Prognostic performance of MRI LI-RADS version 2018 features and clinical-pathological factors in alpha-fetoprotein-negative hepatocellular carcinoma.

PURPOSE: To evaluate the role of the magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS) version 2018 features and clinical-pathological factors for predicting the prognosis of alpha-fetoprotein (AFP)-negative (≤ 20 ng/ml) hepatocellular carcinoma (HCC) patients, and to compare with other traditional staging systems. METHODS: We retrospectively enrolled 169 patients with AFP-negative HCC who received preoperative MRI and hepatectomy between January 2015 and August 2020 (derivation dataset:validation dataset = 118:51). A prognostic model was constructed using the risk factors identified via Cox regression analysis. Predictive performance and discrimination capability were evaluated and compared with those of two traditional staging systems. RESULTS: Six risk factors, namely the LI-RADS category, blood products in mass, microvascular invasion, tumor size, cirrhosis, and albumin-bilirubin grade, were associated with recurrence-free survival. The prognostic model constructed using these factors achieved C-index of 0.705 and 0.674 in the derivation and validation datasets, respectively. Furthermore, the model performed better in predicting patient prognosis than traditional staging systems. The model effectively stratified patients with AFP-negative HCC into high- and low-risk groups with significantly different outcomes (p < 0.05). CONCLUSION: A prognostic model integrating the LI-RADS category, blood products in mass, microvascular invasion, tumor size, cirrhosis, and albumin-bilirubin grade may serve as a valuable tool for refining risk stratification in patients with AFP-negative HCC.

Self-Metallized Whole Cell Vaccines Prepared by Microfluidics for Bioorthogonally Catalyzed Antitumor Immunotherapy.

Tumor whole cell, carrying a complete set of tumor-associated antigens and tumor-specific antigens, has shown great potential in the construction of tumor vaccines but is hindered by the complex engineering means and limited efficacy to cause immunity. Herein, we provided a strategy for the self-mineralization of autologous tumor cells with palladium ions in microfluidic droplets, which endowed the engineered cells with both immune and catalytic functions, to establish a bioorthogonally catalytic tumor whole-cell vaccine. This vaccine showed strong inhibition both in the occurrence and recurrence of tumor by invoking the immediate antitumor immunity and building a long-term immunity.

STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury.

Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. However, the role of STING in the pathogenesis of septic AKI remains unclear. This study demonstrated that the STING was significantly activated in tubular cells induced by lipopolysaccharide (LPS) in vivo and in vitro. Tubule-specific STING knockout attenuated LPS-induced renal dysfunction and pathological changes. Mechanistically, the STING pathway promotes NOD-like receptor protein 3 (NLRP3) activation. STING triggers endoplasmic reticulum (ER) stress to induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting protein activation and association with NLRP3. Eventually, the NLRP3 inflammasome leads to tubular cell inflammation and pyroptosis. This study revealed the STING-regulated network and further identified the STING/ER stress/mtROS/NLRP3 inflammasome axis as an emerging pathway contributing to tubular damage in LPS-induced AKI. Hence, targeting STING may be a promising therapeutic strategy for preventing septic AKI.

Copper(II)-infused porphyrin MOF: maximum scavenging GSH for enhanced photodynamic disruption of bacterial biofilm.

Bacterial biofilm infection is a serious obstacle to clinical therapeutics. Photodynamic therapy (PDT) plays a dynamic role in combating biofilm infection by utilizing reactive oxygen species (ROS)-induced bacterial oxidation injury, showing advantages of mild side effects, spatiotemporal controllability and little drug resistance. However, superfluous glutathione (GSH) present in biofilm and bacteria corporately reduces ROS levels and seriously affects PDT efficiency. Herein, we have constructed a Cu2+-infused porphyrin metal-organic framework (MOF@Cu2+) for the enhanced photodynamic combating of biofilm infection by the maximum depletion of GSH. Our results show that the released Cu2+ from porphyrin MOF@Cu2+ could not only oxidize GSH in biofilm but also consume GSH leaked from ROS-destroyed bacteria, thus greatly weakening the antioxidant system in biofilm and bacteria and dramatically improving the ROS levels. As expected, our dual-enhanced PDT nanoplatform exhibits a strong biofilm eradication ability both in vitro and in an in vivo biofilm-infected mouse model. In addition, Cu2+ can promote biofilm-infected wound closing by provoking cell immigration, collagen sediment and angiogenesis. Besides, no apparent toxicity was detected after treatment with MOF@Cu2+. Overall, our design offers a new paradigm for photodynamic combating biofilm infection.

