Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase Ⅸ(CA Ⅸ)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfo-namide(ABS)as a CA Ⅸ inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag2S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bio-probe(Ag2S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag2S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor im-aging by the near infrared-Ⅱ(NIR-Ⅱ)fluorescence characteristics of Ag2S QDs.PEG modification of Ag2S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal sta-bility and high photothermal conversion efficiency(PCE)of 45.17％.Under laser irradiation,Ag2S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag2S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
Humans ; Signal Transduction ; Stomach Neoplasms/drug therapy* ; Reactive Oxygen Species/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2 ; Cell Line, Tumor

Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Mice ; Animals ; Humans ; Glioblastoma/pathology* ; Endothelial Cells/pathology* ; DNA Copy Number Variations ; Brain/metabolism* ; Brain Neoplasms/pathology*

Objective: To evaluate the effect of depth of remission of induction chemotherapy on the overall prognosis of limited stage small cell lung cancer (L-SCLC). Methods: The study was a retrospective, L-SCLC patients who contained complete imaging data and underwent consecutive standardized treatments at the Department of Thoracic Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University between January 2013 and June 2021 were included. To delineate the volume of tumor before and after induction chemotherapy and to calculate the depth of remission caused by the induced chemotherapy. The time receiver operating characteristic (timeROC) method was used to determine the optimal predictors for prognosis, multi-factor analysis using Cox risk proportional model. Results: A total of 104 patients were included in this study. The median PFS and OS of this cohort were 13.7 months and 20.9 months, respectively. It was observed by timeROC analysis that residual tumor volume after induction chemotherapy had the optimal predictive value of PFS at 1 year (AUC=0.86, 95% CI: 0.78~0.94) and OS at 2 years (AUC=0.76, 95% CI: 0.65~0.87). Multivariate analysis showed residual tumor volume after induction chemotherapy was the independent prognostic factor to PFS (HR=1.006, 95% CI: 1.003~1.009, P<0.01) and OS (HR=1.009, 95% CI: 1.005~1.012, P<0.001). For those whose residual tumor volume remitted to less than 10 cm(3) after induction chemotherapy, the favorable long-term outcomes could be achieved, regardless of their initial tumor load. Conclusion: The depth of remission of induction chemotherapy could be a promising prognostic predictor to the L-SCLC and provide the individualized treatment guidance.
Humans ; Small Cell Lung Carcinoma/pathology* ; Lung Neoplasms/pathology* ; Induction Chemotherapy ; Retrospective Studies ; Neoplasm, Residual ; Prognosis

High-quality donor heart is the prerequisite and fundamental guarantee for successful heart transplantation. Reasonable donor heart preservation technique plays a key role in improving the quality of donor heart and the prognosis of heart transplantation. Static cold storage (SCS) is currently the standard preservation technique for cardiac allograft. However, it is prone to cause severe cold ischemia injury to the donor heart, and it is impossible to evaluate heart function during SCS. As an important emerging technique of organ preservation, machine perfusion better matches with physiological conditions compared with SCS, which may remove metabolic wastes and provide basic substances for metabolic needs during organ preservation, prolong the preservation time and improve the preservation effect to a certain extent. Besides, it may also effectively evaluate organ function and improve clinical prognosis of heart transplantation. Meantime, it can also repair organ damage, significantly optimize organ quality and improve the utilization rate of donor organs. In this article, research status of machine perfusion of donor heart was reviewed.

