A GSH-resistant FK228 analogue containing a stable disulfide bond.

FK228 is a potent natural pan HDAC inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphoma as well as peripheral T-cell lymphoma. It is generally believed that the mechanism of FK228 acting on HDACs is by reducing its disulfide bond after entering the cell, and the dithiol group may chelate with Zn2+ and form a weak reversible covalent bond with cysteine in the catalytic pocket of HDACs, therefore inhibiting the activity of HDACs. However, due to the weak stability of the disulfide bond in FK228, it has been difficult to obtain direct evidence for the above conjecture. Thus, improving the stability of the FK228 disulfide bond will help to explore the exact mechanism of FK228. In this study, based on the stability and target-induced covalent properties of the Cysteine-Penicillamine (Cys-Pen) disulfide bond reported previously, the Pen was introduced into the modification of FK228. Specifically, the d-Cys in FK228 was replaced by d-Pen, the total synthetic pathway was optimized, and the novel synthetic FK228 analogue (FK-P) stability was verified. FK-P can also be used as a new drug molecule in the future to participate in the research of related biological mechanisms or the treatment of diseases.

Development of Lysine Crotonyl-Mimic Probe to Covalently Identify H3K27Cr Interacting Proteins.

Histone lysine crotonylation (Kcr) is one newly discovered acylation modification and regulates numerous pathophysiological processes. The binding affinity between Kcr and its interacting proteins is generally weak, which makes it difficult to effectively identify Kcr-interacting partners. Changing the amide of crotonyl to an ester increased reactivity with proximal cysteines and retained specificity for Kcr antibody. The probe "H3g27Cr" was designed by incorporating the ester functionality into a H3K27 peptide. Using this probe, multiple Kcr-interacting partners including STAT3 were successfully identified, and this has not been reported previously. Further experiments suggested that STAT3 possibly could form complexes with Histone deacetylase HDACs to downregulate the acetylation and crotonylation of Histone H3K27. Our unique design provided intriguing tools to further explore Kcr-interacting proteins and elucidate their working mechanisms.

PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.

OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC). DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.

[Clinical features of intestinal polyps and risk factors for secondary intussusception in children: an analysis of 2 669 cases]. / 2 669ä¾‹å„¿ç«¥è‚ æ¯è‚‰çš„ä¸´åºŠç‰¹å¾åŠç»§å‘è‚ å¥—å çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To study the clinical features of intestinal polyps and the risk factors for secondary intussusception in children. METHODS: A retrospective analysis was performed for the medical data of 2 669 children with intestinal polyps. According to the presence or absence of secondary intussusception, they were divided into two groups: intussusception (n=346) and non-intussusception (n=2 323). Related medical data were compared between the two groups. The multivariate logistic regression analysis was used to identify the risk factors for secondary intussusception. RESULTS: Among the children with intestinal polyps, 62.42% were preschool children, and the male/female ratio was 2.08∶1; 92.66% had hematochezia as disease onset, and 94.34% had left colonic polyps and rectal polyps. There were 346 cases of secondary intussusception, with an incidence rate of 12.96% (346/2 669). Large polyps (OR=1.644, P<0.001), multiple polyps (≥2) (OR=6.034, P<0.001), and lobulated polyps (OR=93.801, P<0.001) were the risk factors for secondary intussusception. CONCLUSIONS: Intestinal polyps in children often occur in preschool age, mostly in boys, and most of the children have hematochezia as disease onset, with the predilection sites of the left colon and the rectum. Larger polyps, multiple polyps, and lobulated polyps may increase the risk of secondary intussusception, and endoscopic intervention is needed as early as possible to improve prognosis.

Cost-effectiveness analysis of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in the first-line setting for Chinese patients with metastatic nasopharyngeal carcinoma.

