Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms.

To identify disease signature genes associated with immune infiltration in nonalcoholic steatohepatitis (NASH), we downloaded 2 publicly available gene expression profiles, GSE164760 and GSE37031, from the gene expression omnibus database. These profiles represent human NASH and control samples and were used for differential genes (DEGs) expression screening. Two machine learning methods, the Least Absolute Shrinkage and Selection Operator regression model and Support Vector Machine Recursive Feature Elimination, were used to identify candidate disease signature genes. The CIBERSORT deconvolution algorithm was employed to analyze the infiltration of 22 immune cell types in NASH. Additionally, we constructed a NASH cell model using HepG2 cells treated with oleic acid and free fatty acids. The construction of the cell model was verified using oil red O staining, and Western blotting was used to detect the protein expression of the disease signature genes in both control and model groups. As a result, a total of 262 DEGs were identified. These DEGs were primarily associated with metal ion transmembrane transporter activity, sodium ion transmembrane transporter protein activity, calcium ion, and neuroactive ligand-receptor interactions. FOS, IGFBP2, dual-specificity phosphatase 1 (DUSP1), and IKZF3 were identified as disease signature genes of NASH by the least absolute shrinkage and selection operator and Support Vector Machine Recursive Feature Elimination algorithms for DEGs analysis. The receiver operating characteristic curves showed that FOS, IGFBP2, DUSP1, and IKZF3 had good diagnostic value (area under receiver operating characteristic curve > 0.8). These findings were validated in the GSE89632 dataset and through cellular assays. Immunocyte infiltration analysis revealed that NASH was associated with CD8 T cells, CD4 T cells, follicular helper T cells, resting NK cells, eosinophils, regulatory T cells, and γδ T cells. The FOS, IGFBP2, DUSP1, and IKZF3 genes were specifically associated with follicular helper T cells. Lipid droplet aggregation significantly increased in HepG2 cells treated with oleic acid and free fatty acids, indicating successful construction of the cell model. In this model, the expression of FOS, IGFBP2, and DUSP1 was significantly decreased, while that of IKZF3 was significantly elevated (P < .01, P < .001) compared with the control group. Therefore, FOS, IGFBP2, DUSP1, and IKZF3 can be considered as disease signature genes associated with immune infiltration in NASH.

Suppression of lysosome metabolism-meditated GARP/TGF-ß1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis.

Regulatory T cells (Tregs) prevent autoimmunity and contribute to cancer progression. They exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-ß1 (TGF-ß1). However, the absence of a specific surface marker makes inhibiting the production of active TGF-ß1 to specifically deplete human Tregs but not other cell types a challenge. TGF-ß1 in an inactive form binds to Tregs membrane protein Glycoprotein A Repetitions Predominant (GARP) and then activates it via an unknown mechanism. Here, we demonstrated that tumour necrosis factor receptor-associated factor 3 interacting protein 3 (TRAF3IP3) in the Treg lysosome is involved in this activation mechanism. Using a novel naphthalenelactam-platinum-based anticancer drug (NPt), we developed a new synergistic effect by suppressing ATP-binding cassette subfamily B member 9 (ABCB9) and TRAF3IP3-mediated divergent lysosomal metabolic programs in tumors and human Tregs to block the production of active GARP/TGF-ß1 for remodeling the tumor microenvironment. Mechanistically, NPt is stored in Treg lysosome to inhibit TRAF3IP3-meditated GARP/TGF-ß1 complex activation to specifically deplete Tregs. In addition, by promoting the expression of ABCB9 in lysosome membrane, NPt inhibits SARA/p-SMAD2/3 through CHRD-induced TGF-ß1 signaling pathway. In addition to expose a previously undefined divergent lysosomal metabolic program-meditated GARP/TGF-ß1 complex blockade by exploring the inherent metabolic plasticity, NPt may serve as a therapeutic tool to boost unrecognized Treg-based immune responses to infection or cancer via a mechanism distinct from traditional platinum drugs and currently available immune-modulatory antibodies.

Enzymatic-related network of catalysis, polyamine, and tumors for acetylpolyamine oxidase: from calculation to experiment.