BACKGROUND: This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines, named Scientific, Transparent and Applicable Rankings tool (STAR), and test its reliability, validity, and usability. METHODS: This study set up a multidisciplinary working group including guideline methodologists, statisticians, journal editors, clinicians, and other experts. Scoping review, Delphi methods, and hierarchical analysis were used to develop the STAR tool. We evaluated the instrument's intrinsic and interrater reliability, content and criterion validity, and usability. RESULTS: STAR contained 39 items grouped into 11 domains. The mean intrinsic reliability of the domains, indicated by Cronbach's α coefficient, was 0.588 (95% confidence interval [CI]: 0.414, 0.762). Interrater reliability as assessed with Cohen's kappa coefficient was 0.774 (95% CI: 0.740, 0.807) for methodological evaluators and 0.618 (95% CI: 0.587, 0.648) for clinical evaluators. The overall content validity index was 0.905. Pearson's r correlation for criterion validity was 0.885 (95% CI: 0.804, 0.932). The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min. CONCLUSION The instrument performed well in terms of reliability, validity, and efficiency, and can be used for comprehensively evaluating and ranking guidelines.
Reproducibility of Results ; Surveys and Questionnaires ; Practice Guidelines as Topic ; Humans

OBJECTIVES: To investigate the effect and mechanism of lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) targeting Cyp2e1 gene on subacute alcoholic liver injury in mice. METHODS: siRNA targeting Cyp2e1 gene was encapsulated in LNP (si-Cyp2e1 LNP) by microfluidic technique and the resulting LNPs were characterized. The optimal dose of si-Cyp2e1 LNP administration was screened. Forty female C57BL/6N mice were randomly divided into blank control group, model control group, si-Cyp2e1 LNP group, LNP control group and metadoxine group. The subacute alcoholic liver injury mouse model was induced by ethanol feeding for 10 d plus ethanol gavage for the last 3 d. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and the superoxide dismutase (SOD) activity as well as malondialdehyde, reactive oxygen species, glutathione, triacylglycerol, total cholesterol contents in liver tissue were measured in each group, and liver index was calculated. The expression of genes related to oxidative stress, lipid synthesis and inflammation in each group of mice were measured by realtime RT-PCR. RESULTS: Compared with the model control group, the levels of liver index, serum ALT, AST activities, malondialdehyde, reactive oxygen species, triacylglycerol, total cholesterol contents in liver tissue decreased, but the SOD activity as well as glutathione increased in the si-Cyp2e1 LNP group (all P<0.01). Hematoxylin-eosin staining result showed disorganized hepatocytes with sparse cytoplasm and a large number of fat vacuoles and necrosis in the model control group, while the si-Cyp2e1 LNP group had uniformly sized and arranged hepatocytes with normal liver tissue morphology and structure. Oil red O staining result showed si-Cyp2e1 LNP group had lower fat content of the liver compared to the model control group (P<0.01), and no fat droplets accumulated. Anti-F4/80 monoclonal antibody fluorescence immunohistochemistry showed that the si-Cyp2e1 LNP group had lower cumulative optical density values compared to the model control group (P<0.01) and no significant inflammatory reaction. Compared with the model control group, the expression of catalytic genes P47phox, P67phox and Gp91phox were reduced (all P<0.01), while the expression of the antioxidant enzyme genes Sod1, Gsh-rd and Gsh-px were increased (all P<0.01). The mRNA expression of the lipid metabolism genes Pgc-1α and Cpt1 were increased (all P<0.01) and the lipid synthesis-related genes Srebp1c, Acc and Fasn were decreased (all P<0.01); the expression of liver inflammation-related genes Tgf-β, Tnf-α and Il-6 were decreased (all P<0.01). CONCLUSIONS The si-Cyp2e1 LNP may attenuate subacute alcoholic liver injury in mice mainly by reducing reactive oxygen levels, increasing antioxidant activity, blocking oxidative stress pathways and reducing ethanol-induced steatosis and inflammation.
Animals ; Female ; Mice ; Antioxidants/metabolism* ; Cholesterol/metabolism* ; Ethanol/pharmacology* ; Glutathione/pharmacology* ; Inflammation ; Lipids/pharmacology* ; Liver ; Malondialdehyde/pharmacology* ; Mice, Inbred C57BL ; Oxidative Stress ; Reactive Oxygen Species/metabolism* ; RNA, Small Interfering/pharmacology* ; Superoxide Dismutase ; Triglycerides/metabolism* ; Cytochrome P-450 CYP2E1/metabolism*

