Effects of electroacupuncture on the PI3K/Akt/CREB signaling pathway and hippocampal neuronal apoptosis in diabetic cognitive impairment rats. / ç”µé’ˆå¯¹ç³–å°¿ç— è®¤çŸ¥åŠŸèƒ½éšœç¢å¤§é¼ PI3K/Akt/CREBä¿¡å·é€šè·¯å’Œæµ·é©¬ç¥žç»å ƒå‡‹äº¡çš„å½±å“.

OBJECTIVES: To observe the effects of electroacupuncture (EA) on the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/cAMP response element binding protein (CREB) signaling pathway-related proteins and hippocampal neuron apoptosis in diabetic cognitive impairment (DCI) rats, and to explore the mechanisms of EA in treating DCI. METHODS: Adult male SD rats were randomly divided into normal, model, and EA groups, with 12 rats in each group. The animal model of DCI was replicated using a high-fat, high-sugar diet combined with low-dose streptozotocin. The EA group received EA stimulation at "Yishu" (EX-B6), "Zusanli" (ST36), "Baihui" (GV20), and "Dazhui" (GV14). Blood glucose contents of the rats in each group were measured. The Morris water maze test was used to assess the learning and memory abilities of rats. Transmission electron microscopy was used to observe the ultrastructure of hippocampal CA1 neurons. Nissl staining was used to observe the pathological changes in hippocampal CA1 neurons. TUNEL staining was used to detect the apoptosis in hippocampal CA1 neurons. Western blot was used to detect the protein expression levels of p-PI3K/PI3K and p-Akt/Akt, as well as CREB, p-CREB, cysteine aspartate pro-tease (Caspase)-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2 related X protein (Bax) in the hippocampal tissue of rats. RESULTS: Compared with the normal group, the rats' random blood glucose contents were significantly increased (P<0.01), the escape latency prolonged (P<0.01), and the original platform crossing counts reduced (P<0.01) in the model group. Significant damage to hippocampal CA1 neurons, a significantly increased neuronal apoptosis index (P<0.01), decreased ratio of p-PI3K/PI3K and p-Akt/Akt and expression of CREB, p-CREB and Bcl-2 proteins, increased expression of Caspase-3 and Bax proteins (P<0.01) were observed in the hippocampal tissue of rats in the model group. Compared with the model group, the rats in the EA group showed decreased random blood glucose content (P<0.01), shortened escape latency (P<0.01), increased original platform crossing counts (P<0.01), improved quantity and pathological morphology and ultrastructure of hippocampal CA1 neurons, reduced neuronal apoptosis index (P<0.01), increased ratio of p-PI3K/PI3K and p-Akt/Akt, and expression of CREB, p-CREB and Bcl-2 proteins (P<0.05, P<0.01) in the hippocampal tissue, and decreased expression of Caspase-3 and Bax proteins (P<0.01). CONCLUSIONS: EA can improve the learning and memory abilities of rats with DCI, and the mechanism may be related to the regulation of the expression of PI3K/Akt/CREB signaling pathway-related proteins, which attenuates the neuronal apoptosis in the hippocampus of rats, and improves the neural function.

Deuterium Magnetic Resonance Spectroscopy Quantifies Tumor Fraction in a Mouse Model of a Mixed Radiation Necrosis / GL261-Glioblastoma Lesion.

