ABSTRACT
BACKGROUND AND AIMS: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Hepatitis B Surface Antigens , Hepatitis B virus/genetics , Hepatitis B e Antigens , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/epidemiology , Liver Neoplasms/drug therapy , Antiviral Agents/therapeutic use , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , DNA, ViralABSTRACT
ConspectusSurface ligands are vital to the colloidal synthesis of noble-metal nanocrystals with well-controlled sizes and shapes for various applications. The surface ligands not only dictate the formation of nanocrystals with diverse shapes but also serve as a colloidal stabilizer to prevent the suspended nanocrystals from aggregation during their synthesis or storage. By leveraging the facet selectivity of some surface ligands, one can further control the sites for growth or galvanic replacement to transform presynthesized nanocrystals into complex structures that are otherwise difficult to fabricate using conventional methods. Furthermore, the presence of surface ligands on nanocrystals also facilitates their applications in areas such as sensing, imaging, nanomedicine, and self-assembly. Despite their popular use in enhancing the properties of nanocrystals and thus optimizing their performance in a wide variety of applications, it remains a major challenge to quantitatively determine the coverage density of ligand molecules, not to mention the difficulty of substituting or removing them without compromising the surface structure and aggregation state of the nanocrystals.In this Account, we recapitulate our efforts in developing methods capable of qualitatively or quantitatively measuring, exchanging, and removing the surface ligands adsorbed on noble-metal nanocrystals. We begin with an introduction to the typical interactions between ligand molecules and surface atoms, followed by a discussion of the Langmuir model that can be used to describe the adsorption of surface ligands. It is also emphasized that the adsorption process may become very complex in the case of a polymeric ligand due to the variations in binding configuration and chain conformation. We then highlight the capabilities of various spectroscopy methods to analyze the adsorbed ligands qualitatively or quantitatively. Specifically, surface-enhanced Raman scattering, Fourier transform infrared, and X-ray photoelectron spectroscopy are three examples of qualitative methods that can be used to confirm the absence or presence of a surface ligand. On the other hand, ultraviolet-visible spectroscopy and inductively coupled plasma mass spectrometry can be used for quantitative measurements. Additionally, the coverage density of a ligand can be derived by analyzing the morphological changes during nanocrystal growth. We then discuss how the ligands present on the surface of metal nanocrystals can be exchanged directly or indirectly to meet the requirements of different applications. The former can be done using a ligand with stronger binding, whereas the latter is achieved by introducing a sacrificial shell to the surface of the nanocrystals. Furthermore, we highlight three additional strategies besides simple washing to remove the surface ligands, including calcination, heating in a solution, and UV-ozone treatment. Finally, we showcase three applications of metal nanocrystals in nanomedicine, tumor targeting, and self-assembly by taking advantage of the diversity of surface ligands bearing different functional groups. We also offer perspectives on the challenges and opportunities in realizing the full potential of surface ligands.
ABSTRACT
Acute promyelocytic leukemia (APL) is a highly curable hematologic malignancy in the era of all-trans retinoic acid (ATRA) combination treatment. However, only a modest change in early mortality rate has been observed despite the wide availability of ATRA. In addition to the clinical characteristics of APL patients, studies on the hospital volume-outcome relationship and the physician volume-outcome relationship remained limited. We aim to evaluate the association between hospital and physician volume and the early mortality rate among APL patients. The patients were collected from Taiwan's National Health Insurance Research Database (NHIRD). Early mortality is defined as death within 30 days of diagnosis. Patients were categorized into four groups according to individual cumulative hospital and physician volume. The risk of all-cause mortality in APL patients with different cumulative volume groups was compared using a Cox proportional hazard model. The probability of overall survival was estimated using the Kaplan-Meier method. All 741 patients were divided into four quartile volume groups. In the multivariate analysis, only physician volume was significantly associated with early mortality rate. The physician volume of the highest quartile was a protective factor for early mortality compared with the physician volume of the lowest quartile (HR 0.10, 95% CI 0.02-0.65). Hospital characteristics were not associated with early mortality. In the sensitivity analyses, the results remained consistent using two other different definitions of early mortality. Higher physician volume was independently associated with lower early mortality, while hospital volume was not. Enhancing the clinical expertise of low-volume physicians may ensure better outcomes.
