Design and construction of chemical-biological module clusters for degradation and assimilation of poly(ethylene terephthalate) waste.

The rising accumulation of poly(ethylene terephthalate) (PET) waste presents an urgent ecological challenge, necessitating an efficient and economical treatment technology. Here, we developed chemical-biological module clusters that perform chemical pretreatment, enzymatic degradation, and microbial assimilation for the large-scale treatment of PET waste. This module cluster included (i) a chemical pretreatment that involves incorporating polycaprolactone (PCL) at a weight ratio of 2% (PET:PCL = 98:2) into PET via mechanical blending, which effectively reduces the crystallinity and enhances degradation; (ii) enzymatic degradation using Thermobifida fusca cutinase variant (4Mz), that achieves complete degradation of pretreated PET at 300 g/L PET, with an enzymatic loading of 1 mg protein per gram of PET; and (iii) microbial assimilation, where Rhodococcus jostii RHA1 metabolizes the degradation products, assimilating each monomer at a rate above 90%. A comparative life cycle assessment demonstrated that the carbon emissions from our module clusters (0.25 kg CO2-eq/kg PET) are lower than those from other established approaches. This study pioneers a closed-loop system that seamlessly incorporates pretreatment, degradation, and assimilation processes, thus mitigating the environmental impacts of PET waste and propelling the development of a circular PET economy.

Contrast-enhanced CT radiomics features to preoperatively identify differences between tumor and proximal tumor-adjacent and tumor-distant tissues of resectable esophageal squamous cell carcinoma.

BACKGROUND: Esophagectomy is the main treatment for esophageal squamous cell carcinoma (ESCC), and patients with histopathologically negative margins still have a relatively higher recurrence rate. Contrast-enhanced CT (CECT) radiomics might noninvasively obtain potential information about the internal heterogeneity of ESCC and its adjacent tissues. This study aimed to develop CECT radiomics models to preoperatively identify the differences between tumor and proximal tumor-adjacent and tumor-distant tissues in ESCC to potentially reduce tumor recurrence. METHODS: A total of 529 consecutive patients with ESCC from Centers A (n = 447) and B (n = 82) undergoing preoperative CECT were retrospectively enrolled in this study. Radiomics features of the tumor, proximal tumor-adjacent (PTA) and proximal tumor-distant (PTD) tissues were individually extracted by delineating the corresponding region of interest (ROI) on CECT and applying the 3D-Slicer radiomics module. Patients with pairwise tissues (ESCC vs. PTA, ESCC vs. PTD, and PTA vs. PTD) from Center A were randomly assigned to the training cohort (TC, n = 313) and internal validation cohort (IVC, n = 134). Univariate analysis and the least absolute shrinkage and selection operator were used to select the core radiomics features, and logistic regression was performed to develop radiomics models to differentiate individual pairwise tissues in TC, validated in IVC and the external validation cohort (EVC) from Center B. Diagnostic performance was assessed using area under the receiver operating characteristics curve (AUC) and accuracy. RESULTS: With the chosen 20, 19 and 5 core radiomics features in TC, 3 individual radiomics models were developed, which exhibited excellent ability to differentiate the tumor from PTA tissue (AUC: 0.965; accuracy: 0.965), the tumor from PTD tissue (AUC: 0.991; accuracy: 0.958), and PTA from PTD tissue (AUC: 0.870; accuracy: 0.848), respectively. In IVC and EVC, the models also showed good performance in differentiating the tumor from PTA tissue (AUCs: 0.956 and 0.962; accuracy: 0.956 and 0.937), the tumor from PTD tissue (AUCs: 0.990 and 0.974; accuracy: 0.952 and 0.970), and PTA from PTD tissue (AUCs: 0.806 and 0.786; accuracy: 0.760 and 0.786), respectively. CONCLUSION: CECT radiomics models could differentiate the tumor from PTA tissue, the tumor from PTD tissue, and PTA from PTD tissue in ESCC.

From basic to clinical: Anatomy of Denonvilliers' fascia and its application in laparoscopic radical resection of rectal cancer.

The total mesorectal excision (TME) approach has been established as the gold standard for the surgical treatment of middle and lower rectal cancer. This approach is widely accepted to minimize the risk of local recurrence and increase the long-term survival rate of patients undergoing surgery. However, standardized TME causes urogenital dysfunction in more than half of patients, thus lowering the quality of life of patients. Of note, pelvic autonomic nerve damage during TME is the most pivotal cause of postoperative urogenital dysfunction. The anatomy of the Denonvilliers' fascia (DVF) and its application in surgery have been investigated both nationally and internationally. Nevertheless, controversy exists regarding the basic to clinical anatomy of DVF and its application in surgery. Currently, it is a hotspot of concern and research to improve the postoperative quality of life of patients with rectal cancer through the protection of their urinary and reproductive functions after radical resection. Herein, this study systematically describes the anatomy of DVF and its application in surgery, thus providing a reference for the selection of surgical treatment modalities and the enhancement of postoperative quality of life in patients with middle and low rectal cancer.

Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity.

BACKGROUND: The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. METHODS: Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. RESULTS: Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. CONCLUSION: Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.

Neuroglobin Facilitates Neuronal Oxygenation through Tropic Migration under Hypoxia or Anemia in Rat: How Does the Brain Breathe?

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His64) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.

A quantitative model based on gross tumor volume of gastric adenocarcinoma corresponding to N-stage measured at multidetector computed tomography for preoperative determination of resectability: A case control study.

Purpose: To develop and validate a quantitative model based on gross tumor volume (GTV) of gastric adenocarcinoma (GA) corresponding to N-stage measured at multidetector computed tomography (CT) for preoperative determination of resectability. Materials and methods: 493 consecutive patients with confirmed GA undergoing contrast-enhanced CT two weeks before treatments were randomly enrolled into the training cohort (TC, n = 271), internal validation cohort (IVC, n = 107) and external validation cohort (EVC, n = 115). GTV was measured on CT by multiplying sums of all tumor areas by section thickness. In TC, univariate and multivariate analyses were performed to select factors associated with resectability. Receiver operating characteristic (ROC) analysis was to determine if N-stage based GTV could identify resectability. In IVC and EVC, unweighted Cohen's Kappa tests were to evaluate performances of the ROC models. Results: According to univariate analysis, age, cT stage, cN stage and GTV were related to resectability in TC (all P-values < 0.05), and multivariate analysis suggested that cN stage and GTV were independent risk factors with odds ratios of 1.594 (95% confidence interval [CI]: 1.105-2.301) and 1.055 (95%CI: 1.035-1.076), respectively. ROC analysis in TC revealed the cutoffs of 21.81, 21.70 and 36.93 cm3 to differentiate between resectable and unresectable cancers in stages cN0-3, cN2 and cN3 with areas under the curves of more than 0.8, respectively, which was validated in IVC and EVC with average Cohen k-values of more than 0.72. Conclusions: GTV and cN stage can be independent risk factors of unresectable GA, and N-stage based GTV can help determine resectability.

Apparent diffusion coefficient derived from diffusion-weighted imaging to differentiate between tumor, tumor-adjacent and tumor-distant tissues in resectable rectal adenocarcinoma.

PURPOSE: To evaluate feasibility of apparent diffusion coefficient (ADC) at different b-values to differentiate between tumor, tumor-adjacent and tumor-distant tissues in rectal adenocarcinoma (RA). MATERIALS AND METHODS: Seventy consecutive patients with RA undergoing preoperative diffusion-weighted imaging were retrospectively enrolled. ADCs of tumor, proximal tumor-adjacent tissue (PTA) and tumor-distant tissue (PTD), and distal tumor-adjacent tissue (DTA) and tumor-distant tissue (DTD) were calculated with b-values of 0 and 800 sec/mm2, 0 and 1000 sec/mm2, 0 and 1500 sec/mm2, and multiple b-values of 0, 50, 100, 800, 1000 and 1500 sec/mm2. Statistical analysis was performed to determine feasibility of ADC to differentiate between pairwise tissues. RESULTS: Mean ADC of tumor was lower than those of PTA, PTD, DTA and DTD; and mean ADCs of PTA and DTA were lower than those of PTD and DTD at all b-values, respectively (all P-values < 0.001). ADC cut-offs of 1.089 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 1.215 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.142 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 0.995 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) achieved excellent performance in differentiating tumor from PTA or PTD, and tumor from DTA or DTD (area under receiver operating characteristic curves [AUCs]: 0.813 or 0.952, and 0.970 or 0.996), respectively. ADC cut-offs of 1.625 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.165 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) could differentiate PTA from PTD, and DTA from DTD (AUCs: 0.709 and 0.673), respectively. CONCLUSION: ADC can help differentiate between tumor, tumor-adjacent and tumor-distant tissues in RA.

