Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Preparation and evaluation of the PD0721­DOX antibody­drug conjugate targeting EGFRvIII to inhibit glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is prominently expressed in various epithelial tumors. PD0721, a single-chain antibody (scFv), has been developed to specifically target EGFRvIII. Although doxorubicin (DOX) is an essential treatment approach for glioblastoma (GBM), its toxic effects and limited targeting capabilities are a challenge. To overcome the above limitations, antibody-drug conjugates (ADCs) have been developed to exploit the specificity of monoclonal antibodies in directing potent cytotoxic drugs to tumor cells expressing the target antigens. The present study aimed to conjugate DOX with PD0721 scFv to construct a PD0721-DOX ADC targeting EGFRvIII and examine its targeting effect and in vitro anti-GBM activity. PD0721-DOX ADC was generated by combining PD0721 scFv with DOX, using dextran T-10 as a linker. The drug-to-antibody ratio (DAR) was measured by ultraviolet and visible spectrophotometry (UV-Vis). A series of techniques, including cytotoxicity assays, immunofluorescence, cell internalization and flow cytometry assays were employed to evaluate the targeting efficacy and anti-GBM activity of the PD0721-DOX ADC. Following the conjugation of PD0721 scFv with DOX, the UV-Vis results showed a noticeable red shift in the maximum absorbance. The DAR of PD0721 scFv and DOX was 9.23:1. Cytotoxicity assays demonstrated that DK-MG cells treatment with PD0721-DOX ADC at 10 and 20 µg/ml significantly increased cytotoxicity compared with U-87MG ATCC cells (all P<0.01). Confocal microscopy revealed distinct green and red fluorescence in EGFRvIII-expressing DK-MG cells, while no fluorescence was observed in EGFRvIII negative U-87MG ATCC cells. Furthermore, compared with U-87MG ATCC cells, DK-MG cells showed effective internalization of the PD0721-DOX ADC (P<0.001). Finally, flow cytometric analyses indicated that the PD0721-DOX ADC significantly promoted the apoptosis of DK-MG cells compared with U-87MG ATCC cells (P<0.01). In summary, the current study suggested that the PD0721-DOX ADC could exhibit a notable targeting efficacy and potent anti-GBM activity.

The active components and potential mechanisms of Wuji Wan in the treatment of ethanol-induced gastric ulcer: An integrated metabolomics, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. AIM OF THE STUDY: The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. MATERIALS AND METHODS: Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. RESULTS: WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. CONCLUSIONS: WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

Periploca forrestii Schltr. ameliorate liver injury caused by fluorosis in rat.

To investigate the impact of the ethanoic fractions of Periploca forrestii Schltr. (P. forrestii) in ameliorating the liver injury caused by fluoride ingestion and to explore the potential mechanisms. Initially, an in vitro fluorosis cell model was constructed using the human normal liver cell line (L-02) induced by fluoride. Cell viability was assessed using the CCK-8 assay kit. The lactate dehydrogenase (LDH) assay kit was utilized to measure LDH content in the cell supernatant, while the malonic dialdehyde (MDA) assay kit was employed to determine MDA levels within the cells. Subsequently, a fluorosis rat model was established, and LDH content in the cell supernatant was measured using the LDH assay kit. Various parameters, including MDA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) content within the cells, were detected using appropriate assay kits. Additionally, cell apoptosis rate was determined using the Annexin V-FITC/PI cell apoptosis assay kit. The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Cleaved Caspase-3, Caspase-9, and Cleaved Caspase-9 were analyzed through Western blotting. Compared to the model group, the ethanolic fraction D of P.forrestii (Fr.D) increased cell viability (P < 0.01) and decreased LDH and MDA levels (P < 0.01). In the high-dose Fr.D treatment group of fluoride-poisoned rats, serum ALT, AST, LDH and MDA levels significantly decreased (P < 0.01). Results from rat primary cells exhibited that the Fr.D administration group exhibited significantly higher cell survival rates than the fluoride group (P < 0.01). Similarly, primary rat cells treated with Fr.D showed enhanced cell viability (P < 0.05) and reduced apoptosis rate, LDH, MDA, SOD, GSH-Px, CAT, and ROS levels (P < 0.05) compared to the model group. Western blot analysis indicated that the Fr.D treatment group elevated the Bcl-2/Bax protein expression ratio and reduced Caspase-3 and Caspase-9 activation levels (P < 0.01) compared to the model group. The results suggest that components within the Fr.D from Periploca forrestii may alleviate fluoride-induced liver injury by potentially counteracting oxidative stress and cell apoptosis.

Synthesis, Structure, and Properties of a Nitrogen-Boron-Nitrogen-Embedded Polycyclic π-System Containing a Pleiaheptalene Framework.

A novel polycyclic π-system (1) featuring both a pleiaheptalene framework (a three-fused heptagon system) and nitrogen-boron-nitrogen (NBN) unit was constructed by electrophilic borylation. A combined experimental and computational study demonstrated that 1 has a highly twisted π-backbone with approximate C2 symmetry, which can undergo conformational isomerization at room temperature in contrast to pleiaheptalene. It was also found that 1 can bind the fluoride ion in the solution, which induces changes in the absorption and emission spectra.

Enteric glial cells aggravate the intestinal epithelial barrier damage by secreting S100ß under high-altitude conditions.

Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100ß under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100ß secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100ß resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100ß secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.

Analysis and Suppression Design of Stray Light Pollution in a Spectral Imager Loaded on a Polar-Orbiting Satellite.

As the non-imaging light of optical instruments, stray light has an important impact on normal imaging and data quantification applications. The FY-3D Medium Resolution Spectral Imager (MERSI) operates in a sun-synchronous orbit, with a scanning field of view of 110° and a surface imaging width of more than 2300 km, which can complete two coverage observations of global targets per day with high detection efficiency. According to the characteristics of the operating orbit and large-angle scanning imaging of MERSI, a stray light radiation model of the polar-orbiting spectrometer is constructed, and the design requirements of stray light suppression are proposed. Using the point source transmittance (PST) as the merit function of the stray light analysis method, the instrument was simulated with all stray light suppression optical paths, and the effectiveness of stray light elimination measures was verified using the stray light test. In this paper, the full-link method of "orbital stray light radiation model-system, internal and external simulation design-system analysis and actual test comparison verification" is proposed, and there is a maximum decrease in the system's PST by about 10 times after applying the stray light suppression's optimization design, which can provide a general method for stray light suppression designs for polar-orbit spectral imagers.

Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway.

INTRODUCTION: Prophylactic antifungal therapy has been widely used for critical patients, but it has failed to improve patient prognosis and has become a hot topic. This may be related to disruption of fungal homeostasis, but the mechanism of fungi action is not clear. As a common pathway in critical patients, intestinal ischemia-reperfusion (IIR) injury is fatal and regulated by gut microbiota. However, the exact role of enteric fungi in IIR injury remains unclear. OBJECTIVES: This is a clinical study that aims to provide new perspectives in clarifying the underlying mechanism of IIR injury and propose potential strategies that could be relevant for the prevention and treatment of IIR injury in the near future. METHODS: ITS sequencing was performed to detect the changes in fungi before and after IIR injury. The composition of enteric fungi was altered by pretreatment with single-fungal strains, fluconazole and mannan, respectively. Intestinal morphology and function impairment were evaluated in the IIR injury mouse model. Intestinal epithelial MODE-K cells and macrophage RAW264.7 cells were cultured for in vitro tests. RESULTS: Fecal fungi diversity revealed the obvious alteration in IIR patients and mice, accompanied by intestinal epithelial barrier dysfunction. Fungal colonization and mannan supplementation could reverse intestinal morphology and function impairment that were exacerbated by fluconazole via inhibiting the expression of SAA1 from macrophages and decreasing pyroptosis of intestinal epithelial cells. Clodronate liposomes were used to deplete the number of macrophages, and it was demonstrated that the protective effect of mannan was dependent on macrophage involvement. CONCLUSION: This finding firstly validates that enteric fungi play a crucial role in IIR injury. Preventive antifungal treatment should consider damaging fungal balance. This study provides a novel clue to clarify the role of enteric fungi in maintaining intestinal homeostasis.

