Association between dietary supplement use and mortality in cancer survivors with different body mass index and frailty status: a cohort study.

Background: The association between Body Mass Index (BMI), frailty index (FI), and dietary supplement in cancer survivors has been a subject of growing interest. This study investigates the relationship of BMI and FI with mortality in American cancer survivors and explores the impact of dietary supplement usage on different BMI and FI groups. Methods: Three thousand nine hundred and thirty-two cancer patients from the National Health and Nutrition Examination Survey (NHANES) database were included in the analyses. BMI, FI, and supplement usage were obtained through the NHANES structured survey and the 49-item FI tool. Weighted logistic and Cox proportional hazards models, Kaplan-Meier survival analyses, and propensity score matching (PSM) were used to elucidate the relationships between BMI, FI, dietary supplement, and mortality outcomes. Results: The study found significant associations between higher BMI and increased frailty (Odds ratio [OR] = 1.04, 95% confidence interval [95% CI], 1.02-1.06). BMI < 25 kg/m2 and FI > 0.2 are associated with an increased mortality rate. Dietary supplement use can reduce all-cause and cancer mortality in cancer patients with BMI < 25 kg/m2 (Hazard ratio [HR] = 0.63, 95% CI, 0.47-0.84; HR = 0.48, 95% CI, 0.29-0.80) or FI ≤ 0.2 (HR = 0.77, 95% CI, 0.60-0.99; HR = 0.59, 95% CI, 0.39-0.89). In cancer patients with BMI < 25 kg/m2 and FI ≤ 0.2, dietary supplement users had lower all-cause and cancer mortality (HR = 0.49, 95% CI, 0.30-0.79; HR = 0.25, 95% CI, 0.10-0.60). Conclusion: The study revealed a negative correlation between BMI and the FI among the cancer patient cohort as well as their complex impact on mortality and highlighted the role of dietary supplement in cancer prognosis, indicating benefits for non-frail patients with BMI < 25 kg/m2.

Exhaled volatolomics profiling facilitates personalized screening for gastric cancer.

Gastric cancer (GC) is one of the most fatal cancers, characterized by non-specific early symptoms and difficulty in detection. However, there are no valid non-invasive screening tools available for GC. Here we establish a non-invasive method that employs exhaled volatolomics and ensemble learning to detect GC. We developed a comprehensive mass spectrometry-based procedure and determined of a wide range of volatolomics from 314 breath samples. The discovery, identification and verification research screened a biomarker panel to distinguish GC from controls. This panel has achieved 0.90 (0.87-0.94, 95%CI) accuracy, with an area under curve (AUC) of 0.92 (0.89-0.94, 95%CI) in discovery cohort and 0.88 (0.83-0.91, 95%CI) accuracy with an AUC of 0.91 (0.87-0.93, 95%CI) in replication cohort, which outperformed traditional serum markers. Single-cell sequencing and gene set enrichment analysis revealed that these exhaled markers originated from aldehyde oxidation and pyruvate metabolism. Our approach advances the design of exhaled analysis for GC detection and holds promise as a non-invasive method to the clinic.

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma.

Neurodevelopmental cell communication plays a crucial role in neuroblastoma prognosis. However, determining the impact of these communication pathways on prognosis is challenging due to limited sample sizes and patchy clinical survival information of single cell RNA-seq data. To address this, we have developed the cell communication pathway prognostic model (CCPPM) in this study. CCPPM involves the identification of communication pathways through single-cell RNA-seq data, screening of prognosis-significant pathways using bulk RNA-seq data, conducting functional and attribute analysis of these pathways, and analyzing the post-effects of communication within these pathways. By employing the CCPPM, we have identified ten communication pathways significantly influencing neuroblastoma, all related to axongenesis and neural projection development, especially the BMP7-(BMPR1B-ACVR2B) communication pathway was found to promote tumor cell migration by activating the transcription factor SMAD1 and regulating UNK and MYCBP2. Notably, BMP7 expression was higher in neuroblastoma samples with distant metastases. In summary, CCPPM offers a novel approach to studying the influence of cell communication pathways on disease prognosis and identified detrimental communication pathways related to neurodevelopment.

RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension.

m6A (N6­methyladenosine) is the most common and abundant apparent modification in mRNA of eukaryotes. The modification of m6A is regulated dynamically and reversibly by methyltransferase (writer), demethylase (eraser), and binding protein (reader). It plays a significant role in various processes of mRNA metabolism, including regulation of transcription, maturation, translation, degradation, and stability. Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by abnormal proliferation of pulmonary artery smooth muscle cells. Despite the existence of several effective and targeted therapies, there is currently no cure for PAH and the prognosis remains poor. Recent studies have highlighted the crucial role of m6A modification in cardiovascular diseases. Investigating the role of RNA m6A methylation in PAH could provide valuable insights for drug development. This review aims to explore the mechanism and function of m6A in the pathogenesis of PAH and discuss the potential targeting of RNA m6A methylation modification as a treatment for PAH.

Targeted Delivery of Catalase and Photosensitizer Ce6 by a Tumor-Specific Aptamer Is Effective against Bladder Cancer In Vivo.

Photodynamic therapy (PDT) is often applied in a clinical setting to treat bladder cancer. However, current photosensitizers report drawbacks such as low efficacy, low selectivity, and numerous side effects, which have limited the clinical values of PDT for bladder cancer. Previously, we developed the first bladder cancer-specific aptamer that can selectively bind to and be internalized by bladder tumor cells versus normal uroepithelium cells. Here, we use an aptamer-based drug delivery system to deliver photosensitizer chlorine e6 (Ce6) into bladder tumor cells. In addition to Ce6, we also incorporate catalase into the drug complex to increase local oxygen levels in the tumor tissue. Compared with free Ce6, an aptamer-guided DNA nanotrain (NT) loaded with Ce6 and catalase (NT-Catalase-Ce6) can specifically recognize bladder cancer cells, produce oxygen locally, induce ROS in tumor cells, and cause mitochondrial apoptosis. In an orthotopic mouse model of bladder cancer, the intravesical instillation of NT-Catalase-Ce6 exhibits faster drug internalization and a longer drug retention time in tumor tissue compared with that in normal urothelium. Moreover, our modified PDT significantly inhibits tumor growth with fewer side effects such as cystitis than free Ce6. This aptamer-based photosensitizer delivery system can therefore improve the selectivity and efficacy and reduce the side effects of PDT treatment in mouse models of bladder cancer, bearing a great translational value for bladder cancer intravesical therapy.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

Deficient gait function despite effect index of the Western Ontario and McMaster university osteoarthritis index score considered cured one year after bilateral total knee arthroplasty.

BACKGROUND: To clarify the value of gait analysis and its consistency with traditional scoring scales for the evaluation of knee joint function after total knee arthroplasty (TKA). METHODS: This study included 25 patients with knee osteoarthritis (KOA) who underwent bilateral TKA, and 25 conditionally matched healthy individuals, categorised into the experimental and control groups, respectively. Patients in the experimental group underwent gait analysis and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) evaluation before and 1 year after TKA. Weight-bearing balance and walking stability were assessed using discrete trends of relevant gait indicators. Pearson's correlation analysis was performed on the gait and WOMAC score data of the experimental group before and after TKA. RESULTS: One year after TKA, patients' gait indices (except gait cycle) were significantly better than before surgery, but significantly worse than that of the control group (P < 0.01). The shape of patients' plantar pressure curves did not return to normal. Additionally, the discrete trend of related gait indicators reflecting weight-bearing balance and walking stability were smaller than before TKA, but still greater than that of the control group. The WOMAC scores of patients 1 year after TKA were significantly lower than those before TKA (P < 0.001), and the efficacy index was > 80%. The WOMAC scores and gait analysis results were significantly correlated before TKA (P < 0.05). CONCLUSIONS: Gait analysis should be used in conjunction with scoring scales to assess joint functions.

An oncolytic system produces oxygen selectively in pancreatic tumor cells to alleviate hypoxia and improve immune activation.

INTRODUCTION: Hypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor. METHODS: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing. RESULTS: The adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment. CONCLUSION: The responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.

CAFs Homologous Biomimetic Liposome Bearing BET Inhibitor and Pirfenidone Synergistically Promoting Antitumor Efficacy in Pancreatic Ductal Adenocarcinoma.

BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.

Estimates of the global burden of non-Hodgkin lymphoma attributable to HIV: a population attributable modeling study.

Background: Human immunodeficiency virus (HIV) significantly increases the risk of non-Hodgkin lymphoma (NHL) development, yet the population-level impact on NHL burden is unquantified. We aim to quantify this association and estimate the global burden of HIV-associated NHL. Methods: In this meta-analysis, we searched five databases (PubMed, EMBASE, Cochrane Library, Web of Science, Scopus) from database inception up to September 13, 2023, identifying cohort, case-control, or cross-sectional studies with an effective control group to assess NHL risk among individuals with HIV infection, with two authors extracting summary data from reports. Global and regional HIV-associated population attributable fraction (PAF) and NHL disease burden were calculated based on the pooled risk ratio (RR). HIV prevalence and NHL incidence were obtained from the Joint United Nations Programme on HIV/AIDS (UNAIDS) and Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Trends in NHL incidence due to HIV were assessed using age-standardised incidence rate (ASIR) and estimated annual percentage change (EAPC). This study was registered with PROSPERO (CRD42023404150). Findings: Out of 14,929 literature sources, 39 articles met our inclusion criteria. The risk of NHL was significantly increased in the population living with HIV (pooled RR 23.51, 95% CI 17.62-31.37; I2 = 100%, p < 0.0001), without publication bias. Globally, 6.92% (95% CI 2.18%-11.57%) of NHL new cases in 2019 were attributable to HIV infection (30,503, 95% CI 9585-52,209), which marked a more than three-fold increase from 1990 (8340, 95% CI 3346-13,799). The UNAIDS region of Eastern and Southern Africa was the highest affected region, with 44.46% (95% CI 19.62%-58.57%) of NHL new cases attributed to HIV infection. The Eastern Europe and Central Asia region experienced the highest increase in ASIR of NHL due to HIV in the past thirty years, wherein the EAPC was 8.74% (95% CI 7.66%-9.84%), from 2010 to 2019. Interpretation: People with HIV infection face a significantly increased risk of NHL. Targeted prevention and control policies are especially crucial for countries in Eastern and Southern Africa, Eastern Europe and Central Asia, to achieve the UNAIDS's '90-90-90' Fast-Track targets. Limited studies across diverse regions and heterogeneity between research have hindered precise estimations for specific periods and regions. Funding: Sichuan Provincial People's Hospital, Chengdu, China; Health Care for Cadres of Sichuan Province, Chengdu, China; Science and Technology Department of Sichuan Province, Chengdu, China.

Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR+) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR+ cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating ß2 and ß3 adrenergic receptor signalling in LepR+ cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR+ cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR+ cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR+ cells.

High systemic immune-inflammation index predicts poor prognosis and response to intravesical BCG treatment in patients with urothelial carcinoma: a systematic review and meta-analysis.

Background: The systemic immune-inflammation index (SII) has emerged as a promising marker predicting the prognosis of some cancers, while its role in urothelial carcinoma (UC) remains uncertain, especially in upper urinary tract urothelial carcinoma (UTUC). This meta-analysis aimed to investigate the association of SII with the prognosis of UC and the response to intravesical Bacillus Calmette-Guerin (BCG) therapy of non-muscle invasive bladder cancer (NMIBC). Methods: A systematic search in PubMed, Embase, Web of Science, and the Cochrane Library was performed to identify relevant studies. The extracted hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the association between SII and overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) of patients with UC. Additionally, we pooled odds ratios (ORs) and 95% CIs to assess the relationship between SII and BCG response in patients with NMIBC. Subgroup and sensitivity analyses were performed to explore potential sources of heterogeneity. Results: Twenty studies comprising a total of 12,645 patients were eligible. This meta-analysis revealed that high SII levels independently increased the risk of OS (HR 1.55, 95%CI 1.25-1.92), CSS (HR 1.82, 95%CI 1.36-2.45), and RFS (HR 1.26, 95% CI 1.18-1.35) in patients with UC, including those with upper tract urothelial carcinoma. Additionally, elevated SII levels could predict a lower response to intravesical BCG treatment (OR 0.18, 95%CI 0.07-0.45) and higher disease recurrence (HR 1.61, 95%CI 1.31-1.98) in patients with NMIBC. Furthermore, elevated SII levels were positively associated with advanced age, lymphovascular invasion, hydronephrosis, and high tumor grade and stage (pT ≥ 3). Conclusions: Elevated preoperative SII levels are associated with poor survival outcomes in patients with UC, as well as worse response to BCG treatment in patients with NMIBC. Therefore, SII can serve not only as an independent prognostic predictor of patients with UC but also as a guide for BCG therapy in NMIBC. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023409077, identifier CRD42023409077.

Lithium chloride induces apoptosis by activating endoplasmic reticulum stress in pancreatic cancer.

Lithium compounds, a classic class of metal complex medicine that target GSK 3ß and are widely known as mood-stabilizer, have recently been reported as potential anti-tumor drugs. The objective of this investigation was to explore the anticancer potential of lithium chloride (LiCl) and elucidate its mode of action in pancreatic cancer cells. The MTT, colony formation, and Edu assay were used to evaluate the impact of LiCl on pancreatic cancer cell proliferation. Various methods were employed to investigate the anti-tumor activity of LiCl and its underlying mechanisms. Cell cycle analysis and apoptosis detection assays were utilized for in vitro experiments, while the orthotopic pancreatic cancer mouse model was employed to evaluate the effectiveness of LiCl treatment in vivo. Furthermore, the impact of LiCl on the proliferation of patient-derived organoids was also studied. The results demonstrated that LiCl inhibited the proliferation of pancreatic cancer (PC) cells, induced G2/M phase arrest, and activated apoptosis. Notably, the triggering of endoplasmic reticulum (ER) stress by LiCl was observed, leading to the activation of the PERK/CHOP/GADD34 pathway, which subsequently promoted apoptosis in PC cells. In the future, Lithium compounds could become an essential adjunct in the treatment of human pancreatic cancer.

Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities.

Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound 4a significantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood-brain barrier permeability, 4a improved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of 4a. Further experiments indicated that 4a might be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated autophagy and apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.

Effect of two surgical approaches on the lung function and prognosis of patients with combined esophagogastric cancer.

BACKGROUND: Adenocarcinoma of the esophagogastric junction has a center of origin within 5 cm of the esophagogastric junction. Surgical resection remains the main treatment. A transthoracic approach is recommended for Siewert I adenocarcinoma of the esophagogastric junction and a transabdominal approach is recommended for Siewert III adenocarcinoma of the esophagogastric junction. However, there is a need to determine the optimal surgical approach for Siewert II adenocarcinoma of the esophagogastric junction to improve lung function and the prognosis of patients. AIM: To investigate and compare the surgical effects, postoperative changes in pulmonary function, and prognoses of two approaches to treating combined esophagogastric cancer. METHODS: One hundred and thirty-eight patients with combined esophagogastric cancer treated by general and thoracic surgeries in our hospital were selected. They were divided into group A comprising 70 patients (transabdominal approach) and group B comprising 68 patients (transthoracic approach) based on the surgical approach. The indexes related to surgical trauma, number of removed lymph nodes, indexes of lung function before and after surgery, survival rate, and survival duration of the two groups were compared 3 years after surgery. RESULTS: The duration of surgery, length of hospital stay, and postoperative drainage duration of the patients in group A were shorter than those of the patients in group B, and the volume of blood loss caused by surgery was lower for group A than for group B (P < 0.05). At the one-month postoperative review, the first second, maximum ventilation volume, forceful lung volume, and lung volume values were higher for group A than for group B (P < 0.05). Preoperatively, the QLQ-OES18 scale scores of the patients in group A were higher than those in group B on re-evaluation at 3 mo postoperatively (P < 0.05). The surgical complication rate of the patients in group A was 10.00%, which was lower than that of patients in group B, which was 23.53% (P < 0.05). CONCLUSION: Transabdominal and transthoracic surgical approaches are comparable in treating combined esophagogastric cancer; however, the former results in lesser surgical trauma, milder changes in pulmonary function, and fewer complications.

ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways.

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Perfluoropentane/apatinib-encapsulated metal-organic framework nanoparticles enhanced the microwave ablation of hepatocellular carcinoma.

Microwave ablation (MWA) is a promising minimally invasive therapy for hepatocellular carcinoma (HCC). However, the efficiency of MWA in treating HCC is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Here we designed an iron-based metal-organic framework nanomedicine (PFP-Apa-MOF) by loading perfluoropentane (PFP) and apatinib (Apa). After being absorbed by HCC, iron could induce ferroptosis. PFP could be activated into bubbles and act as an ultrasound agent for detecting the ablation margin. As an effective antiangiogenic drug, Apa could inhibit tumor residual growth after MWA. The high efficiency of PFP-Apa-MOF was fully demonstrated in vitro and in vivo. The results showed that MWA combined with PFP-Apa-MOF clearly enhanced the ablation efficiency, leading to apparent tumor inhibition, and increased tumor apoptosis and lipid peroxide. PFP-Apa-MOF could play a valuable role in enhancing MWA to achieve better therapeutic efficacy in HCC.

Fast-Charging Sodium-Ion Batteries Enabled by Molecular-Level Designed Nitrogen and Phosphorus Codoped Mesoporous Soft Carbon.

Soft carbons have attracted extensive interests as competitive anodes for fast-charging sodium-ion batteries (SIBs); however, the high-rate performance is still restricted by their large ion migration barriers and sluggish reaction kinetics. Herein, we show a molecular design approach toward the fabrication of nitrogen and phosphorus codoped mesoporous soft carbon (NPSC). The key to this strategy lies in the chemical cross-linking reaction between polyphosphoric acid and p-phenylenediamine, associated with pyrolysis induced in-situ self-activation that creates mesoporous structures and rich heteroatoms within the carbon matrix. Thanks to the enlarged interlayer spacing, reduced ion diffusion length, and plentiful active sites, the obtained NPSC delivers a superb rate capacity of 215 mAh g-1 at 10 A g-1 and an ultralong cycle life of 4,700 cycles at 5 A g-1. Remarkably, the full cell shows 99% capacity retention during 100 continuous cycles, and maximum energy and power densities of 191 Wh kg-1 and 9.2 kW kg-1, respectively. We believe that such a synthetic protocol could pave a novel venue to develop soft carbons with unique properties for advanced SIBs.

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin.

BACKGROUND: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignancies effectively. Our study aimed to explore the effect of VE-821 on enhancing the chemical sensitivity to cisplatin and clarify the potential molecular mechanisms. METHODS: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay respectively. Western blotting was used to detect the expression of target proteins. TCGA database was used to analyze the correlation between the ATR expression with the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence. RESULTS: Cisplatin inhibited the proliferation and induced apoptosis of GC cells with a relatively high IC50 value, and increased the phosphorylation levels of ATR-CHK1 and H2AX. VE-821 achieved the same effects but by downregulating the phosphorylation levels of the ATR-CHK1 pathway. Besides, higher ATR expression in GC tissues was positively correlated with higher pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-induced STAT3 activation and enhanced H2AX levels. Moreover, VE-821 significantly sensitized GC cells to cisplatin, and these two drugs had synergistic effects in GC cell lines, organoids, and in vivo. CONCLUSION: Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance.