Circulating tumor cells shielded with extracellular vesicle-derived CD45 evade T cell attack to enable metastasis.

Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45+ CTCs) that resisted T cell attack. A higher percentage of CD45+ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45+ tumor cells orchestrated an immunosuppressive milieu and CD45+ CTCs exhibited remarkably stronger metastatic potential than CD45- CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

Gold nanoparticles exhibit anti-osteoarthritic effects via modulating interaction of the "microbiota-gut-joint" axis.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.

Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism.

Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.

Sishen Pill and its active phytochemicals in treating inflammatory bowel disease and colon cancer: an overview.

The incidence of inflammatory bowel disease (IBD) and the associated risk of colon cancer are increasing globally. Traditional Chinese medicine (TCM) treatment has unique advantages. The Sishen Pill, a common Chinese patented drug used to treat abdominal pain and diarrhea, consists mainly of Psoraleae Fructus, Myristicae Semen, Euodiae Fructus, and Schisandra Chinensis. Modern research has confirmed that Sishen Pill and its active secondary metabolites, such as psoralen, myristicin, evodiamine, and schisandrin, can improve intestinal inflammation and exert antitumor pharmacological effects. Common mechanisms in treating IBD and colon cancer mainly include regulating inflammation-related signaling pathways such as nuclear factor-kappa B, mitogen-activated protein kinase, phosphatidylinositol 3-kinase, NOD-like receptor heat protein domain-related protein 3, and wingless-type MMTV integration site family; NF-E2-related factor 2 and hypoxia-inducible factor 1α to inhibit oxidative stress; mitochondrial autophagy and endoplasmic reticulum stress; intestinal immune cell differentiation and function through the Janus kinase/signal transducer and activator of transcription pathway; and improving the gut microbiota and intestinal barrier. Overall, existing evidence suggests the potential of the Sishen pill to improve IBD and suppress inflammation-to-cancer transformation. However, large-scale randomized controlled clinical studies and research on the safety of these clinical applications are urgently required.

Tolerance to decentration of biaspheric intraocular lenses with refractive phase-ring extended depth of focus and diffractive trifocal designs.

PURPOSE: This study aimed to investigate the in vitro tolerance to decentration of biaspheric intraocular lens (IOLs) with refractive phase-ring extended depth-of-focus (EDOF) and diffractive trifocal designs. METHODS: This experimental study was carried out at the Department of Optics and Optometry and Vision Science, University of Valencia, Spain. The modulation transfer function (MTF) of the ETLIO130C EDOF and the TFLIO130C trifocal IOLs (AST Products Inc., Billerica, MA, USA) were determined at different levels of decentration for a given wavelength and pupil diameter using the PMTF optical bench (Lambda-X Ophthalmics, Nivelles, Belgium). The modulation transfer function (MTF) curves, the through-focus MTF curves, and the Strehl ratios were measured at 3-mm pupil aperture for 0.25-, 0.50- and 0.75-mm decentration. RESULTS: The optical design of the trifocal TFLIO130C IOL is robust to small decentrations, with virtually no change in MTF response for 0.25 mm decentration. For greater decentration levels, the MTF response is slightly reduced with increasing decentration. The ETLIO130C EDOF design is robust to decentration, as the MTF response is only minimally affected when increasing the decentration up to 0.75 mm. CONCLUSIONS: MTF responses are slightly reduced with greater levels of decentration, but the range of focus provided by both trifocal and EDOF designs are preserved. The effects for average levels of decentration reported in the literature are minimum for both IOL designs.

Small-molecule agents for cancer immunotherapy.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.

FURION: modeling of FEL pulses propagation in dispersive soft X-ray beamline systems.

Modern X-ray free-electron lasers (XFELs) can generate pulses with durations ranging from femtoseconds to attoseconds. The numerical evaluation of ultra-short XFEL pulses through beamline systems is a critical process of beamline system design. However, the bandwidth of such ultra-short XFEL pulses is often non-negligible, and the propagation cannot be simply approximated using the central wavelength, especially in dispersive beamline systems. We developed a numerical model which is called Fourier optics based Ultrashort x-Ray pulse propagatION tool (FURION). This model can not only be used to simulate dispersive beamline systems but also to evaluate non-dispersive beamline systems. The FURION model utilizes Fresnel integral and angular spectrum integral to perform ultra-short XFEL pulse propagation in free space. We also present the method for XFEL pulse propagation through different types of dispersive gratings, which are commonly used in soft X-ray beamline systems. By using FURION, a start-to-end simulation of the FEL-1 beamline system at Shenzhen superconducting soft X-ray free electron laser (S3FEL) is carried out. This model can also be used to evaluate gratings-based spectrometers, beam splitters, pulse compressors, and pulse stretchers. This work provides valuable insights into the start-to-end simulation of X-ray beamline systems.