Portable and Rapid Dual-Biomarker Detection Using Solution-Gated Graphene Field Transistors in the Accurate Diagnosis of Prostate Cancer.

Prostate-specific antigen (PSA) is the common serum-relevant biomarker for early prostate cancer (PCa) detection in clinical diagnosis. However, it is difficult to accurately diagnose PCa in the early stage due to the low specificity of PSA. Herein, a new solution-gated graphene field transistor (SGGT) biosensor with dual-gate for dual-biomarker detection is designed. The sensing mechanism is that the designed aptamers immobilized on the surface of the gate electrodes can capture PSA and sarcosine (SAR) biomolecules and induce the capacitance changes of the electric double layers of SGGT. The limit of detections of PSA and SAR biomarkers can reach 0.01 fg mL-1 , which is three-to-four orders of magnitude lower than previously reported assays. The detection time of PSA and SAR is ≈4.5 and ≈13 min, which is significantly faster than the detection time (1-2 h) of conventional methods. The clinical serum samples testing demonstrates that the biosensor can distinguish the PCa patients from the control group and the diagnosis accuracy can reach 100%. The SGGT biosensor can be integrated into the portable platform and the diagnostic results can directly display on the smartphone/Pad. Therefore, the integrated portable platform of the biosensor can distinguish cancer types through the dual-biomarker detection.

Interplay of lipid metabolism and inflammation in podocyte injury.

Podocytes are critical for maintaining permselectivity of the glomerular filtration barrier, and podocyte injury is a major cause of proteinuria in various primary and secondary glomerulopathies. Lipid dysmetabolism and inflammatory activation are the distinctive hallmarks of podocyte injury. Lipid accumulation and lipotoxicity trigger cytoskeletal rearrangement, insulin resistance, mitochondrial oxidative stress, and inflammation. Subsequently, inflammation promotes the progression of glomerulosclerosis and renal fibrosis via multiple pathways. These data suggest that lipid dysmetabolism positively or negatively regulates inflammation during podocyte injury. In this review, we summarize recent advances in the understanding of lipid metabolism and inflammation, and highlight the potential association between lipid metabolism and podocyte inflammation.

PTPN13 rs989902 and CHEK2 rs738722 are associated with esophageal cancer.

PURPOSE: Individual genetic background can play an essential role in determining the development of esophageal squamous cell carcinoma (ESCC). PTPN13 and CHEK2 play important roles in the pathogenesis of ESCC. This case-control study aimed to analyze the association between gene polymorphisms and ESCC susceptibility. METHODS: DNA was extracted from the peripheral blood of patients. The Agena MassARRAY platform was used for the genotyping. Statistical analysis was conducted using the chi-squared test or Fisher's exact test, logistic regression analysis, and stratification analysis. RESULTS: The 'G' allele of rs989902 (PTPN13) and the 'T' allele of rs738722 (CHEK2) were both associated with an increased risk of ESCC (rs989902: OR = 1.23, 95% CI = 1.02-1.47, p = 0.028; rs738722: OR = 1.28, 95% CI = 1.06-1.55, p = 0.011). Stratification analysis showed that SNPs (rs989902 and rs738722) were notably correlated with an increased risk of ESCC after stratification for age, sex, smoking, and drinking status. In addition, rs738722 might be associated with lower stage, while rs989902 had a lower risk of metastasis. CONCLUSION: Our findings display that PTPN13 rs989902 and CHEK2 rs738722 are associated with an increased risk of ESCC in the Chinese Han population.

