Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.

BACKGROUND AND AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

Antimony precipitation and removal by antimony hyper resistant strain Achromobacter sp. 25-M.

Microbes have been confirmed to play key role in biogeochemistry of antimony. However, the impact of indigenous bacteria (from active mines) on the behavior of dissolved antimony remained poorly understood. In current study, the hyper antimony-resistant strain, Achromobacter sp. 25-M, isolated from the world largest antimony deposit, Xikuangshan antimony deposit, was evaluated for its role in dissolved Sb(V) and Sb(III) precipitation and removal. Despite of the high resistance to Sb(III) (up to 50 mM), the facultative alkaliphile, 25-M was not capable of Sb(III) oxidation. Meanwhile 25-M can produce high amount of exopolymeric substance (EPS) with the presence of Sb, which prompted us to investigate the potential role of EPS in the precipitation and removal of Sb. To this end, 2 mM of Sb(III) and Sb(V) were added into the experimental systems with and without 25-M to discern the interaction mechanism between microbe and antimony. After 96 hrs' incubation, 88% [1.73 mM (210 mg/L)] of dissolved Sb(V) and 80% [1.57 mM (190 mg/L)] of dissolved Sb(III) were removed. X-ray diffraction and energy dispersive spectroscopy analysis confirmed the formation of valentinite (Sb2O3) in Sb(III) amended system and a solitary Sb(V) mineral mopungite [NaSb(OH)6] in Sb(V) amended group with microbes. Conversely, no precipitate was detected in abiotic systems. Morphologically valentinite was bowtie and mopungite was pseudo-cubic as indicated by scanning electronic microscopy. EPS was subjected to fourier transform infrared (FT-IR) analysis. FT-IR analysis suggested that -OH and -COO groups were responsible for the complexation and ligand exchange with Sb(III) and Sb(V), respectively. Additionally, the C-H group and N-H group could be involved in π-π interaction and chelation with Sb species. All these interactions between Sb and functional groups in EPS may subsequently favore the formation of valentinite and mopungite. Collectively, current results suggested that EPS play fundamental role in bioprecipitation of Sb, which offered a new strategy in Sb bioremediation.

Distribution characteristics of stress on the vertebrae following different ranges of excision during Modified Anterior Cervical Discectomy and Fusion: A correlation study based on finite element analysis.

BACKGROUND: Modified Anterior Cervical Discectomy and Fusion with specific resection ranges is an effective surgical method for the treatment of focal ossification of the posterior longitudinal ligament (OPLL). Herein, we compare and analyse the static stress area distribution by performing different cuts on an original ideal finite element model. METHOD: A total of 96 groups of finite element models of the C4-C6 cervical spine with different vertebral segmentation ranges (width: 1-12 mm, height: 1-8 mm) were established. The same pressure direction and size were applied to observe the size and distribution area of stress following various ranges of excision of the C5 vertebral body. RESULTS: Different cutting areas had similar stress aggregation points. As the contact area decreased, the stress and the bearing above area increased. The correlation of stress area variation was highest between the 1-2 MPa and 6 MPa-Max regions (Rho = - 0.975). In the surface visualisation model fitting, the width and height were of different ratios in different stress regions. The model with the best fitting degree was the 1-2 MPa group, and the equation fitting (Rho = 0.966) was as follows: Area = 908.80 - 25.92 × Width + 2.71 × Height. CONCLUSION: Modified Anterior Cervical Discectomy and Fusion with different resection ranges exhibited different stress areas. In a specific resection range of the cervical spine (1-12 mm, 0-8 mm), area conversion occurred at a threshold of 4 MPa. Additionally, the stress was concentrated at the contact points between the vertebral body and the rigid fixator.

Activating Organic Electrode via Trace Dissolved Organic Molecules.

Organic electrode materials have gained attention for their tunable structures and sustainability, but their low electronic conductivity requires the use of large amounts of carbon additives (30 wt %) and low mass loadings (<2 mg cm-2) in electrodes. Here, we synthesize dibenzo[b,i]phenazine-5,7,12,14-tetrone (DPT) as a cathode active material for an aqueous Zn battery and find that Zn2+ storage dominates the cathode reaction. This battery demonstrates high capacity (367 mAh g-1), high-rate performance, and superlong life (12000 cycles). Remarkably, despite DPT's insulative nature, even with a high mass loading (10 mg cm-2) and only 10 wt % carbon additives, the DPT-based cathode exhibits promising performance due to trace dissolved discharge product (DPTx-). During discharge, the DPT is reduced to trace amounts of dissolved DPTx- at the cathode surface, which in turn reduces the remaining solid DPT as a redox mediator. Furthermore, dissolution-redeposition results in the reduction of DPT size and the formation of pores, further activating the electrode.