Subject(s)
Leukemia, Promyelocytic, Acute , Humans , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/complications , Tretinoin/therapeutic use , Proportional Hazards Models , Combined Modality Therapy , Treatment OutcomeABSTRACT
Introduction: Several studies indicated that teledermatology is good for people living on offshore islands. However, what disease benefits the most from interactive dermatology geographically in offshore islands remain uncertain. Objectives: This study aimed to investigate the seasonal and geographical distribution with different diseases in remote regions of Penghu islands in Taiwan Strait, thus to study the medical needs for specific disease in remote islands. The cost differences among three models by professional dermatologists were analyzed. Methods: This interactive teledermatology program serving Penghu Hospital, Ministry of Health and Welfare (MOHW-PH, March 2020 to February 2021) from a medical center in Taiwan recruited 145 patients with 280 patient-visits. The seasons, the timing from residential houses to MOHW-PH, the number of disease diagnosis, and the numbers of teledermatology visits are compared. The association of the distance from residential houses to MOHW-PH with different disease diagnosis was analyzed. Results: Eczema (33%), dermatophytosis (13%), and psoriasis (11%) were most common. Seasonal analysis showed dermatophytosis and eczema are more common in summer and winter, respectively. Geographical analysis showed that psoriasis has relatively higher case numbers, higher visits per case, with cases living in longer distances. The patient satisfaction was good (>95%). Among the three care modes of dermatologist, the cost estimation of interactive teledermatology and in-person clinic were similar yearly (2.4-2.9 million New Taiwan Dollars, roughly 80,000-90,000 USD). Conclusions: The study indicates that health care for psoriasis, being underprivileged but in desperate need in distant regions, could be delivered with quality and satisfaction by interactive teledermatology.
Subject(s)
Dermatology , Eczema , Psoriasis , Skin Diseases , Telemedicine , Tinea , Humans , Islands , Psoriasis/diagnosis , Skin Diseases/diagnosis , TaiwanABSTRACT
Background: Unhealthy western dietary patterns lead to over-consumption of fat and advanced glycation end-products (AGEs), and these account for the developments of obesity, diabetes, and related metabolic disorders. Certain amino acids (AAs) have been recently demonstrated to improve glycemia and reduce adiposity. Therefore, our primary aims were to examine whether feeding an isoleucine-enriched AA mixture (4.5% AAs; Ile: 3.0%, Leu: 1.0%, Val: 0.2%, Arg: 0.3% in the drinking water) would affect adiposity development and prevent the impairments of glycemic control in rats fed with the fat/AGE-containing diet (FAD). Methods: Twenty-four male Sprague-Dawley rats were assigned into 1) control diet (CD, N = 8), 2) FAD diet (FAD, N = 8), and 3) FAD diet plus AA (FAD/AA, N = 8). After 9-weeks intervention, the glycemic control capacity (glucose level, ITT, and HbA1c levels), body composition, and spontaneous locomotor activity (SLA) were evaluated, and the fasting blood samples were collected for analyzing metabolic related hormones (insulin, leptin, adiponectin, and corticosterone). The adipose tissues were also surgically collected and weighed. Results: FAD rats showed significant increases in weight gain, body fat %, blood glucose, HbA1c, leptin, and area under the curve of glucose during insulin tolerance test (ITT-glucose-AUC) in compared with the CD rats. However, the fasting levels of blood glucose, HbA1c, leptin, and ITT-glucose-AUC did not differ between CD and FAD/AA rats. FAD/AA rats also showed a greater increase in serum testosterone. Conclusion: The amino acid mixture consisting of Ile, Leu, Val, and Arg showed clear protective benefits on preventing the FAD-induced obesity and impaired glycemic control.
Subject(s)
Adiposity/drug effects , Amino Acids/pharmacology , Glycation End Products, Advanced/adverse effects , Adipokines/blood , Adipose Tissue/drug effects , Animals , Blood Glucose/metabolism , Body Composition/drug effects , Corticosterone/blood , Diet, Western/adverse effects , Dietary Fats/adverse effects , Energy Intake/drug effects , Insulin Resistance , Male , Obesity/drug therapy , Obesity/etiology , Rats, Sprague-Dawley , Testosterone/bloodSubject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Renal Insufficiency, Chronic , Humans , Hydroxychloroquine/therapeutic use , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Lupus Nephritis/drug therapy , Renal Insufficiency, Chronic/complicationsABSTRACT
Deciphering the structure of gene regulatory networks across the tree of life remains one of the major challenges in postgenomic biology. We present a novel ChIP-seq workflow for the archaea using the model organism Halobacterium salinarum sp. NRC-1 and demonstrate its application for mapping the genome-wide binding sites of natively expressed transcription factors. This end-to-end pipeline is the first protocol for ChIP-seq in archaea, with methods and tools for each stage from gene tagging to data analysis and biological discovery. Genome-wide binding sites for transcription factors with many binding sites (TfbD) are identified with sensitivity, while retaining specificity in the identification the smaller regulons (bacteriorhodopsin-activator protein). Chromosomal tagging of target proteins with a compact epitope facilitates a standardized and cost-effective workflow that is compatible with high-throughput immunoprecipitation of natively expressed transcription factors. The Pique package, an open-source bioinformatics method, is presented for identification of binding events. Relative to ChIP-Chip and qPCR, this workflow offers a robust catalog of protein-DNA binding events with improved spatial resolution and significantly decreased cost. While this study focuses on the application of ChIP-seq in H. salinarum sp. NRC-1, our workflow can also be adapted for use in other archaea and bacteria with basic genetic tools.
Subject(s)
Archaeal Proteins/metabolism , Chromatin Immunoprecipitation , High-Throughput Nucleotide Sequencing , Sequence Analysis, DNA , Transcription Factors/metabolism , Binding Sites , Genome, Archaeal , Halobacterium salinarum/genetics , SoftwareABSTRACT
BACKGROUND: The use of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal impairment has been approved; however, limited clinical data exist. Accordingly, we aimed to compare outcomes and adverse events associated with remdesivir in hospitalized patients with COVID-19, with and without severe renal impairment. METHODS: Hospitalized patients with COVID-19 undergoing a 5-day remdesivir course at Taipei Veterans General Hospital from April 1 to July 31, 2022, were enrolled. Comparative analysis of outcomes and safety between patients with or without severe renal impairment (estimated glomerular filtration rate of < 30 mL/min per 1.73 m2) were conducted. Prognostic factors associated with 28-day mortality in patients with severe renal impairment were investigated using logistic regression analysis. RESULTS: A total of 671 hospitalized patients, including 132 patients with severe renal impairment, who received a 5-day course of remdesivir were analyzed. The 28-day mortality was higher in patients with severe renal impairment than in patients without severe renal impairment (15.2% vs. 7.8%). The proportion of patients with acute kidney injury (AKI) and deteriorated liver function after completing remdesivir therapy was similar between the patients with and without severe renal impairment, and the recovery rate of AKI was similar in both groups. The sequential organ failure assessment score was an independent factor associated with 28-day mortality in patients with severe renal impairment. CONCLUSIONS: Remdesivir was well-tolerated in hospitalized patients with COVID-19, regardless of renal function. Our findings support the recent recommendation to administer remdesivir in patients with severe renal impairment.
