment cessation (SVR). Adverse events (AEs) were also evaluated., Results: SVR rates did not significantly differ (p > 0.05) between patients with FIB-4 scores of ≤ 3.25 and those with scores of > 3.25. In the per protocol analysis, 99.2% (593/598) of the FIB-4 ≤ 3.25 group and 100% (172/172) of the FIB-4 > 3.25 group achieved SVR; in the evaluable population analysis, 93.4% (593/635) of the FIB-4 ≤ 3.25 group and 91.5% (172/188) of the FIB-4 > 3.25 group achieved SVR. Five patients with FIB-4 scores of ≤ 3.25 did not attain SVR: two relapsed and three had no response. The most common AEs were comparable (p > 0.05) for the FIB-4 ≤ 3.25 group and the FIB-4 > 3.25 group and included abdominal discomfort (4.4% vs. 5.9%), fatigue (4.1% vs. 5.9%), and skin itching (3.6% vs. 3.2%). Laboratory abnormalities were more common in the FIB-4 > 3.25 group (p < 0.001). Six patients with FIB-4 scores of > 3.25 had total bilirubin elevation > 3 × the upper normal limit (UNL). Alanine transaminase elevation > 5 × the UNL was observed in two patients with FIB-4 scores of ≤ 3.25 and one patient with a FIB-4 score of > 3.25. No AEs resulted in treatment discontinuation., Conclusions: SOF/VEL treatment is well tolerated and achieves high SVR rates for patients of Taiwanese ethnicity with HCV, regardless of cirrhosis status.

Background: Giardia lamblia differentiates into resistant cysts as an established model for dormancy. Myeloid leukemia factor (MLF) proteins are important regulators of cell differentiation. Giardia possesses a MLF homolog which was up-regulated during encystation and localized to unknown cytosolic vesicles named MLF vesicles (MLFVs)., Methods: We used double staining for visualization of potential factors with role in protein metabolism pathway and a strategy that employed a deletion mutant, CDK2m3, to test the protein degradation pathway. We also explored whether autophagy or proteasomal degradation are regulators of Giardia encystation by treatment with MG132, rapamycin, or chloroquine., Results: Double staining of MLF and ISCU or CWP1 revealed no overlap between their vesicles. The aberrant CDK2m3 colocalized with MLFVs and formed complexes with MLF. MG132 increased the number of CDK2m3-localized vesicles and its protein level. We further found that MLF colocalized and interacted with a FYVE protein and an ATG8-like (ATG8L) protein, which were up-regulated during encystation and their expression induced Giardia encystation. The addition of MG132, rapamycin, or chloroquine, increased their levels and the number of their vesicles, and inhibited the cyst formation. MLF and FYVE were detected in exosomes released from culture., Conclusions: The MLFVs are not mitosomes or encystation-specific vesicles, but are related with degradative pathway for CDK2m3. MLF, FYVE, and ATG8L play a positive role in encystation and function in protein clearance pathway, which is important for encystation and coordinated with Exosomes., General Significance: MLF, FYVE, and ATG8L may be involved an encystation-induced protein metabolism during Giardia differentiation., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Erinacine S, the new bioactive diterpenoid compound isolated from the ethanol extract of the mycelia of Hericium erinaceus, displays great health-promoting properties. However, the effects of erinacine S on inductive apoptosis in cancer cells such as gastric cancer and its molecular mechanisms remain unclear. Our results demonstrated that erinacine S treatment significantly induces cell apoptosis with increased ROS production in gastric cancer cells, but not in normal cells. Significantly, erinacine S also showed its inhibitory effects on tumor growth in an in vivo xenograft mouse model. Furthermore, immunohistochemical analyses revealed that erinacine S treatment significantly increases the FasL and TRAIL protein, whereas it decreases the levels of PCNA and cyclin D1 in the gastric cancer xenograft mice. Consistently, in AGS cells, erinacine S treatment not only triggers the activation of extrinsic apoptosis pathways (TRAIL, Fas-L and caspase-8, -9, -3), but it also suppresses the expression of the anti-apoptotic molecules Bcl-2 and Bcl-XL in a time-dependent manner. In addition, erinacine S also causes cell cycle G1 arrest by the inactivation of CDKs/cyclins. Moreover, our data revealed that activation of the ROS-derived and AKT/FAK/PAK1 pathways is involved in the erinacine S-mediated transcriptional activation of Fas-L and TRAIL through H3K4 trimethylation on their promoters. Together, this study sheds light on the anticancer effects of erinacine S on gastric cancer and its molecular mechanism in vitro and in vivo.

The capacity to synthesize a protective cyst wall is critical for infectivity of Giardia lamblia . It is of interest to know the mechanism of coordinated synthesis of three cyst wall proteins (CWPs) during encystation, a differentiation process. Multiprotein bridging factor 1 (MBF1) gene family is a group of transcription coactivators that bridge various transcription factors. They are involved in cell growth and differentiation in yeast and animals, or in stress response in fungi and plants. We asked whether Giardia has MBF1-like genes and whether their products influence gene expression. BLAST searches of the Giardia genome database identified one gene encoding a putative MBF1 protein with a helix-turn-helix domain. We found that it can specifically bind to the AT-rich initiator promoters of the encystation-induced cwp1-3 and myb2 genes. MBF1 localized to cell nuclei and cytoplasm with higher expression during encystation. In addition, overexpression of MBF1 induced cwp1-3 and myb2 gene expression and cyst generation. Mutation of the helixes in the helix-turn-helix domain reduced cwp1-3 and myb2 gene expression and cyst generation. Chromatin immunoprecipitation assays confirmed the binding of MBF1 to the promoters with its binding sites in vivo. We also found that MBF1 can interact with E2F1, Pax2, WRKY, and Myb2 transcription factors that coordinately up-regulate the cwp genes during encystation. Using a CRISPR/Cas9 system for targeted disruption of mbf1 gene, we found a downregulation of cwp1-3 and myb2 genes and decrease of cyst generation. Our results suggest that MBF1 is functionally conserved and positively regulates Giardia cyst differentiation.