The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up.

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

The predictive value of γ-glutamyl transferase to serum albumin ratio in hepatocellular carcinoma patients after liver transplantation.

Background: Elevated preoperative γ-glutamyl transferase (GGT) levels or reduced serum albumin levels have been established as negative prognostic factors for patients with hepatocellular carcinoma (HCC) and various other tumors. Nonetheless, the prognostic significance of the GGT to serum albumin ratio (GAR) in liver transplantation (LT) therapy for HCC is still not well-defined. Methods: A retrospective analysis was conducted on the clinical data of 141 HCC patients who underwent LT at Shulan (Hangzhou) Hospital from June 2017 to November 2020. Using the receiver operating characteristic (ROC) curve, the optimal GAR cutoff value to predict outcomes following LT was assessed. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent risk factors associated with both overall survival (OS) and recurrence-free survival (RFS). Results: A GAR value of 2.04 was identified as the optimal cutoff for predicting both OS and RFS, with a sensitivity of 63.2% and a specificity of 74.8%. Among these patients, 80 (56.7%) and 90 (63.8%) met the Milan and the University of California San Francisco (UCSF) criteria, respectively. Univariate Cox regression analysis showed that microvascular invasion (MVI), maximum tumor size (>5 cm), total tumor size (>8 cm), liver cirrhosis, TNM stage (III), and GAR (≥2.04) were significantly associated with both postoperative OS and RFS in patients with HCC (all p < 0.05). Multivariate Cox regression analysis indicated that GAR (≥2.04) was independently linked with RFS and OS. Conclusion: Pre-transplant GAR ≥2.04 is an independent correlate of prognosis and survival outcomes after LT for HCC and can be used as a prognostic indicator for both mortality and tumor recurrence following LT.

Ligand Phase Separation-Promoted, "Squeezing-Out" Mode Explaining the Mechanism and Implications of Neutral Nanoparticles That Escaped from Lysosomes.

Neutral nanomaterials functionalized with PEG or similar molecules have been popularly employed as nanomedicines. Compared to positive counterparts that are capable of harnessing the well-known proton sponge effect to facilitate their escape from lysosomes, it is yet unclear how neutral substances got their entry into the cytosol. In this study, by taking PEGylated, neutral Au nanospheres as an example, we systematically investigated their time-dependent translocation postuptake. Specifically, we harnessed dissipative particle dynamics simulations to uncover how nanospheres bypass lysosomal entrapment, wherein a mechanism termed as "squeezing-out" mode was discovered. We next conducted a comprehensive investigation on how nanomaterials implicate lysosomes in terms of integrity and functionality. By using single-molecule imaging, specific preservation of PEG-terminated with targeting moieties in lysosomes supports the "squeezing-out" mode as the mechanism underlying the lysosomal escape of nanomaterials. All evidence points out that such a process is benign to lysosomes, wherein the escape of nanomaterials proceeds at the expense of targeting moieties loss. Furthermore, we proved that by fine-tuning of the efficacy of nanomaterials escaping from lysosomes, modulation of distinct pathways and metabolic machinery can be achieved readily, thereby offering us a simple and robust tool to implicate cells.

Dynamics of the intestinal bacterial community in black soldier fly larval guts and its influence on insect growth and development.

Black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), is a prominent insect for the bioconversion of various organic wastes. As a saprotrophic insect, the BSF inhabits microbe-rich environments. However, the influences of the intestinal microorganisms on BSF growth and development are not very clear. In this study, the dynamics of the intestinal bacterial community of BSF larvae (BSFL) were analyzed using pyrosequencing. Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria were the most prevalent bacterial phyla in the intestines of all larval instars. The dynamic changes in bacterial community compositions among different larval instars were striking at the genus level. Klebsiella, Clostridium, Providencia, and Dysgonomonas were the relatively most abundant bacteria in the 1st- to 4th-instar BSFL, respectively. Dysgonomonas and Providencia also dominated the 5th- and 6th-instar larvae, at ratios of 31.1% and 47.2%, respectively. In total, 148 bacterial strains affiliated with 20 genera were isolated on different media under aerobic and anaerobic conditions. Among them, 6 bacteria, BSF1-BSF6, were selected for further study. The inoculation of the 6 isolates independently into germ-free BSFL feeding on an artificial diet showed that all the bacteria, except BSF4, significantly promoted BSF growth and development compared with the germ-free control. Citrobacter, Dysgonomonas, Klebsiella, Ochrobactrum, and Providencia promoted BSF development significantly by increasing the weight gains of larvae and pupae, as well as increasing the prepupae and eclosion rates. In addition, Citrobacter, Klebsiella and Providencia shortened the BSF life cycle significantly. The results illustrate the promotive effects of intestinal bacteria on BSF growth and development.

First identification of multidrug-resistant Acinetobacter bereziniae isolates harboring bla NDM-1 from hospitals in South China.

This study is a first report on the identification of multidrug-resistant (MDR) Acinetobacter bereziniae among non-baumannii acinetobacters that had previously escaped automated laboratory detection, and characterize their clinical courses of infection at two tertiary-care hospitals in Shenzhen city, China (2015-2017). Herein, definitive identification by PCR was performed with universal and species-specific primers targeting 16S rDNA and rpoB genes, respectively, followed by Sanger sequencing and blast analysis. Antimicrobial susceptibility of A. bereziniae isolates was assessed accordingly. Three of the five identified A. bereziniae isolates exhibited carbapenem-resistance and were subjected to a multiplex PCR assay to detect drug-resistance genes. Sequences of the rpoB amplicon were aligned with curated sequences from global databases for phylogenetic analysis on evolutionary relations. Five clinical isolates of A. bereziniae were thereby re-identified, whose infections were primarily nosocomial. Automated identification and susceptibility testing systems (Phoenix-100 and VITEK 2) proved insufficient for discriminating A. bereziniae from other acinetobacters such as Acinetobacter baumannii and Acinetobacter guillouiae. Among these isolates, three exhibited carbapenem-resistant phenotypes indistinguishable from that of carbapenem-resistant A. baumannii. The carbapenem-resistant A. bereziniae isolates were subsequently confirmed to carry a bla NDM-1 (New Delhi metallo-ß-lactamase-1) gene downstream of ISAba125. Phylogenetic analysis revealed that A. bereziniae isolates evolved slowly but independently in local habitats. A. bereziniae isolates are difficult to distinguish by traditional automated detection systems. PCR-based identification via amplification and sequencing of selected house-keeping genes provides sufficient resolution for discriminating the isolates.

Intravascular ultrasound-guided stent implantation in reimplanted left main coronary artery of a 15-year-old child: a case report.

BACKGROUND: Only a few cases have been reported about clinical value of percutaneous coronary intervention (PCI) and intravascular ultrasound (IVUS) in patients with stenosis of a re-implanted left main coronary artery (LMCA). CASE SUMMARY: We herein report a rare case of restenosis after direct reimplantation of an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) in a 15-year-old girl. At the first evaluation, she had mildly reduced systolic dysfunction with left ventricular ejection fraction of 47%. Three months after surgical repair, the patient developed recurrent precordial pain. Consequent imaging tests and IVUS revealed a restenosis of the LMCA characterized as an attenuated plaque with a large plaque burden. A drug-eluting stent was implanted with IVUS guidance. Follow-up revealed a patent LMCA and preserved systolic function. DISCUSSION: The current case demonstrated that IVUS-guided PCI can be feasible in the treatment of coronary artery stenosis after repair of an ALCAPA. Further study is needed to explore the pathophysiological mechanism of this condition and the clinical value of PCI and IVUS in patients with stenosis of the LMCA.

[Research Progress of Oral BCL-2 Inhibitor Venetoclax in the Treatment of Non-Hodgkin's Lymphoma --Review].

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.

Effect of indobufen vs. aspirin on platelet accumulation in patients with stable coronary heart disease after percutaneous coronary intervention: An open-label crossover study.

Purpose: This study compared the effect of indobufen with that of aspirin on platelet function in patients with stable coronary heart disease after percutaneous coronary intervention (PCI). Methods: Patients with stable coronary heart disease who had undergone PCI and received dual antiplatelet therapy (aspirin 100 mg + clopidogrel 75 mg once daily) for at least 12 months were allocated to receive indobufen 100 mg twice daily + clopidogrel 75 mg once daily, clopidogrel 75 mg once daily alone, indobufen 100 mg twice daily alone, and aspirin 100 mg once daily alone for 1 month each in an open-label crossover manner. Platelet function was assessed by using the rates of arachidonic acid (AA)-induced platelet aggregation (AA-PAR) and adenosine diphosphate (ADP)-induced platelet aggregation (ADP-PAR) measured by light transmission aggregometry, the platelet reactivity index measured by vasodilator-stimulated phosphoprotein (PRI-VASP), and the plasma and urinary thromboxane B2 (TXB2) concentrations recorded at baseline and during each treatment phase. Results: Of 56 patients enrolled, 52 completed the study. The AA-PAR was lower in the indobufen alone group than in the aspirin alone group [5.21% (3.39, 7.98) vs. 5.27% (4.06, 6.60), p = 0.038], while biologically, a difference of 0.06% may represent no significant difference; there was no significant between-group difference in the plasma [531.16 pg/ml (203.89, 1035.06) vs. 373.93 pg/ml (194.04, 681.71), p = 0.251] or urinary [3951.97 pg/ml (2006.95, 6077.01) vs. 3610.48 pg/ml (1664.60, 6247.61), p = 0.717] TXB2 concentration. When the aspirin + clopidogrel group and indobufen + clopidogrel group were compared, similar results were found for AA-PAR [3.97% (3.05, 5.12) vs. 3.83% (3.10, 5.59), p = 0.947] and both plasma [849.47 pg/ml (335.96, 1634.54) vs. 455.41 pg/ml (212.47, 1489.60), p = 0.629], and urinary [4122.97 pg/ml (2044.96, 7459.86) vs. 3812.81 pg/ml (1358.95, 6021.07), p = 0.165] TXB2 concentrations. ADP-PAR was lower in the clopidogrel alone group than in the indobufen alone group (47.04% ± 16.89 vs. 61.7% ± 10.50, p < 0.001), as was PRI-VASP (66.53% ± 18.06 vs. 77.72% ± 19.87, p = 0.002). Conclusion: These findings suggest that indobufen has antiplatelet effects similar to those of aspirin in patients with stable coronary heart disease after PCI, and may be an alternative for patients with aspirin intolerance after coronary stenting.