Subject(s)
Acute Kidney Injury , Adenosine Monophosphate , Alanine , Antiviral Agents , COVID-19 Drug Treatment , COVID-19 , Hospitalization , Renal Insufficiency , SARS-CoV-2 , Humans , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adenosine Monophosphate/adverse effects , Alanine/analogs & derivatives , Alanine/therapeutic use , Alanine/adverse effects , Male , Female , Aged , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Middle Aged , Treatment Outcome , Hospitalization/statistics & numerical data , Acute Kidney Injury/chemically induced , Acute Kidney Injury/mortality , COVID-19/mortality , COVID-19/complications , Aged, 80 and over , Retrospective Studies , Taiwan/epidemiology , Glomerular Filtration RateABSTRACT
DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive upstream regulator of Lck during T-cell activation. DUSP22 dephosphorylates UBR2 at specific Serine residues, leading to ubiquitin-mediated UBR2 degradation. UBR2 is also modified by the SCF E3 ubiquitin ligase complex via Lys48-linked ubiquitination at multiple Lysine residues. Single-cell RNA sequencing analysis and UBR2 loss of function experiments showed that UBR2 is a positive regulator of proinflammatory cytokine expression. Mechanistically, UBR2 induces Lys63-linked ubiquitination of Lck at Lys99 and Lys276 residues, followed by Lck Tyr394 phosphorylation and activation as part of TCR signalling. Inflammatory phenotypes induced by TCR-triggered Lck activation or knocking out DUSP22, are attenuated by genomic deletion of UBR2. UBR2-Lck interaction and Lck Lys63-linked ubiquitination are induced in the peripheral blood T cells of human SLE patients, which demonstrate the relevance of the UBR2-mediated regulation of inflammation to human pathology. In summary, we show here an important regulatory mechanism of T cell activation, which finetunes the balance between T cell response and aggravated inflammation.
Subject(s)
Dual-Specificity Phosphatases , Ubiquitin-Protein Ligases , Humans , Ubiquitination , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Phosphorylation , Dual-Specificity Phosphatases/genetics , Dual-Specificity Phosphatases/metabolism , Inflammation/genetics , Receptors, Antigen, T-Cell/metabolism , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Mitogen-Activated Protein Kinase Phosphatases/genetics , Mitogen-Activated Protein Kinase Phosphatases/metabolismABSTRACT
The yearly epidemics and unpredictable outbreaks of influenza have raisedserious concernsglobally and led to prioritizing the development of an effective vaccine toprotectagainst newly emerging variants. Previously, we demonstrated that monoglycosylated influenza virus vaccines derived from A/California/7/2009 or an updated A/Brisbane/02/2018 (IVR-190) vaccine strain recommended by WHO are superior to fully glycosylated vaccines and could broadly protect against past and new coming H1N1 variants. However, whether such a monoglycosylated virus vaccine can be mass-produced to meet clinical demands and stable enough to provide consistent efficacy against H1N1 viruses remains unclear. Herein, we developed a platform for the pilot-scale production of the monoglycosylated split virus vaccine from the IVR-190 strain (IVR-190mg) with a robust and cost-effective manufacturing process. The critical parameters of inoculum dose, concentration of kifunensine, and optimized Endo H treatment process were comprehensively investigated. Several aims for preclinical studies of IVR-190mg were achieved, including [i] the execution of three engineering batch runs to validate lot-to-lot consistency, [ii] the establishment of IVR-190mg specifications to meet the acceptance criteria of a conventional influenza vaccine, [iii] an investigation of the stability profile of IVR-190mg, and completion of a safety evaluation by conducting an animal toxicology study. The toxicology study under GLP guidance found no systemic toxicity after rabbits were vaccinated with IVR-190mg. The serological data showed that IVR-190mg is highly immunogenic and effective in inducing a cross-strain protective level of antibody immune responses, including hemagglutination-inhibition titers, viral neutralization activity, and broad HA- and NA-inhibiting antibody titers against past and new H1N1 viruses. In conclusion, this study provides efficacy and safety profiles of IVR-190mg for further clinical study and shows that this vaccine without a glycan shield has great potential to be safe and protective against H1N1 variants.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Orthomyxoviridae Infections , Animals , Rabbits , Humans , Influenza, Human/prevention & control , Antibodies, Viral , Hemagglutinin Glycoproteins, Influenza Virus , Influenza A Virus, H3N2 SubtypeABSTRACT
Gestational diabetes mellitus (GDM) is a common pregnancy disorder associated with an increased risk of pre-eclampsia and macrosomia. Recent research has shown that the buildup of excess lipids within the placental trophoblast impairs mitochondrial function. However, the exact lipids that impact the placental trophoblast and the underlying mechanism remain unclear. GDM cases and healthy controls were recruited at Kaohsiung Medical University Hospital. The placenta and cord blood were taken during birth. Confocal and electron microscopy were utilized to examine the morphology of the placenta and mitochondria. We determined the lipid composition using liquid chromatography-mass spectrometry in data-independent analysis mode (LC/MSE). In vitro studies were carried out on choriocarcinoma cells (JEG3) to investigate the mechanism of trophoblast mitochondrial dysfunction. Results showed that the GDM placenta was distinguished by increased syncytial knots, chorangiosis, lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) overexpression, and mitochondrial dysfunction. Lysophosphatidylcholine (LPC) 16:0 was significantly elevated in the cord blood LDL of GDM patients. In vitro, we demonstrated that LPC dose-dependently disrupts mitochondrial function by increasing reactive oxygen species (ROS) levels and HIF-1α signaling. In conclusion, highly elevated LPC in cord blood plays a pivotal role in GDM, contributing to trophoblast impairment and pregnancy complications.
