Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis.

Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.

Directed osteogenic differentiation of human bone marrow mesenchymal stem cells via sustained release of BMP4 from PBVHx-based nanoparticles.

Bone Morphogenetic Protein 4 (BMP4) is crucial for bone and cartilage tissue regeneration, essential in medical tissue engineering, cosmetology, and aerospace. However, its cost and degradation susceptibility pose significant clinical challenges. To enhance its osteogenic activity while reducing dosage and administration frequency, we developed a novel long-acting BMP4 delivery system using poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PBVHx) nanoparticles with soybean lecithin-modified BMP4 (sBP-NPs). These nanoparticles promote directed osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) through sustained BMP4 release. sBP-NPs exhibited uniform size (100-200 nm) and surface charges, with higher BMP4 entrapment efficiency (82.63 %) compared to controls. After an initial burst release within 24 h, sBP-NPs achieved 80 % cumulative BMP4 release within 20 days, maintaining levels better than control BP-NPs with unmodified BMP4. Co-incubation and nanoparticle uptake experiments confirmed excellent biocompatibility of sBP-NPs, promoting hBMSC differentiation towards osteogenic lineage with increased expression of type I collagen, calcium deposition, and ALP activity (> 20,000 U/g protein) compared to controls. Moreover, hBMSCs treated with sBP-NPs exhibited heightened expression of osteogenic genetic markers, surpassing control groups. Hence, this innovative strategy of sustained BMP4 release from sBP-NPs holds potential to revolutionize bone regeneration in minimally invasive surgery, medical cosmetology or space environments.

Myocarditis: A multi-omics approach.

Myocarditis, an inflammatory condition of weakened heart muscles often triggered by a variety of causes, that can result in heart failure and sudden death. Novel ways to enhance our understanding of myocarditis pathogenesis is available through newer modalities (omics). In this review, we examine the roles of various biomolecules and associated functional pathways across genomics, transcriptomics, proteomics, and metabolomics in the pathogenesis of myocarditis. Our analysis further explores the reproducibility and variability intrinsic to omics studies, underscoring the necessity and significance of employing a multi-omics approach to gain profound insights into myocarditis pathogenesis. This integrated strategy not only enhances our understanding of the disease, but also confirms the critical importance of a holistic multi-omics approach in disease analysis.

Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of FDA-approved KRASG12C inhibitors in patients with KRASG12C-mutated solid tumors. METHODS: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest. RESULTS: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRASG12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77). CONCLUSIONS: This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.

Myocardial infarction complexity: A multi-omics approach.

Myocardial infarction (MI), a prevalent cardiovascular disease, is fundamentally precipitated by thrombus formation in the coronary arteries, which subsequently decreases myocardial perfusion and leads to cellular necrosis. The intricacy of MI pathogenesis necessitates extensive research to elucidate the disease's root cause, thereby addressing the limitations present in its diagnosis and prognosis. With the continuous advancement of genomics technology, genomics, proteomics, metabolomics and transcriptomics are widely used in the study of MI, which provides an excellent way to identify new biomarkers that elucidate the complex mechanisms of MI. This paper provides a detailed review of various genomics studies of MI, including genomics, proteomics, transcriptomics, metabolomics and multi-omics studies. The metabolites and proteins involved in the pathogenesis of MI are investigated through integrated protein-protein interactions and multi-omics analysis by STRING and Metascape platforms. In conclusion, the future of omics research in myocardial infarction offers significant promise.

Endovascular Treatment of Superior Mesenteric Artery Pseudoaneurysm Due to Infective Endocarditis With Stent-Graft.

