Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study.

BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Gastric cancer secreted miR-214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells.

Different from necrosis, apoptosis, autophagy and other forms of cell death, ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated fatty acids under the action of iron divalent or lipoxygenase, leading to cell death. Apatinib is currently used in the third-line standard treatment of advanced gastric cancer, targeting the anti-angiogenesis pathway. However, Apatinib-mediated ferroptosis in vascular endothelial cells has not been reported yet. Tumor-secreted exosomes can be taken up into target cells to regulate tumor development, but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered. Here, we show that exosomes secreted by gastric cancer cells carry miR-214-3p into vascular endothelial cells and directly target zinc finger protein A20 to negatively regulate ACSL4, a key enzyme of lipid peroxidation during ferroptosis, thereby inhibiting ferroptosis in vascular endothelial cells and reducing the efficiency of Apatinib. In conclusion, inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib, thereby promoting the antiangiogenic effect of Apatinib, suggesting a potential combination therapy for advanced gastric cancer.

STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts.

Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models. SIGNIFICANCE: These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release. See related commentary by Kearney and Vasan, p. 2313. This article is featured in Selected Articles from This Issue, p. 2293.

Sintilimab Plus Apatinib and Chemotherapy as Second­/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial.

BACKGROUND: The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. METHODS: In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. RESULTS: From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. CONCLUSION: Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05025033, 27/08/2021.

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

N-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.

Synthesis of biotinylated-LPG as a chemical biology tool enabling discovery of ALCAT1 modulators.

As a mitochondrial signature phospholipid, cardiolipin (CL) is required for membrane structure, respiration, dynamics, fragmentation, and mitophagy. Alteration of CL by reactive oxygen species (ROS) can cause mitochondrial dysfunction, which is implicated in the pathogenesis of many diseases. The enzyme ALCAT1 (acyl-CoA: lysocardiolipin acyltransferase-1) facilitates the conversion of CL by incorporating polyunsaturated fatty acids into lysocardiolipin. Accumulating evidence suggests that overexpression of ALCAT1 is involved in pathological cardiolipin remodeling and mitochondrial bioenergetics. Few ALCAT1 modulators are reported in the literature, and the enzymatic activity was tested via a low-throughput TLC (thin layer chromatography) assay. To identify small molecule ALCAT1 inhibitors, a robust assay was needed to enable a full deck high throughput screen. Scintillation proximity assay (SPA) was the method of choice because it permits the rapid and sensitive measurement of a broad range of biological processes in a homogeneous system. A biotinylated ALCAT1 substrate was required as a chemical biology tool in developing SPA. Among a panel of phospholipids, lysophosphatidyl glycerol (LPG) was identified as the best substrate for ALCAT1. Herein we report the synthesis of biotinylated-LPG analogs with varied linker lengths and their activity towards ALCAT1.

Identification of Two Non-Peptidergic Small Molecule Inhibitors of CBX2 Binding to K27 Trimethylated Oligonucleosomes.

The dysregulation of the PRC1/2 complex plays a key role in lineage plasticity in prostate cancer and may be required to maintain neuroendocrine phenotype. [1] CBX2, a key component of the canonical PRC1 complex, is an epigenetic reader, recognizing trimethylated lysine on histone 3 (H3K27me3) [2] and is overexpressed in metastatic neuroendocrine prostate cancer. [3,4] We implemented a screening strategy using nucleosome substrates to identify inhibitors of CBX2 binding to chromatin. Construct design and phosphorylation state of CBX2 were critical for successful implementation and execution of an HTS library screen. A rigorous screening funnel including counter and selectivity assays allowed us to quickly focus on true positive hit matter. Two distinct non-peptide-like chemotypes were identified and confirmed in orthogonal biochemical and biophysical assays demonstrating disruption of CBX2 binding to nucleosomes and direct binding to purified CBX2, respectively.

Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells.

Cancer stem cells (CSCs) are an important cause of tumor recurrence and drug resistance. As a new type of cell death that relies on iron ions and is strictly regulated by intracellular and extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Mass spectrum was applied to screen for ferroptosis-related proteins in gastric cancer (GC). Sphere-formation assay was used to estimate the stemness of gastric cancer stem cells (GCSCs). Exosomal lnc-ENDOG-1:1 (lncFERO) was isolated by ultracentrifugation. Ferroptosis was induced by erastin and was assessed by detecting lipid ROS, mitochondrial membrane potential, and cell death. Furthermore, a series of functional in vitro and in vivo experiments were conducted to evaluate the effects of lncFERO on regulating ferroptosis and chemosensitivity in GCSCs. Here, we showed that stearoyl-CoA-desaturase (SCD1) played a key role in regulating lipid metabolism and ferroptosis in GCSCs. Importantly, exosomal lncFERO (exo-lncFERO) derived from GC cells was demonstrated to promote SCD1 expression by directly interacting with SCD1 mRNA and recruiting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which resulted in the dysregulation of PUFA levels and the suppression of ferroptosis in GCSCs. Moreover, we found that hnRNPA1 was also involved in lncFERO packing into exosomes in GC cells, and both in vitro and in vivo data suggested that chemotoxicity induced lncFERO secretion from GC cells by upregulating hnRNPA1 expression, leading to enhanced stemness and acquired chemo-resistance. All these data suggest that GC cells derived exo-lncFERO controls GCSC tumorigenic properties through suppressing ferroptosis, and targeting exo-lncFERO/hnRNPA1/SCD1 axis combined with chemotherapy could be a promising CSC-based strategy for the treatment of GC.

Diagnosis of Peripheral Pulmonary Lesions with Transbronchial Lung Cryobiopsy by Guide Sheath and Radial Endobronchial Ultrasonography: A Prospective Control Study.

Objective: We design a prospective control study on the utilization of transbronchial cryobiopsy guided by EBUS-GS (EBUS-GS-TBCB) to diagnose PPLs. Methods: PPLs were defined as pulmonary nodules or masses with a diameter from 10 mm to 50 mm. PPLs were randomly divided into group EBUS-GS-TBCB and transbronchial biopsy by forceps guided under EBUS-GS (EBUS-GS-TBB). Results: 28 cases were involved in group EBUS-GS-TBCB and 31 cases were in group EBUS-GS-TBB. The mean sizes of PPLs were 30.23 ± 11.10 mm in group EBUS-GS-TBCB and 28.69 ± 8.62 mm in group EBUS-GS-TBB (t = 0.600, p=0.551). The diagnostic yields of EBUS-GS-TBCB and EBUS-GS-TBB were 75% and 64.52% respectively, and the difference between the two groups was not significant (χ 2 value = 0.137, p=0.711). If only the first specimen was taken into account, the diagnostic yields from EBUS-GS-TBCB and EBUS-GS-TBB were 64.29% (18/28 cases) and 35.48% (11/31 cases), respectively. The difference was statistically significant by Fisher's Exact Test (χ 2 value = 4.883, p=0.038). The total incidence rates of bleeding were 21.43% and 6.45%, respectively, in groups EBUS-GS-TBCB and EBUS-GS-TBB. The total incidence rates of pneumothorax were 7.14% and 0, respectively, in groups EBUS-GS-TBCB and EBUS-GS-TBB. Conclusion: The diagnostic yield of EBUS-GS-TBCB was slightly higher than that of EBUS-GS-TBB for the diagnosis of PPLs. EBUS-GS-TBCB might be useful if only the first sample was taken into account.

Discovery of an Allosteric, Inactive Conformation-Selective Inhibitor of Full-Length HPK1 Utilizing a Kinase Cascade Assay.

Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Assays using active, phosphorylated protein kinases bias hits toward poorly selective inhibitors that bind within the highly conserved adenosine triphosphate (ATP) pocket. Targeting inactive (vs active) kinase conformations offers advantages in achieving selectivity because of their more diversified structures. Kinase cascade assays are typically initiated with target kinases in their unphosphorylated inactive forms, which are activated during the assays. Therefore, these assays are capable of identifying inhibitors that preferentially bind to the unphosphorylated form of the enzyme in addition to those that bind to the active form. We applied this cascade assay to the emerging cancer immunotherapy target hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase that negatively regulates T cell receptor signaling. Using this approach, we discovered an allosteric, inactive conformation-selective triazolopyrimidinone HPK1 inhibitor, compound 1. Compound 1 binds to unphosphorylated HPK1 >24-fold more potently than active HPK1, is not competitive with ATP, and is highly selective against kinases critical for T cell signaling. Furthermore, compound 1 does not bind to the isolated HPK1 kinase domain alone but requires other domains. Together, these data indicate that 1 is an allosteric HPK1 inhibitor that attenuates kinase autophosphorylation by binding to a pocket consisting of residues within and outside of the kinase domain. Our study demonstrates that cascade assays can lead to the discovery of highly selective kinase inhibitors. The triazolopyrimidinone described in this study may represent a privileged chemical scaffold for further development of potent and selective HPK1 inhibitors.

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.

Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.

Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.

G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.

The significance of multidisciplinary classifications based on transbronchial pathology in possible idiopathic interstitial pneumonias.

