KRAS and YAP1 converge to regulate EMT and tumor survival.

Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.

HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia.

The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.

ß-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis.

Wnt/ß-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic ß-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of ß-catenin in transformation, we classified ß-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that ß-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with ß-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of ß-catenin-dependent cancers in both cell lines and animal models. These observations define a ß-catenin-YAP1-TBX5 complex essential to the transformation and survival of ß-catenin-driven cancers.

Developing High-Capacity Solid "Molecular Basket" Sorbents for Selective CO2 Capture and Separation.

ConspectusSince carbon-based energy continues to dominate (over 80%) the global primary energy supply, carbon dioxide capture, utilization, and sequestration (CCUS) is deemed to be a promising and viable option to mitigate greenhouse gas emissions and climate change, for which CO2 capture is critical to the overall success of CCUS. Although liquid amine scrubbing is a mature technology for carbon capture, it is energy-intensive and costly due to energy consumption in solvent heating and water evaporation apart from the energy needed to break amine-CO2 bonding. To address this challenge, Song's group developed a new design approach for adsorptive CO2 capture and separation, namely, "molecular basket" sorbents (MBS), without the need for dealing with solvent heating and water evaporation. The solid MBS consisting of polymeric amines (such as PEI) immobilized into nanoporous materials (such as SBA-15) possesses a high capacity for CO2 capture with high selectivity, fast kinetics, and good regenerability. Consequently, MBS can greatly reduce energy consumption and carbon capture cost. Conventional adsorbents such as zeolites, activated carbon, alumina, and silica have low adsorption capacities, and their use of CO2 adsorption requires prior removal of moisture and cooling of flue gas (∼35 °C). On the contrast, the CO2 sorption capacity of MBS can even be promoted by the presence of moisture/steam and reaches the best performance closer to flue gas temperature (∼75 °C). This Account presents an overview of our research progress in the material development and fundamental understanding of MBS for CO2 capture and the separation of CO2 from various gas streams. It begins with an illustration of the MBS concept, followed by efforts to improve the performance and pilot-scale demonstration of MBS for CO2 capture. With the systematic characterization of MBS by various ex situ and in situ techniques, a better understanding is developed for the CO2 sorption process mechanistically. Furthermore, this Account demonstrates how the fundamental understanding of the CO2 sorption mechanism promotes the further development of more robust and advanced sorbent materials with improved CO2 sorption capacity, kinetics of sorption and desorption, and cyclic stability. Finally, an outlook is provided for the future design and development of novel sorbent materials and the CO2 sorption process for various gas streams including flue gas, biogas, air, and hydrogen streams.

Synthesis of Biobased Poly(butylene Furandicarboxylate) Containing Polysulfone with Excellent Thermal Resistance Properties.

A synthetic biopolymer derived from furandicarboxylic acid monomer and hydroxyethyl-terminated poly(ether sulfone) is presented. The synthesis involves 4,4'-dichlorodiphenyl sulfone and 4,4-dihydroxydiphenyl sulfone, resulting in poly(butylene furandicarboxylate)-poly(ether sulfone) copolyesters (PBFES) through melt polycondensation with titanium-catalyzed polymerization. This facile method yields segmented polyesters incorporating polysulfone, creating a versatile group of high-temperature thermoplastics with adjustable thermomechanical properties. The PBFES copolyesters demonstrate an impressive tensile modulus of 2830 MPa and a tensile strength of 84 MPa for PBFES55. Additionally, the poly(ether sulfone) unit imparts a relatively high glass transition temperature (Tg), ranging from 36.6 °C for poly(butylene 2,5-furandicarboxylate) to 112.3 °C for PBFES62. Moreover, the complete amorphous film of PBFES exhibits excellent transparency and solvent resistance, making it suitable for applications, such as food packaging materials.

The effects of nirmatrelvir/ritonavir on tacrolimus levels in lung transplant recipients: A single-center study.