ABSTRACT
BACKGROUND: Fertility-sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early-stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. METHODS: A total of 1297 patients aged between 20 and 44 years with newly diagnosed early-stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site-specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier method with log-rank test and Cox regression model. RESULTS: There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high-grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66-1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06-0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. CONCLUSION: FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.
Subject(s)
Fertility Preservation , Ovarian Neoplasms , Humans , Female , Young Adult , Adult , Retrospective Studies , Carcinoma, Ovarian Epithelial/surgery , Carcinoma, Ovarian Epithelial/pathology , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/surgery , Ovarian Neoplasms/drug therapy , Neoplasm StagingABSTRACT
We report a catalyst family of high-entropy alloy (HEA) atomic layers having three elements from iron-group metals (IGMs) and two elements from platinum-group metals (PGMs). Ten distinct quinary compositions of IGM-PGM-HEA with precisely controlled square atomic arrangements are used to explore their impact on hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR). The PtRuFeCoNi atomic layers perform enhanced catalytic activity and durability toward HER and HOR when benchmarked against the other IGM-PGM-HEA and commercial Pt/C catalysts. Operando synchrotron x-ray absorption spectroscopy and density functional theory simulations confirm the cocktail effect arising from the multielement composition. This effect optimizes hydrogen-adsorption free energy and contributes to the remarkable catalytic activity observed in PtRuFeCoNi. In situ electron microscopy captures the phase transformation of metastable PtRuFeCoNi during the annealing process. They transform from random atomic mixing (25°C), to ordered L10 (300°C) and L12 (400°C) intermetallic, and finally phase-separated states (500°C).
ABSTRACT
In the context of optimizing dental care for patients who are elderly, the purpose of this in vitro study was to evaluate the surface gloss (with a micro-area gloss meter) of, surface roughness (with a compact surface roughness measuring instrument) of, and color change (with a dental colorimeter) in two commercially available injectable resin-based composites (Estelite Universal Flow (EUF) and Beautifil Flow Plus F00 (BFP)) as well as two glass-ionomer cements (GC Fuji II LC CAPSULE (FLC) and GC Fuji IX GP EXTRA CAPSULE (FGP)), before and after dental prophylaxis. After 24 h, the surfaces of each specimen were polished at 2500 rpm with a prophy brush (Mersage Brush, Shofu) and one-step prophylaxis paste (Prophy Paste Pro, Directa): under 100 or 300 gf load, and for 10 or 30 s, 4× cycles of cleaning. After mechanical cleaning, conditions were found for a significant reduction in the gloss level (EUF, BFP, or FLC; p < 0.05) and a significant increase in surface roughness (BFP; 300 gf load, 10 s × four cycles of cleaning). Overall, the longer time or higher prophylaxis load tended to decrease the surface gloss. However, the observed change in surface roughness varied between the restorative materials. There was no color change post-prophylaxis.
ABSTRACT
To evaluate the uterine corpus cancer incidence rates, age-specific trends, and birth cohort patterns by different histologic types. We conducted a retrospective cohort study of uterine cancer patients (n = 28,769) of all ages from the National Cancer Registry of Taiwan between 1998 and 2017. We estimated the incidence trends, average annual percent changes (AAPCs), and cancer-specific survival (CSS) rate for the two main subtypes (endometrioid and nonendometrioid) of uterine cancer in Taiwan. During the study period, uterine corpus cancer incidence rates increased over time from 5.3 to 15.21 per 100,000 women. Incidence trends for endometrioid carcinoma increased in all age groups (positive AAPCs > 5% for each age group), and the rise was steeper among women aged 50 years and younger. For nonendometrioid carcinomas, incidence rates increased among women over 50 years. The CSS rate improved among women with stage I (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49-0.81) and stage III (HR 0.72, 95% CI 0.58-0.90) endometrioid carcinomas after 2013 compared with those during 2009-2012. However, the CSS rate remained unchanged for nonendometrioid carcinomas. Age, diagnostic period, stage and histologic types were significant factors associated with the 5-year CSS rate. We found that the incidences of both endometrioid and nonendometrioid carcinomas continued to increase among contemporary birth cohorts. Etiologic research is needed to explain the causes of these trends.
Subject(s)
Carcinoma, Endometrioid , Uterine Neoplasms , Humans , Female , Birth Cohort , Retrospective Studies , Uterine Neoplasms/epidemiology , Uterine Neoplasms/pathology , Carcinoma, Endometrioid/epidemiology , Carcinoma, Endometrioid/pathology , Incidence , Age FactorsABSTRACT
The SARS-CoV-2 and influenza pandemics have posed a devastating threat to global public health. The best strategy for preventing the further spread of these respiratory viruses worldwide is to administer a vaccine capable of targeting both viruses. Here, we show that a novel monoglycosylated vaccine designed based on the influenza virus HAstem conserved domain fused with the SARS-CoV-2 spike-RBD domain (HSSRmg) can present proper antigenicity that elicits sufficient neutralization efficacy against various SARS-CoV-2 variants while simultaneously providing broad protection against H1N1 viruses in mice. Compared with the fully glycosylated HSSR (HSSRfg), HSSRmg induced higher ELISA titers targeting HAstem and spike-RBD and exhibited significantly enhanced neutralization activity against the Wuhan pseudovirus. The enhanced immune responses raised by JR300-adjuvanted HSSRmg compared to HSSRmg alone include more anti-HAstem and anti-spike-RBD antibodies that provide cross-protection against H1N1 challenges and cross-neutralization of SARS-CoV-2 pseudoviruses. Furthermore, the enhanced immune response raised by JR300-adjuvanted-HSSRmg skews toward a more balanced Th1/Th2 response than that raised by HSSRmg alone. Notably, HSSRmg elicited more plasma B cells and memory B cells, and higher IL-4 and IFN-γ cytokine immune responses than spike (S-2P) in mice with preexisting influenza-specific immunity, suggesting that B-cell activation most likely occurs through CD4+ T-cell stimulation. This study demonstrated that HSSRmg produced using a monoglycosylation process and combined with the JR300 adjuvant elicits superior cross-strain immune responses against SARS-CoV-2 and influenza viruses in mice compared with S-2P. JR300-adjuvanted HSSRmg has great potential as a coronavirus-influenza vaccine that provides dual protection against SARS-CoV-2 and influenza infections.
Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Influenza, Human , Viral Vaccines , Animals , Mice , Humans , SARS-CoV-2 , COVID-19/prevention & control , Antibodies, Viral , Antibodies, Neutralizing , Spike Glycoprotein, CoronavirusABSTRACT
Influenza epidemics and pandemics caused by newly emerging virus strains highlight an urgent need to develop a universal vaccine against viruses. Previously, a monoglycosylated X-181mg vaccine demonstrated that the HA possessing a single N-acetylglucosamine at each N-glycosylation site is superior to confer broader protection in mice than conventional vaccines. However, the greatest challenge in conducting clinical trials is the need to develop robust manufacturing processes capable of producing vaccines at the pilot scale with the desired stability, potency, and efficacy. Whether the monoglycosylated virus vaccine platform can be applied to the new vaccine strain in a timely manner and whether the mass-produced vaccine has the proper immunogenicity to induce cross-protective immunity remains unclear. Here, we show that a pilot-scale manufacturing process produced a monoglycosylated A/Brisbane/02/2018(H1N1) virus vaccine (IVR-190mg) with a single glycan at each glycosylation site of HA and NA. Compared with the fully glycosylated virus vaccine (IVR-190fg), the IVR-190mg provided broader cross-protection in mice against a wide range of H1N1 variants. The enhanced antibody responses induced by IVR-190mg immunization include higher hemagglutination-inhibition titers, higher neutralization activity, more anti-HA head domain, more anti-HA stem antibodies, higher neuraminidase activity inhibition titers, and notably, higher antibody-dependent cellular cytotoxicity. Additionally, the IVR-190mg also induced a more balanced Th1/Th2 response and elicited broader splenic CD4+ and CD8+ T-cell responses than IVR-190fg. This study demonstrated that IVR-190mg produced using a pilot-scale manufacturing process elicits comprehensive cross-strain immune responses that have great potential to substantially mitigate the need for yearly reformulation of strain-specific inactivated vaccines.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Orthomyxoviridae Infections , Animals , Mice , Humans , Antibodies, Viral , Vaccines, Inactivated , Hemagglutinin Glycoproteins, Influenza VirusABSTRACT
BACKGROUND: Gallstone disease (GD) can have prolonged, subacute inflammatory period before biliary events. The intricate relationship between GD and inflammatory processes can possible lead to prothrombotic tendency that can result in confusing clinical course before diagnosis. CASE SUMMARY: A 51-year-old man, presented with a 1-year history of self-relief occasional postprandial upper abdominal pain, had sudden onset severe left upper quadrant pain and visited our emergency room. Contrast enhanced computed tomography (CECT) showed filling defect in celiac trunk, common hepatic, part of splenic arteries and wedge-shaped hypo-enhancing region of spleen, consistent with splenic infarction secondary to splenic arterial occlusion. No convincing predisposing factors were found during first hospitalization. Abdominal pain mildly subsided after low molecular weight heparin and bridge to oral anticoagulant use. However, in the following six months, the patient was admitted twice due to acute cholangitis and finally cholecystitis. Second CECT revealed biliary impacted stone was adjacent to poor dissoluble thrombus. The abdominal pain did not achieve a clinical full remission until endoscopic retrograde cholangiopancreatography stone removal and series laparoscopic cholecystectomy was performed. CONCLUSION: This is the first case to present serious thrombotic complication due to inflammation status in chronic GD. It could be a rare, confusing and difficult recognizing cause of a celiac trunk thromboembolic event.
ABSTRACT
Begomoviruses frequently inflict upward or downward leaf curling symptoms on infected plants, leading to severe economic damages. Knowledge of the underlying mechanism controlling the leaf curling severity may facilitate the development of alternative disease management strategies. In this study, through genomic recombination between Ageratum yellow vein virus Nan-Tou strain (AYVV-NT) and Tomato leaf curl virus Tai-Chung Strain (TLCV-TC), which caused upward and downward leaf curling on Nicotiana benthamiana, respectively, it was found that the coding region of C4 protein might be involved in the determination of leaf curling directions. Sequence comparison and mutational analysis revealed that the cysteine and glycine at position 8 and 14 of AYVV-TC C4 protein, respectively, are involved in the modulation of leaf curling symptoms. Cross-protection assays further demonstrated that N. benthamiana inoculated with AYVV-carrying mutations of the aforementioned amino acids exhibited attenuated leaf curling symptoms under the challenge of wild-type AYVV-NT. Together, these findings revealed a new function of begomovirus C4 proteins involved in the modulation of leaf curling severity during symptom formation and suggested potential applications for managing viral diseases through manipulating the symptoms.