Mechanistic study of cytochrome P450 enzyme-mediated cytotoxicity of psoralen and isopsoralen.

Psoralen and isopsoralen are the major components responsible for Psoraleae Fructus-induced hepatotoxicity. This study explored the role of metabolic activation by cytochrome P450 (CYP) enzymes in psoralen- and isopsoralen-induced cytotoxicity and its potential mechanisms. Inhibitors of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 were used to screen specific CYP enzymes responsible for the metabolic activation of psoralen and isopsoralen in mouse primary hepatocytes, which was verified using the corresponding transfected cell lines. Network toxicology and transcriptome analyses were performed to explore the mechanisms underlying toxicity. Psoralen and isopsoralen decreased the viability of mouse primary hepatocytes, whereas the inhibition of CYP2C9, 2C19, 2D6, and 2E1 significantly increased their viability. Psoralen-induced cytotoxicity was significantly enhanced by the overexpression of CYP2C19 in Chinese hamster ovary cells, whereas the overexpression of the above CYP enzymes did not affect the cytotoxicity of isopsoralen. Psoralen- and isopsoralen-induced cytotoxic effects were associated with putative core targets (i.e., Fn1, Thbs1, and Tlr2) and multiple signaling pathways (e.g., PI3K-Akt, MAPK, and TNF pathways). Our results demonstrate that the metabolic activation of psoralen and isopsoralen is mediated by CYP enzymes, thereby regulating multiple core targets and signaling pathways and resulting in cytotoxicity.

Assessment of the Risk and Symptoms of SARS-CoV-2 Infection Among Healthcare Workers During the Omicron Transmission Period: A Multicentric Study from Four Hospitals of Mainland China.

Purpose: The SARS-CoV-2 omicron variant emerged and spread rapidly among the population in the early stage of China's normalized prevention and control in December 2022. Healthcare workers (HCWs) are particularly exposed to SARS-CoV-2, it is important to evaluate the impact of the omicron pandemic on HCWs in China. Methods: A self-administered online survey was conducted on infected HCWs from four hospitals of Taizhou. A total of 748 HCWs received the survey via DingTalk, and 328 responded to the questionnaire. The risk factors were investigated using univariate and multivariate logistic regression analysis. Results: By December 20, 2022, 748 HCWs tested positive by PCR, and the infection rate was 11.4% (748/6581). Among 328 respondents, the most common symptoms were cough (88.4%), fever (83.5%), runny nose (77.1%), sore throat (73.2%), headache (70.1%), muscle aches (67.1%), and fatigue (53.4%). 69.8% (229/328) of the participants had five or more major onset symptoms, while no severe case was observed. The multivariate analysis indicated that the poor sleep quality (OR = 2.29, 95% CI: 1.31-4.02, P = 0.004) was an independent risk factor for more major onset symptoms, while wore gloves ≥95% times in working (OR = 0.49, 95% CI: 0.28-0.85, P = 0.011) was significantly related to fewer symptoms. In addition, 239 (72.9%) recipients reported high fever (temperature ≥38.5°C), less common cold (≤3 vs >3 times/year, OR = 2.20, 95% CI: 1.05-4.65, P = 0.038) was significantly associated with high fever. Conclusion: Our findings imply rapid transmissibility of omicron and multiple-onset symptoms among HCWs. Improved autoimmunity and self-protection measures for HCWs may be helpful in controlling infection and clinical symptoms. Our results provide empirical reference values for improved countermeasures and protective measures for major public health emergencies.

A mesoporous polydopamine-derived nanomedicine for targeted and synergistic treatment of inflammatory bowel disease by pH-Responsive drug release and ROS scavenging.