Association of time in range with postoperative wound healing in patients with diabetic foot ulcers.

Time in range (TIR) is a novel indicator of glycaemic control that has been reported to have an association with diabetic complications. The objective of the study was to explore the association of TIR with postoperative wound healing in patients with diabetic foot ulcers (DFUs). We retrospectively analysed the data of DFU patients who had undergone surgical treatment from 2015 to 2019. A 1:1 ratio in propensity score matching (PSM) was adopted to compare patients with TIR ≥50% with those <50%. Data were summarised using chi-squared, Fisher's exact, and Mann-Whitney U tests. Patients with TIR <50% underwent a higher rate of secondary surgery within a month (P = .032) and had a longer hospital stay (P = .045) with greater hospital charges (P < .001) than the TIR ≥50% group. Multivariate analysis revealed that TIR (P = .034), Wagner score (P = .009), diabetes treatment (P = .006), and type of surgery (P = .013) were independent risk factors for secondary surgery. Additionally, patient subgroups with TIR <50% and baseline HbA1c < 7.5% (P = .025), albumin level ≥ 30 g/L (P = .039), HDL < 1.16 (P = .021), or Wagner score ≥ 3 (P = .048) also experienced a higher incidence of secondary surgery. TIR was correlated with postoperative wound healing in patients with DFUs. Strict glycaemic targets should be established for surgical patients.

Rapid tumor recurrence in a novel murine GBM surgical model is associated with Akt/PD-L1/vimentin signaling.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor without curable therapy. Surgical resection remains the first choice of patients with GBM but tumors relapse rapidly even combined with conventional chemoradiotherapy. The mechanism of GBM rapid recurrence is poorly understood, which is largely due to the lack of an appropriate animal model, thus heavily impedes the improvement of postoperative therapy. Here we established a highly reproducible mouse GBM surgical model by using the syngeneic G422TN-GBM cells, which faithfully recapitulates the features of rapid recurrence of human GBM after surgery. Implanting 2 × 103-5 × 104 of G422TN-GBM cells in mouse cerebral cortex caused death in all animal within 23 days, while surgery was an effective therapy but not curable. After complete removal of visible tumors on day 5-9 of tumor growth, the tumors recurred macroscopically within 5 days accompanied by increasing infiltrative cancer foci. Mechanistically, the rapid recurrence of resected tumors was positively correlated to early Akt activation, which subsequently upregulated PD-L1/Vimentin and promoted proliferation/migration of cancer cells. In addition, environmental astrocytic activation with strong PD-L1 signal was prominent. Taken together, we provided a novel GBM surgical recurrence model for preclinical studies and suggested complicated recurring mechanisms involving in strong oncogenic signaling as well as immune inhibitory signals from both GBM cells and their neighboring astrocytes.

The Binding of PD-L1 and Akt Facilitates Glioma Cell Invasion Upon Starvation via Akt/Autophagy/F-Actin Signaling.

Glioma, especially glioblastoma, is pathologically characterized by high aggressiveness, which largely contributed to the ineffectiveness of current therapies. It has been recently reported that intrinsic PD-L1 can regulate tumor malignancy, whereas underlying mechanisms remain mostly unclear. Here, we report a novel mechanism by which PD-L1 promotes glioma cell infiltration. In orthotopic glioma models, PD-L1 expression was up-regulated predominantly in glioma cells in the infiltrating front. For PD-L1-overexpressed glioma cells, PI3K/Akt and actin regulations were among the top six most altered signaling pathways as detected by RNA-sequencing. PD-L1 significantly activated Akt/F-actin signaling while suppressed autophagic signaling upon cell starvation. Mechanistically, PD-L1 preferentially bound to Akt among various PI3K/Akt signaling proteins. Serial truncation identified the interaction between the 128-237aa fragment of PD-L1 and the 112-480aa fragment of Akt, which facilitates the membrane translocation/activation of Akt, and was unaffected by Perifosin (specific p-Akt inhibitor targeting Akt PH-domain). Taken together, our data indicate that in glioma cells, PD-L1 is induced to prevent autophagic cytoskeleton collapse via Akt binding/activation, facilitating glioma cell invasion upon starvation stress.

PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt-dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.

Neuroglobin boosts axon regeneration during ischemic reperfusion via p38 binding and activation depending on oxygen signal.

Cerebral ischemia causes severe cell death or injury including axon breakdown or retraction in the brain. Axon regeneration is crucial for the functional recovery of injured neurons or brains after ischemia/reperfusion (I/R); however, this process has been proved extremely difficult in adult brains and there is still no effective therapy for it. Here we reported that neuroglobin (Ngb), a novel oxygen-binding or sensor protein existing predominantly in neurons or brains, functions as a driving factor for axon regeneration during I/R. Ngb was upregulated and accumulated in growth cones of ischemic neurons in primary cultures, rat, and human brains, correlating positively to the elevation of axon-regeneration markers GAP43, neurofilament-200, and Tau-1. Ngb overexpression promoted while Ngb knockdown suppressed axon regeneration as well as GAP43 expression in neurons during oxygen-glucose deprivation/reoxygenation (OGD/Re). By using specific pharmacological inhibitors, we identified p38 MAPK as the major downstream player of Ngb-induced axon regeneration during OGD/Re. Mechanistically, Ngb directly bound to and activated p38 in neurons upon OGD/Re. Serial truncation and point mutation of Ngb revealed that the 7-105 aa fragment of Ngb was required and the oxygen-binding site (His64) of Ngb was the major regulatory site for its p38 interaction/activation. Finally, administration of exogenous TAT-Ngb peptides significantly enhanced axon regeneration in cultured neurons upon OGD/Re. Taken together, Ngb promotes axon regeneration via O2-Ngb-p38-GAP43 signaling during I/R. This novel mechanism suggests potential therapeutic applications of Ngb for ischemic stroke and other related axonopathy.

The Prognostic and Therapeutic Value of PD-L1 in Glioma.

Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization.

Piperlongumine (PL), a natural alkaloid isolated from longer pepper plants, is recently found to be a potent selective anti-cancer compound. We first tested its anti-cancer effects on bladder cancer, the fifth most common and aggressive cancer worldwide, to further explore the therapeutic spectrum and molecular mechanisms of PL. PL significantly suppressed bladder cancer cell proliferation, the transition of G2/M phase to next phase, migration/invasion in vitro and bladder cancer growth/development in vivo. PL markedly elevated reactive oxygen species (ROS) and the administration of antioxidants abolished PL induced cell proliferation inhibition, G2/M phase arrest and migration suppression on bladder cancer cells. In vivo studies demonstrated that PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, ß-catenin, ZEB1 and N-Cadherin. Further, we first reported PL effects on cytoskeleton with prominently reduced lamellipodia formation and decreased F-actin intensity in bladder cancer cells. Taken together, our results first revealed that PL suppressed bladder cancer proliferation and migration in vivo and in vitro, suggesting novel mechanism underlying PL's anti-cancer effect and providing a new anticancer drug strategy for bladder cancer therapy.

Insulin sensitizers improve the GLP-1 secretion and the amount of intestinal L cells on high-fat-diet-induced catch-up growth.

OBJECTIVE: The aim of this study was to investigate whether insulin resistance can result in impaired glucagon-like peptide (GLP)-1 secretion and to determine whether insulin-sensitizing drugs could improve the secretion of GLP-1 in catch-up growth rats. METHODS: Male Sprague Dawley rats were used to establish a catch-up growth model. At the end of weeks 6 and 14, these rats were euthanized to measure energy intake, body weight, plasma triacylglycerol, and nonesterified fatty acid. Fat mass percentage was analyzed by dual-energy x-ray absorptiometry scan. The GLP-1 concentrations were measured by enzyme-linked immunosorbent assay, the glucose infusion rates were measured by hyperinsulinemic-glucose clamp experiment. Quantification of the GLP-1 positive cells in distal ileum was done by immunohistochemical staining method. The L cell line NCI-H716 cells were treated in vitro with palmitate acid, the cells' viability, the carnitine palmitoyl transferase-1, and the insulin signaling pathway were detected. RESULTS: Rats fed a high-fat diet rats had rapidly developed insulin resistance, impaired incretin effect, and a reduction in the number of intestinal L cells. The insulin sensitizers, metformin and pioglitazone, improved insulin resistance and the concentration of circulating GLP-1, increased the relative number of intestinal L cells to a certain degree. In vitro, the NCI-H716 cell viability was decreased and impaired insulin signaling pathway with palmitate acid treatment, metformin treatment could reverse these effects, whereas pioglitazone could not. CONCLUSIONS: Insulin resistance caused by a high-fat diet could result in reduced GLP-1 secretion; the insulin sensitizing drugs were able to improve the incretin effect in catch-up growth rats.

Identification of repaglinide as a therapeutic drug for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients.

14-3-3 Isoforms Differentially Regulate NFκB Signaling in the Brain After Ischemia-Reperfusion.

Mammalian 14-3-3 isoforms exist predominantly in the brain and are heavily involved in neurological diseases. However, the isoform-specific role of 14-3-3 proteins in the brain remains largely unclear. Here, we investigated the role of 14-3-3 isoforms in rat brains after transient middle cerebral artery occlusion and reperfusion. 14-3-3ß, η, γ and ζ but not ε or τ were selectively upregulated in cerebral cortical neurons after ischemia-reperfusion (I/R). Selectively, 14-3-3ß, γ and ζ were translocated from cytoplasm into the nuclei of neurons after I/R. 14-3-3 bound to p65 and suppressed p65 expression in N2a cells. In the brain, 14-3-3 could either colocalize with p65 in the nuclei of neurons or segregate from p65 expression in cortical neurons after I/R. All evidence together suggests that 14-3-3 isoforms are differentially induced to enter into the nuclei of neurons after I/R, which might regulate NFκB signaling directly or indirectly. Since 14-3-3 proteins are essential for cell survival and NFκB is a key transcriptional factor, our data suggest that the 14-3-3/p65 signaling pathway might be a potential therapeutic target for stroke.

Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and its therapies. However, direct and accurate measurement of oxygen concentration and evaluation of hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions shown by measuring partial pressure of oxygen (pO2), the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia-inducible factor and neuroglobin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, sorafenib, 2-methoxyestradiol, and celastrol. This review focuses primarily on the results of clinical and animal studies.

The Value of Tumor Diameter in Predicting Prognosis of Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiotherapy.

Objective The tumor, node, and metastasis staging system of nasopharyngeal carcinoma (NPC) has limitations in predicting prognosis. The aim of this study was to explore the prognostic value of tumor diameter for patients with NPC who were treated with intensity-modulated radiotherapy. Study Design Case series with chart review. Setting Affiliated Cancer Hospital of Guangxi Medical University. Subjects and Methods The cases of 137 NPC patients treated with intensity-modulated radiotherapy were retrospectively reviewed. Tumor diameter was measured on pretreatment magnetic resonance images. Receiver operating characteristic curve was used to find the optimal cutoff value of tumor diameter and to examine the predictive ability of tumor diameter combined with T classification. Results The mean tumor diameter increased with the advancing of T classification. The 5-year cumulative survival rates for patients with a tumor diameter <43 mm vs ≥43 mm were 88.4% vs 61.8% ( P < .001), respectively. In multivariate analysis, tumor diameter was an independent prognostic factor for 5-year cumulative survival. For patients with T3 + T4, the 5-year cumulative survival rate was higher in the group with a tumor diameter <43 mm vs ≥43 mm (86.2% vs 60.2%, P = .022). The area under the receiver operating characteristic curve was 70.3% for tumor diameter combined with T classification, superior to T classification (area under the curve = 66.2%). Conclusion Tumor diameter may be related to the extent of tumor invasion and can provide important information on prognosis. The incorporation of 43 mm as a cutoff value of tumor diameter may help to refine the predictive power of the current staging system for NPC.