The regulation of enzymes and development of polyamine analogs capable of controlling the dynamics of endogenous polyamines to achieve anti-tumor effects is one of the biggest challenges in polyamine research. However, the root of the problem remains unsolved. This study represents a significant milestone as it unveils, for the first time, the comprehensive catalytic map of acetylpolyamine oxidase that includes chemical transformation and product release kinetics, by utilizing multiscale simulations with over six million dynamical snapshots. The transportation of acetylspermine is strongly exothermic, and high binding affinity of enzyme and reactant is observed. The transfer of hydride from polyamine to FAD is the rate-limiting step, via an H-shift coupled electron transfer mechanism. The two products are released in a detour stepwise mechanism, which also impacts the enzymatic efficiency. Inspired by these mechanistic insights into enzymatic catalysis, we propose a novel strategy that regulates the polyamine level and catalytic progress through the action of His64. Directly suppressing APAO by mutating His64 further inhibited growth and migration of tumor cells and tumor tissue in vitro and in vivo. Therefore, the network connecting microcosmic and macroscopic scales opens up new avenues for designing polyamine compounds and conducting anti-tumor research in the future.

7-Dehydrocholesterol dictates ferroptosis sensitivity.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

NUAK1 promotes tumor metastasis through upregulating slug transcription in esophageal squamous cell carcinoma.

BACKGROUND: Metastasis is still a major cause of poor pathological outcome and prognosis in esophageal squamous cell carcinoma (ESCC) patients. NUAK1 has been reported highly expressed in many human cancers and is associated with the poor prognosis of cancer patients. However, the role of NUAK1 and its underlying signaling mechanism in ESCC metastasis remain unclear. METHODS: Expression of NUAK1 in ESCC was detected by real-time quantitative RT-PCR (qRT-PCR), Western blotting and immunohistochemical staining. MTT, colony formation, wound-healing and transwell assays were used to determine the role NUAK1 in vitro. Metastasis was evaluated by use of an experimental pulmonary metastasis model in BALB/c-nu/nu mice. The mechanisms were assessed by using coimmunoprecipitation, immunofluorescence and dual-luciferase reporter gene experiments. RESULTS: NUAK1 was highly expressed in ESCC tissues compared with the adjacent normal esophageal epithelial tissues. Moreover, the elevated expression of NUAK1 positively correlated with tumor invasion depth, lymph node metastasis, pathological TNM stage, and poor survival in ESCC patients. Further experiments showed that NUAK1 overexpression did not change the cell viability and colony formation of ESCC cells, while remarkably promoted the migration and invasion in vitro and experimental pulmonary metastasis in vivo. Mechanistically, NUAK1 enhanced the transcription level of Slug, which enhanced the migratory and invasive capability of ESCC cells. Consistently, silencing Slug almost completely diminished the migration and invasion of NUAK1-overexpressing ESCC cells. Further studies demonstrated that NUAK1 upregulated the transcription activity of Slug through activating the JNK/c-Jun pathway. CONCLUSION: These results demonstrated that NUAK1 promoted the metastasis of ESCC cells through activating JNK/c-Jun/Slug signaling, indicating NUAK1 is a promising therapeutic target for metastatic ESCC.

Natural products for the treatment of depression: Insights into signal pathways influencing the hypothalamic-pituitary-adrenal axis.

Depression, a prevalent psychiatric malady, afflicts a substantial global demographic, engendering considerable disease burden due to its elevated morbidity and mortality rates. Contemporary therapeutic approaches for depression encompass the administration of serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants, albeit these pharmaceuticals potentially induce adverse neurological and gastrointestinal effects. Traditional Chinese Medicine (TCM) natural products proffer the benefits of multi-target, multi-level, and multi-channel depression treatment modalities. In this investigation, we conducted a comprehensive literature review of the past 5 years in PubMed and other databases utilizing the search terms "Depression," "Natural medicines," "Traditional Chinese Medicine," and "hypothalamic-pituitary-adrenal axis." We delineated the 5 most recent and pertinent signaling pathways associated with depression and hypothalamic-pituitary-adrenal (HPA) axis dysregulation: nuclear factor kappa light-chain-enhancer of activated B cell, brain-derived neurotrophic factor, mitogen-activated protein kinase, cyclic AMP/protein kinase A, and phosphoinositide 3-kinase/protein kinase B. Additionally, we deliberated the antidepressant mechanisms of natural medicines comprising alkaloids, flavonoids, polyphenols, saponins, and quinones via diverse pathways. This research endeavor endeavored to encapsulate and synthesize the progression of TCMs in modulating HPA axis-associated signaling pathways to mitigate depression, thereby furnishing robust evidence for ensuing research in this domain.