Association study for the role of MMP8 gene polymorphisms in Colorectal cancer susceptibility.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors, influenced by several genetic loci in its clinical phenotypes. The aim of this study was to determine the relationship between the MMP8 gene polymorphism and CRC risk in the Chinese Han population. METHOD: This study recruited 688 CRC patients and 690 healthy controls. The relationship between MMP8 polymorphism and CRC susceptibility was assessed by calculating the odds ratio (OR) and 95% confidence interval (CI) after stratifying by age, gender, body mass index (BMI), smoking, and alcohol consumption under a multi-genetic model. RESULTS: MMP8 rs3740938 was associated with increased CRC predisposition (p = 0.016, OR = 1.24, 95% CI: 1.04-1.48), and this association was detected particularly in subjects aged > 60 years, females, people with BMI > 24 kg/m2, smokers, and drinkers. Moreover, rs3740938 was found to be associated with the pathological type of rectal cancer. CONCLUSIONS: Our results first displayed that rs3740938 in MMP8 was a risk factor for CRC predisposition. This finding may provide a new biological perspective for understanding the role of the MMP8 gene in CRC pathogenesis.

Progress in controllable bioorthogonal catalysis for prodrug activation.

Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native biochemical reactions, has gained ever-increasing momentum in prodrug delivery over the past few decades. Albeit great progress has been attained in developing new bioorthogonal catalytic reactions and optimizing the catalytic performance of transition metal catalysts (TMCs), the use of TMCs to activate chemotherapeutics at the site of interest in vivo remains a challenging endeavor. To translate the bioorthogonal catalysis-mediated prodrug activation paradigm from flasks to animals, TMCs with targeting capability and stimulus-responsive behavior have been well-designed to perform chemical transformations in a controlled manner within highly complex biochemical systems, rendering on-demand drug activation to mitigate off-target toxicity. Here, we review the recent advances in the development of controllable bioorthogonal catalysis systems, with an emphasis on different strategies for engineering TMCs to achieve precise control over prodrug activation. Furthermore, we outline the envisaged challenges and discuss future directions of controllable bioorthogonal catalysis for disease therapy.

Microvascular invasion-negative hepatocellular carcinoma: Prognostic value of qualitative and quantitative Gd-EOB-DTPA MRI analysis.

OBJECTIVES: The purpose of this study was to establish a model for predicting the prognosis of patients with microvascular invasion (MVI)-negative hepatocellular carcinoma (HCC) based on qualitative and quantitative analyses of Gd-EOB-DTPA magnetic resonance imaging (MRI). MATERIALS AND METHODS: Consecutive patients with MVI-negative HCC who underwent preoperative Gd-EOB-DTPA MRI between January 2015 and December 2019 were retrospectively enrolled.In total, 122 patients were randomly assigned to the training and validation groups at a ratio of 7:3. Univariate and multivariate logistic regression analyses were performed to identify significant clinical parameters and MRI features, including quantitative and qualitative parameters associated with prognosis, which were incorporated into a predictive nomogram. The end-point of this study was recurrence-free survival. Outcomes were compared between groups using the Kaplan-Meier method with the log-rank test. RESULTS: During a median follow-up period of 58.86 months, 38 patients (31.15 %) experienced recurrence. Multivariate analysis revealed that lower relative enhancement ratio (RER), hepatobiliary phase hypointensity without arterial phase hyperenhancement, Liver Imaging Reporting and Data System category, mild-moderate T2 hyperintensity, and higher aspartate aminotransferase levels were risk factors associated with prognosis and then incorporated into the prognostic model. C-indices for training and validation groups were 0.732 and 0.692, respectively. The most appropriate cut-off value for RER was 1.197. Patients with RER ≤ 1.197 had significantly higher postoperative recurrence rates than those with RER > 1.197 (p = 0.004). CONCLUSION: The model integrating qualitative and quantitative imaging parameters and clinical parameters satisfactorily predicted the prognosis of patients with MVI-negative HCC.