PURPOSE: To report a successful case of pseudoaneurysm of the superior mesenteric artery (SMA) caused by infected endocarditis treated with a covered stent. CASE REPORT: A patient was diagnosed with infective endocarditis and 2 months later a proximal SMA pseudoaneurysm was identified on computed tomography. Daptomycin was started on admission and continued for approximately 4 months until the inflammatory markers normalized, and then the SMA pseudoaneurysm was successfully excluded with a stent-graft and antibiotics were continued for 1 year after the procedure. There were no associated complications or recurrences at the 3-year follow-up. CONCLUSION: Placing a covered stent with a full course of antibiotics before and after surgery may be a successful alternative to open surgery in the treatment of pseudoaneurysms of the SMA due to infective endocarditis. CLINICAL IMPACT: This case report reports a rare case of pseudoaneurysm of the superior mesenteric artery due to infective endocarditis, which was successfully treated with an overlapping stent and confirmed by complete imaging data at a three-year follow-up. This report suggests that endovascular treatment may be an alternative to open surgery in the treatment of pseudoaneurysms of the superior mesenteric artery caused by infective endocarditis.

Growth of wafer-scale chromium sulphide and selenide semiconductor films.

Two-dimensional (2D) transition metal chalcogenides have attracted enormous attention due to their stunning properties and great prospects for applications. Most of the reported 2D materials have layered structure, and non-layered transition metal chalcogenides are rare. Particularly, chromium chalcogenides are highly complexed in terms of structural phases. Researches on their representative chalcogenides, Cr2S3and Cr2Se3, are insufficient and most of them focus on individual crystal grains. In this study, large-scale Cr2S3and Cr2Se3films with controllable thickness are successfully grown, and their crystalline qualities are confirmed by multiple characterizations. Moreover, the thickness-dependent Raman vibrations are investigated systematically, presenting slight redshift with increasing thickness. The fundamental physical properties of grown Cr2S3and Cr2Se3films, including optical bandgap, activation energy and electrical properties, are measured with different thicknesses. The 1.9 nm thick Cr2S3and Cr2Se3films show narrow optical bandgap of 0.732 and 0.672 eV, respectively. The electrical properties of Cr2S3films demonstratep-type semiconductor behaviours, while the Cr2Se3films exhibit no gate response. This work can provide a feasible method for growing large-scale Cr2S3and Cr2Se3films, and reveal fundamental information of their physical properties, which is helpful for future applications.

Biomimetic CuS nanoparticles for radiosensitization with mild photothermal therapy and GSH-depletion.

Due to its non-invasive and highly effective characteristics, radiotherapy has attracted significant interest in cancer treatment. However, radioresistance of solid tumors caused by a unique tumor microenvironment diminishes the therapeutic effect of cancer radiotherapy. To address this issue, we developed a nanoplatform for tumor-specific targeting to improve radiotherapy. Specifically, hollow CuS nanoparticles were decorated with the platelet cell membrane (PC), endowing this nanoplatform with the therapeutic property of navigating to the tumor region for glutathione (GSH)-depletion photothermal therapy. It was discovered that mild photothermal therapy mediated by PC ameliorated hypoxia in the tumor microenvironment. Meanwhile, GSH, which contributes to repairing radiotherapy-induced DNA double-strand breaks, was depleted by PC in an acidic microenvironment. Therefore, radioresistance could be diminished while cancer cell self-repair was prevented. At therapeutic doses, PC nanoparticles have negligible toxic effects on normal tissues. PC demonstrates promise for both in vivo and in vitro radiosensitization due to its GSH-depletion, photothermal efficiency, and tumor-specific properties.

A data set of distributed global population and water withdrawal from 1960 to 2020.

Population and water withdrawal data sets are currently faced with difficulties in collecting, processing and verifying multi-source time series, and the spatial distribution characteristics of long series are also relatively lacking. Time series is the basic guarantee for the accuracy of data sets, and the production of long series spatial distribution is a realistic requirement to expand the application scope of data sets. Through the time-consuming and laborious basic processing work, this research focuses on the population and water intake time series, and interpolates and extends them to specific land uses to ensure the accuracy of the time series and the demand of spatially distributed data sets. This research provides a set of population density and water intensity products from 1960 to 2020 distributed to the administrative units or the corresponding regions. The data set fills the gaps in the multi-year data set for the accuracy of population density and the intensity of water withdrawal.

A rapid and label-free platform for virus enrichment based on electrostatic microfluidics.

Virus surveillance and discovery are crucial for virus prediction and outbreak preparedness. Virus samples are frequently bulky and complicated so that effective virus detection remain challenging. Herein, we develop an 3D electrostatic microfluidic platform to rapidly and label-free enrich viruses from bulky samples at low concentrations. The platform consists of double microchannels for streamlining large volume processing and electrodes for enriching viruses by electrostatic interaction. The trajectories of simulation show that particle is successfully enriched under different forces of electrostatic field and different sample flow rates. We demonstrate that the electrostatic microfluidic platform can increase the limit of detection in 100-fold higher based on real-time PCR quantified analysis. Our design thus provides a simple, rapid, label-free and high-throughput viruses concentration platform and would thus have significant utility for various viral detection.

An integrated microfluidic chip for alginate microsphere generation and 3D cell culture.

Three-dimensional (3D) hydrogel microspheres have attracted increasing attention as cell culture carriers. The system of hydrogel microspheres provides great advantages for cell growth owing to its high surface-to-volume ratio and biocompatible environment. However, an integrated system that includes microsphere generation, microsphere capture and in situ culture together has not been realized yet. Here we present a multifunctional microfluidic device to accomplish the overall process including cell-laden microsphere generation, online demulsification and dynamic-culture. The microfluidic device can produce massive monodispersed alginate microspheres and allows us to immobilize the alginate microspheres and record bacterial growth. Moreover, the microspheres provide a suitable environment through the mechanical properties of soft tissues, leading to high cell viability, proliferation, activity and biocompatibility. We believe that this versatile and biocompatible platform will provide a more reliable analysis tool for tissue engineering and cell therapy.

Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis.

BACKGROUND: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies. METHODS: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I2 statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617). FINDINGS: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I2=75%) for all-grade adverse events and 68·3% (60·7-75·0; I2=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I2=86%) for all-grade adverse events and 47·3% (37·3-57·5; I2=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I2=94%) for all-grade adverse events and 35·9% (29·5-42·9; I2=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I2=74%) for all-grade adverse events and 12·4% (4·4-30·6; I2=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias. INTERPRETATION: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care. FUNDING: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.

Survival and prognostic factors of lung cancer patients with preexisting connective tissue disease: a retrospective cohort study.

BACKGROUND: Connective tissue diseases (CTDs) are a group of special commodities in lung cancer (LC). This study aimed to analyze the survival and prognostic factors of LC patients with preexisting CTDs. METHODS: A total of 84 LC patients with preexisting CTDs that presented at Peking Union Medical College Hospital (PUMCH) were retrospectively recruited in this study between January 2000 and June 2017. Patient survival was compared using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were used to assess prognostic variables. RESULTS: Of the 84 LC patients, 36 (41.8%) had underlying rheumatoid arthritis (RA), 20 (23.8%) had idiopathic inflammatory myopathy (IIM), 18 (21.4%) had Sjögren syndrome (SS), 6 (7.1%) had systemic sclerosis (SSc), and 4 (4.8%) had systemic lupus erythematosus (SLE). The median overall survival (OS) was 21 months (IQR, 8-72 months), and the 1-, 3-, and 5-year survival rates were 61.3%, 36.7%, and 29.5%, respectively. The survival rates between different CTD subgroups, histopathologies, and disease stages were significantly different (P<0.05). Multivariate analysis showed that the independent prognostic factors for OS were IIM [hazard ratio (HR), 3.61; 95% confidence intervals (CI), 1.69-8.21; P=0.002], SS (HR, 2.72; 95% CI, 1.01-7.33; P=0.048), and radical resection (HR, 0.11; 95% CI, 0.04-0.35; P<0.001). CONCLUSIONS: Different CTD subtypes and the radical resection of LC are closely related to patient prognosis. This indicates a need for both identifications of CTD types and active treatment strategies for LC.

Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma.