The Influence of Different Curing Environments on the Mechanical Properties and Reinforcement Mechanism of Dredger Fill Stabilized with Cement and Polypropylene Fibers.

An effective method widely used in geotechnical engineering to solve the shrinkage and cracking issues in cement-stabilized soil (CS) is evenly mixing randomly distributed fibers into it. Dredger fills stabilized with cement and polypropylene fibers (PFCSs) are exposed to rainwater immersion and seawater erosion in coastal areas, influencing their mechanical performance and durability. In this study, direct shear and consolidation compression tests were conducted to investigate the influence of different curing environments on the mechanical properties and compressive behavior of PFCSs. Dominance and regression analyses were used to study the impact of each factor under different curing regimes. The reinforcement mechanism of different curing environments was also explored using scanning electron microscopy (SEM) imaging. The results show that the cohesion and elastic modulus of the specimens cured in seawater were reduced compared with those cured in freshwater and standard curing environments. The best fiber content for the strength and compressive modulus of PFCSs was determined to be 0.9% of the mass of dredged fill. The results of value-added contributions and the relative importance of each factor in different curing environments show that the overall average contribution of cement content in the seawater curing environment is reduced by 6.79% compared to the freshwater environment. Multiple linear regression models were developed, effectively describing the quantitative relationships of different properties under different curing conditions. Further, the shear strength was improved by the coupling effect of soil particles, a C-S-H gel, and polypropylene fibers in the PFCSs. However, the shear strength of the PFCSs was reduced due to the structural damage of the specimens in the freshwater and seawater curing environments.

Traditional Chinese medicine for smoking cessation: An umbrella review of systematic reviews and meta-analysis of randomized controlled trials.

INTRODUCTION: Traditional Chinese medicine (TCM) may have special advantages in facilitating smoking cessation, but consensus on effectiveness is lacking. We aim to comprehensively review, update, and refine current evidence on TCM effectiveness and safety. METHODS: Nine databases were searched from their inception up to 28 February 2023. Systematic reviews (SRs) and meta-analysis of TCM for smoking cessation were identified and retrieved. Additional databases and hand searches of RCTs from included SRs were performed for data pooling. Cochrane ROB tools and AMSTAR-2 were used to evaluate the methodological quality of RCTs and SRs, respectively. RCT data are presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI) using RevMan 5.4. RESULTS: Thirteen SRs involving 265 studies with 33081 participants were included. Among these 265 studies, 157 were duplicates (58.36%) and 52 were non-RCTs (19.62%). Combined with the remaining 56 RCTs identified through hand searches, 88 RCTs involving 12434 participants were finally included for data synthesis. All the SRs focused on acupoint stimulation, and the majority were of low or very low quality. The methodological quality of RCTs was either unclear or high risk. For continuous abstinence rate, TCM external interventions were better than placebo in 6 months to 1 year (RR=1.60; 95% CI: 1.14-2.25; I2=27%; n=5533 participants). Compared with placebo, TCM external application was effective in reducing nicotine withdrawal symptoms, and the effect was gradually stable and obvious in the fourth week (MD= -4.46; 95% CI: -5.43 - -3.49; n=165 participants). Twelve RCTs reported adverse events as outcome indicators for safety evaluation, and no serious adverse events occurred. CONCLUSIONS: Despite the methodological limitations of the original studies, our review suggests that TCM intervention shows potential effectiveness on the continuous abstinence rate. Extending the intervention time can enhance the effect of TCM on nicotine withdrawal symptoms. Referred to adverse events, more data for safety evaluation are required.