PURPOSE: Distinguishing recurrent brain tumor from treatment effects, including late time-to-onset radiation necrosis (RN), presents an on-going challenge in post-treatment imaging of neuro-oncology patients. Experiments were performed in a novel mouse model that recapitulates the relevant clinical histologic features of recurrent glioblastoma growing in a RN environment, the mixed tumor/RN model. The goal of this work was to apply single-voxel deuterium (2H) magnetic resonance spectroscopy (MRS), in concert with administration of deuterated glucose, to determine if the metabolic signature of aerobic glycolysis (Warburg effect: glucose → lactate in the presence of O2), a distinguishing characteristic of proliferating tumor, provides a quantitative readout of the tumor fraction (percent) in a mixed tumor/RN lesion. PROCEDURES: 2H MRS employed the SPin-ECho full-Intensity Acquired Localized (SPECIAL) MRS pulse sequence and outer volume suppression at 11.74 T. For each subject, a single 2H MRS voxel was placed over the mixed lesion as defined by contrast enhanced (CE) 1H T1-weighted MRI. Following intravenous administration of [6,6-2H2]glucose (Glc), 2H MRS monitored the glycolytic conversion to [3,3-2H2]lactate (Lac) and glutamate + glutamine (Glu + Gln = Glx). RESULTS: Based on previous work, the tumor fraction of the mixed lesion was quantified as the ratio of tumor volume, defined by 1H magnetization transfer experiments, vs. the total mixed-lesion volume. Metabolite 2H MR spectral-amplitude values were converted to metabolite concentrations using the natural-abundance semi-heavy water (1HO2H) resonance as an internal concentration standard. The 2H MR-determined [Lac] / [Glx] ratio was strongly linearly correlated with tumor fraction in the mixed lesion (n = 9), Pearson's r = 0.87, and 77% of the variation in the [Lac] / [Glx] ratio was due to tumor percent r2 = 0.77. CONCLUSIONS: This preclinical study supports the proposal that 2H MR could occupy a well-defined secondary role when standard-of-care 1H imaging is non-diagnostic regarding tumor presence and/or response to therapy.

Application of checklist-based nursing care process in patients undergoing intervention for coronary chronic total occlusions: a quasi-randomized study.

BACKGROUND: Coronary chronic total occlusion (CTO) interventions are more complex than general percutaneous coronary intervention (PCI) procedures. However, only a few nursing methods are specifically applied to patients undergoing CTO interventions. And the conventional nursing effect is not ideal, urgent need to explore more effective nursing methods. The checklist is a simple and effective tool for error management and performance improvement that has been widely used in many fields. But there have been no reports of the checklist being used to improve care for CTO patients. OBJECTIVE: This study aimed to investigate the effectiveness of a checklist-based nursing care process in patients undergoing Coronary chronic total occlusion (CTO) interventions, including duration of care, patient anxiety, improved patient satisfaction, and occurrence of adverse events. METHODS: A total of 120 CTO patients undergoing percutaneous coronary intervention (PCI) were selected at our hospital and divided into an intervention group (n = 60, adopted the checklist-based nursing care process for patient care) and a control group (n = 60, adopted nursing care according to the existing workflow) according to different nursing interventions. After surgery, the nurse in charge of the patient completed the nursing according to the "List of postoperative care for CTO patients" filled in by the patient within 24 h after surgery, conducted a doctor satisfaction survey, recorded adverse events, and completed the postoperative Self-Rating Anxiety Scale (SAS) score and patient satisfaction survey before the patient was discharged. Subsequently, the Qc team checks the completion of the patient's checklist for safety and the completion of the questionnaire. Finally, the differences between the two groups in preoperative nursing time, incidence of adverse events caused by nurses' omission or inadequate guidance, patient anxiety, and doctor and patient satisfaction were compared. RESULTS: The intervention grouphad significantly shorter preoperative nursing care time and significantly lower the total number of adverse events than the control group (P < 0.05).The postoperative Self-Rating Anxiety Scale (SAS) score of the intervention group was significantly lower than that of the control group (P < 0.05).The satisfaction of doctors and patients in the intervention groupwas significantly higher than that in the control group (P < 0.05). CONCLUSION: The application of the checklist-based nursing care process in patients with CTO intervention can significantly reduce the preoperative nursing care time, reduce patient anxiety, improve patients' and doctors' satisfaction with nursing care, and effectively reduce the occurrence of adverse events caused by nurses' omissions or inadequate instructions. TRIAL REGISTRATION: The protocol of the trial was registered retrospectively of Chinese Clinical Trial Registry (registration number ChiCTR2200056804, reg date17/02/2022).

Preoperative and postoperative complications as risk factors for delayed gastric emptying following pancreaticoduodenectomy: A single-center retrospective study.

BACKGROUND: Mortality rates after pancreaticoduodenectomy (PD) have significantly decreased in specialized centers. However, postoperative morbidity, particularly delayed gastric emptying (DGE), remains the most frequent complication following PD. AIM: To identify risk factors associated with DGE after the PD procedure. METHODS: In this retrospective, cross-sectional study, clinical data were collected from 114 patients who underwent PD between January 2015 and June 2018. Demographic factors, pre- and perioperative characteristics, and surgical complications were assessed. Univariate and multivariate analyses were performed to identify risk factors for post-PD DGE. RESULTS: The study included 66 males (57.9%) and 48 females (42.1%), aged 33-83 years (mean: 62.5), with a male-to-female ratio of approximately 1.4:1. There were 63 cases (55.3%) of PD and 51 cases (44.7%) of pylorus-preserving pancreatoduodenectomy. Among the 114 patients who underwent PD, 33 (28.9%) developed postoperative DGE. Univariate analysis revealed significant differences in four of the 14 clinical indexes observed: pylorus preservation, retrocolonic anastomosis, postoperative abdominal complications, and early postoperative albumin (ALB). Logistic regression analysis further identified postoperative abdominal complications [odds ratio (OR) = 4.768, P = 0.002], preoperative systemic diseases (OR = 2.516, P = 0.049), and early postoperative ALB (OR = 1.195, P = 0.003) as significant risk factors. CONCLUSION: Postoperative severe abdominal complications, preoperative systemic diseases, and early postoperative ALB are identified as risk factors for post-PD DGE.

Performance of multigene testing in cytologically indeterminate thyroid nodules and molecular risk stratification.

Objective: Thyroid cancer is the third most prevalent cancer among females. Genetic testing based on next-generation sequencing may provide an auxiliary diagnosis to reduce cytologically diagnostic uncertainty. However, commercial multigene tests are not widely available and are not well-tested in the Chinese population. Methods: In this study, we designed a multigene testing panel and evaluated its performance in 529 cytologically indeterminate thyroid nodules (Bethesda III, IV and V). The molecular data of the DNA mutations and RNA fusions of fine needle aspiration samples were reviewed in conjunction with a clinical diagnosis, pathological reports, and definitive surgery for retrospective analysis. Then, the molecular risk stratification was investigated for its accuracy in malignant risk prediction. Results: The overall combined consistency revealed substantial agreement (Kappa = 0.726) with the sensitivity, specificity, positive predictive value, and negative predictive values of 97.80%, 82.14%, 98.99%, and 67.65%, respectively. The most common aberration was BRAFV600E (82.59%), followed by NRAS mutants (4.07%), RET fusions (3.70%), and KRAS mutants (3.15%). Two cases (0.44%) were categorized into a high-risk group, 426 cases (94.67%) were categorized into a BRAF-like group with totally histopathologic papillary patterned tumors, and 22 cases (4.89%) were categorized into a RAS-like group with 14 papillary and eight follicular patterned tumors when the cohort concurrent aberrations were excluded. Potentially aggressive features may be related to concurrent molecular alterations of BRAFV600E with TERTQ302R, and AKT1L52R, NRASG12C, NRASQ61R, and CCDC6-RET fusions. Conclusions: This study provided a multigene panel for identifying benign nodules from cytologically indeterminate thyroid nodules to avoid unnecessary surgery. We provide further evidence for using molecular risk stratification as a promising predictor of disease outcomes. The results of this study may be limited by the extremely high prevalence of cancer in the cohort for clinical reference.

Enhanced degradation of poly(ethylene terephthalate) by the addition of lactic acid / glycolic acid: composting degradation, seawater degradation behavior and comparison of degradation mechanism.