BACKGROUND: RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial. METHODS: We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognostic role of RASSF1A promoter hypermethylation in HCC. RESULTS: Forty-four articles involving 4777 individuals were enrolled in the pooled analyses. The RASSF1A promoter methylation rate was notably higher in the HCC cases than the non-tumor cases and healthy individuals, and was significantly related to hepatitis B virus (HBV) infection-positivity and large tumor size. Kaplan-Meier survival analysis revealed that HCC cases with RASSF1A promoter hypermethylation had worse outcomes. Receiver operating characteristic curves confirmed that RASSF1A promoter methylation may be a marker of HCC-related prognoses. CONCLUSIONS: RASSF1A promoter hypermethylation is a promising biomarker for the diagnosis of HCC from tissue and peripheral blood, and is an emerging therapeutic target against HCC.

Comparison of Multiple Displacement Amplification (MDA) and Multiple Annealing and Looping-Based Amplification Cycles (MALBAC) in Limited DNA Sequencing Based on Tube and Droplet.

Whole genome amplification (WGA) is crucial for whole genome sequencing to investigate complex genomic alteration at the single-cell or even single-molecule level. Multiple displacement amplification (MDA) and multiple annealing and looping based amplification cycles (MALBAC) are two most widely applied WGA methods, which have different advantages and disadvantages, dependent on research objectives. Herein, we compared the MDA and MALBAC to provide more information on their performance in droplets and tubes. We observed that the droplet method could dramatically reduce the amplification bias and retain the high accuracy of replication than the conventional tube method. Furthermore, the droplet method exhibited higher efficiency and sensitivity for both homozygous and heterozygous single nucleotide variants (SNVs) at the low sequencing depth. In addition, we also found that MALBAC offered a greater uniformity and reproducibility and MDA showed a better efficiency of genomic coverage and SNV detection. Our results provided insights that will allow future decision making.

Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.

BACKGROUND: A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial. METHODS: Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed. RESULTS: This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45-0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44-0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44-0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35-0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43-0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42-0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49-1.61; p = 0.706). Additionally, the association was significant in patients with cancer who were treated with ICIs as a monotherapy (OS: HR, 0.53, 95% CI, 0.43-0.65; p < 0.001), but not as a combination therapy (OS: HR, 0.62, 95% CI, 0.36-1.05; p = 0.073). CONCLUSIONS: The occurrence of irAEs was significantly associated with a better ICI efficacy in patients with cancer, particularly endocrine, dermatological, and low-grade irAEs. Further large-scale prospective studies are warranted to validate our findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019129310.

Immune-related adverse events of checkpoint inhibitors: Insights into immunological dysregulation.

Immune checkpoint inhibitors (ICIs) targeting against programmed cell death-1(PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have shown efficacy in cancer treatment. However, a spectrum of immune-related adverse events (irAEs) have raised concerns about their clinical application. IrAEs are distinct from traditional chemo- and radiotherapy-induced toxicities, as they are related in particular to the dysregulation of immune system and autoimmunity. The underlying pathogenesis of irAEs remains elusive. Understanding of the potential underlying mechanism is of great importance for the management of irAEs and the development of new ICIs with insignificant irAEs. In this review, we summarize the current evidence to provide insights into the biological basis of irAEs and provide a potential explanation for their pathogenesis, with focus on the relationship between checkpoint molecules and immune cell regulation.

Continuous Microfluidic Purification of DNA Using Magnetophoresis.

Automatic microfluidic purification of nucleic acid is predictable to reduce the input of original samples and improve the throughput of library preparation for sequencing. Here, we propose a novel microfluidic system using an external NdFeB magnet to isolate DNA from the polymerase chain reaction (PCR) mixture. The DNA was purified and isolated when the DNA-carrying beads transported to the interface of multi-laminar flow under the influence of magnetic field. Prior to the DNA recovery experiments, COMSOL simulations were carried out to study the relationship between trajectory of beads and magnet positions as well as fluid velocities. Afterwards, the experiments to study the influence of varying velocities and input of samples on the DNA recovery were conducted. Compared to experimental results, the relative error of the final position of beads is less than 10%. The recovery efficiency decreases with increase of input or fluid velocity, and the maximum DNA recovery efficiency is 98.4% with input of l00 ng DNA at fluid velocity of 1.373 mm/s. The results show that simulations significantly reduce the time for parameter adjustment in experiments. In addition, this platform uses a basic two-layer chip to realize automatic DNA isolation without any other liquid switch value or magnet controller.