Objective: To verify the feasibility and accuracy of the transanal multipoint full-layer puncture biopsy (TMFP) technique in determining the residual status of cancer foci after neoadjuvant therapy (nCRT) in rectal cancer. Methods: Between April 2020 and November 2022, a total of 78 patients from the Beijing Chaoyang Hospital of Capital Medical University, the Beijing Friendship Hospital of Capital Medical University, the Qilu Hospital of Shandong University, the Zhongnan Hospital of Wuhan University with advanced rectal cancer received TMFP after nCRT participated in this prospective multicenter trial. There were 53 males and 25 females, aged (M(IQR)) 61 (13) years (range: 35 to 77 years). The tumor distance from the anal verge was 5 (3) cm (range: 2 to 10 cm). The waiting time between nCRT and TMFP was 73 (26) days (range: 33 to 330 days). 13-point transanal puncture was performed with a 16 G tissue biopsy needle with the residual lesion as the center. The specimens were submitted for independent examination and the complications of the puncture were recorded. The consistency of TMFP and radical operation specimen was compared. The consistency of TMPF with clinical remission rates for the diagnosis of complete pathological remission was compared by sensitivity, specificity, negative predictive value, positive predictive value and accuracy. Statistical analysis between groups was performed using the χ² analysis, and a paired χ² test was used to compare diagnostic validity. Results: Before TMFP, clinical complete response (cCR) was evaluated in 27 cases. Thirty-six cases received in vivo puncture, the number of punctures in each patient was 13 (8) (range: 4 to 20), 24 cases of tumor residue were found in the puncture specimens. The sensitivity to judgment (100% vs. 60%, χ²=17.500, P<0.01) and accuracy (88.5% vs. 74.4%, χ²=5.125, P=0.024) of TMFP for the pathologic complete response (pCR) were significantly higher than those of cCR. Implement TMFP based on cCR judgment, the accuracy increased from 74.4% to 92.6% (χ²=4.026, P=0.045). The accuracy of the in vivo puncture was 94.4%, which was 83.3% of the in vitro puncture (χ²=1.382, P=0.240). Overall, the accuracy of TMFP improved gradually with an increasing number of cases (χ²=7.112, P=0.029). Conclusion: TMFP is safe and feasible, which improves the sensitivity and accuracy of rectal cancer pCR determination after nCRT, provides a pathological basis for cCR determination, and contributes to the safe development of the watch and wait policy.

Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.

【Objective】 To investigate the effects and molecular mechanism of Elafibranor (ELA) on the proliferation, migration and apoptosis of human prostate cancer (PCa) cells. 【Methods】 After PCa DU145 cells were treated with culture media containing different dosages of ELA, the proliferation, migration and apoptosis were determined with MTT assay, wound healing assay and Transwell assay, respectively. The expressions of genes related to lipid metabolism were detected with real-time quantitative polymerase chain reaction (real-time qPCR). 【Results】 The relative cell proliferation rate at 48 h was 100% in the blank control group, (86.9±7.8)% in the low-dose (5 μmol/L) group and (58.5±9.4)% in the high-dose (15 μmol/L) group;the wound healing rate at 24 h was (74.7±3.2)%, (61.8±2.9)% and (53.2±3.3)%;the relative percentage of migrated cells at 24 h was 100%, (32.4±11.2)% and (15.4±3.2)%;the cell apoptosis rate at 48 h was (9.3±1.4)%, (11.3±0.3)%, and (15.2±4.5)%, respectively, all P<0.05. After ELA treatment for 48 h, the genes related to fatty acid intake (SCPX, PLTP) and fatty acid oxidation (PDK1, ACOX2) were significantly down-regulated in the high-dose group, while the gene related to fatty acid deposition (PLIN2) was significantly up-regulated, indicating that the lipid metabolism pathway of DU145 cells was seriously interfered by the ELA treatment. 【Conclusion】 ELA can inhibit the proliferation and migration, and promote the apoptosis of prostate cancer cells by interfering in the lipid metabolism pathway, which exhibits remarkable potential of clinical translation in the field of anti-tumor chemotherapy.