Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

Background: Active surveillance (AS) has emerged as a viable management strategy for low-risk papillary thyroid microcarcinoma (PTMC), following pioneering trials at Kuma Hospital and the Cancer Institute Hospital in Japan. Numerous prospective cohort studies have since validated AS as a management option for low-risk PTMC, leading to its inclusion in thyroid cancer guidelines across various countries. From 2016 to 2020, the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) enrolled 1,177 patients, providing comprehensive data on PTMC progression, sonographic predictors of progression, quality of life, surgical outcomes, and cost-effectiveness when comparing AS to immediate surgery. The second phase of MAeSTro (MAeSTro-EXP) expands AS to low-risk papillary thyroid carcinoma (PTC) tumors larger than 1 cm, driven by the hypothesis that overall risk assessment outweighs absolute tumor size in surgical decision-making. Methods: This protocol aims to address whether limiting AS to tumors smaller than 1 cm may result in unnecessary surgeries for low-risk PTCs detected during their rapid initial growth phase. By expanding the AS criteria to include tumors up to 1.5 cm, while simultaneously refining and standardizing the criteria for risk assessment and disease progression, we aim to minimize overtreatment and maintain rigorous monitoring to improve patient outcomes. Conclusion This study will contribute to optimizing AS guidelines and enhance our understanding of the natural course and appropriate management of low-risk PTCs. Additionally, MAeSTro-EXP involves a multinational collaboration between South Korea and Australia. This cross-country study aims to identify cultural and racial differences in the management of low-risk PTC, thereby enriching the global understanding of AS practices and their applicability across diverse populations.

In this study, a novel phthalic acid ester (1) and a known iridoid glycoside (2) were isolated from the root bark of Anthocleista vogelii. The structures of the novel compound and iridoid glycoside were elucidated on the basis of their chemical and spectral data (UV, FT-IR, EI-MS, 1D and 2D NMR) and found to be phthalic acid ester, 4-ethyl-6-propyl-4,5,6,7-tetrahydro- 3H-2,8-benzodioxacycloundecine-1,9-dione (1) and sweroside (2). The compounds were evaluated for their in vitro inhibitory activities against pancreatic lipase, α-amylase and α- glucosidase, and in vivo laxative activity in rats. The metabolite phthalic acid ester (1) exhibited moderate inhibitory activity against pancreatic lipase (IC50 = 24.43 ± 0.096 μg/mL) and relatively good activity against α-glucosidase (IC50 = 10.28 ± 0.015 μg/mL). Sweroside (2) displayed weak activity against α-glucosidase (IC50 = 40.28 ± 0.063 μg/mL) but significantly (p<0.05) increased the feacal output of the treated animals compared to the normal and sodium picosulfate controls.

The aim of this study was to investigate the antiviral property of Eurycoma longifolia Jack (EL) against dengue virus. A propriety standardized extract of Eurycoma longifolia Jack (Physta®) was tested for anti-viral activity after viral adsorption in Vero cell line. Viral yield was measured by qRT-PCR in four serotypes of dengue virus. The antiviral activity was further investigated in an in vivo AG129 mouse model for dengue inhibitory candidates. 100 mg/kg EL extract was fed twice daily and challenged with a lethal dose of (~1x105 PFU per mouse) of DENV-2 over a period of six days. Antiviral activity with IC50 of 33.84, 33.55, 58.35 and 119 μg/ml for DENV-1, DENV-2, DENV-3 and DENV-4 serotypes respectively was observed. The selectivity index (SI) values determined as the ratio of cytotoxic concentration (CC50) to inhibitory concentration (IC50) was the lowest for DENV-2 at 28.9. The dengue virus (DENV) replication measured by qRT-PCR showed a reduction of 100% for DENV-1, DENV-2, DENV-3 and 80% for DENV-4 at day 2 of exposure. In the in vivo AG129 mouse model, a lower weight reduction, 30% lower viral load and 12% higher platelet in the extract group compared to the control was observed at day 6. The extract of E. longifolia has potential anti-dengue properties with improving trends in platelet counts. E. longifolia supplementation is potentially a two-pronged approach in treating dengue fever.