The novel CDK9 inhibitor, XPW1, alone and in combination with BRD4 inhibitor JQ1, for the treatment of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly lethal malignancy with few therapeutic options. Cyclin­dependent kinase 9 (CDK9), a potential therapeutic target of many cancers, has been recently observed to be upregulated in ccRCC patients. Therefore, we aimed to investigate the therapeutic potential of CDK9 in ccRCC and develop a novel CDK9 inhibitor with low toxicity for ccRCC treatment. METHODS: The expression of CDK9 in ccRCC was checked using the online database and tissue microarray analysis. shRNA-mediated CDK9 knockdown and CDK inhibitor were applied to evaluate the effect of CDK9 on ccRCC. Medicinal chemistry methods were used to develop a new CDK9 inhibitor with drugability. RNA-seq and ChIP-seq experiments were conducted to explore the mechanism of action. MTS, western blotting, and colony formation assays were performed to evaluate the anti-ccRCC effects of CDK9 knockdown and inhibition in vitro. The in vivo anti-tumour efficacy was evaluated in a xenograft model. RESULTS: CDK9 is overexpressed and associated with poor survival in ccRCC. Knockdown or inhibition of CDK9 significantly suppressed ccRCC cells. XPW1 was identified as a new potent and selective CDK9 inhibitor with excellent anti-ccRCC activity and low toxicity. In mechanism, XPW1 transcriptionally inhibited DNA repair programmes in ccRCC cells, resulting in an excellent anti-tumour effect. CDK9 and BRD4 were two highly correlated transcriptional regulators in ccRCC patients, and the BRD4 inhibitor JQ1 enhanced XPW1's anti-ccRCC effects in vitro and in vivo. CONCLUSIONS: This work provides valuable insights into the therapeutic potential of CDK9 in ccRCC. The CDK9 inhibitor XPW1 would be a novel therapeutic agent for targeting ccRCC, alone or in rational combinations.

The efficacy and safety of sintilimab combined with chemotherapy as the first-line treatment for metastatic esophageal squamous cell carcinoma.

Immunotherapy is a new treatment option for patients with esophageal squamous cell carcinoma (ESCC). However, no study has investigated the efficacy and safety of sintilimab combined with nanoparticle albumin-bound paclitaxel (Nab-PTX) and platinum as first-line treatment for metastatic ESCC. In this retrospective study, eligible patients with metastatic ESCC were administered sintilimab plus Nab-PTX, cisplatin, or nedaplatin for up to 4 to 6 cycles. Subsequently, patients without progressive disease (PD) continued to receive sintilimab every 3 weeks as maintenance treatment until unacceptable toxicity, PD, withdrawal of consent, or for up to 2 years. The primary endpoint was the objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. A total of 22 patients diagnosed with metastatic ESCC were enrolled, 1 patient reached a complete response (CR), 15 patients achieved a partial response (PR), 4 patients had stable disease, and 2 had PD. The ORR was 72.7% (16/22) and the DCR was 90.9% (20/22). The time to response was 1.9 months (95% confidence interval [CI]:1.7-2.2 months). The median PFS was 8.9 months (95% CI, 7.1-10.7 months), and the median OS was 19.0 months. Exploratory biomarker analysis revealed that lactic dehydrogenase (LDH) was a potential marker for OS, and patients with high LDH levels had shorter mOS (13.0 months, 95% CI:7.5-18.5 months). Treatment-related adverse events (AEs) occurred in 21 patients (95.5%), most of which were grade 1 or 2. No treatment-related deaths occurred in this study. The results of this study suggested that sintilimab combined with Nab-PTX and platinum in patients with metastatic ESCC had a significantly high ORR and encouraging mPFS and mOS. LDH was a potential marker for OS, and the safety profile was manageable.

Activation of endoplasmic reticulum stress by harmine suppresses the growth of esophageal squamous cell carcinoma.

The worldwide overall 5-year survival rate of esophageal squamous cell carcinoma (ESCC) patients is less than 20%, and novel therapeutic strategies for these patients are urgently needed. Harmine is a natural ß-carboline alkaloid, which received great interest in cancer research because of its biological and anti-tumor activities. The aim of this study is to examine the effects of harmine on ESCC and its mechanism. We investigated the effects of harmine on proliferation, cell cycle, apoptosis, and tumor growth in vivo. RNA sequencing (RNA-seq), real-time PCR, and western blotting were used to detect the mechanism. Harmine inhibited ESCC cell growth in vitro and tumor growth in vivo. Differentially expressed genes in harmine-treated ESCC cells were mainly involved in protein processing in the endoplasmic reticulum (ER). Real-time PCR and western blotting confirmed harmine-induced cellular ER stress. CRISPR-Cas9 knockout of C/EBP homologous protein (CHOP) abolished harmine-induced expression of death receptor 5 and apoptosis. Harmine also induced the expression of CHOP-mediated sestrin-2, which in turn contributes to autophagosome formation via suppressing the AMP-activated protein kinase-protein kinase B-mammalian target of rapamycin signaling pathway. In conclusion, our results demonstrate that harmine inhibits the growth of ESCC through its regulation of ER stress, suggesting that it is a promising candidate for ESCC treatment.

