The antigenic anatomy of SARS-CoV-2 receptor binding domain.

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 µg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.

Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors.

Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common "off-the-shelf" cancer vaccines.

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

The presence of broadly neutralizing anti-SARS-CoV-2 RBD antibodies elicited by primary series and booster dose of COVID-19 vaccine.

Antibody-mediated immunity plays a key role in protection against SARS-CoV-2. We characterized B-cell-derived anti-SARS-CoV-2 RBD antibody repertoires from vaccinated and infected individuals and elucidate the mechanism of action of broadly neutralizing antibodies and dissect antibodies at the epitope level. The breadth and clonality of anti-RBD B cell response varies among individuals. The majority of neutralizing antibody clones lose or exhibit reduced activities against Beta, Delta, and Omicron variants. Nevertheless, a portion of anti-RBD antibody clones that develops after a primary series or booster dose of COVID-19 vaccination exhibit broad neutralization against emerging Omicron BA.2, BA.4, BA.5, BQ.1.1, XBB.1.5 and XBB.1.16 variants. These broadly neutralizing antibodies share genetic features including a conserved usage of the IGHV3-53 and 3-9 genes and recognize three clustered epitopes of the RBD, including epitopes that partially overlap the classically defined set identified early in the pandemic. The Fab-RBD crystal and Fab-Spike complex structures corroborate the epitope grouping of antibodies and reveal the detailed binding mode of broadly neutralizing antibodies. Structure-guided mutagenesis improves binding and neutralization potency of antibody with Omicron variants via a single amino-substitution. Together, these results provide an immunological basis for partial protection against severe COVID-19 by the ancestral strain-based vaccine and indicate guidance for next generation monoclonal antibody development and vaccine design.

Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

Clinical and Genotypic Insights Into Higher Prevalence of Palbociclib Associated Neutropenia in Asian Patients.

BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.

Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study.

BACKGROUND & AIMS: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. METHODS: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). RESULTS: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups. CONCLUSIONS: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. CLINICALTRIALS: gov number: NCT04033445.

Highly Biocompatible Antibacterial Hydrogel for Wearable Sensing of Macro and Microscale Human Body Motions.

Flexible electronics, like electronic skin (e-skin), rely on stretchable conductive materials that integrate diverse components to enhance mechanical, electrical, and interfacial properties. However, poor biocompatibility, bacterial infections, and limited compatibility of functional additives within polymer matrices hinder healthcare sensors' performance. This study addresses these challenges by developing an antibacterial hydrogel using polyvinyl alcohol (PVA), konjac glucomannan (KGM), borax (B), and flower-shaped silver nanoparticles (F-AgNPs), referred as PKB/F-AgNPs hydrogel. The developed hydrogel forms a hierarchical network structure, with a tensile strength of 96 kPa, 83% self-healing efficiency within 60 minutes, and 128% cell viability in Cell Counting Kit-8 (CCK-8) assays, indicating excellent biocompatibility. It also shows strong antibacterial efficacy against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). Blue light irradiation enhances its antibacterial activity by 1.3-fold for E. coli and 2.2-fold for S. aureus. The hydrogel's antibacterial effectiveness is assessed by monitoring changes in electrical conductivity, providing a cost-effective alternative to traditional microbial culture assays. The PKB/F-AgNPs hydrogel's flexibility and electrical conductivity enable it to function as strain sensors for detecting body movements and facial expressions. This antibacterial hydrogel underscores its potential for future human-machine interfaces and wearable electronics.

Antigenic Characterization of Human Monoclonal Antibodies for Therapeutic Use against H7N9 Avian Influenza Virus.