Characterization of anti-CD79b/CD3 bispecific antibody, a potential therapy for B cell malignancies.

High rates of relapse and poor prognosis confer an urgent need for novel therapeutic agents for B cell non-Hodgkin lymphomas (B-NHLs). Herein, we describe a human IgG-like anti-CD79b/CD3 bispecific antibody (IBI38D9-L) that selectively depletes antigen-positive malignant B cells as an alternative treatment option for relapsed or refractory NHL patients. The antitumor activity and mechanism of action of IBI38D9-L were investigated in vitro using B-NHL cell lines and human primary effector cells and in vivo using xenograft models reconstituted with human PBMCs (peripheral blood mononuclear cells). Pharmacokinetic (PK) properties and preclinical toxicology were evaluated in cynomolgus monkeys and HSC-NPG mice. IBI38D9-L exerted potent B cell killing as well as T cell activation and proliferation in a tumor cell-dependent manner in vitro and was active against B-NHL cell lines with various CD79b expression levels. Subcutaneous xenograft tumors in NOG mice engrafted with human PBMCs were eradicated by IBI38D9-L treatment. Moreover, IBI38D9-L-treated mice showed a strong infiltration of activated T cells. In HSC-NPG mice, IBI38D9-L resulted in potent B cell depletion in peripheral blood and induced only slight body weight loss and cytokine release syndrome without significant toxicological findings. In cynomolgus monkeys, IBI38D9-L was well tolerated with good pharmacokinetic profiles. Collectively, these preclinical efficacy and safety data provide strong scientific rationales for using anti-CD79b/CD3 bispecific antibody as a promising therapeutic agent for B cell malignancies.

The effect of arteriosclerosis on new-onset renal damage in diabetic patients.

The aim of this study was to investigate the effect of arteriosclerosis on new-onset renal damage in a Chinese community population with diabetes. Patients with diabetes who had attended at least one physical examination after the Brachial-ankle pulse wave velocity (BaPWV) test from 2010 to 2018 were selected as subjects. A total of 4,462 patients were included in the study cohort. BaPWV levels <1,400 cm/s, 1,400-1,799 cm/s, and ≥1,800 cm/s were applied to divide the subjects into a normal arterial stiffness group, borderline atherosclerosis group and atherosclerosis group. Renal damage was defined by isolated proteinuria, isolated eGFR <60 mL/min/1.73 m2, proteinuria and eGFR <60 mL/min/1.73 m2. A Cox proportional risk model was used to analyze the effect of different groups on new-onset renal damage. After a median follow-up of 2.85 (1.88-4.90) years, Cox proportional risk models showed that after adjusting for risk factors, compared with the normal group, the HR and 95% CI of the risk of new-onset renal damage were 1.29 (95% CI: 0.95-1.76) and 1.59 (95% CI: 1.14-2.22) in the borderline atherosclerosis group and the atherosclerosis group, respectively. Atherosclerosis is a risk factor for new-onset renal damage, especially new-onset proteinuria, in diabetic patients.

Boosting Zn Anode Utilization by Trace Iodine Ions in Organic-Water Hybrid Electrolytes through Formation of Anion-rich Adsorbing Layers.

Aqueous Zn batteries are attracting extensive attentions, but their application is still hindered by H2 O-induced Zn-corrosion and hydrogen evolution reactions. Addition of organic solvents into aqueous electrolytes to limit the H2 O activity is a promising solution, but at the cost of greatly reduced Zn anode kinetics. Here we propose a simple strategy for this challenge by adding 50 mM iodine ions into an organic-water (1,2-dimethoxyethane (DME)+water) hybrid electrolyte, which enables the electrolyte simultaneously owns the advantages of low H2 O activity and accelerated Zn kinetics. We demonstrate that the DME breaks the H2 O hydrogen-bond network and exclude H2 O from Zn2+ solvation shell. And the I- is firmly adsorbed on the Zn anode, reducing the Zn2+ de-solvation barrier from 74.33 kJ mol-1 to 32.26 kJ mol-1 and inducing homogeneous nucleation behavior. With such electrolyte, the Zn//Zn symmetric cell exhibits a record high cycling lifetime (14.5 months) and achieves high Zn anode utilization (75.5 %). In particular, the Zn//VS2 @SS full cell with the optimized electrolyte stably cycles for 170 cycles at a low N : P ratio (3.64). Even with the cathode mass-loading of 16.7 mg cm-2 , the full cell maintains the areal capacity of 0.96 mAh cm-2 after 1600 cycles.

Conjugated and Non-conjugated Polymers Containing Two-Electron Redox Dihydrophenazines for Lithium-Organic Batteries.

Organic p-type cathode materials have recently attracted increasing attention due to their higher redox potentials and rate capabilities in comparison to n-type cathodes. However, most of the p-type cathodes based on one-electron redox still suffer from limited stability and low specific capacity (<150 mAh g-1 ). Herein, two polymers, conjugated poly(diethyldihydrophenazine vinylene) (CPP) and non-conjugated poly(diethyldihydrophenazine ethylidene) (NCPP) containing two-electron redox dihydrophenazine, have been developed as p-type cathode materials. It is experimentally and theoretically found that the conjugated linkage among the redox centers in polymer CPP is more favorable for the effective charge delocalization on the conjugated polymer backbone and the sufficient oxidation in the higher potential region (3.3-4.2 V vs. Li/Li+ ). Consequently, the CPP cathode displays a higher reversible specific capacity of 184 mAh g-1 with excellent cycling stability.

Molecular Tailoring of p-type Organics for Zinc Batteries with High Energy Density.

P-type organic electrode materials are known for their high redox voltages and fast kinetics. However, single-electron p-type organic materials generally exhibit low capacity despite high operating voltage and stability, while some multi-electron p-type organic materials have high theoretical capacity but low stability. To address this challenge, we explore the possibility of combining single-electron and multi-electron units to create high-capacity and stable p-type organic electrodes. We demonstrate the design of a new molecule, 4,4'-(10H-phenothiazine-3,7-diyl) bis (N,N-diphenylaniline) (PTZAN), which is created by coupling the triphenylamine molecule and the phenothiazine molecule. The resulting PTZAN||Zn battery shows excellent stability (2000 cycles), high voltage (1.3 V), high capacity (145 mAh g-1 ), and energy density of 187.2 Wh kg-1 . Theoretical calculations and in/ex situ analysis reveal that the charge storage of the PTZAN electrode is mainly driven by the redox of phenothiazine heterocycles and triphenylamine unit, accompanied by the combination/release of anions and Zn2+ .

Predictive Value of Free Triiodothyronine in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Background: Homeostasis of thyroid hormones has significant effects on the cardiovascular system. The aim of this study was to investigate the association between free triiodothyronine (FT3) and adverse cardiovascular events in patients with acute coronary syndrome (ACS) who were undergoing percutaneous coronary intervention (PCI). Methods: A total of 1701 patients with ACS undergoing PCI were included in this study. All patients were divided into three groups according to the tertiles of FT3 level: the lowest tertile (FT3 < 4.51 pmol/L), the middle tertile (4.51 pmol/L ≤ FT3 < 4.89 pmol/L) and the highest tertile group (FT3 ≥ 4.89 pmol/L). The primary study endpoint was a composite of major adverse cardiovascular events (MACE), which included all-cause death, ischemic stroke, myocardial infarction, or unplanned repeat revascularization. Results: During a median follow-up period of 927 days, 349 patients had at least one event. Compared with patients with the highest tertile, those with the lowest tertile had a significantly higher incidence of MACE, all-cause death, MI, ischemic stroke and repeat revascularization (all p values < 0.05). In the multivariate Cox regression analysis, the middle tertile had similar risk of MACE (HR = 0.986, 95% CI 0.728-1.336, p = 0.929) as the highest tertile, but the patients with the lowest tertile had a 92.9% higher risk of MACE (HR = 1.929, 95% CI 1.467-2.535, p < 0.001). There was a non-linear relationship between FT3 and MACE and unplanned repeat revascularization (all p values for non-linear association < 0.001). Adding the tertiles of FT3 level into the baseline model yielded a significant improvement in discrimination for predicting MACE ( Δ AUC = 0.013, p = 0.025). Conclusions: A significantly reduced FT3 level was independently associated with a worse prognosis in patients with ACS undergoing PCI.