Repurposing clinically approved drugs to construct novel nanomedicines is currently a very attractive therapeutic approach. Selective enrichment of anti-inflammatory drugs and reactive oxygen species (ROS) scavenging at the region of inflammation by stimuli-responsive oral nanomedicine is an effective strategy for the treatment of inflammatory bowel disease (IBD). This study reports a novel nanomedicine, which is based on the excellent drug loading and free radical scavenging ability of mesoporous polydopamine nanoparticles (MPDA NPs). By initiating polyacrylic acid（PAA）polymerization on its surface, a "core-shell" structure nano-carrier with pH response is constructed. Then, under alkaline conditions, using the π-π stacking and hydrophobic interaction between the anti-inflammatory drug sulfasalazine (SAP) and MPDA, the nanomedicines (PAA@MPDA-SAP NPs) loaded efficiently (928 µ g mg-1) of SAP was successfully formed. Our results reveal that PAA@MPDA-SAP NPs can pass through the upper digestive tract smoothly and finally accumulate in the inflamed colon. Through the synergistic effect of anti-inflammation and antioxidation, it can effectively reduce the expression of pro-inflammatory factors and enhance the intestinal mucosal barrier, and finally significantly alleviate the symptoms of colitis in mice. Furthermore, we confirmed that PAA@MPDA-SAP NPs have good biocompatibility and anti-inflammatory repair ability under inflammation induction through human colonic organoids. In summary, this work provides a theoretical basis for the development of nanomedicines for IBD therapy.

Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.

Fully biobased sustainable elastomers derived from chitin, lignin, and plant oil via grafting strategy and Schiff-base chemistry.

With the dramatically increased environmental problems, the rational design of sustainable polymers from renewable feedstocks opens new avenues to reduce the huge pollution impact. The major challenge for sustainable polymers is the decreased mechanical performance compared to that of petroleum-based materials. In this work, fully biobased sustainable elastomers were developed by integrating renewable chitin, lignin, and plant oil into one macromolecule, in which chitin was chosen as the rigid backbone, while a lignin-derived monomer vanillin acrylate (VA) and a plant oil-based monomer lauryl acrylate (LA) were selected as the hard and soft segments for the grafted side chains. A series of Chitin-graft-poly(vanillin acrylate-co-lauryl acrylate) (Chitin-g-P(VA-co-LA)) copolymers with varied feed ratios and chitin contents were synthesized by using reversible addition-fragmentation chain transfer (RAFT) polymerization as an effective grafting strategy. In addition, a dynamic cross-linked network was incorporated via Schiff-base reaction to improve the macroscopic behavior of such kind of chitin graft elastomers. These sustainable elastomers are mechanically strong and show excellent reprocessablity, as well as outstanding UV-blocking property. This strategy is versatile and can inspire the further development of fully biobased sustainable materials from natural resources.

[Effects of Gukang Capsules on activity and protein expression of hepatic cytochrome P450 enzymes in rats].

Gukang Capsules are often used in combination with drugs to treat fractures, osteoarthritis, and osteoporosis. Cytochrome P450(CYP450) mainly exists in the liver and participates in the oxidative metabolism of a variety of endogenous and exogenous substances and serves as an important cause of drug-metabolic interactions and adverse reactions. Therefore, it is of great significance to study the effect of Gukang Capsules on the activity and expression of CYP450 for increasing its clinical rational medication and improving the safety of drug combination. In this study, the Cocktail probe method was used to detect the changes in the activities of CYP1A2, CYP3A2, CYP2C11, CYP2C19, CYP2D4, and CYP2E1 in rat liver after treatment with high-, medium-and low-dose Gukang Capsules. The rat liver microsomes were extracted by the calcium chloride method, and protein expression of the above six CYP isoform enzymes was detected by Western blot. The results showed that the low-dose Gukang Capsules could induce CYP3A2 and CYP2D4 in rats, medium-dose Gukang Capsules had no effect on them, and high-dose Gukang Capsules could inhibit them in rats. The high-dose Gukang Capsules did not affect CYP2C11 in rats, but low-and medium-dose Gukang Capsules could induce CYP2C11 in rats. Gukang Capsules could inhibit CYP2C19 in rats and induce CYP1A2 in a dose-independent manner, but did not affect CYP2E1. If Gukang Capsules were co-administered with CYP1A2, CYP2C19, CYP3A2, CYP2C11, and CYP2D4 substrates, the dose should be adjusted to avoid drug interactions.

Ataxia with oculomotor apraxia type 2 caused by a novel homozygous mutation in SETX gene, and literature review.

Objectives: Autosomal recessive inherited ataxia with oculomotor apraxia type 2 (AOA2), caused by SETX gene mutations, is characterized by early-onset, progressive cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and elevated serum α-fetoprotein (AFP). This study aimed to expand and summarize the clinical and genetic characteristics of SETX variants related to AOA2. Methods: The biochemical parameters, electromyogram and radiological findings of the patient were evaluated. Whole-exome sequencing (WES) was performed on the patient using next-generation sequencing (NGS), the variants were confirmed by Sanger sequencing and the pathogenicity of the variants was classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We reviewed 57 studies of AOA2 patients with SETX mutations and collected clinical and genetic information. Results: The patient was a 40-year-old Chinese woman who primarily presented with numbness and weakness of the lower limbs in her teenage years. She had elevated AFP, increased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and decreased anti-Müllerian hormone (AMH) levels. We identified a novel homozygous missense mutation of the SETX gene, c.7118 C>T (p. Thr2373Ile), in the patient via Whole-exome and Sanger sequencing. The variant was located in the DNA/RNA helicase domain and is highly conserved. The protein prediction analysis verified the SETX variant as a damaging alteration and ACMG/AMP guidelines classified it as likely pathogenic. Through a literature review, we identified 229 AOA2 cases with SETX variants, and among the variants, 156 SETX variants were exonic. We found that 107 (46.7%) patients were European, 50 (21.8%) were African and 48 (21.0%) were Asian. Among the Asian patients, five from two families were Mainland Chinese. The main clinical features were cerebellar ataxia (100%), peripheral neuropathy (94.6%), cerebellar atrophy (95.3%) and elevated AFP concentration (92.0%). Most reported SETX mutations in AOA2 patients were missense, frameshift and nonsense mutations. Conclusion: We discovered a novel homozygous variant of the SETX gene as a cause of AOA2 in the current patient and expanded the genotypic spectrum of AOA2. Moreover, the clinical features of AOA2 and genetic findings in SETX were assessed in reported cohorts and are summarized in the present study.

NFIL3 and its immunoregulatory role in rheumatoid arthritis patients.

Nuclear-factor, interleukin 3 regulated (NFIL3) is an immune regulator that plays an essential role in autoimmune diseases. However, the relationship between rheumatoid arthritis (RA) and NFIL3 remains largely unknown. In this study, we examined NFIL3 expression in RA patients and its potential molecular mechanisms in RA. Increased NFIL3 expression levels were identified in peripheral blood mononuclear cells (PBMCs) from 62 initially diagnosed RA patients and 75 healthy controls (HCs) by quantitative real-time PCR (qRT-PCR). No correlation between NFIL3 and disease activity was observed. In addition, NFIL3 expression was significantly upregulated in RA synovial tissues analyzed in the Gene Expression Omnibus (GEO) dataset (GSE89408). Then, we classified synovial tissues into NFIL3-high (≥75%) and NFIL3-low (≤25%) groups according to NFIL3 expression levels. Four hundred five differentially expressed genes (DEGs) between the NFIL3-high and NFIL3-low groups were screened out using the "limma" R package. Enrichment analysis showed that most of the enriched genes were primarily involved in the TNF signaling pathway via NFκB, IL-17 signaling pathway, and rheumatoid arthritis pathways. Then, 10 genes (IL6, IL1ß, CXCL8, CCL2, PTGS2, MMP3, MMP1, FOS, SPP1, and ADIPOQ) were identified as hub genes, and most of them play a key role in RA. Positive correlations between the hub genes and NFIL3 were revealed by qRT-PCR in RA PBMCs. An NFIL3-related protein-protein interaction (PPI) network was constructed using the STRING database, and four clusters (mainly participating in the inflammatory response, lipid metabolism process, extracellular matrix organization, and circadian rhythm) were constructed with MCODE in Cytoscape. Furthermore, 29 DEGs overlapped with RA-related genes from the RADB database and were mainly enriched in IL-17 signaling pathways. Thus, our study revealed the elevated expression of NFIL3 in both RA peripheral blood and synovial tissues, and the high expression of NFIL3 correlated with the abnormal inflammatory cytokines and inflammatory responses, which potentially contributed to RA progression.

Bridging sheet size controls densification of MXene films for robust electromagnetic interference shielding.

Numerous voids among the incompact layer-structure of MXene films result in their low ambient stability and poor innate conductivity for electromagnetic interference (EMI) shielding. Herein, we report a bridging-sheet-size-controlled densification process of MXene films by applying graphene oxide (GO) as a bridging agent. Specifically, the sheet size of GO is tailored to quantify a negative correlation of sheet size with densification for directing the preparation of most compact MXene-GO films. Benefiting from the shortest electron-transport-distance in the most compact structure, the conductivity of the MXene-GO film achieves 1.7 times (∼1.6 × 105 S/m) that of MXene film. The EMI shielding performance (5.2 × 106 dB/m) reaches the record-value among reported MXene films at 10 µm-scale thickness. Moreover, the compact structure boosts the ambient stability of MXene-GO films where the conductivity and EMI shielding performance remain 88.7% and 90.0% after 15 days, respectively. The findings rationale the structure-activity relationship of compact MXene films for flexible electronics.

Preoperative prealbumin-to-fibrinogen ratio to predict survival outcomes in hepatocellular carcinoma patients after hepatic resection.

Background: This study aimed to evaluate the clinical application of the preoperative prealbumin-to-fibrinogen ratio (PFR) in the clinical diagnosis of hepatocellular carcinoma (HCC) patients and its prognostic value. Methods: The clinical and laboratory data of 269 HCC patients undergoing surgical treatment from January 2012 to January 2017 in Taizhou Hospital were retrospectively analysed. The Cox regression model was used to analyse the correlation between the PFR and other clinicopathological factors in overall survival (OS) and disease-free survival (DFS). Results: Cox regression analysis showed that the PFR (hazard ratio (HR)=2.123; 95% confidence interval (95% CI), 1.271-3.547; P=0.004) was an independent risk factor affecting the OS of HCC patients. Furthermore, a nomogram was built based on these risk factors. The C-index for the OS nomogram was 0.715. Conclusions: Nomograms based on the PFR can be recommended as the correct and actual model to evaluate the prognosis of patients with HCC.

Development and validation of a hypoxia-stemness-based prognostic signature in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is one of the most aggressive and fatal gastrointestinal malignancies with high morbidity and mortality worldwide. Accumulating evidence has revealed the clinical significance of the interaction between the hypoxic microenvironment and cancer stemness in pancreatic cancer progression and therapies. This study aims to identify a hypoxia-stemness index-related gene signature for risk stratification and prognosis prediction in PAAD. Methods: The mRNA expression-based stemness index (mRNAsi) data of PAAD samples from The Cancer Genome Atlas (TCGA) database were calculated based on the one-class logistic regression (OCLR) machine learning algorithm. Univariate Cox regression and LASSO regression analyses were then performed to establish a hypoxia-mRNAsi-related gene signature, and its prognostic performance was verified in both the TCGA-PAAD and GSE62452 corhorts by Kaplan-Meier and receiver operating characteristic (ROC) analyses. Additionally, we further validated the expression levels of signature genes using the TCGA, GTEx and HPA databases as well as qPCR experiments. Moreover, we constructed a prognostic nomogram incorporating the eight-gene signature and traditional clinical factors and analyzed the correlations of the risk score with immune infiltrates and immune checkpoint genes. Results: The mRNAsi values of PAAD samples were significantly higher than those of normal samples (p < 0.001), and PAAD patients with high mRNAsi values exhibited worse overall survival (OS). A novel prognostic risk model was successfully constructed based on the eight-gene signature comprising JMJD6, NDST1, ENO3, LDHA, TES, ANKZF1, CITED, and SIAH2, which could accurately predict the 1-, 3-, and 5-year OS of PAAD patients in both the training and external validation datasets. Additionally, the eight-gene signature could distinguish PAAD samples from normal samples and stratify PAAD patients into low- and high-risk groups with distinct OS. The risk score was closely correlated with immune cell infiltration patterns and immune checkpoint molecules. Moreover, calibration analysis showed the excellent predictive ability of the nomogram incorporating the eight-gene signature and traditional clinical factors. Conclusion: We developed a hypoxia-stemness-related prognostic signature that reliably predicts the OS of PAAD. Our findings may aid in the risk stratification and individual treatment of PAAD patients.