Since 2013, H7N9 avian influenza viruses (AIVs) have caused more than 1,500 human infections and the culling of millions of poultry. Despite large-scale poultry vaccination, H7N9 AIVs continue to circulate among poultry in China and pose a threat to human health. Previously, we isolated and generated four monoclonal antibodies (mAbs) derived from humans naturally infected with H7N9 AIV. Here, we investigated the hemagglutinin (HA) epitopes of H7N9 AIV targeted by these mAbs (L3A-44, K9B-122, L4A-14, and L4B-18) using immune escape studies. Our results revealed four key antigenic epitopes at HA amino acid positions 125, 133, 149, and 217. The mutant H7N9 viruses representing escape mutations containing an alanine-to-threonine substitution at residue 125 (A125T), a glycine-to-glutamic acid substitution at residue 133 (G133E), an asparagine-to-aspartic acid substitution at residue 149 (N149D), or a leucine-to-glutamine substitution at residue 217 (L217Q) showed reduced or completely abolished cross-reactivity with the mAbs, as measured by a hemagglutination inhibition (HI) assay. We further assessed the potential risk of these mutants to humans should they emerge following mAb treatment by measuring the impact of these HA mutations on virus fitness and evasion of host adaptive immunity. Here, we showed that the L4A-14 mAb had broad neutralizing capabilities, and its escape mutant N149D had reduced viral stability and human receptor binding and could be neutralized by both postinfection and antigen-induced sera. Therefore, the L4A-14 mAb could be a therapeutic candidate for H7N9 AIV infection in humans and warrants further investigation for therapeutic applications. IMPORTANCE Avian influenza virus (AIV) H7N9 continues to circulate and evolve in birds, posing a credible threat to humans. Antiviral drugs have proven useful for the treatment of severe influenza infections in humans; however, concerns have been raised as antiviral-resistant mutants have emerged. Monoclonal antibodies (mAbs) have been studied for both prophylactic and therapeutic applications in infectious disease control and have demonstrated great potential. For example, mAb treatment has significantly reduced the risk of people developing severe disease with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition to the protection efficiency, we should also consider the potential risk of the escape mutants generated by mAb treatment to public health by assessing their viral fitness and potential to compromise host adaptive immunity. Considering these parameters, we assessed four human mAbs derived from humans naturally infected with H7N9 AIV and showed that the mAb L4A-14 displayed potential as a therapeutic candidate.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Incidence and progression of diabetic retinopathy in patients treated with glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors: A population-based cohort study.

AIM: Glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown. METHODS: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new-onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non-DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD. RESULTS: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non-DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre-existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01-2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups. CONCLUSIONS: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use.

Qualitative and Psychometric Evaluation of 29-Item Patient-Reported Outcomes Measurement Information System® to Assess General Health-Related Quality of Life in Patients With Moderately to Severely Active Inflammatory Bowel Disease.

OBJECTIVES: To evaluate content validity and psychometric properties of the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) to determine its suitability in inflammatory bowel disease (IBD) clinical trials. METHODS: Content validity of PROMIS-29 was evaluated using qualitative interviews, including concept elicitation and cognitive debriefing, among patients living with Crohn's disease (Crohn's disease n = 20) or ulcerative colitis (UC, n = 19). PROMIS-29 validity, reliability, and responsiveness were assessed using data from phase II clinical trials of Crohn's disease (N = 360) and UC (N = 518). RESULTS: Common (≥74%) symptoms reported in qualitative interviews were increased stool frequency, fatigue, abdominal pain/cramping, blood/mucus in stool, bowel urgency, and diarrhea. Disease impact aligned with PROMIS-29 content (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles/activities). Cognitive debriefing indicated that PROMIS-29 instructions were easily understood, items were relevant, and the recall period was appropriate. Psychometric evaluations demonstrated that PROMIS-29 scores indicating worse symptoms/functioning were associated with lower health-related quality of life and greater disease activity and severity. PROMIS-29 domain scores correlated (rs ≥ 0.40) with IBD Questionnaire domains and EuroQol-5-Dimension-5-Level dimensions measuring similar concepts. Test-retest reliability among patients with stable disease was moderate-to-excellent (0.64-0.94) for nearly all domains in all studies. PROMIS-29 was responsive to change in disease status from baseline to week 12. Thresholds for clinically meaningful improvement ranged from ≥3 to ≥8, depending on domain. CONCLUSIONS: PROMIS-29 is valid, reliable, and responsive for assessing general health-related quality of life and treatment response in IBD clinical trials.

Meta-Analysis and Machine Learning Models for Anaerobic Biodegradation Rates of Organic Contaminants in Sediments and Sludge.

Anaerobic biodegradation rates (half-lives) of organic chemicals are pivotal for environmental risk assessment and remediation. Traditional experimental evaluation, constrained by prolonged, oxygen-free conditions, struggles to keep pace with emerging contaminants. Data-driven machine learning (ML) models serve as promising complements. However, reported quantitative structure-biodegradation relationships or ML models on anaerobic biodegradation are mostly based on small data sets (<100 records) and neglect experimental conditions, usually achieving compromised predictions. This work aimed to develop ML models for predicting the biodegradation half-lives of organic pollutants in anaerobic environments (i.e., sediment/soil and sludge). Focusing on important features of both chemicals and experimental conditions, we first curated two data sets, one for sediment/soil (SED) and the other for sludge (SLD), covering 978 records for 206 chemicals from the literature, and then conducted a meta-analysis. Next, we built a binary classification (half-life of 30 days as the cutoff) model with an accuracy of 81% and a regression model with R2 of 0.56 for SED based on LightGBM (80% and 0.31 for SLD based on Extra tree, respectively). The model interpretations underscored the significance of experimental conditions (e.g., temperature and inoculum dosage), as evidenced by their high feature importance, and the models were found to correctly capture the effects of chemical substructures, for example, branched structures and aromatic rings prolonged half-lives while methyl group and ortho-substitution on rings shortened half-lives. The applicability domains of the models were also defined, resulting in reasonable prediction for the half-lives of 41% (SED) or 67% (SLD) of over 4000 persistent, bioaccumulative, and toxic chemicals. Overall, this study pioneers ML models for predicting the anaerobic degradation half-lives, offering valuable support for future evaluation and implementation of chemical anaerobic biodegradation.

Predicting Odor Sensory Attributes of Unidentified Chemicals in Water Using Fragmentation Mass Spectra with Machine Learning Models.

Knowing odor sensory attributes of odorants lies at the core of odor tracking when addressing waterborne odor issues. However, experimental determination covering tens of thousands of odorants in authentic water is not pragmatic due to the complexity of odorant identification and odor evaluation. In this study, we propose the first machine learning (ML) model to predict odor perception/threshold aiming at odorants in water, which can use either molecular structure or MS2 spectra as input features. We demonstrate that model performance using MS2 spectra is nearly as good as that using unequivocal structures, both with outstanding accuracy. We particularly show the model's robustness in predicting odor sensory attributes of unidentified chemicals by using the experimentally obtained MS2 spectra from nontarget analysis on authentic water samples. Interpreting the developed models, we identify the intricate interaction of functional groups as the predominant influence factor on odor sensory attributes. We also highlight the important roles of carbon chain length, molecular weight, etc., in the inherent olfactory mechanisms. These findings streamline the odor sensory attribute prediction and are crucial advancements toward credible tracking and efficient control of off-odors in water.

A Green High-k Dielectric from Modified Carboxymethyl Cellulose-Based with Dextrin.

Many crucial components inside electronic devices are made from non-renewable, non-biodegradable, and potentially toxic materials, leading to environmental damage. Finding alternative green dielectric materials is mandatory to align with global sustainable goals. Carboxymethyl cellulose (CMC) is a bio-polymer derived from cellulose and has outstanding properties. Herein, citric acid, dextrin, and CMC based hydrogels are prepared, which are biocompatible and biodegradable and exhibit rubber-like mechanical properties, with Young modulus values of 0.89 MPa. Hence, thin film CMC-based hydrogel is explored as a suitable green high-k dielectric candidate for operation at low voltages, demonstrating a high dielectric constant of up to 78. These fabricated transistors reveal stable high capacitance (2090 nF cm-2) for ≈±3 V operation. Using a polyelectrolyte-type approach and poly-(2-vinyl anthracene) (PVAn) surface modification, this study demonstrates a thin dielectric layer (d ≈30 nm) with a small voltage threshold (Vth ≈-0.8 V), moderate transconductance (gm ≈65 nS), and high ON-OFF ratio (≈105). Furthermore, the dielectric layer exhibits stable performance under bias stress of ± 3.5 V and 100 cycles of switching tests. The modified CMC-based hydrogel demonstrates desirable performance as a green dielectric for low-voltage operation, further highlighting its biocompatibility.

Long-term Effect of Thyrotropin-binding Inhibitor Immunoglobulin on Atrial Fibrillation in Euthyroid Patients.

OBJECTIVE: Individuals with hyperthyroidism are at an increased risk of atrial fibrillation (AF), but the association between autoantibodies and AF or cardiovascular mortality in individuals who have returned to normal thyroid function remains unclear. METHODS: The study utilized electronic medical records from National Taiwan University Hospital between 2000 and 2022. Each hyperthyroidism patient had at least 1 thyrotropin-binding inhibiting immunoglobulin (TBII) measurement. The relationship between TBII levels and the risk of AF and cardiovascular mortality was assessed using multivariable Cox regression models and Kaplan-Meier survival analysis. RESULTS: Among the 14 618 enrolled patients over a 20-year timeframe, 173 individuals developed AF, while 46 experienced cardiovascular mortality. TBII values exceeding 35% were significantly associated with an elevated risk of AF for both the first TBII (hazard ratio {HR} 1.48 [1.05-2.08], P = .027) and mean TBII (HR 1.91 [1.37-2.65], P < .001). Furthermore, after free T4 levels had normalized, a borderline association between first TBII and AF (HR 1.59 [0.99-2.56], P = .056) was observed, while higher mean TBII increased AF (HR 1.78 [1.11-2.85], P = .017). Higher first and mean TBII burden continued to significantly impact the incidence of cardiovascular mortality (HR 6.73 [1.42-31.82], P = .016; 7.87 [1.66-37.20], P = .009). Kaplan-Meier analysis demonstrated that elevated TBII levels increased the risk of AF and cardiac mortality (log-rank P = .035 and .027, respectively). CONCLUSION: In euthyroid individuals following antithyroid treatment, elevated circulating TBII levels and burden are associated with an elevated risk of long-term incident AF and cardiovascular mortality. Further reduction of TBII level below 35% will benefit to clinical outcomes.

A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment.

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.

Multicenter registry of multisystem inflammatory syndrome in children (MIS-C) and Paired comparison with Kawasaki disease.

OBJECTIVES: This study aimed to identify clinical characteristics to differentiate multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) in Taiwan, an island with a delayed cluster of MIS-C and a high incidence of KD. Additionally, we studied risk factors for developing severe complications in patients with MIS-C. METHODS: We conducted a retrospective, multicenter, cohort, and observational study that linked data on patients with MIS-C between May and December 2022 and patients with KD between 2019 and 2021 from 12 medical centers. Hemodynamic compromise, defined as the need for inotropic support or fluid challenge, was recorded in patients with MIS-C. We also evaluated maximal coronary Z-scores before treatment and one month after disease onset. RESULTS: A total of 83 patients with MIS-C and 466 patients with KD were recruited. A 1:1 age and gender-matched comparison of 68 MIS-C and KD pairs showed that MIS-C patients had a lower percentage of positive BCG red halos, lower leukocyte/platelet counts, more gastrointestinal symptoms, and a higher risk of hemodynamic compromise. In Taiwan, 38.6% of MIS-C patients experienced hemodynamic compromise, with presence of conjunctivitis and elevated levels of procalcitonin (>1.62 ng/mL) identified as independent risk factors. CONCLUSIONS: We identified two independent risk factors associated with hemodynamic compromise in MIS-C patients. The comparison between matched MIS-C and KD patients highlighted significant differences in clinical presentations, like BCG red halos, which may aid in the differential diagnosis of the two disease entities, especially in regions with a high incidence rate of KD.

Associations of Circulating Biomarkers with Disease Risks: A Two-Sample Mendelian Randomization Study.

Circulating biomarkers play a pivotal role in personalized medicine, offering potential for disease screening, prevention, and treatment. Despite established associations between numerous biomarkers and diseases, elucidating their causal relationships is challenging. Mendelian Randomization (MR) can address this issue by employing genetic instruments to discern causal links. Additionally, using multiple MR methods with overlapping results enhances the reliability of discovered relationships. Here, we report an MR study using multiple methods, including inverse variance weighted, simple mode, weighted mode, weighted median, and MR-Egger. We use the MR-base resource (v0.5.6) from Hemani et al. 2018 to evaluate causal relationships between 212 circulating biomarkers (curated from UK Biobank analyses by Neale lab and from Shin et al. 2014, Roederer et al. 2015, and Kettunen et al. 2016 and 99 complex diseases (curated from several consortia by MRC IEU and Biobank Japan). We report novel causal relationships found by four or more MR methods between glucose and bipolar disorder (Mean Effect Size estimate across methods: 0.39) and between cystatin C and bipolar disorder (Mean Effect Size: -0.31). Based on agreement in four or more methods, we also identify previously known links between urate with gout and creatine with chronic kidney disease, as well as biomarkers that may be causal of cardiovascular conditions: apolipoprotein B, cholesterol, LDL, lipoprotein A, and triglycerides in coronary heart disease, as well as lipoprotein A, LDL, cholesterol, and apolipoprotein B in myocardial infarction. This Mendelian Randomization study not only corroborates known causal relationships between circulating biomarkers and diseases but also uncovers two novel biomarkers associated with bipolar disorder that warrant further investigation. Our findings provide insight into understanding how biological processes reflecting circulating biomarkers and their associated effects may contribute to disease etiology, which can eventually help improve precision diagnostics and intervention.