PURPOSE: A randomized phase III trial demonstrated that gemcitabine plus cisplatin (GP) prolonged progression-free survival and overall survival compared with fluorouracil plus cisplatin (FP) as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma (NPC). The cost-effectiveness analysis was designed to identify the economic option for metastatic NPC from a Chinese societal perspective. METHODS: We established a Markov model that involved three health states representing the stages of disease to simulate therapy. Survival data of clinical outcomes were derived from the trial and adjusted to quality-adjusted life years (QALYs). Transition probabilities and health utilities were obtained from the clinical trial and published literatures. The cost-effective strategy was estimated for these treatments using a willing-to-pay (WTP) threshold. A one-way sensitivity analysis was conducted to study the influences of parameters. RESULTS: GP treatment group produced a gain of 0.37 QALYs with an incremental cost of $2520.80, yielding an incremental cost-effectiveness ratio (ICER) of $6812.97 per QALY, compared with FP treatment ($15,530.96 versus $13,010.16). The ICER was lower than the accepted WTP threshold, which was 3 times gross domestic product per capita of China ($25,749 per QALY). CONCLUSION: GP regimen is more cost-effective compared with FP regimen as the first-line treatment for Chinese patients with metastatic NPC.

[Analysis of metabolites of 4,5-dicaffeoylquinic acid in rat plasma and urine based on LC-MS].

Ultra high performance liquid chromatography tandem high field orbital trap mass spectrometry(UPLC-Orbitrap Elite-MS/MS) method was applied in this paper to analyze the metabolites of 4,5-dicaffeoylquinic acid in rat plasma and urine after oral administration. A gradient elution was performed by using Thermo C_(18) column(2.1 mm×100 mm, 1.9 µm), with 0.1% formic acid solution-acetonitrile as the mobile phase. Mass spectral data of biological samples were collected in negative ion mode. The data were extracted by Compound Discovery 2.1 software. Then the blank group samples and the drug samples were compared for exact molecular weight and the mass fragmentation information, and the secondary fragment fitting ratio was calculated to finally attribute the metabolites. As a result, 15 metabolites were detected in rat plasma, and 16 metabolites were detected in urine. The involving metabolic reactions included methylation, hydration, dehydration, reduction, glucuronide conjugation, and sulfation reaction. The metabolites in plasma and urine complemented each other and initially revealed the migration and excretion patterns of this compound in the body. A method for pre-processing biological samples, high-resolution LC-MS instrumentation data, and qualitative software was established in this study to identify metabolite structures, laying the foundation for the study of the active ingredients and in vivo pharmacodynamics forms of Chinese medicines.

Versatile, Robust, and Facile Approach for in Situ Monitoring Electrocatalytic Processes through Liquid Electrochemical NMR Spectroscopy.

With the strength of liquid nuclear magnetic resonance (NMR) to noninvasively and specifically realize the structural elucidation and quantitative analysis of small organic molecules, in principle, liquid in situ electrochemical-NMR (EC-NMR) possesses great advantages for detecting dissolved species during the electrochemical process. However, the intrinsic incompatibilities between the coupling techniques as well as the sophisticated setups modification still limit the applications toward a wide range. To overcome these bottlenecks, herein we propose an easy-to-construct design with good compatibility and presenting improved electrochemical and NMR performances. As proof of concept, model experiments of alcohol electrooxidation were performed to confirm the capacity of this device for liquid in situ EC-NMR study. The temporal evolution of both the product and the current distributions can be reliably recorded to aid mechanistic and kinetic understanding of electrocatalysis. The depiction of the selective electrooxidation reveals the surface structure-catalytic functionality. This work demonstrates the universality and effectivity of the proposed platform to develop the liquid in situ EC-NMR technique as a useful tool for the dynamic analysis of electrochemical processes at a molecular level.

Chronic kidney disease promotes chronic inflammation in visceral white adipose tissue.

White adipose tissue plays an important role in the development of metabolic disturbance, which is a common feature in patients with chronic kidney disease (CKD). The effect of CKD on white adipose tissue remains poorly appreciated. Here, we evaluated the inflammatory potential of visceral white adipose tissue in a rat model of CKD. The results showed that production of proinflammatory cytokines and infiltration of macrophage in the tissue were increased significantly in CKD rats compared with sham rats. Moreover, the primary adipocytes and stromal vascular fraction under the condition of CKD could trigger the inflammatory response in each other. Free fatty acid induced robust inflammatory response in ex vivo peritoneal-derived macrophages from CKD rats, which was associated with reduced activity of silent information regulator T1 (SIRT1). Improvement of SIRT1 activity by an activator could alleviate free fatty acid-induced inflammatory response in the macrophages and inflammation in the white adipose tissue. Moreover, oxidative stress occurred in the tissue and linked with the reduced activity of SIRT1 in macrophages and enhanced release of free fatty acid in the tissue. We thus identified CKD as a risk factor for chronic inflammation in white adipose tissue. These observations might open up new therapeutic strategies for metabolic disturbance in CKD via the modulation of adipose tissue-related pathways.

Automated Processing of Imaging Data through Multi-tiered Classification of Biological Structures Illustrated Using Caenorhabditis elegans.

Quantitative imaging has become a vital technique in biological discovery and clinical diagnostics; a plethora of tools have recently been developed to enable new and accelerated forms of biological investigation. Increasingly, the capacity for high-throughput experimentation provided by new imaging modalities, contrast techniques, microscopy tools, microfluidics and computer controlled systems shifts the experimental bottleneck from the level of physical manipulation and raw data collection to automated recognition and data processing. Yet, despite their broad importance, image analysis solutions to address these needs have been narrowly tailored. Here, we present a generalizable formulation for autonomous identification of specific biological structures that is applicable for many problems. The process flow architecture we present here utilizes standard image processing techniques and the multi-tiered application of classification models such as support vector machines (SVM). These low-level functions are readily available in a large array of image processing software packages and programming languages. Our framework is thus both easy to implement at the modular level and provides specific high-level architecture to guide the solution of more complicated image-processing problems. We demonstrate the utility of the classification routine by developing two specific classifiers as a toolset for automation and cell identification in the model organism Caenorhabditis elegans. To serve a common need for automated high-resolution imaging and behavior applications in the C. elegans research community, we contribute a ready-to-use classifier for the identification of the head of the animal under bright field imaging. Furthermore, we extend our framework to address the pervasive problem of cell-specific identification under fluorescent imaging, which is critical for biological investigation in multicellular organisms or tissues. Using these examples as a guide, we envision the broad utility of the framework for diverse problems across different length scales and imaging methods.

Src mediates the mechanical activation of myogenesis by activating TNFα-converting enzyme.

Mechanical stimulation affects many biological aspects in living cells through mechanotransduction. In myogenic precursor cells (MPCs), mechanical stimulation activates p38 mitogen-activated protein kinase (MAPK), a key regulator of myogenesis, via activating TNFα-converting enzyme (TACE, also known as ADAM17), to release autocrine TNFα. However, the signaling mechanism of mechanical activation of TACE is unknown. Because TACE possesses the structural features of substrates of the non-receptor tyrosine kinase Src, we tested the hypothesis that Src mediates mechanical activation of TACE in MPCs. We observed that mechanical stretch of C2C12 or primary rat myoblasts rapidly activates Src, which in turn interacts and colocalizes with TACE, resulting in tyrosine phosphorylation and activation of TACE. Particularly, Src activates TACE via the phosphorylation of amino acid residue Tyr702 in the intracellular tail of TACE, resulting in increased TNFα release and p38 activation. Src inhibition or deficiency blocks stretch activation of the TACE-p38-MAPK signaling, resulting in impaired myogenic gene expression. In response to functional overloading, Src and TACE are activated in mouse soleus muscle. Further, overloading-induced myogenesis and regeneration are impaired in the soleus of Src(+/-) mice. Therefore, Src mediates mechano-activation of TACE and myogenesis.

A generalizable, tunable microfluidic platform for delivering fast temporally varying chemical signals to probe single-cell response dynamics.

Understanding how biological systems transduce dynamic, soluble chemical cues into physiological processes requires robust experimental tools for generating diverse temporal chemical patterns. The advent of microfluidics has seen the development of platforms for rapid fluid exchange allowing ease of changes in the cellular microenvironment and precise cell handling. Rapid exchange is important for exposing systems to temporally varying signals. However, direct coupling of macroscale fluid flow with microstructures is potentially problematic due to the high shear stresses that inevitably add confounding mechanical perturbation effects to the biological system of interest. Here, we have devised a method of translating fast and precise macroscale flows to microscale flows using a monolithically integrated perforated membrane. We integrated a high-density cell trap array for nonadherent cells that are challenging to handle under flow conditions with a soluble chemical signal generator module. The platform enables fast and repeatable switching of stimulus and buffer at low shear stresses for quantitative live, single-cell fluorescent studies. This modular design allows facile integration of any cell-handling chip design with any chemical delivery module. We demonstrate the utility of this device by characterizing heterogeneity of oscillatory response for cells exposed to alternating Ca(2+) waveforms at various periodicities. This platform enables the analysis of cell responses to chemical perturbations at a single-cell resolution that is necessary in understanding signal transduction pathways.

Genetic variants in the KDR gene is associated with the prognosis of transarterial chemoembolization treated hepatocellular carcinoma.

Kinase insert domain receptor (KDR) is the principal receptor that promotes the proangiogenic action of vascular endothelial growth factor and is involved in the tumorigenesis and progression of many malignancies, including hepatocellular carcinoma (HCC). Single-nucleotide polymorphisms (SNPs) of KDR have been reported to be with the risk and prognosis of several malignancies. Our aim was to determine whether SNPs in KDR gene are associated with clinical outcomes in HCC patients treated with transcatheter arterial chemoembolization. A total of 192 HCC patients were tested for KDR SNPs, and the SNP results were correlated with progression-free survival (PFS) and overall survival (OS). The association of the SNPs with the overall survival (OS) of patients was assessed by Kaplan-Meier method, and then Cox proportional hazards model was used to assess the variables resulted significant at univariate analysis. No significant differences were found in correlation between KDR SNPs and patients' PFS. Our data showed that genotype AA+TA of rs1870377 and genotype CC+TC of rs2071559 were significantly associated with overall survival of HCC patients (P<0.001 and P<0.001, respectively) and remained as significant predictors for OS adjusting for high level of serum AFP (>400 µg/L), existence of portal vein tumor thrombus, and high BCLC stage (HR=0.61; 95% CI, 0.36-0.88; P=0.003 and HR=0.54; 95% CI, 0.40-0.94; P=0.002, respectively). Our results suggest that SNPs rs1870377 and rs2071559 in the KDR gene may serve as independent prognosis biomarkers for unresectable HCC patient, which warranted further validating investigation.

Cost-effectiveness analysis of fruquintinib in Chinese patients with refractory metastatic colorectal cancer.

BACKGROUND: Colorectal cancer is a significant health concern worldwide, with metastatic CRC (mCRC) presenting a particularly challenging prognosis. The FRESCO-2 trial highlighted the potential of fruquintinib in heavily pretreated mCRC patients. AIM: Given the recent changes in drug pricing in China and the evolving mCRC treatments, this study aimed to evaluate the cost-effectiveness of fruquintinib in the context of current Chinese healthcare standards. METHOD: This study utilized data from the FRESCO-2 trial, incorporating a partitioned-survival model to simulate three health states: Progression-Free Survival, Progressive Disease, and death. Costs and utility values were derived from published literature and the FRESCO-2 trial. Sensitivity analyses were conducted to assess the robustness of the base-case result and to understand the impact of various parameters on the ICER. RESULTS: The base-case analysis revealed a total cost of $11,089.05 for the fruquintinib group and $5,374.48 for the placebo group. The overall QALYs were higher in the fruquintinib group (0.61 QALYs) compared to the placebo group (0.43 QALYs). The ICER was calculated to be $31,747.67 per QALY. Sensitivity analyses identified the utility of progression-free survival, the cost of fruquintinib, and the costs of best supportive care as significant determinants of ICER. CONCLUSION: Fruquintinib emerges as a promising therapeutic option for refractory mCRC. However, its cost-effectiveness depends on selected willingness-to-pay (WTP) threshold. While the drug's ICER surpasses the WTP based on China's 2022 GDP per capita, it remains below the threshold set at three times the national GDP.

Multi-Mode Damage and Fracture Mechanisms of Thin-Walled Tubular Parts with Cross Inner Ribs Manufactured via Flow Forming.

In order to study the multi-mode damage and fracture mechanisms of thin-walled tubular parts with cross inner ribs (longitudinal and transverse inner ribs, LTIRs), the Gurson-Tvergaard-Needleman (GTN) model was modified with a newly proposed stress state function. Thus, tension damage and shear damage were unified by the new stress state function, which was asymmetric with respect to stress triaxiality. Tension damage dominated the modification, which coupled with the shear damage variable, ensured the optimal prediction of fractures of thin-walled tubular parts with LTIRs by the modified GTN model. This included fractures occurring at the non-rib zone (NRZ), the longitudinal rib (LIR) and the interface between the transverse rib (TIR) and the NRZ. Among them, the stripping of material from the outer surface of the tubular part was mainly caused by the shearing of built-up material in front of the rollers under a large wall thickness reduction (ΔT). Shear and tension deformation were the causes of fractures occurring at the NRZ, while axial tension under a large TIR interval (l) mainly resulted in fractures on LIRs. Fractures at the interface between the TIR and NRZ were due to the shearing applied by rib grooves and radial tension during the formation of ribs. This study can provide guidance for the manufacturing of high-performance aluminum alloy thin-walled tubular components with complex inner ribs.

Biomimetic ZIF-8 Nanoparticles: A Novel Approach for Biomimetic Drug Delivery Systems.

Metal-organic frameworks (MOFs) are porous materials resulting from the coordination of metal clusters or ions with organic ligands, merging macromolecular and coordination chemistry features. Among these, zeolitic imidazolate framework-8 (ZIF-8) stands out as a widely utilized MOF known for its robust stability in aqueous environments owing to the robust interaction between its constituent zinc ions (Zn2+) and 2-methylimidazole (2-MIM). ZIF-8 readily decomposes under acidic conditions, serving as a promising candidate for pH-responsive drug delivery systems. Moreover, biomimetic materials typically possess good biocompatibility, reducing immune reactions. By mimicking natural structures or surface features within the body, they enhance the targeting of nanoparticles, prolong their circulation time, and increase their bioavailability in vivo. This review explores the latest advancements in biomimetic ZIF-8 nanoparticles for drug delivery, elucidating the primary obstacles and future prospects in utilizing ZIF-8 for drug delivery applications.

Prediction and analysis of albumin-bilirubin score combined with liver function index and carcinoembryonic antigen on liver metastasis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor, and liver metastasis is one of the main recurrence and metastasis modes that seriously affect patients' survival rate and quality of life. Indicators such as albumin bilirubin (ALBI) score, liver function index, and carcinoembryonic antigen (CEA) have shown some potential in the prediction of liver metastasis but have not been fully explored. AIM: To evaluate its predictive value for liver metastasis of CRC by conducting the combined analysis of ALBI, liver function index, and CEA, and to provide a more accurate liver metastasis risk assessment tool for clinical treatment guidance. METHODS: This study retrospectively analyzed the clinical data of patients with CRC who received surgical treatment in our hospital from January 2018 to July 2023 and were followed up for 24 months. According to the follow-up results, the enrolled patients were divided into a liver metastasis group and a nonliver metastasis group and randomly divided into a modeling group and a verification group at a ratio of 2:1. The risk factors for liver metastasis in patients with CRC were analyzed, a prediction model was constructed by least absolute shrinkage and selection operator (LASSO) logistic regression, internal validation was performed by the bootstrap method, the reliability of the prediction model was evaluated by subject-work characteristic curves, calibration curves, and clinical decision curves, and a column graph was drawn to show the prediction results. RESULTS: Of 130 patients were enrolled in the modeling group and 65 patients were enrolled in the verification group out of the 195 patients with CRC who fulfilled the inclusion and exclusion criteria. Through LASSO regression variable screening and logistic regression analysis. The ALBI score, alanine aminotransferase (ALT), and CEA were found to be independent predictors of liver metastases in CRC patients [odds ratio (OR) = 8.062, 95% confidence interval (CI): 2.545-25.540], (OR = 1.037, 95%CI: 1.004-1.071) and (OR = 1.025, 95%CI: 1.008-1.043). The area under the receiver operating characteristic curve (AUC) for the combined prediction of CRLM in the modeling group was 0.921, with a sensitivity of 78.0% and a specificity of 95.0%. The H-index was 0.921, and the H-L fit curve had χ2 = 0.851, a P value of 0.654, and a slope of the calibration curve approaching 1. This indicates that the model is extremely accurate, and the clinical decision curve demonstrates that it can be applied effectively in the real world. We conducted internal verification of one thousand resamplings of the modeling group data using the bootstrap method. The AUC was 0.913, while the accuracy was 0.869 and the kappa consistency was 0.709. The combination prediction of liver metastasis in patients with CRC in the verification group had an AUC of 0.918, sensitivity of 85.0%, specificity of 95.6%, C-index of 0.918, and an H-L fitting curve with χ 2 = 0.586, P = 0.746. CONCLUSION: The ALBI score, ALT level, and CEA level have a certain value in predicting liver metastasis in patients with CRC. These three criteria exhibit a high level of efficacy in forecasting liver metastases in patients diagnosed with CRC. The risk prediction model developed in this work shows great potential for practical application.

Landscape and prognostic values of lymphocytes in patients with hepatocellular carcinoma undergoing transarterial embolization.

Transarterial embolization, the first-line treatment for hepatocellular carcinoma, does not always lead to promising outcomes in all patients. A better understanding of how the immune lymphocyte changes after transarterial embolization might be the key to improve the efficacy of transarterial embolization. However, there are few studies evaluating immune lymphocytes in transarterial embolization patients. Therefore, we aimed to evaluate the short- and long-term effects of transarterial embolization on lymphocyte subsets in patients with hepatocellular carcinoma to identify those that predict transarterial embolization prognosis. Peripheral blood samples were collected from 44 patients with hepatocellular carcinoma at the following time points: 1 d before the initial transarterial embolization, 3 d after the initial transarterial embolization, and 1 mo after the initial transarterial embolization and subjected to peripheral blood mononuclear cell isolation and flow cytometry. Dynamic changes in 75 lymphocyte subsets were recorded, and their absolute counts were calculated. Tumor assessments were made every 4 to 6 wk via computed tomography or magnetic resonance imaging. Our results revealed that almost all lymphocyte subsets fluctuated 3 d after transarterial embolization, but only Tfh and B cells decreased 1 mo after transarterial embolization. Univariate and multivariate Cox regression showed that high levels of Th2 and conventional killer Vδ2 cells were associated with longer progressive-free survival after transarterial embolization. Longer overall survival after transarterial embolization was associated with high levels of Th17 and viral infection-specific Vδ1 cells and low levels of immature natural killer cells. In conclusion, transarterial embolization has a dynamic influence on the status of lymphocytes. Accordingly, several lymphocyte subsets can be used as prognostic markers for transarterial embolization.

Effect of negative remodeling of the side branch ostium on the efficacy of a two-stent strategy for distal left main bifurcation lesions: an intravascular ultrasound study.

OBJECTIVES: To investigate whether negative remodeling (NR) detected by intravascular ultrasound (IVUS) of the side branch ostium (SBO) would affect in-stent neointimal hyperplasia (NIH) at the one-year follow-up and the clinical outcome of target lesion failure (TLF) at the long-term follow-up for patients with left main bifurcation (LMb) lesions treated with a two-stent strategy. METHODS: A total of 328 patients with de novo true complex LMb lesions who underwent a 2-stent strategy of percutaneous coronary intervention (PCI) treatment guided by IVUS were enrolled in this study. We divided the study into two phases. Of all the patients, 48 patients who had complete IVUS detection pre- and post-PCI and at the 1-year follow-up were enrolled in phase I analysis, which aimed to analyze the correlation between NR and in-stent NIH at SBO at the 1-year follow-up. If the correlation was confirmed, the cutoff value of the remodeling index (RI) for predicting NIH ≥ 50% was analyzed next. The phase II analysis focused on the incidence of TLF as the primary endpoint at the 1- to 5-year follow-up for all 328 patients by grouping based on the cutoff value of RI. RESULTS: In phase I: according to the results of a binary logistic regression analysis and receiver operating characteristic (ROC) analysis, the RI cutoff value predicting percent NIH ≥ 50% was 0.85 based on the ROC curve analysis, with a sensitivity of 85.7%, a specificity of 88.3%, and an AUC of 0.893 (0.778, 1.000), P = 0.002. In phase II: the TLR rate (35.8% vs. 5.3%, P < 0.0001) was significantly higher in the several NR (sNR, defined as RI ≤ 0.85) group than in the non-sNR group. CONCLUSION: The NR of LCxO is associated with more in-stent NIH post-PCI for distal LMb lesions with a 2-stent strategy, and NR with RI ≤ 0.85 is linked to percent NIH area ≥ 50% at the 1-year follow-up and more TLF at the 5-year follow-up.

Enabling systems biology approaches through microfabricated systems.

With the experimental tools and knowledge that have accrued from a long history of reductionist biology, we can now start to put the pieces together and begin to understand how biological systems function as an integrated whole. Here, we describe how microfabricated tools have demonstrated promise in addressing experimental challenges in throughput, resolution, and sensitivity to support systems-based approaches to biological understanding.

[Prognostic significance of serum level of vascular endothelial growth factor receptor-2 in hepatocellular carcinoma patients after transcatheter arterial chemoembolization].

OBJECTIVE: To explore the prognostic significance of serum vascular endothelial growth factor receptor-2 (VEGFR-2) in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). METHODS: A total of 69 HCC patients undergoing TACE from October 2008 to April 2012 were recruited and examined. Their serum level of VEGFR-2 level was measured by enzyme-linked immunosorbent assay (ELISA). The relationship between VEGFR-2 and their clinicopathologic features were observed. Prognostic significance of VEGFR-2 was assessed for their survival. RESULTS: Significant differences existed when the serum level of VEGFR-2 was categorized by tumor number and liver cirrhosis (P = 0.021, P = 0.049). The post-treatment serum level of VEGFR-2 was significant higher than that at pre-treatment (P = 0.045). When the mean pre-treatment serum level of VEGFR-2 (8709 ng/L) was used as a cut-off point, the patients with a low serum level of VEGFR-2 had better overall and progression-free survival than those with a high serum level of VEGF (17 vs. 28 months, P = 0.001 and 10 vs. 15 months P = 0.031 respectively). As revealed by multivariate Cox analysis, the pre-treatment serum level of VEGFR-2 was an independent and significant prognostic factor of survival for HCC patients at post-TACE. CONCLUSION: The pre-treatment serum level of VEGFR-2 may predict the post-TACE prognosis in HCC patients.