Association of PTGER4 and PRKAA1 genetic polymorphisms with gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common malignancies, affected by several genetic loci in the clinical phenotype. This study aimed to determine the association between PTGER4 and PRKAA1 gene polymorphisms and the risk of GC. METHODS: A total of 509 GC patients and 507 age and sex-matched healthy controls were recruited to explore the association between PTGER4 and PRKAA1 genetic polymorphisms and GC susceptibility. Logistic regression analysis was used to study the correlation between these SNPs and GC, with odd ratio (OR) and 95% confidence interval (CI) as indicators. Multifactor dimensionality reduction was utilized to analyze the genetic relationships among SNPs. was conducted to predict gene expression, the impact of SNPs on gene expression, and the signaling pathways involved in PTGER4 and PRKAA1. RESULTS: Overall, rs10036575 in PTGER4 (OR = 0.82, p = 0.029), rs10074991 (OR = 0.82, p = 0.024) and rs13361707 (OR = 0.82, p = 0.030) in PRKAA1 were associated with susceptibility to GC. Stratification analysis revealed that the effects of these SNPs in PTGER4 and PRKAA1 on GC susceptibility were dependent on smoking and were associated with a reduced risk of adenocarcinoma (p < 0.05). Bioinformatics analysis showed an association between SNPs and corresponding gene expression (p < 0.05), and PRKAA1 may affect GC by mediating RhoA. CONCLUSION: This study suggests that PTGER4 and PRKAA1 SNPs might affect the susceptibility of GC, providing a new biological perspective for GC risk assessment, pathogenesis exploration, and personalized treatment.

Association study between C10orf90 gene polymorphisms and colorectal cancer.

Background: Colorectal cancer (CRC) is the third most common malignant tumor in the world. The morbidity and mortality rates in Western countries have decreased, but they are still on the rise in China. C10orf90 is associated with a variety of cancers, but the correlation between C10orf90 and CRC is not yet known. Methods: A total of 1,339 subjects were randomly enrolled in our study. After extracting their DNA, three single-nucleotide polymorphisms (SNPs) of C10orf90 were genotyped to analyze the potential relationship between these variants and CRC risk. PLINK software packages (version 1.07) were used to evaluate multiple genetic models by calculating the odds ratio (OR) and 95% confidence interval (95% CI). The best SNP-SNP interaction model was defined by the multifactor dimensionality reduction (MDR) analysis. Results: C10orf90 rs12412320 was significantly associated with CRC risk (p = 0.006) and might be associated with the lower CRC risk (OR: 0.78; 95% CI: 0.65-0.93). The relationship of rs12412320 with lower CRC risk was found in people aged >60 years and ≤60 years, women, non-smokers, or non-drinkers. Rs11245008 in people aged ≤60 years and rs11245007 among men had a higher CRC susceptibility. Rs12412320 was related to the lower risk of advanced stages (III/IV stage), while rs11245007 might be associated with the higher risk of advanced stages (III/IV stage). Moreover, rs12412320 had the most significant relationship with the susceptibility to rectal cancer. Conclusion: This study is the first to report between C10orf90 gene polymorphisms and CRC risk in Chinese people, which suggests that C10orf90 rs12412320 might play a crucial role in preventing CRC occurrence.

Determination of prognostic predictors in patients with solitary hepatocellular carcinoma: histogram analysis of multiparametric MRI.