The degradability improvement of poly(ethylene terephthalate) (PET), one of the most widely used but non-degradable disposable packaging material, is of great significance. However, the balance between degradability and mechanical properties remains a huge challenge. Herein, simple hydroxy acids, lactic acid (LA) and glycolic acid (GA) as easy hydrolysis sites were introduced into non-degradable PET via melt polycondensation. A series of high molecular weight poly(ethylene terephthalate-co-L­lactide) (PETL) and poly(ethylene terephthalate-co-glycolate) (PETG) copolyesters were synthesized with an excellent tensile strength greater than 50 MPa, much higher than that of most commercially available degradable polymers. The introduction of hydroxy acid endows PET with significantly improved composting and seawater degradation performance. Furtherly, the degradation rate of PETG with hydrophilic GA unit was faster than that of PETL, and the mineralization rate of PETG80 reaches 22.0%. The density of functional theory (DFT) calculation revealed that adding hydroxy acid to the PET molecular chain reduced the energy barrier of the hydrolysis reaction. The molecular polarity index (MPI) analysis furtherly confirmed that the higher affinity between the GA unit and water may be the primary reason for the faster degradation of PETG.

Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling.

A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors.

Distinguishing Tumor Admixed in a Radiation Necrosis (RN) Background: 1H and 2H MR With a Novel Mouse Brain-Tumor/RN Model.

Purpose: Distinguishing radiation necrosis (RN) from recurrent tumor remains a vexing clinical problem with important health-care consequences for neuro-oncology patients. Here, mouse models of pure tumor, pure RN, and admixed RN/tumor are employed to evaluate hydrogen (1H) and deuterium (2H) magnetic resonance methods for distinguishing RN vs. tumor. Furthermore, proof-of-principle, range-finding deuterium (2H) metabolic magnetic resonance is employed to assess glycolytic signatures distinguishing RN vs. tumor. Materials and Methods: A pipeline of common quantitative 1H MRI contrasts, including an improved magnetization transfer ratio (MTR) sequence, and 2H magnetic resonance spectroscopy (MRS) following administration of 2H-labeled glucose, was applied to C57BL/6 mouse models of the following: (i) late time-to-onset RN, occurring 4-5 weeks post focal 50-Gy (50% isodose) Gamma Knife irradiation to the left cerebral hemisphere, (ii) glioblastoma, growing ~18-24 days post implantation of 50,000 mouse GL261 tumor cells into the left cerebral hemisphere, and (iii) mixed model, with GL261 tumor growing within a region of radiation necrosis (1H MRI only). Control C57BL/6 mice were also examined by 2H metabolic magnetic resonance. Results: Differences in quantitative 1H MRI parametric values of R1, R2, ADC, and MTR comparing pure tumor vs. pure RN were all highly statistically significant. Differences in these parameter values and DCEAUC for tumor vs. RN in the mixed model (tumor growing in an RN background) are also all significant, demonstrating that these contrasts-in particular, MTR-can effectively distinguish tumor vs. RN. Additionally, quantitative 2H MRS showed a highly statistically significant dominance of aerobic glycolysis (glucose ➔ lactate; fermentation, Warburg effect) in the tumor vs. oxidative respiration (glucose ➔ TCA cycle) in the RN and control brain. Conclusions: These findings, employing a pipeline of quantitative 1H MRI contrasts and 2H MRS following administration of 2H-labeled glucose, suggest a pathway for substantially improving the discrimination of tumor vs. RN in the clinic.

Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia.

To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.

Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy.

PURPOSE: Clinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI2M) model. METHOD AND MATERIALS: C57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife® Perfexion™, a dose that does not produce frank/gross radiation necrosis. Non-irradiated GL261 glioblastoma tumor cells were implanted six weeks later into the irradiated hemisphere. Lesion volume was measured longitudinally by in vivo MRI. In a separate experiment, tumors were implanted into either previously irradiated (30 Gy) or non-irradiated mouse brain, mice were treated with anti-PD-L1 antibody, and Kaplan-Meier survival curves were constructed. Mouse brains were assessed by conventional hematoxylin and eosin (H&E) staining, IBA-1 staining, which detects activated microglia and macrophages, and fluorescence-activated cell sorting (FACS) analysis. RESULTS: Tumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior intracranial irradiation are unresponsive to anti-PD-L1 therapy. K-M curves demonstrate a statistically significant difference in survival for tumor-bearing mice treated with anti-PD-L1 antibody between RI2M vs. non-irradiated mice. The most prominent immunologic change in the post-irradiated brain parenchyma is an increased frequency of activated microglia. CONCLUSIONS: The RI2M model focuses on the persisting (weeks-to-months) impact of radiation applied to normal, control-state brain on the growth characteristics and immunotherapy response of subsequently implanted tumor. GL261 tumors growing in the RI2M grew markedly more aggressively, with tumor cells admixed with regions of hemorrhage and necrosis, and showed a dramatic loss of response to anti-PD-L1 therapy compared to tumors in non-irradiated brain. IHC and FACS analyses demonstrate increased frequency of activated microglia, which correlates with loss of sensitivity to checkpoint immunotherapy. Given that standard-of-care for primary brain tumor following resection includes concurrent radiation and chemotherapy, these striking observations strongly motivate detailed assessment of the late effects of the RI2M on tumor growth and therapeutic efficacy.

Test-Retest Performance of a 1-Hour Multiparametric MR Image Acquisition Pipeline With Orthotopic Triple-Negative Breast Cancer Patient-Derived Tumor Xenografts.

Preclinical imaging is critical in the development of translational strategies to detect diseases and monitor response to therapy. The National Cancer Institute Co-Clinical Imaging Resource Program was launched, in part, to develop best practices in preclinical imaging. In this context, the objective of this work was to develop a 1-hour, multiparametric magnetic resonance image-acquisition pipeline with triple-negative breast cancer patient-derived xenografts (PDXs). The 1-hour, image-acquisition pipeline includes T1- and T2-weighted scans, quantitative T1, T2, and apparent diffusion coefficient (ADC) parameter maps, and dynamic contrast-enhanced (DCE) time-course images. Quality-control measures used phantoms. The triple-negative breast cancer PDXs used for this study averaged 174 ± 73 µL in volume, with region of interest-averaged T1, T2, and ADC values of 1.9 ± 0.2 seconds, 62 ± 3 milliseconds, and 0.71 ± 0.06 µm2/ms (mean ± SD), respectively. Specific focus was on assessing the within-subject test-retest coefficient-of-variation (CVWS) for each of the magnetic resonance imaging metrics. Determination of PDX volume via manually drawn regions of interest is highly robust, with ∼1% CVWS. Determination of T2 is also robust with a ∼3% CVWS. Measurements of T1 and ADC are less robust with CVWS values in the 6%-11% range. Preliminary DCE test-retest time-course determinations, as quantified by area under the curve and Ktrans from 2-compartment exchange (extended Tofts) modeling, suggest that DCE is the least robust protocol, with ∼30%-40% CVWS.

Wolbachia Infection in Two Species: Novel Views on the Colonization Ability of Wolbachia in Aphids.

Wolbachia pipientis (Rickettsiales: Anaplasmataceae) is an intracellular symbiont residing in arthropods and filarial nematodes. Sixteen supergroups have been described from different host taxa. Four supergroups A, B, M, and N were found in aphids according to prior studies. The cotton aphid, Aphis gossypii, and the green peach aphid, Myzus persicae, are typical polyphagous species with global distributions. We conducted an extensive and systematic survey of Wolbachia infections in these aphids from China. High incidences of Wolbachia infection were detected. The total infection incidence was 60% in A. gossypii and 88% in M. persicae. Both aphid species were infected with supergroups A, B and M. Different incidences of infection were observed among the seven geographical regions in China, which suggested a positive relationship between Wolbachia infections and the geographical distribution of aphid species. Furthermore, multiple infection patterns (M, B, A&M, B&M, and A&B&M) were observed. Infection patterns M and B&M were detected in almost all populations. Patterns A&B&M and B showed geographical restriction in North China. Three factors can possibly influence the Wolbachia infection incidences and patterns: the geographical distribution, aphid species, and different supergroup types.

The genes expression difference between winged and wingless bird cherry-oat aphid Rhopalosiphum padi based on transcriptomic data.