MitraClip used for severe mitral regurgitation after surgery for type A aortic dissection combined with Marfan syndrome.

Mitral regurgitation is a rare but catastrophic condition in patients after surgery for type A aortic dissection. The second thoracotomy to complete the mitral valve operation could be fatal. Here, we report a case of severe mitral regurgitation treated with MitraClip in a 53-year-old woman after surgery for type A aortic dissection combined with Marfan syndrome. She was discharged uneventfully, and a significant reduction of regurgitation of mitral valve and tricuspid valve was observed at the 6-month follow-up. MitraClip could be an alternative device for such high-risk patients.

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

BACKGROUND: Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. METHODS: Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. RESULTS: We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. CONCLUSIONS: This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

Feasibility and safety of inserting transient biodegradable stents in the pylorus during pylorus-preserving gastrectomy for gastric cancer: a preliminary study in a porcine for proof of concept.

BACKGROUND: To evaluate whether insertion of self-biodegradable stent into the pylorus to prevent delayed-gastric emptying after pylorus-preserving gastrectomy is feasible and safe through porcine experiment. METHODS: Self-biodegradable dumbbell-shaped pyloric stents were designed from absorbable suture materials: poly(glycolide-co-caprolactone) (PGCL) or poly-p-dioxanone (PPDO). After gastrotomy on ten pigs, each stent was inserted: two shams, four PGCL stents, and four PPDO stents. Body weight (Bwt), body temperature (BT), complete blood cell (CBC) count, and plain X-ray were evaluated. On postoperative day (POD) 13, euthanasia was performed for histologic evaluation. RESULTS: Operation was successfully performed in all ten pigs. Without tagging suture, both stents migrated before POD 3. The migration was delayed up to POD 13, when the tagging sutures (-t) were applied between stent and stomach wall. Self-degradation of PGCL started from POD 3, and stents were completely excreted from the abdomen by POD 8. Although PPDO were also weakened as self-degradation progressed, its shape was maintained in gastrointestinal tract for 13 days. Unexpected sudden death occurred in the pig with PPDO-t2 on POD 10, which is more likely due to acute volvulus rather than stent-related complication. There was no significant difference between three groups in terms of Bwt, BT, CBC, and histology (sham vs. PGCL vs. PPDO, all p > 0.05). CONCLUSION: The concept of biodegradable stents made of absorbent suture material seems feasible in porcine experiment. Among them, PGCL which has shown rapid absorption, appears to be a more suitable material for transient pyloric absorbable stent when considering safety aspect.

Hematopoietic Stem Cell Development in Mammalian Embryos.

Hematopoietic stem cells (HSCs) are situated at the top of the adult hematopoietic hierarchy in mammals and give rise to the majority of blood cells throughout life. Recently, with the advance of multiple single-cell technologies, researchers have unprecedentedly deciphered the cellular and molecular evolution, the lineage relationships, and the regulatory mechanisms underlying HSC emergence in mammals. In this review, we describe the precise vascular origin of HSCs in mouse and human embryos, emphasizing the conservation in the unambiguous arterial characteristics of the HSC-primed hemogenic endothelial cells (HECs). Serving as the immediate progeny of some HECs, functional pre-HSCs of mouse embryos can now be isolated at single-cell level using defined surface marker combinations. Heterogeneity regrading cell cycle status or lineage differentiation bias within HECs, pre-HSCs, or emerging HSCs in mouse embryos has been figured out. Several epigenetic regulatory mechanisms of HSC generation, including long noncoding RNA, DNA methylation modification, RNA splicing, and layered epigenetic modifications, have also been recently uncovered. In addition to that of HSCs, the cellular and molecular events underlying the development of multiple hematopoietic progenitors in human embryos/fetus have been unraveled with the use of series of single-cell technologies. Specifically, yolk sac-derived myeloid-biased progenitors have been identified as the earliest multipotent hematopoietic progenitors in human embryo, serving as an important origin of fetal liver monocyte-derived macrophages. Moreover, the development of multiple hematopoietic lineages in human embryos such as T and B lymphocytes, innate lymphoid cells, as well as myeloid cells like monocytes, macrophages, erythrocytes, and megakaryocytes has also been depicted and reviewed here.

