Crosstalk in extrahepatic and hepatic system in NAFLD/NASH.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non-alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter-organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra- and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver-gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra-hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH.

Decreased Cerebral Perfusion in Chronic Migraine: A Voxel-based Cerebral Blood Flow Analysis Using 3D Pseudo-continuous Arterial Spin Labeling.

BACKGROUND: A contrast agent-free approach would be preferable to the frequently used invasive approaches for evaluating cerebral perfusion in chronic migraineurs (CM). In this work, non-invasive quantitative volumetric perfusion imaging was used to evaluate alterations in cerebral perfusion in CM. METHODS: We used conventional brain structural imaging sequences and 3D pseudo-continuous arterial spin labeling (3D PCASL) to examine thirteen CM patients and fifteen normal controls (NCs). The entire brain gray matter underwent voxel-based analysis, and the cerebral blood flow (CBF) values of the altered positive areas were retrieved to look into the clinical variables' significant correlation. RESULTS: Brain regions with the decreased perfusion were located in the left postcentral gyrus, bilateral middle frontal gyrus, left middle occipital gyrus, left superior parietal lobule, left medial segment of superior frontal gyrus, and right orbital part of the inferior frontal gyrus. White matter fibers with decreased perfusion were located in bilateral superior longitudinal tracts, superior corona radiata, external capsules, anterior and posterior limbs of the internal capsule, anterior corona radiata, inferior longitudinal fasciculus, and right corticospinal tract. However, the correlation analysis showed no significant correlation between the CBF value of the above positive brain regions with clinical variables (p > 0.05). CONCLUSION: The current study provided more useful information to comprehend the pathophysiology of CM and revealed a new insight into the neural mechanism of CM from the pattern of cerebral hypoperfusion.

Interscanner reproducibility of volumetric quantitative susceptibility mapping about cerebral subcortical gray nuclei at different MR vendors with the same magnetic strength.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping (QSM) technique was a new quantitative magnetic resonance imaging technique to evaluate the cerebral iron deposition in clinical practice. The current study was aimed to investigate the reproducibility of the volumetric susceptibility value of the subcortical gray nuclei at two different MR vendor with the same magnetic strength. METHODS: Cerebral magnitude and phase images of 21 normal subjects were acquired from a 3D multiecho enhanced gradient recalled echo sequence at two different 3.0T MR scanner, and then the magnetic susceptibility images were generated by STI software. The brain structural images were coregistered with magnitude images and generated the normalized parameters, and then generated the normalized susceptibility images. The subcortical gray nuclei template was applied to extract the volumetric susceptibility value of the target nuclei. RESULTS: ICC value (95% CI) of the caudate, putamen and GP were 0.847 (0.660-0.935), 0.848 (0.663-0.935) and 0.838 (0.643-0.931), respectively. The ICC value of the thalamus was 0.474 (0.064-0.747). Ninety-five point two percent (20/21) of the difference points of the susceptibility located between the 95% LA for the caudate at the two different 3.0T MR scanner, while the less than 95% of the difference points of the susceptibility value located between the 95% LA for the putamen, globus pallidus and thalamus. CONCLUSION: The current study identified that the caudate had the stable reproducibility of the magnetic susceptibility value, and the other basal ganglion nuclei should be cautious for the quantitative evaluation of the magnetic susceptibility value at different 3.0T MR scanner.

Hypoperfusion of Amygdala in Chronic Migraine: An Exploratory Quantitative Perfusion Imaging Using 3D Pseudo-Continuous Arterial Spin Labeling.