Surgical lung biopsy is regarded as the golden standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). Here, we attempted to show the diagnostic accuracy of multidisciplinary classifications based on transbronchial pathology including transbronchial lung cryobiopsy (TBLC) , bronchoalveolar lavage fluid (BALF) and endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA).Patients with suspected interstitial lung diseases admitted from June 1, 2016 to December 31, 2018 were involved. Patients with known causes of interstitial lung diseases and typical idiopathic pulmonary fibrosis diagnosed through clinical, radiological information were excluded. Patients with atypical idiopathic pulmonary fibrosis and possible IIPs accepted transbronchial pathological evaluation. Initial multidisciplinary diagnosis (MDD) classifications were made depending on clinical, radiological and transbronchial pathological information by a multidisciplinary team (MDT). The final MDD classifications were confirmed by subsequent therapeutic effects. All patients were followed up for at least 6 months.A total of 70 patients were finally involved. The samples of lung parenchyma extracted through TBLC were enough for confirmation of pathological diagnoses in 68.6% (48/70) cases. Samples of 6 cases were extracted by EBUS-TBNA. Bacteriological diagnoses were positive in 1 case by BALF. Pathological diagnoses of 77.1% (54/70) cases were achieved through TBLC, EBUS-TBNA and BALF. During the follow up study, the pulmonary lesions of 60% patients were improved, 11.43% were relapsed when glucocorticoid was reduced to small dose or withdrawal, 14.29% were leveled off and 8.57% were progressed. The diagnoses of 4 patients with progressed clinical feature were revised. As a result, 94.3% initial MDD classifications based on transbronchial pathology were consistent with the final MDD, and the difference of diagnostic yield wasn't significant between initial and final MDD (Z = -1.414, P = .157).Classifications of IIPs based on transbronchial pathology were useful and quite agreed with final MDD.

Clinical features of syphilitic myelitis with longitudinally extensive myelopathy on spinal magnetic resonance imaging.

BACKGROUND: Syphilitic myelitis caused by Treponema pallidum is an extremely rare disease. However, symptomatic neurosyphilis, especially syphilitic myelitis, and its clinical features have been infrequently reported. Only a few cases of syphilitic myelitis have been documented. To the best of our knowledge, there are only 19 reported cases of syphilitic myelitis. However, the clinical features of syphilitic myelitis with longitudinally extensive myelopathy have been still not clear. AIM: To explore the clinical features of syphilitic myelitis with longitudinally extensive myelopathy on spinal magnetic resonance imaging (MRI). METHODS: First, we report a patient who suffered from syphilitic myelitis with symptoms of sensory disturbance, with longitudinally extensive myelopathy with "flip-flop sign" on spinal MRI. Second, we performed a literature search to identify other reports (reviews, case reports, or case series) from January 1987 to December 2018, using the PubMed and Web of Science databases with the terms including "syphilis", "neurosyphilis", "syphilitic myelitis", "meningomyelitis", "central nervous system", and "spine". We also summarized the clinical features of syphilitic myelitis with longitudinally extensive myelopathy. RESULTS: A total of 16 articles of 20 cases were identified. Sixteen patients presented with the onset of sensory disturbance (80%), 15 with paraparesis (75%), and 9 with urinary retention (45%). Eleven patients had a high risk behavior (55%). Five patients had concomitant human immunodeficiency virus infection (25%). Serological data showed that 15 patients had positive venereal disease research laboratory test (VDRL)/treponema pallidum particle agglutination (TPHA), and 17 had positive VDRL/TPHA in cerebrospinal fluid (CSF). Seventeen patients were found to have elevated leukocytosis and protein in CSF. On MRI, 16 patients showed abnormal hyperintensities involved the thoracic spine, 6 involved the cervical spine, and 3 involved both the cervical and thoracic spine. There were 3 patients with the "flip-flop sign". All the patients were treated with penicillin, and 15 patients had a good prognosis. CONCLUSION: Our case further raises awareness of syphilitic myelitis as an important complication of neurosyphilis due to homosexuality, especially in developing countries such as China.

FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways.

High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF. Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, α-smooth muscle actin (α-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated α-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling.

Pd Nanoparticles Confined in the Porous Graphene-like Carbon Nanosheets for Olefin Hydrogenation.

As a novel type of defective graphene, porous graphene has been considered an excellent support material for metal clusters, as the interaction between defective carbon atoms surrounded with the metal nanoparticles (NPs) is very different from that on the ordinary supported catalyst. In this work, we reported a facile three-step method to confine the Pd NPs and grow the graphene-like carbon nanosheets (GLCs) in the same interlayer space of the layered silicate, generating embedded Pd NPs in the pores of porous GLCs in situ. The Pd@GLC nanocomposite exhibited not only high activity and stability than the common commercial Pd/C catalyst for the hydrogenation of olefins but also superior ability of resisting high temperature, which benefitted from the two-dimensional structure of layered GLCs, the confinement of Pd, and the increased edge and defect of the unsaturated carbon atoms in GLCs.