Aphids produce wing and wingless morphs, depending on the environmental conditions during their complex life cycles. Wing and wingless variations play an important role in migration and host alternation, affecting the migration and host alternation processes. Several transcriptional studies have concentrated on aphids and sought to determine how an organism perceives environmental cues and responds in a plastic manner, but the underlying mechanisms have remained unclear. Therefore, to better understand the molecular mechanisms underlying the wing polyphenism of this fascinating phenomenon, we provide the first report concerning the wing development of aphids in bird cherry-oat aphid Rhopalosiphum padi with comparative transcriptional analysis of all the developmental stages by RNA-Seq. We identified several candidate genes related to biogenic amines and hormones that may be specifically involved in wing development. Moreover, we found that the third instar stage might be a critical stage for visibility of alternative morphs as well as changes in the expression of thirty-three genes associated with wing development. Several genes, i.e., Wnt2, Fng, Uba1, Hh, Foxo, Dpp, Brk, Ap, Dll, Hth, Tsh, Nub, Scr, Antp, Ubx, Asc, Srf and Fl, had different expression levels in different developmental stages and may play important roles in regulating wing polyphenism.

Effects of an artificial placenta on brain development and injury in premature lambs.

PURPOSE: We evaluated whether brain development continues and brain injury is prevented during Artificial Placenta (AP) support utilizing extracorporeal life support (ECLS). METHODS: Lambs at EGA 118days (term=145; n=4) were placed on AP support (venovenous ECLS with jugular drainage and umbilical vein reinfusion) for 7days and sacrificed. Early (EGA 118; n=4) and late (EGA 127; n=4) mechanical ventilation (MV) lambs underwent conventional MV for up to 48h and were sacrificed, and early (n=5) and late (n=5) tissue control (TC) lambs were sacrificed at delivery. Brains were harvested, formalin-fixed, rehydrated, and studied by magnetic resonance imaging (MRI). The gyrification index (GI), a measure of cerebral folding complexity, was calculated for each brain. Diffusion-weighted imaging was used to determine fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple structures to assess white matter (WM) integrity. RESULTS: No intracranial hemorrhage was observed. GI was similar between AP and TC groups. ADC and FA did not differ between AP and late TC groups in any structure. Compared to late MV brains, AP brains demonstrated significantly higher ADC (0.45±0.08 vs. 0.27±0.11, p=0.02) and FA (0.61±0.04 vs. 0.44±0.05; p=0.006) in the cerebral peduncles. CONCLUSIONS: After 7days of AP support, WM integrity is preserved relative to mechanical ventilation. TYPE OF STUDY: Research study.

Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

PURPOSE: There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1α (HIF-1α)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late-onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model. METHODS AND MATERIALS: Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1α inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo magnetic resonance imaging (MRI) from 4 to 12 weeks after irradiation. Conventional hematoxylin-eosin staining and immunohistochemistry staining were performed to evaluate the treatment response. RESULTS: The progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100 compared with control animals. MRI-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By hematoxylin-eosin staining, both treated groups demonstrated reduced irradiation-induced tissue damage compared with controls. Furthermore, immunohistochemistry results revealed that expression levels of vascular endothelial growth factor, CXC chemokine ligand 12, CD68, CD3, and tumor necrosis factor α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains versus control brains, while ionized calcium-binding adapter molecule 1 (Iba1) and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while interleukin 6 expression was unaffected by either topotecan or AMD3100. CONCLUSIONS: By reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in the mouse brain. When combined with first-line, antiangiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, postirradiation management of tumors, with additional benefits in the mitigation of RN development.

Correlation of the expressions of IGF1R-RACK1-STAT3 and Bcl-xl in nasopharyngeal carcinoma with the clinicopathological features and prognosis of nasopharyngeal carcinoma.

The aim of this study was to investigate the correlation of expression of IGF1R-RACK1-STAT3 and Bcl-xl in nasopharyngeal carcinoma (NPC) with the clinicopathological features and the prognosis of NPC. Our study selected 215 NPC tissues and 178 chronic nasopharyngitis tissues (control group). Positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl were tested by immunohistochemical method, and expression of IGF1R, RACK1, STAT3, Bcl-xl, Bcl-2, and Bax by western blotting. Correlation of IGF1R, RACK1, STAT3, and Bcl-xl with the clinicopathological features of NPC was analyzed. The correlation among those four expression was analyzed by Spearman. The survival of NPC and independent factors of prognosis were tested by Kaplan-Meier and COX proportional hazards model respectively. The NPC group had higher positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl, and elevated expression of IGF1R, RACK1, STAT3, Bcl-xl, Bcl-2, and Bax. The lymph node metastasis (LNM) group had higher positive expression rates of IGF1R and RACK1 when compared with the non-LNM group. Patients with stage III and IV had higher positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl. There was positive correlation between expression of IGF1R and RACK1, STAT3. Such correlation was found between RACK1 and STAT3. Patients with negative expression of IGF1R, RACK1, STAT3, and Bcl-xl had higher survival rates. The risky factors of poor prognosis of NPC were positive expression of IGF1R, RACK1, STAT3 and Bcl-xl, and LNM. IGF1R-RACK1-STAT3 and Bcl-xl expression correlated with the clinicopathological features and poor prognosis of NPC.

Differences in airway remodeling and airway inflammation among moderate-severe asthma clinical phenotypes.

BACKGROUND: To identify asthma clinical phenotypes using cluster analysis and improve our understanding of heterogeneity in asthma. METHODS: Clustering approaches were applied to 203 patients who were diagnosed with asthma in XinHua Hospital (January 2012 to December 2015). One hundred and twenty patients underwent multi-slice spiral computed tomography (MSCT) examination and 30 underwent bronchial mucosal biopsy for evaluation of airway remodeling and airway inflammation among the phenotypes. RESULTS: Four groups were identified. Patients in cluster 1 (n=52) had early onset atopic asthma and patients in cluster 2 (n=65) had small airway obstruction and atopic asthma. Cluster 3 (n=52) was a unique group of patients with late-onset and non-atopic asthma. Patients in cluster 4 (n=34) had severe airflow obstruction and obvious airway remodeling as observed on MSCT (P<0.05). According to the immunohistochemistry of IL-5 and IL-17 (P<0.05), the results of clusters 1 and 2 may be attributable to the Th2 immune response, whereas those of clusters 3 and 4 to the Th17 immune response. CONCLUSIONS: Four distinct clinical phenotypes of asthma were identified by cluster analysis. The results of the MSCT and pathological examinations may suggest specific pathogeneses among the phenotypes.

Bone Marrow Mesenchymal Stem Cells Inhibit the Function of Dendritic Cells by Secreting Galectin-1.

This study aimed to investigate whether bone marrow-derived mesenchymal stem cells (BM-MSCs) can inhibit function of dendritic cells (DCs) by secreting Galectin-1 (Gal-1). BM-MSCs have been shown to inhibit the maturation and function of DCs, further inhibiting the activation and proliferation of T cells. However, the detailed mechanism remains unknown. In this current study, MSCs and DCs derived from mouse bone marrow were cocultured using Transwell culture plates under different in vitro conditions. The results showed that as the ratio of MSC to DC of the coculture system increased and the coculture time of the two cells prolonged, the concentrations of Gal-1, interleukin- (IL-) 10, and IL-12 in the supernatants were increased and the protein expression of Gal-1 on and within DCs was also enhanced. The phosphorylation of extracellular signal-regulated kinase (ERK) pathway in DCs was boosted, whereas p38 mitogen-activated protein kinase (MAPK) pathway phosphorylation was weakened. Meanwhile, the expression of costimulatory molecules on the surface of DCs was decreased, and the proliferative effect of DCs on allogeneic T cells was also decreased. Therefore, this present study indicated that Gal-1 secreted from MSCs upregulated expression of Gal-1 and stimulated formation of tolerance immunophenotype on DCs, where the underlying mechanism was the regulation of the MAPK signaling pathway in DCs, thereby inhibiting the function of DCs.

Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma.

PURPOSE: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C-acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo EXPERIMENTAL DESIGN: Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution. RESULTS: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment. CONCLUSIONS: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-Acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-Acetate-PET also detected response to therapy in vivo Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate-PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416-29. ©2016 AACR.

Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer.