EphA2 promotes the transcription of KLF4 to facilitate stemness in oral squamous cell carcinoma.

Ephrin receptor A2 (EphA2), a member of the Ephrin receptor family, is closely related to the progression of oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play essential roles in OSCC development and occurrence. The underlying mechanisms between EphA2 and CSCs, however, are not yet fully understood. Here, we found that EphA2 was overexpressed in OSCC tissues and was associated with poor prognosis. Knockdown of EphA2 dampened the CSC phenotype and the tumour-initiating frequency of OSCC cells. Crucially, the effects of EphA2 on the CSC phenotype relied on KLF4, a key transcription factor for CSCs. Mechanistically, EphA2 activated the ERK signalling pathway, promoting the nuclear translocation of YAP. Subsequently, YAP was bound to TEAD3, leading to the transcription of KLF4. Overall, our findings revealed that EphA2 can enhance the stemness of OSCC cells, and this study identified the EphA2/KLF4 axis as a potential target for treating OSCC.

Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis.

Lipid metabolic reprogramming of tumor cells has been proven to play a critical role in tumor initiation and development. However, lipid metabolism in cancer-associated fibroblasts (CAFs) has rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Additionally, the molecular mechanism by which tumor cells regulate lipid metabolism in fibroblasts is unclear. In this study, we found that phosphorylated ATP citrate lyase (p-ACLY), a key lipid metabolic enzyme, was upregulated in OSCC CAFs. Compared to paracancerous normal fibroblasts, CAFs showed enhanced lipid synthesis, such as elevated cytosolic acetyl-CoA level and accumulation of lipid droplets. Conversely, reduction of p-ACLY level blocked this biological process. In addition, blocking lipid synthesis in CAFs or inhibiting fatty acid uptake by OSCC cells reduced the promotive effects of CAFs on OSCC cell proliferation, invasion, and migration. These findings suggested that CAFs are one of lipid sources required for OSCC progression. Mechanistically, AKT signaling activation was involved in the upregulation of p-ACLY level and lipid synthesis in CAFs. Interleukin-8 (IL8), an exocrine cytokine of OSCC cells, could activate AKT and then phosphorylate ACLY in fibroblasts. This study suggested that the IL8/AKT/p-ACLY axis could be considered as a potential target for OSCC treatment.

A Versatile Platform to Generate Prodrugs with Rapid and Precise Albumin Hitchhiking and High Cargo Loading for Tumor-Targeted Chemotherapy.

Due to its tumor homing and long serum half-life, albumin is an ideal drug carrier for chemotherapy. For endogenous albumin hitchhiking with high cargo loading, a trimeric albumin-binding domain (ABD), i.e., ABD-Tri is designed by fusing an ABD with high specificity and affinity for albumin to a self-trimerizing domain (Tri) with an additional cysteine residue. ABD-Tri is highly (40 mg L-1) expressed as soluble and trimeric proteins in Escherichia coli (E. coli). Once mixed together, ABD-Tri rapidly and specifically forms a stable complex with albumin under physiological conditions without obviously changing its receptor- and cell-binding and tumor-homing properties. Maleimide-modified prodrugs are highly effectively conjugated to ABD-Tri to produce homogenous ABD-Tri-prodrugs with triple cargo loading under physiological conditions by thiol-maleimide click chemistry. Unlike the maleimide moiety, which can only mediate time- and concentration-dependent albumin binding, ABD-Tri mediated fast (within several minutes) albumin binding of drugs even at extremely low concentrations (µg mL-1). Compared to maleimide-modified prodrugs, ABD-Tri-prodrugs exhibit better tumor homing and greater in vivo antitumor effect, indicating that conjugation of chemical drug to ABD-Tri outperforms maleimide modification for endogenous albumin hitchhiking. The results demonstrate that ABD-Tri may serve as a novel platform to produce albumin-binding prodrugs with high cargo-loading capacity for tumor-targeted chemotherapy.

The effectiveness of urinary TIMP-2 and IGFBP-7 in predicting acute kidney injury in critically ill neonates.

BACKGROUD: Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP-7) and the combination of TIMP-2 and IGFBP-7 ([TIMP-2]•[IGFBP7]) are proposed to be predictive biomarkers for acute kidney injury (AKI). The intention of our study was to determine whether there is any significant predictive value of these biomarkers for the occurrence of AKI and severe AKI in critically ill neonates. METHODS: Urinary samples were serially collected in 237 neonates during neonatal intensive care unit (NICU) stay for measurements of TIMP-2 and IGFBP-7 in this prospective study. AKI diagnosis was based on KDIGO classification without urine output or serum creatinine >1.2 mg/dL. RESULTS: Twenty neonates developed AKI, including 11 with KDIGO stage 1, defined as mild AKI, and 9 with stages 2 and 3, defined as severe AKI. Urinary IGFBP-7 and [TIMP-2]•[IGFBP7] remained associated with AKI after adjustment for gestational age, gender and illness severity. Urinary [TIMP-2]•[IGFBP7] achieved an AUC of 0.71 (P = 0.034) and displayed a sensitivity of 88.9% and a specificity of 50.9% for discriminating severe AKI at the optimal cut-off value of 0.045. CONCLUSION: The combination of TIMP-2 and IGFBP-7 had independent discriminative value for severe AKI in critically ill neonates.

Bactericidal Antibody Responses to Meningococcal Recombinant Outer Membrane Proteins.

Secretin PilQ is an antigenically conserved outer membrane protein that is present in most meningococci and PorA is a major protein that elicits bactericidal immune response in humans following natural disease and immunization. In the present study, BALB/c mice were immunized subcutaneously with rPilQ406-770 or rPorA together with Freund's adjuvant (FA). Serum antibody responses to serogroup A and B Neisseria meningitides whole cells or purified proteins and functional activity of antibodies were determined by ELISA and serum bactericidal assay (SBA), respectively. Serum IgG responses were significantly increased in the immunized group with rPilQ406-770 or rPorA together with FA compared to control groups. IgG antibody response of mice immunized with rPilQ406-770 was significantly more than mice immunized with rPorA (OD at 450 nm was 1.6 versus 0.83). The booster injections were effective in increasing the responses of antirPilQ406-770 or anti-rPorA IgG significantly. Antisera produced against rPilQ406-770 or rPorA demonstrated strong surface reactivity to serogroup B N. meningitides in comparison with control groups. Antisera raised against rPorA or rPilQ406-770 and FA demonstrated SBA titers from 1/1024 to 1/2048 against serogroup B. The strongest bactericidal activity was detected in sera from mice immunized with rPilQ406-770 mixed with FA. These results suggest that rPilQ406-770 is a potential vaccine candidate for serogroup B N. meningitidis.

Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy.

Despite obvious tumor shrinkage, relapse after chemotherapy remains a main cause of cancer-related mortality, indicating that a subpopulation of cancer cells acquires chemoresistance and lingers after treatment. However, the mechanism involved in the emergence of chemoresistant cells remains largely unknown. Here, we demonstrate that the degradation of mitochondria via autophagy leads to a dormant state in a subpopulation of cancer cells and confers on them resistance to lethal cisplatin (DDP) exposure. The surviving DDP-resistant cells (hereafter, DRCs) have a lower metabolic rate but a stronger potential malignant potential. In the absence of DDP, these DRCs exhibit an ever-increasing self-renewal ability and heightened tumorigenicity. The combination of chloroquine and DDP exerts potent tumor-suppressive effects. In summary, our findings illuminate the mechanism between mitophagy and tumor dormancy and prove that targeting mitophagy might be a promising approach for overcoming chemoresistance in head and neck squamous cell carcinoma (HNSCC).

Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma.

Lactate is known to play a crucial role in the progression of malignancies. However, its mechanism in regulating the malignant phenotype of head and neck squamous cell carcinoma (HNSCC) remains unclear. This study found that lactate increases cancer stem cell (CSC) characteristics of HNSCC by influencing the deposition of type I collagen (Col I). Lactate promotes Col I deposition through two distinct pathways. One is to convert lactate to pyruvate, a substrate for Col I hydroxylation. The other is the activation of HIF1-α and P4HA1, the latter being a rate-limiting enzyme for Col I synthesis. Inhibition of these two pathways effectively counteracts lactate-induced enhanced cell stemness. Further studies revealed that Col I affects CSC properties by regulating cell cycle dynamics. In conclusion, our research proposes that lactate-driven Col I deposition is essential for the acquisition of CSC properties, and lactate-centric Col I deposition may be an effective target for CSCs.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

aMAP Score as a Predictor for Long-Term Outcomes in Patients with HBV-Related Acute-on-Chronic Liver Failure.

BACKGROUND AND AIM: The long-term outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remain not well known. This study aimed to investigate whether aMAP score can predict re-hospitalization, hepatocellular carcinoma (HCC) occurrence and long-term mortality in patients with HBV-ACLF. METHODS: A total of 82 patients diagnosed with HBV-ACLF and survived over 6 months were enrolled. The median follow-up period was 105 (75.9, 134.1) months. The Cox proportional hazards or logistic regression analysis was used to determine independent risk factors. Cumulative incidence of HCC and survival rate were evaluated using Kaplan-Meier analysis. RESULTS: Multivariate analysis identified that the aMAP risk score was an independent predictor of re-hospitalization (odds ratio [OR] = 1.112, 95% confidence interval [CI]: 1.021-1.211, p = 0.015), hepatocellular carcinoma occurrence (hazards ratio [HR] = 2.277, 95% CI: 1.014-5.114, p = 0.046) and mortality (HR = 1.366, 95% CI: 1.040-1.794, p = 0.025). High-risk aMAP scores were associated with higher risk of HCC occurrence and mortality. CONCLUSION: A higher aMAP score was an independent risk predictor of re-hospitalization, HCC occurrence and mortality, respectively, in HBV-ACLF patients who survived over 6 months, which can be applicable for early risk stratification and clinical decision.

[Electric pulse duration and windows effect of nuclear envelope].

Nuclear envelope voltages of T cells were analyzed with a lumped circuitry for cells in combination with frequency domain power density of Gaussian pulses and monocycle pulses. According to the differences in geometric and electric parameters between normal and malignant T cells, circuitry analysis was performed. Theoretical evaluations indicated that apoptosis of malignant T cells was of feasibility, which could be applied in cancer therapy. The evaluations were in accord with the published experimental findings.

Urinary Nephrin as a Biomarker of Glomerular Maturation and Injury Is Associated with Acute Kidney Injury and Mortality in Critically Ill Neonates.

BACKGROUND: Nephrin is a key component of the slit diaphragm of the glomerular podocyte, and increased urinary nephrin level may reflect glomerular injury. OBJECTIVES: To determine whether urinary nephrin is a useful biomarker of glomerular maturation and injury and whether it is associated with acute kidney injury (AKI) and neonatal intensive care unit (NICU) mortality in critically ill neonates. METHODS: Urinary samples were serially collected in 234 neonates during NICU stay for measurements of nephrin, cystatin C (CysC), and albumin. AKI diagnosis was based on neonatal Kidney Disease: Improving Global Outcome (KDIGO) criteria. RESULTS: Of the neonates, 26 developed AKI and 24 died during NICU stay. The independent contributors to the initial urinary nephrin level obtained on the first 24 h admitted to NICU were gestational age (p = 0.004) and initial urinary CysC level (p < 0.001). Both initial (p = 0.037) and peak (p = 0.039) urinary nephrin were significantly associated with AKI, even after controlling for significant covariates, and had an area under the receiver-operating characteristic curve (AUC) of 0.71 and 0.70, respectively, for predicting AKI. At the optimal cutoff value of 0.375 µg/mg urinary creatinine, the initial urinary nephrin displayed sensitivity of 61.5% and specificity of 76.9% for predicting AKI. The AUCs for initial and peak urinary nephrin to predict NICU mortality were 0.81 and 0.83, respectively. CONCLUSIONS: Urinary nephrin, which may decrease with increasing glomerular maturity, is significantly associated with increased risk for AKI and NICU mortality even after adjustment for potential confounders. A higher level of urinary nephrin may be independently predictive of AKI and NICU mortality in critically ill neonates.