PURPOSE: To evaluate the histogram parameters of preoperative multiparametric magnetic resonance imaging (MRI) and clinical-radiological (CR) characteristics as prognostic predictors in patients with solitary hepatocellular carcinoma ≤ 5 cm and to determine the optimal time window for histogram analysis. METHODS: We retrospectively included 151 patients who underwent preoperative MRI between January 2012 and December 2017. All patients were randomly separated into training and validation cohorts (n = 105 and 46). Eight whole-lesion histogram parameters were extracted from T2-weighted images, apparent diffusion coefficient maps, and dynamic contrast-enhanced images. Univariate and multivariate logistic regression analyses were performed to evaluate these histogram parameters and CR variables related to early recurrence (ER) and recurrence-free survival. A nomogram was derived from the clinical-radiological-histogram (CRH) model that incorporated these risk factors. Kaplan-Meier survival analysis was performed to evaluate the prognostic performance of the CRH model. RESULTS: In total, 151 patients (male: female, 130: 21; median age, 54.46 ± 9.09 years) were evaluated. Multivariate logistic regression analysis revealed that the significant risk factors of ER were Mean Absolute Deviation and Minimum in the histogram analysis of the delayed phase images, as well as three important CR variables: albumin-bilirubin grade, microvascular invasion, and tumor size. The nomogram built by incorporating these risk factors showed satisfactory predictive ability in the training and validation cohorts with AUC values of 0.747 and 0.765, respectively. Furthermore, the prognostic nomogram can effectively classify patients into high- and low-risk groups (p < 0.05). CONCLUSION: Multiparametric MRI-derived histogram parameters provide additional value in predicting patient prognosis. The CRH model may be a useful and noninvasive method for achieving prognostic stratification and personalized disease management.

Biomechanical study of two-level oblique lumbar interbody fusion with different types of lateral instrumentation: a finite element analysis.

Objective: The aim of this study was to verify the biomechanical properties of a newly designed angulated lateral plate (mini-LP) suited for two-level oblique lumbar interbody fusion (OLIF). The mini-LP is placed through the lateral ante-psoas surgical corridor, which reduces the operative time and complications associated with prolonged anesthesia and placement in the prone position. Methods: A three-dimensional nonlinear finite element (FE) model of an intact L1-L5 lumbar spine was constructed and validated. The intact model was modified to generate a two-level OLIF surgery model augmented with three types of lateral fixation (stand-alone, SA; lateral rod screw, LRS; miniature lateral plate, mini-LP); the operative segments were L2-L3 and L3-L4. By applying a 500 N follower load and 7.5 Nm directional moment (flexion-extension, lateral bending, and axial rotation), all models were used to simulate human spine movement. Then, we extracted the range of motion (ROM), peak contact force of the bony endplate (PCFBE), peak equivalent stress of the cage (PESC), peak equivalent stress of fixation (PESF), and stress contour plots. Results: When compared with the intact model, the SA model achieved the least reduction in ROM to surgical segments in all motions. The ROM of the mini-LP model was slightly smaller than that of the LRS model. There were no significant differences in surgical segments (L1-L2, L4-L5) between all surgical models and the intact model. The PCFBE and PESC of the LRS and the mini-LP fixation models were lower than those of the SA model. However, the differences in PCFBE or PESC between the LRS- and mini-LP-based models were not significant. The fixation stress of the LRS- and mini-LP-based models was significantly lower than the yield strength under all loading conditions. In addition, the variances in the PESF in the LRS- and mini-LP-based models were not obvious. Conclusion: Our biomechanical FE analysis indicated that LRS or mini-LP fixation can both provide adequate biomechanical stability for two-level OLIF through a single incision. The newly designed mini-LP model seemed to be superior in installation convenience, and equally good outcomes were achieved with both LRS and mini-LP for two-level OLIF.

PFKFB3 downregulation aggravates Angiotensin II-induced podocyte detachment.