Reconstruction of aortic sinus using patches in patients with acute type A aortic dissection.

OBJECTIVES: Acute type A aortic dissection involving the aortic sinus is often combined with varying degrees of aortic regurgitation, while the structure of the aortic valve is often undamaged. The aim of this study was to evaluate the clinical effects of reconstruction of the aortic sinus using patches in patients with acute type A aortic dissection. METHODS: From January 2016 to December 2019, 52 patients with acute type A aortic dissection involving the aortic sinus were treated with aortic sinus reconstruction using pericardial or artificial vascular patches. The clinical and follow-up data were summarized. RESULTS: Bovine pericardial patches were used in 31 cases and artificial vascular patches were used in 21 cases for aortic sinus reconstruction. Cardiopulmonary bypass time was (250.4 ± 65.7) min, aortic cross clamp time was (143.7 ± 42.3) min, and hypothermic circulatory arrest time was (9.6 ± 8.1) min. Three patients died in hospital, with a mortality rate of 5.8%. Fifteen patients (28.8%) had mild postoperative aortic regurgitation. The follow-up duration was 40 ± 12 (range, 21-66) months. Five patients (10.2%) developed moderate to severe aortic regurgitation and 3 (6.1%) died during the follow-up period. CONCLUSIONS: The application of patches for aortic sinus reconstruction is a relatively easy method in aortic valve-sparing root reconstruction for acute type A aortic dissection involving the aortic sinus. The clinical and follow-up results are favorable.

The role of Platinum(IV)-based antitumor drugs and the anticancer immune response in medicinal inorganic chemistry. A systematic review from 2017 to 2022.

Platinum-based antitumor drugs have been used in many types of tumors due to its broad antitumor spectrum in clinic. Encouraged by the cisplatin's (CDDP) worldwide success in cancer chemotherapy, the research in platinum-based antitumor drugs has evolved from traditional platinum drug to multi-ligand and multifunctional platinum prodrugs over half a century. With the rapid development of metal drugs and the anticancer immune response, challenges and opportunities in platinum drug research have been shifted from traditional platinum-based drugs to platinum-based hybrids and the direction of development is tending toward photodynamic therapy, nano-delivery therapy, drug combination, targeted therapy, diagnostic therapy, immune-combination therapy and tumor stem cell therapy. In this review, we first exhaustively overviewed the role of platinum-based antitumor prodrugs and the anticancer immune response in medicinal inorganic chemistry based on the special nanomaterials, the modification of specific ligands, and the multiple functions obtained that are beneficial for tumor therapy in the last five years. We also categorized them according to drug potency and function. There hasn't been a comprehensive evaluation of precursor platinum drugs in prior articles. And a multifarious approach to distinguish and detail the variety of alterations of platinum-based precursors in various valence states also hasn't been summarized. In addition, this review points out the main problems at the interface of chemistry, biology, and medicine from their action mechanisms for current platinum drug development, and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks. And a promising idea is also enlightened for researchers in the development and discovery of platinum prodrugs.

Delivery of LINC00589 via mesoporous silica nanoparticles inhibits peritoneal metastasis in gastric cancer.

Peritoneal metastasis is one of the common forms of metastasis in gastric cancer (GC). In this study, we identified the expression pattern of LINC00589 in GC patients and investigate the biological function in GC cells. RNA-pulldown assay was performed to explore the underlying molecular mechanism. Further, we utilize polyethyleneimine-modified mesoporous silica nanoparticles (PMSNs) as the nanocarriers for delivery of LINC00589 encoding plasmid and tested its therapeutic potential for GC with peritoneal dissemination. We revealed that LINC00589 was downregulated in GC tissues and suppressed the metastatic ability of GC cells. Mechanistically, LINC00589 exerted tumor suppressive function by promoting hnRNPA1 protein ubiquitination and proteasomal degradation, thus blocking alternative splicing of PKM to PKM2. Furthermore, LINC00589 delivered by PMSNs could suppress the peritoneal metastasis of GC in vivo and in vitro. This work may provide a new treatment option in GC peritoneal metastasis.