BACKGROUND: Lung transplant recipients (LTRs) have a higher risk of hospitalization and mortality due to COVID-19 compared with the immunocompetent population. The use of nirmatrelvir/ritonavir (NR), an effective oral treatment for COVID-19, is quite challenging due to its potent drug-drug interactions with immunosuppressants and azole antifungals. As there are few clinical reports of the use of NR in LTRs, we measured tacrolimus levels in patients receiving NR in our hospital to improve safety when prescribing NR. METHODS: In total, 48 adult LTRs who received NR between November 19, 2022, and January 19, 2023, at China-Japan Friendship Hospital were retrospectively included and followed for 20 days after initiating NR. Tacrolimus was held at least 12 h before initiating NR and re-administered based on the trough levels after completing NR treatment. All concomitant medications, drug concentrations, laboratory results, and genotypes were recorded and analyzed. RESULTS: Most patients showed stable tacrolimus trough levels despite high individual variability. Four patients exhibited supratherapeutic trough levels of tacrolimus (more than 15 ng/mL). Two patients who received 0.5 mg of tacrolimus during NR treatment had trough levels below 3.0 ng/mL. In addition, we found that in 13 patients, the trough levels were 130% of baseline after cessation of tacrolimus, and logistic regression revealed that increased trough level was significantly associated with age more than 60 years. CONCLUSIONS: NR can be safely used in LTRs with close monitoring of tacrolimus levels and appropriate dose adjustments. However, more attention should be paid to elderly patients, as NR may more severely affect their drug metabolism. Due to the limited sample size, further studies are needed to guide the optimal use of tacrolimus following treatment with NR and explore the risk factors significantly affecting the interactions between NR and tacrolimus.

Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: A retrospective, single center experience.

PURPOSE: This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. METHODS: This retrospective observational study enrolled a total of 228 lung transplant recipients. TAC trough levels (C0) were collected for 3 intervals: 0-3 months, 3-12 months, and 12-24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C0 cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C0 and IPV on outcomes of interests, including de-novo donor-specific antibodies (dnDSA), chronic lung allograft dysfunction (CLAD) and mortality. RESULTS: The influence of CYP3A5*3 polymorphism was only significant for C0 and IPV during the first 3 months. Low C0 (< 8 ng/mL) at 3-12 months increased the risk of dnDSA (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.046-6.953) and mortality (HR 2.531, 95% CI 1.368-4.685), while High IPV (≥ 30%) during this period was associated with an increased risk of mortality (HR 2.543, 95% CI 1.336-4.839). Patients with Low C0/High IPV combination had significantly higher risks for dnDSA (HR 4.381, 95% CI 1.279-15.008) and survival (HR 6.179, 95% CI 2.598-14.698), surpassing the predictive power provided by C0 or IPV alone. CONCLUSION: A combination of Low C0/High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.

M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6.

Macrophages in the tumor microenvironment (TME) can serve as potential targets for therapeutic intervention. The aim of this study was to investigate the molecular mechanism by which M2 macrophage-derived exosomes (M2-Ex) affect lung cancer progression through miRNA transport. The THP-1 cells were differentiated into M0 and M2 macrophages. M2-Ex were isolated and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Cancer tissues and adjacent tissues of non-small-cell lung cancer (NSCLC) patients were collected. H1299 and A549 cells were co-cultured with M2-Ex. Subcutaneous xenograft mouse model was established. miR-3917 is highly expressed in lung cancer tissues and M2-Ex. Interference of miR-3917 in M2-Ex inhibits H1299 cell proliferation, migration and invasion, while overexpression of miR-3917 had the opposite effect in A549 cells. M2-Ex promote tumor growth by delivering miR-3917 in vivo. miR-3917 could target G protein-coupled receptor kinase 6 (GRK6), and interference of miR-3917 in M2-Ex inhibits H1299 cells proliferation, migration and invasion by up-regulating GRK6 level, while overexpression of miR-3917 had the opposite effect in A549 cells. M2-Ex can transfer miR-3917 into lung cancer cells and promote lung cancer progression, providing theoretical basis for the diagnosis and effective treatment of lung cancer.

Argonaute, Vault, and Ribosomal Proteins Targeted by Autoantibodies in Systemic Lupus Erythematosus.

OBJECTIVE: To expand, in an unbiased manner, our knowledge of autoantigens and autoantibodies in patients with systemic lupus erythematosus (SLE) and evaluate their associations with serological and clinical variables. METHODS: Human proteome arrays (> 21,000 proteins) were screened with serum from patients with SLE (n = 12) and healthy controls (n = 6) for IgG and IgA binding. Top hits were validated with 2 cohorts of patients with SLE (cohort 1, n = 49; cohort 2, n = 46) and other rheumatic diseases by ELISA. Clinical associations of the autoantibodies were tested. RESULTS: Ro60 was the top hit in the screen, and the 10 following proteins included 2 additional known SLE autoantigens plus 8 novel autoantigens involved in microRNA processing (Argonaute protein 1 [AGO1], AGO2, and AGO3), ribosomes (ribosomal protein lateral stalk subunit P2 and ovarian tumor deubiquitinase 5 [OTUD5]), RNA transport by the vault (major vault protein), and the immune proteasome (proteasome activator complex subunit 3). Patient serum contained IgG reactive with these proteins and IgA against the AGO proteins. Using the 95th percentile of healthy donor reactivity, 5-43% were positive for the novel antigens, with OTUD5 and AGO1 showing the highest percentages of positivity. Autoantibodies against AGO1 proteins were more prevalent in patients with oral ulcers in a statistically significant manner. IgG autoantibodies against AGO proteins were also seen in other rheumatic diseases. CONCLUSION: We discovered new autoantigens existing in cytosolic macromolecular protein assemblies containing RNA (except the proteasome) in cells. A more comprehensive list of autoantigens will allow for a better analysis of how proteins are targeted by the autoimmune response. Future research will also reveal whether specific autoantibodies have utility in the diagnosis or management of SLE.

Impact of statin treatment and exposure on the risk of chronic allograft dysfunction in Chinese lung transplant recipients.

PURPOSE: Chronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. METHODS: A retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. RESULTS: The statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007-2.053), P = 0.046). CONCLUSION: Statin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

Visible-Light-Promoted Trifluoromethylthiolation and Trifluoromethylselenolation of 1,4-Dihydropyridines.

We report a metal-free trifluoromethylthiolation and trifluoromethylselenolation of 1,4-dihydropyridines with S-(trifluoromethyl) 4-methylbenzenesulfonothioate and Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate under visible light irradiation. This transformation was tolerated with a wide range of functional groups and provided an alternative and green strategy for the synthesis of trifluoromethylthioesters and trifluoromethylselenoesters.

Copper-catalyzed ring-opening trifluoromethylthiolation/trifluoromethylselenolation of cyclopropanols with TsSCF3 or Se-(trifluoromethyl) 4-methoxybenzenesulfonoselenoate.

We report a ring-opening trifluoromethylthiolation of cyclopropanols with TsSCF3 by using Cu(OAc)2 as the catalyst. Moreover, by using this strategy, the trifluoromethylselenolation of cyclopropanols with Se-(trifluoromethyl) 4-methoxybenzenesulfonoselenoate to access ß-SeCF3-substituted carbonyl compounds is achieved for the first time. The broad substrate scope, readily accessible reagents and cheap catalyst make this protocol an alternative and efficient method for the synthesis of ß-SCF3-substituted or ß-SeCF3-substituted carbonyl compounds.

ELANE Promotes M2 Macrophage Polarization by Down-Regulating PTEN and Participates in the Lung Cancer Progression.

BACKGROUND: Macrophages are one of the most important immunoinflammatory cell populations in the tumor microenvironment (TME). In this study, we preliminarily investigated the upstream pathway of M2 macrophage polarization affecting lung cancer progression. METHODS: Bioinformatics analysis was used to evaluate genes closely associated with lung adenocarcinoma and their relationship with immune cells. THP-1 monocytes were induced into M2 macrophages. The expression of markers in M2 macrophages was detected by quantitative reverse transcription-PCR (qRT-PCR), enzyme linked immunosorbent assay (ELISA), and flow cytometry. The effects of neutrophil elastase (ELANE)-mediated M2 macrophages on lung cancer cell proliferation, migration and invasion and tumor growth were investigated by in vitro and in vivo experiments after co-culture of macrophage conditioned medium (CM) and lung cancer cell lines A549 and H1299. The PTEN protein expression was detected by Western blotting. RESULTS: ELANE was significantly positively correlated with M2 macrophages. ELANE up-regulated the expression of the M2 macrophage markers CD206, CCL22, IL-10 and CCL18 and increased the proportion of CD206+ macrophages. Compared with M0-CM, M2-CM promoted cell proliferation, migration, and invasion, and (M2+ELANE)-CM further enhanced this effect. In vivo, ELANE promoted M2 macrophage-induced tumor growth in lung cancer mice model. In vitro experiments showed that ELANE can down-regulate the expression of PTEN and promote the polarization of M2 macrophages. CONCLUSION: ELANE promotes the polarization of M2 macrophages by down-regulating PTEN, thus promoting cell proliferation, migration, and invasion in vitro and growth of lung cancer cells in vivo.

Chemical and metabolic profiling of Codonopsis Radix extract with an integrated strategy using ultra-high-performance liquid chromatography coupled with mass spectrometry.

Codonopsis radix was commonly used as food materials or herbal medicines in many countries. However, the comprehensive analysis of chemical constituents, and in vivo xenobiotics of Codonopsis radix remain unclear. In the present study, an integrated strategy with feature-based molecular networking using ultra-high-performance liquid chromatography coupled with mass spectrometry was established to systematically screen the chemical constituents and the in vivo xenobiotics of Codonopsis radix. A step-by-step manner based on a composition database, visual structure classification, discriminant ions, and metabolite software prediction was proposed to overcome the complexities due to the similar structure of chemical constituents and metabolites of Codonopsis radix. As a result, 103 compounds were tentatively characterized, 20 of which were identified by reference standards. Besides, a total of 50 xenobiotics were detected in vivo, including 26 prototypes and 24 metabolites, while the metabolic features of the pyrrolidine alkaloids were elucidated for the first time. The metabolism reactions of pyrrolidine alkaloids and sesquiterpene lactones included oxidation, methylation, hydration, hydrogenation, demethylation, glucuronidation, and sulfation. This study provided a generally applicable approach to the comprehensive investigation of the chemical and metabolic profile of traditional Chinese medicine and offered reasonable guidelines for further screening of quality control indicators and pharmacodynamics mechanism of Codonopsis radix.

Nitrogen-rich based conjugated microporous polymers for highly efficient adsorption and removal of COVID-19 antiviral drug chloroquine phosphate from environmental waters.

Chloroquine phosphate (CQP) has been suggested as an important and effective clinical reliever medication for the 2019 coronavirus (COVID-19). Nevertheless, its excessive use will inevitably cause irreparable damage to the entire ecosystem, thereby posing a considerable environmental safety concern. Hence, the development of highly-efficient methods of removing CQP from water pollution sources, e.g., effluents from hospitals and pharmaceutical factories is significant. This study reported the fabrication of novel C-N bond linked conjugated microporous polymers (CMPs) (BPT-DMB-CMP) with multiple nitrogen-rich anchoring sites for the quick and efficient removal of CQP from aqueous solutions. The irreversible covalent C-N bond linked in the internal framework of BPT-DMB-CMP endowed it with good chemical stability and excellent adsorbent regeneration. With its predesigned functional groups (i.e., rich N-H bonds, triazine rings, and benzene rings) and large area surface (1,019.89 m2·g-1), BPT-DMB-CMP demonstrated rapid adsorption kinetics (25 min) and an extraordinary adsorption capacity (334.70 mg·g-1) for CQP, which is relatively higher than that of other adsorbents. The adsorption behavior of CQP on BPT-DMB-CMP corresponded with Liu model and mixed-order model. Based on the density functional theory (DFT) calculations, X-ray photoelectron spectroscopy (XPS), and adsorption comparisons test, the halogen bonding, and hydrogen bonding cooperates with π - π, C - H···π interactions and size-matching effect in the CQP adsorption system on BPT-DMB-CMP. The excellent practicability for the removal of CQP from real wastewater samples verified the prospect of practical application of BPT-DMB-CMP. BPT-DMB-CMP exhibited the application potentials for the adsorption of other antiviral drugs. This work opens up an efficient, simple, and high adsorption capacity way for removal CQP.

Buchwald-Hartwig coupled conjugated microporous polymer for efficient removal COVID-19 antiviral drug famciclovir from waters: Adsorption behavior and mechanism.

The consumption of famciclovir (FCV) has been increased dramatically since the outbreak of coronavirus in 2019, and the pollution and harm of FCV in waters are concerned. Here, by utilizing aryl halides on 2, 4, 6-tris(4-bromophenyl)- 1, 3, 5-triazine (BPT) and primary amine groups on benzidine (BZ), a novel conjugated microporous polymer, namely BPT-BZ-CMP, was synthesized by Buchwald-Hartwig coupling reaction and applied in the removal of FCV from aqueous solution firstly. The synthesized BPT-BZ-CMP were characterized by various methods, including FTIR, SEM, BET, and Zeta-potential. Due to the micropore structure and high specific surface area, it took only 30 min for BPT-BZ-CMP to adsorb FCV to reach an equilibrium, and the maximum adsorption capacity was 347.8 mg·g-1. The Liu and pseudo-second-order kinetic models properly fit the adsorption equilibrium and kinetic data, respectively. The adsorption process was a spontaneous process, and the hydrogen bonding, π-π interaction and C-H···π interaction enhanced the adsorption of FCV on BPT-BZ-CMP. BPT-BZ-CMP maintained a good adsorption capacity after four consecutive adsorption-desorption cycle experiments. This study confirmed the potential of BPT-BZ-CMP as efficient sorbent to remove FCV from aqueous solutions.

Advanced data post-processing method for rapid identification and classification of the major triterpenoids of Alismatis rhizoma by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry.

INTRODUCTION: Alismatis rhizoma (AR), a distinguished diuretic traditional Chinese herbal medicine, is widely used for the treatment of diarrhea, edema, nephropathy, hyperlipidemia, and tumors in clinical settings. Most beneficial effects of AR are attributed to the major triterpenoids, whose contents are relatively high in AR. To date, only 25 triterpenoids in AR have been characterized by LC-MS because the low-mass diagnostic ions are hardly triggered in MS, impeding structural identification. Herein, we developed an advanced data post-processing method with abundant characteristic fragments (CFs) and neutral losses (NLs) for rapid identification and classification of the major triterpenoids in AR by UPLC-Q-TOF-MSE . OBJECTIVE: We aimed to establish a systematic method for rapid identification and classification of the major triterpenoids of AR. METHODS: UPLC-Q-TOF-MSE coupled with an advanced data post-processing method was established to characterize the major triterpenoids of AR. The abundant CFs and NLs of different types of triterpenoids were discovered and systematically summarized. The rapid identification and classification of the major triterpenoids of AR were realized by processing the data and comparing with information described in the literature. RESULTS: In this study, a total of 44 triterpenoids were identified from AR, including three potentially new compounds and 41 known ones, which were classified into six types. CONCLUSION: The newly established approach is suitable for the chemical profiling of the major triterpenoids in AR, which could provide useful information about chemical constituents and a basis for further exploration of its active ingredients in vivo.

Population pharmacokinetic-pharmacodynamic modelling of platelet time-courses following administration of abrocitinib.

AIMS: Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib. METHODS: This analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16. A semi-mechanistic model was developed to assess the impact of baseline platelet counts (170, 220 and 270 × 1000/µL), age and race on the platelet nadir and week 12 counts with once-daily abrocitinib 200 mg or 100 mg. RESULTS: Decreases in platelet counts were transient with the nadir occurring on average 24 days (95% prediction interval, 23-24) after continuous administration of abrocitinib 200 mg QD. Following administration of once-daily abrocitinib 200 mg, the probabilities of thrombocytopaenia (<150 × 1000/µL) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 × 1000/µL or 170 × 1000/µL, respectively. Adolescents had a lower probability of thrombocytopaenia compared with adults; platelet count distribution was similar in Asian and Western patients at the nadir and at week 12. CONCLUSION: This analysis supports the safety of once-daily abrocitinib 200 mg and 100 mg dosing regimens, with low probability of thrombocytopaenia during treatment, except for higher risk of low-grade thrombocytopaenia that diminished after 4 weeks in patients with low baseline platelet counts.

Autoantibodies against the envelope proteins of endogenous retroviruses K102 and K108 in patients with systemic lupus erythematosus correlate with active disease.

OBJECTIVES: To determine if patients with systemic lupus erythematosus (SLE), a disease characterised by elevated type I interferons reminiscent of anti-viral immunity, have expression of human endogenous retrovirus K (HERV-K) proviruses capable of producing envelope (Env) protein, as well as associated autoantibodies against the Env protein. METHODS: ELISAs were conducted with recombinant Env protein and sera from SLE patients with active (n=60) or inactive (n=49) disease, healthy controls (n=47), other rheumatic disorders (n=59), as well as plasma from paediatric lupus patients with active (n=30) or inactive (n=30) disease, and 17 healthy children. Antibody reactivity was evaluated for correlations with clinical and laboratory parameters of the patients. Expression of HERV-K transcripts were profiled in SLE leukocytes by RNA-Seq. RESULTS: Both adult and paediatric SLE patients had autoantibodies against HERV-K Env with higher titres than healthy controls or patients with Sjögren's syndrome, small- or large-vessel vasculitis, or psoriatic arthritis. Transcripts from only two HERV-K loci capable of producing Env, HERV-K102 and -K108, were detected among the 10 expressed loci in SLE patients. CONCLUSIONS: Our data reveal that HERV-K proviruses are expressed in SLE and that the HERV-K-encoded Env protein elicits an immune response in patients, particularly during active disease.

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation.

Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study. Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (Cmax /D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban Cmax /D than non-carriers. Logistic regression showed that rivaroxaban Cmax /D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban Cmax /Dose and the incidence of hemorrhage events significantly.