Podocytes play a critical role in maintaining normal glomerular filtration, and podocyte loss from the glomerular basement membrane (GBM) initiates and worsens chronic kidney disease (CKD). However, the exact mechanism underlying podocyte loss remains unclear. Fructose-2,6-biphosphatase 3 (PFKFB3) is a bifunctional enzyme that plays crucial roles in glycolysis, cell proliferation, cell survival, and cell adhesion. This study aimed to determine the role of PFKFB3 in angiotensin II (Ang II) kidney damage. We found that mice infused with Ang II developed glomerular podocyte detachment and impaired renal function accompanied by decreased PFKFB3 expression in vivo and in vitro. Inhibition of PFKFB3 with the PFKFB3 inhibitor 3PO further aggravated podocyte loss induced by Ang II. In contrast, activating PFKFB3 with the PFKFB3 agonist meclizine alleviated the podocyte loss induced by Ang II. Mechanistically, PFKFB3 knockdown likely aggravate Ang II-induced podocyte loss by suppressing talin1 phosphorylation and integrin beta1 subunit (ITGB1) activity. Conversely, PFKFB3 overexpression protected against Ang II-induced podocyte loss. These findings suggest that Ang II leads to a decrease in podocyte adhesion by suppressing PFKFB3 expression, and indicates a potential therapeutic target for podocyte injury in CKD.

Dual-Responsive Turn-On T1 Imaging-Guided Mild Photothermia for Precise Apoptotic Cancer Therapy.

Apoptosis has gained increasing attention in cancer therapy as an intrinsic signaling pathway, which leads to minimal leakage of waste products from a dying cell to neighboring normal cells. Among various stimuli to trigger apoptosis, mild hyperthermia is attractive but confronts limitations of non-specific heating and acquired resistance from elevated expression of heat shock proteins. Here, a dual-stimulation activated turn-on T1 imaging-based nanoparticulate system (DAS) is developed for mild photothermia (≈43 °C)-mediated precise apoptotic cancer therapy. In the DAS, a superparamagnetic quencher (ferroferric oxide nanoparticles, Fe3 O4 NPs) and a paramagnetic enhancer (Gd-DOTA complexes) are connected via the N6-methyladenine (m6 A)-caged, Zn2+ -dependent DNAzyme molecular device. The substrate strand of the DNAzyme contains one segment of Gd-DOTA complex-labeled sequence and another one of HSP70 antisense oligonucleotide. When the DAS is taken up by cancer cells, overexpressed fat mass and obesity-associated protein (FTO) specifically demethylates the m6 A group, thereby activating DNAzymes to cleave the substrate strand and simultaneously releasing Gd-DOTA complex-labeled oligonucleotides. The restored T1 signal from the liberated Gd-DOTA complexes lights up the tumor to guide the location and time of deploying 808 nm laser irradiation. Afterward, locally generated mild photothermia works in concert with HSP70 antisense oligonucleotides to promote apoptosis of tumor cells. This highly integrated design provides an alternative strategy for mild hyperthermia-mediated precise apoptotic cancer therapy.

STING deletion alleviates podocyte injury through suppressing inflammation by targeting NLRP3 in diabetic kidney disease.

An increasing number of studies have shown that immune inflammatory response plays a vital role in diabetic kidney disease (DKD). Nod-like receptor protein 3 (NLRP3) inflammasome-dependent inflammatory response is a key mechanism in the initiation and development of DKD. The stimulator of interferon genes (STING) is an adaptor protein that can drive noninfectious inflammation and pyroptosis. However, the mechanism of STING regulating immune inflammation and the interaction with NLRP3-dependent pyroptosis in high glucose state still remains unclear. This study evaluated the potential role of STING in high glucose (HG)-induced podocyte inflammation response. STING expression was significantly increased in db/db mice, STZ-treated diabetic mice, and HG-treated podocytes. Podocyte-specific deletion of STING alleviated podocyte injury, renal dysfunction, and inflammation in STZ-induced diabetic mice. STING inhibitor (H151) administration ameliorated inflammation and improved renal function in db/db mice. STING deletion in podocytes attenuated the activation of the NLRP3 inflammasome and podocyte pyroptosis in STZ-induced diabetic mice. In vitro, modulated STING expression by STING siRNA alleviated pyroptosis and NLRP3 inflammasome activation in HG-treated podocytes. NLRP3 over-expression offset the beneficial effects of STING deletion. These results indicate that STING deletion suppresses podocyte inflammation response through suppressing NLRP3 inflammasome activation and provide evidence that STING may be a potential target for podocyte injury in DKD.

[Application of live biotherapeutic products and perspective in the treatment of inherited metabolic disease].

Live biotherapeutic products (LBPs) refer to the living bacteria derived from human body intestinal gut or in nature that can be used to treat the human disease. However, the naturally screened living bacteria have some disadvantages, such as deficient therapeutic effect and great divergence, which fall short of the personalized diagnosis and treatment needs. In recent years, with the development of synthetic biology, researchers have designed and constructed several engineered strains that can respond to external complex environmental signals, which speeded up the process of development and application of LBPs. Recombinant LBPs modified by gene editing can have therapeutic effect on specific diseases. Inherited metabolic disease is a type of disease that causes a series of clinical symptoms due to the genetic defect of some enzymes in the body, which may cause abnormal metabolism the corresponding metabolites. Therefore, the use of synthetic biology to design LBPs targeting specific defective enzymes will be promising for the treatment of inherited metabolic defects in the future. This review summarizes the clinic applications of LBPs and its potential for the treatment of inherited metabolic defects.

Combined CT and serum CA19-9 for stratifying risk for progression in patients with locally advanced pancreatic cancer receiving intraoperative radiotherapy.

Background and purpose: The aim of this study was to evaluate the significance of baseline computed tomography (CT) imaging features and carbohydrate antigen 19-9 (CA19-9) in predicting prognosis of locally advanced pancreatic cancer (LAPC) receiving intraoperative radiotherapy (IORT) and to establish a progression risk nomogram that helps to identify the potential beneficiary of IORT. Methods: A total of 88 LAPC patients with IORT as their initial treatment were enrolled retrospectively. Clinical data and CT imaging features were analyzed. Cox regression analyses were performed to identify the independent risk factors for progression-free survival (PFS) and to establish a nomogram. A risk-score was calculated by the coefficients of the regression model to stratify the risk of progression. Results: Multivariate analyses revealed that relative enhanced value in portal-venous phase (REV-PVP), peripancreatic fat infiltration, necrosis, and CA19-9 were significantly associated with PFS (all p < 0.05). The nomogram was constructed according to the above variables and showed a good performance in predicting the risk of progression with a concordance index (C-index) of 0.779. Our nomogram stratified patients with LAPC into low- and high-risk groups with distinct differences in progression after IORT (p < 0.001). Conclusion: The integrated nomogram would help clinicians to identify appropriate patients who might benefit from IORT before treatment and to adapt an individualized treatment strategy.

Reduction of anaerobic glycolysis contributes to angiotensin II-induced podocyte injury with foot process effacement.

Activation of the renin-angiotensin system is associated with podocyte injury and has been well demonstrated as a pivotal factor in the progression of chronic kidney disease. Podocyte energy metabolism is crucial for maintaining their physiological functions. However, whether renin-angiotensin system activation promotes chronic kidney disease progression by disturbing the energy metabolism of podocytes has not been elucidated. Angiotensin II, the main active molecule of the renin-angiotensin system, plays a crucial role in chronic kidney disease initiation and progression, but its impact on podocyte metabolism remains unclear. Here, we demonstrate a rapid decrease in the expression of pyruvate kinase M2, a key glycolytic enzyme, and reduced glycolytic flux in podocytes exposed to angiotensin II in vivo and in vitro. Podocyte-specific deletion of pyruvate kinase M2 in mice aggravated angiotensin II-induced glomerular and podocyte injury with foot process effacement and proteinuria. The inhibition of glycolysis was accompanied by adenosine triphosphate deficiency, cytoskeletal remodeling and podocyte apoptosis. Mechanistically, we found that angiotensin II-induced glycolysis impairment contributed to an insufficient energy supply to the foot process, leading to podocyte injury. Additionally, pyruvate kinase M2 expression was found to be reduced in podocytes from kidney biopsies of patients with hypertensive nephropathy and diabetic kidney disease. Thus, our findings suggest that glycolysis activation is a potential therapeutic strategy for podocyte injury.