Transvenous endocardial pacing with SelectSecure™ 3830 lead in pediatric patients: case series of two infants and a literature review.

BACKGROUND: The SelectSecure™ 3830 lead is an innovative, lumenless, and thin active fixed lead with a nonretractable screw-in tip and a diameter of 4.1 Fr, making it the thinnest pacing lead available. Its high anti-extrusion properties and durability have shown favorable outcomes in cardiac pacing, especially in pediatric patients. The superfine design and easy implantation of the lead have rendered it a preferred choice in children, particularly in cases of congenital heart disease. CASE PRESENTATION: This case series presents two infant patients who underwent transvenous endocardial pacing using the SelectSecure™ 3830 lead, along with a comprehensive literature review on the topic. The study followed the patients for 5 years and 3 years, respectively, and observed stable pacing parameters, indicating a positive therapeutic outcome and safety. This article discusses the optimal age and body shape for transvenous lead implantation in infants and highlights the advantages and disadvantages of endocardial and epicardial pacing approaches. Although endocardial pacing offers several benefits such as minimal trauma, short hospital stay, and longer battery life, it may not be suitable for intracardiac shunts, and venous occlusion remains a concern. On the other hand, epicardial pacing may be considered for children with challenging endocardial access but comes with higher risk of lead failure and coronary artery compression. This study emphasizes the importance of careful follow-up in pediatric patients with pacing, as lead failure can occur in young patients owing to growth and development, leading to syncope and battery depletion. The article also underscores the significance of selecting the appropriate pacing location to minimize the impact of cardiac function, with right ventricular septal pacing emerging as a preferable option. CONCLUSIONS: The SelectSecure™ 3830 lead presents a promising solution for transvenous endocardial pacing in pediatric patients with high degree atrioventricular block and bradycardia, ensuring safe and effective pacing as they grow and develop.

Human chorionic gonadotrophin indirectly activates peripheral γδT cells to produce interleukin-10 during early pregnancy.

BACKGROUNDS: The immunomodulatory properties of human chorionic gonadotrophin (hCG) have been identified to be critical for successful pregnancy. However, the effects of hCG on peripheral γδT cells during early pregnancy have not been reported previously. METHODS: We cocultured the purified γδT cells and peripheral blood mononuclear cells (PBMCs) with early pregnancy-relevant hCG concentrations and investigated the changes in the immune functional characteristics of γδT cells via flow cytometry assays. RESULTS: The ratios of CD69+ and IL-10+ γδT cells were increased in early pregnant women compared to nonpregnant women. γδT cells expressed low levels of the mannose receptor (CD206) instead of the classical hCG/LH receptor for hCG. The direct treatment of purified γδT cells with early pregnancy-relevant hCG concentrations may have no significant effects on their immune functions. Interestingly, when PBMCs were treated with the same broad range of hCG concentrations, the ratios of CD69+ and IL-10+ γδT cells to total γδT cells were significantly increased. CONCLUSION: Certain early pregnancy-relevant hCG concentrations could enhance the ratios of peripheral CD69+ and IL-10+ γδT cells, contributing to the activation of γδT cells and immunological tolerance during early pregnancy. However, these affects may not be strongly mediated by direct ligand-receptor interactions and they may highly depend on immune microenvironment. Our novel observations propose a perspective into the endocrine-immune dialog that exists between the fetus and maternal immune cells.

Chemical Proteomics and Morphological Profiling Revealing MYDGF as a Target for Synthetic Anticancer Macromolecules.

Biodegradable guanidinium-functionalized polycarbonates kill cancer cells via membrane translocation without causing resistance after repeated use, but the exact molecular targets of the polycarbonates are unknown. Here, we investigate the protein targets of the polycarbonates through affinity-based protein profiling and report myeloid-derived growth factor (MYDGF) as the main protein target. Direct binding of the polycarbonates to MYDGF protein is validated through biolayer interferometry. MYDGF is overexpressed in a range of cancer cells, and knockdown of MYDGF is shown to reduce cell proliferation in cancer cells. Through morphological profiling, we also identify similarities in phenotypic effects of the functionalized polycarbonates with topoisomerase I inhibitors, MDM2 inhibitors, and phosphatidylinositol 3kinase inhibitors against cancer cells, suggesting a common mechanism through the PIK3/AKT pathway leading to apoptosis. These findings present the first macromolecular compound targeting MYDGF and may serve as an example for MYDGF modulation as a potential new target for macromolecular chemotherapeutic development.

To What Extent Do Low-Voltage Electrostatic Fields Play a Role in the Physicochemical Properties of Pork during Freezing and Storage?

Low-voltage electrostatic fields (LVEF) are recognized as a new technology that can improve the quality of frozen meat. To determine the extent to which LVEF assistance affects the quality of frozen pork for long-term storage, pork was frozen and stored at -18 and -38 °C for up to 5 months. Water-holding capacity, muscle microstructure, and protein properties were investigated after up to 5 months of frozen storage with and without LVEF assistance. In comparison to traditional -18 and -38 °C frozen storage, LVEF treatment inhibited water migration during frozen storage and thawing. As a result, thawing losses were reduced by 15.97% (-18 °C) and 3.38% (-38 °C) in LVEF-assisted compared to conventional freezing methods. LVEF helped to maintain the muscle fiber microstructure and reduce muscle protein denaturation by miniaturizing ice crystal formation by freezing. As a result of this study, LVEF is more suitable for freezing or short-term frozen storage, while a lower temperature plays a more significant role in long-term frozen storage.

Identification and interruption of inheritance of familial cryptic translocations: A case report.

BACKGROUND: Cryptic translocations can be identified via genetic analysis of aborted tissues or malformed infants, but it is difficult to deduce the parental origins of the translocations. In the absence of such information, it is not easy to distinguish translocations from normal embryos during pre-implantation genetic testing, that seeks to block familial transmission of translocations. METHODS: Here, we present a new method that detects cryptic translocations and blocks familial transmission thereof. Whole-genome, low-coverage mate-pair sequencing (WGLMPS) revealed chromosome breakpoint sequences, and preimplantation genetic haplotyping (PGH) was then used to discard embryos with cryptic translocations. RESULTS: Cryptic translocations were found in all four families, and familial transmission was successfully blocked in one family. CONCLUSION: Whole-genome, low-coverage mate-pair sequencing combined with preimplantation genetic haplotyping methods powerfully and practically identify cryptic translocations and block familial transmissions.

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles.

A visible-light-promoted research protocol for constructing dihydropyrido[1,2-a]indolone skeletons is herein described proceeding through a cascade cyclization mediated by trifluoromethyl radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method enables a rapid access to heterocycles containing a trifluoromethyl group.

Delivery room resuscitation intensity and associated neonatal outcomes of 24+0-31+6 weeks' preterm infants in China: a retrospective cross-sectional study.

BACKGROUND: The aim of this study was to review current delivery room (DR) resuscitation intensity in Chinese tertiary neonatal intensive care units and to investigate the association between DR resuscitation intensity and short-term outcomes in preterm infants born at 24+0-31+6 weeks' gestation age (GA). METHODS: This was a retrospective cross-sectional study. The source population was infants born at 24+0-31+6 weeks' GA who were enrolled in the Chinese Neonatal Network 2019 cohort. Eligible infants were categorized into five groups: (1) regular care; (2) oxygen supplementation and/or continuous positive airway pressure (O2/CPAP); (3) mask ventilation; (4) endotracheal intubation; and (5) cardiopulmonary resuscitation (CPR). The association between DR resuscitation and short-term outcomes was evaluated by inverse propensity score-weighted logistic regression. RESULTS: Of 7939 infants included in this cohort, 2419 (30.5%) received regular care, 1994 (25.1%) received O2/CPAP, 1436 (18.1%) received mask ventilation, 1769 (22.3%) received endotracheal intubation, and 321 (4.0%) received CPR in the DR. Advanced maternal age and maternal hypertension correlated with a higher need for resuscitation, and antenatal steroid use tended to be associated with a lower need for resuscitation (P < 0.001). Severe brain impairment increased significantly with increasing amounts of resuscitation in DR after adjusting for perinatal factors. Resuscitation strategies vary widely between centers, with over 50% of preterm infants in eight centers requiring higher intensity resuscitation. CONCLUSIONS: Increased intensity of DR interventions was associated with increased mortality and morbidities in very preterm infants in China. There is wide variation in resuscitative approaches across delivery centers, and ongoing quality improvement to standardize resuscitation practices is needed.

A Novel Prognostic Model Using Pan-Immune-Inflammation Value and Programmed Death Ligand 1 in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitors: A Retrospective Multicenter Analysis.

BACKGROUND: Little is known regarding the prognostication of the Pan-Immune-Inflammation Value (PIV) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). OBJECTIVES: This study aimed to investigate the prognostic role of PIV in patients with R/M HNSCC receiving immune checkpoint inhibitors (ICI). PATIENTS AND METHODS: Patients who were diagnosed to have R/M HNSCC and treated with ICI were reviewed retrospectively. The cutoff value of PIV was set at the median. Patients were stratified into high PIV and low PIV. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 192 patients were included in our study for oncologic outcomes evaluation. For the total population, the median PFS was 5.5 months and OS was 18.2 months. After stratification by PIV, median PFS was 11.7 months in the low PIV and 2.8 months in the high PIV groups (p < 0.001). The median OS was 21.8 months in the low PIV and 11.5 months in the high PIV groups (p < 0.001). Multivariate analysis demonstrated that PIV and PD-L1 were independent predictors associated with survival. A prognostic model using both PIV and PD-L1 was constructed. The median PFS was 12.2, 6.4, and 3.0 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). The median OS was 23.7, 18.1, and 11.4 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). CONCLUSIONS: PIV is a prognostic biomarker in patients with R/M HNSCC treated with ICI. A prognostic model using PIV and PD-L1 could provide outcome prediction and risk stratification.

Dynamic chromatin accessibility landscapes of osteoblast differentiation and mineralization.

Bone acts as a self-healing organ, which undergoes continuous regeneration process that is tightly regulated by the cooperation of osteoclasts with the capability of bone resorption and osteoblasts with the capability of bone formation. Generally, bone marrow derived mesenchymal stem cells (BMSCs) differentiated to final osteoblasts have been considered as critical role in bone remodeling. In this regard, several transcription factors (TFs) whose binding sites are initially hidden deep within accessible chromatin that participate in modulating osteoblast differentiation and bone matrix mineralization. Then, it is necessary to explore further the dynamic changes about the epigenetic transcription machinery during osteoblastogenesis. Here, we performed the chromatin accessibility and transcriptomic landscape of osteoblast differentiation and mineralization by using transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-Seq). Our data found that global chromatin accessibility during osteoblastogenesis was extensively improved. Above this, it is shown that key target genes including Col6a3, Serpina3n, Ms4a4d, Lyz2, Phf11b and Grin3a were enriched in differential loci RNA-seq and ATAC-Seq peaks with continuous changed tendency during osteoblasts differentiation and mineralization. In addition, Analysis of Motif Enrichment (AME) was used to elucidate TFs which modulated these target genes. In this study, it was shown for the first time that these important TFs including MEF2A, PRRX1, Shox2 and HOXB13 could alter promoter accessibility of target genes during osteoblastogenesis. This helps us understand how TF binding motif accessibility influences osteoblast differentiation. In addition, it also suggests that modulating the chromatin accessibility of osteogenesis could be developed as the promising strategies to regulate bone regeneration.

Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers in the world. The therapeutic outlook for HCC patients has significantly improved with the advent and development of systematic and targeted therapies such as sorafenib and lenvatinib; however, the rise of drug resistance and the high mortality rate necessitate the continuous discovery of effective targeting agents. To discover novel anti-HCC compounds, we first constructed a deep learning-based chemical representation model to screen more than 6 million compounds in the ZINC15 drug-like library. We successfully identified LGOd1 as a novel anticancer agent with a characteristic levoglucosenone (LGO) scaffold. The mechanistic studies revealed that LGOd1 treatment leads to HCC cell death by interfering with cellular copper homeostasis, which is similar to a recently reported copper-dependent cell death named cuproptosis. While the prototypical cuproptosis is brought on by copper ionophore-induced copper overload, mechanistic studies indicated that LGOd1 does not act as a copper ionophore, but most likely by interacting with the copper chaperone protein CCS, thus LGOd1 represents a potentially new class of compounds with unique cuproptosis-inducing property. In summary, our findings highlight the critical role of bioavailable copper in the regulation of cell death and represent a novel route of cuproptosis induction.