BACKGROUND/OBJECTIVES: Evidence indicates that berry anthocyanins are anti-atherogenic, antioxidant, and anti-inflammatory. However, berries differ vastly in their anthocyanin composition and thus potentially in their biological and metabolic effects. The present study compared hypolipidemic, antioxidant, and anti-inflammatory properties of blueberry (BB), blackberry (BK), and blackcurrant (BC) in a diet-induced obesity (DIO) mouse model. MATERIALS/METHODS: Male C57BL/6J mice were fed a high fat (HF; 35% fat, w/w) control diet or a HF diet supplemented with freeze-dried 5% BB, 6.3% BK or 5.7% BC for 12 weeks (10 mice/group) to achieve the same total anthocyanin content in each diet. Plasma lipids, antioxidant status and pro-inflammatory cytokines were measured. The expression of genes involved in antioxidant defense, inflammation, and lipid metabolism was determined in the liver, epididymal adipose tissue, proximal intestine, and skeletal muscle. Histological analysis was performed to identify crown-like structure (CLS) in epididymal fat pads to determine macrophage infiltration. RESULTS: No differences were noted between the control and any berry-fed groups in plasma levels of liver enzymes, insulin, glucose, ferric reducing antioxidant power, superoxide dismutase, and tumor necrosis factor α. However, BK significantly lowered plasma triglyceride compared with the HF control and other berries, whereas BC significantly reduced F4/80 mRNA and the number of CLS in the epididymal fat pad, indicative of less macrophage infiltration. CONCLUSIONS: The present study provides evidence that BB, BK and BC with varying anthocyanin composition differentially affect plasma lipids and adipose macrophage infiltration in DIO mice, but with no differences in their antioxidant capacity and anti-inflammatory potential.
Adipose Tissue ; Animals ; Anthocyanins ; Blueberry Plant* ; Cytokines ; Diet ; Fruit ; Glucose ; Humans ; Inflammation ; Insulin ; Intestines ; Lipid Metabolism ; Liver ; Macrophages ; Male ; Mice* ; Muscle, Skeletal ; Obesity* ; Plasma* ; RNA, Messenger ; Rubus* ; Superoxide Dismutase ; Triglycerides ; Tumor Necrosis Factor-alpha

The C-terminal domain of RNA polymerase II is an unusual series of repeated residues appended to the C-terminus of the largest subunit and serves as a flexible binding scaffold for numerous nuclear factors. The binding of these factors is determined by the phosphorylation patterns on the repeats in the domain. In this study, we generated a synthetic antibody library by replacing the third heavy chain complementarity-determining region of an anti-HER2 (human epidermal growth factor receptor 2) antibody (trastuzumab) with artificial sequences of 7–18 amino-acid residues. From this library, antibodies were selected that were specific to serine phosphopeptides that represent typical phosphorylation patterns on the functional unit (YSPTSPS)₂ of the RNA polymerase II C-terminal domain (CTD). Antibody clones pCTD-1stS2 and pCTD-2ndS2 showed specificity for peptides with phosphoserine at the second residues of the first or second heptamer repeat, respectively. Additional clones specifically reacted to peptides with phosphoserine at the fifth serine of the first repeat (pCTD-1stS5), the seventh residue of the first repeat and fifth residue of the second repeat (pCTD-S7S5) or the seventh residue of either the first or second repeat (pCTD-S7). All of these antibody clones successfully reacted to RNA polymerase II in immunoblot analysis. Interestingly, pCTD-2ndS2 precipitated predominately RNA polymerase II from the exonic regions of genes in genome-wide chromatin immunoprecipitation sequencing analysis, which suggests that the phosphoserine at the second residue of the second repeat of the functional unit (YSPTSPS)2 is a mediator of exon definition.
Antibodies ; Chromatin Immunoprecipitation ; Clone Cells ; Complementarity Determining Regions ; DNA-Directed RNA Polymerases* ; Exons* ; Peptides ; Phosphopeptides ; Phosphorylation* ; Phosphoserine ; Receptor, Epidermal Growth Factor ; RNA Polymerase II* ; RNA* ; Sensitivity and Specificity ; Serine

Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.
Animals ; Antioxidants/*metabolism/*pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Line ; Cisplatin/*toxicity ; Cysteine/*analogs & derivatives/pharmacology ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Glutathione/*metabolism ; Heme Oxygenase-1/genetics ; Intracellular Space/metabolism ; Male ; Metabolic Detoxication, Phase II/genetics ; Mice ; NF-E2-Related Factor 2/genetics ; Nitric Oxide/biosynthesis ; Organ of Corti/*drug effects/*metabolism ; RNA Interference ; Rats ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.
Amino Acid Sequence ; Antigens, CD ; chemistry ; genetics ; pharmacology ; Autoimmunity ; Biological Assay ; Cell Line ; Cytotoxicity, Immunologic ; genetics ; immunology ; Dose-Response Relationship, Immunologic ; Humans ; Immunoglobulins ; immunology ; metabolism ; Immunologic Factors ; chemistry ; genetics ; pharmacology ; Kinetics ; Leukocyte Immunoglobulin-like Receptor B1 ; Lymphocyte Activation ; genetics ; immunology ; Major Histocompatibility Complex ; genetics ; immunology ; Molecular Sequence Data ; Molecular Targeted Therapy ; Mutagenesis, Site-Directed ; Peptide Library ; Polyethylene Glycols ; Protein Binding ; genetics ; immunology ; Receptors, Immunologic ; chemistry ; genetics ; Recombinant Fusion Proteins ; genetics ; metabolism ; T-Lymphocytes, Cytotoxic ; immunology ; metabolism