BACKGROUND: Although the amygdala has structural and functional abnormalities in Chronic Migraine (CM), less is known about the altered perfusion of the amygdala in CM. OBJECTIVE: The current study aimed to assess amygdala perfusion in CM using a contrast agent-free and quantitative approach. METHODS: 15 Normal Controls (NC) and 13 patients with CM during the migraine interval were assessed for brain structure and subjected to 3D Pseudo- Continuous Arterial Spin Labeling (3D-PCASL) MR imaging. The Cerebral Blood Flow (CBF) value of the amygdala was automatically extracted based on the individual amygdala mask for all participants. The independent sample t-test, Receiver Operating Characteristic (ROC) curve, and correlation analysis were used to evaluate the perfusion changes in CM. RESULTS: Bilateral amygdala cerebral perfusion was lower in CM (left amygdala, 42.21±4.49 ml/100mg/min; right amygdala, 42.38±4.41 ml/100mg/min) than in NC (left amygdala, 48.31±6.92 ml/100mg/min; right amygdala, 47.88±6.53 ml/100mg/min) (left, p = 0.01; right, p = 0.02). There was no significant correlation between the perfusion of bilateral amygdalas and the clinical variables. Also, there was no significant difference in the volume of bilateral amygdalas between the two groups. The Area Under the Curve (AUC) of the CBF values of the left and right amygdala was 0.78 (95%CI: 0.58-0.91) and 0.75 (95%CI: 0.55-0.89), respectively. The cut-off value was 44.24 ml/100mg/min (left amygdala, with sensitivity 76.90% and specificity 78.70%) and 46.75 ml/100mg/min (right amygdala, with sensitivity 92.3% and specificity 58.80%), respectively. CONCLUSION: CM presented bilateral hypoperfusion in the amygdala, offering potential diagnostic value in distinguishing CM from NC. The 3D-PCASL could be regarded as a simple and efficient neuroimaging tool to assess the perfusion status in CM patients.

Potential 18F-RGD PET/CT and DCE-MRI Imaging-Based Biomarkers for Postoperative Survival Prediction Among Patients With Newly Diagnosed Glioblastoma Treated With Bevacizumab and Chemoradiotherapy.

Purpose: To investigate the ability of potential imaging biomarkers based on 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (18F-RGD PET/CT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) imaging to predict the response to bevacizumab combined with conventional therapy in postoperative newly diagnosed glioblastoma. Methods: Twenty patients with newly diagnosed with glioblastoma after surgery were prospectively enrolled to receive bevacizumab plus conventional concurrent radiotherapy and temozolomide (CCRT). 18F-RGD PET/CT and DCE-MRI were performed at baseline, week 3, and week 10 for each patient. Statistical methods included the analysis of variance (ANOVA), Kaplan-Meier method and Cox proportional hazard analysis. Results: All patients completed CCRT plus bevacizumab therapy without interruption. The median follow-up time was 33.9 months (95% confidence interval [CI], 28.3-39.5 months). The median progression-free survival (PFS) and overall survival (OS) was 9.66 months (95% CI, 6.20-13.12 months) and 15.89 months (95% CI, 13.89-17.78), respectively. Treatment was generally well tolerated, and there were no Treatment emergent adverse events (TEAEs) with a toxicity grade equal to or exceeding 3 or that led to termination of treatment or patient death.Over the treatment interval of bevacizumab therapy from week 3 to week 10, patients with a large decrease of SUVmean was associated with a better PFS with a hazard ratio (HR) of 6.562, 95% CI (1.318-32.667), p=0.022. According to Kaplan-Meier analysis, patients with a decrease in the SUVmean of more than 0.115 on 18F-RGD PET/CT had a longer PFS than those with a decrease in the SUVmean of 0.115 or less (12.25 months vs.7.46 months, p=0.009). For OS, only a small decrease of Ktrans was also found to have certain prognostic value (HR=0.986, 95% CI (0.975-0.998), p=0.023). Patients with a decrease in Ktrans larger than 37.03 (min-1) on DCE-MRI had worse OS than those with a decrease in Ktrans of 37.03 (min-1) or less (15.93 months vs. 26.42 months, p=0.044). Conclusion: 18F-RGD PET/CT and DCE-MRI may be valuable in evaluating the response of glioblastoma to treatment with the combination of bevacizumab and CCRT, with a greater decrease in SUVmean predicting better PFS as well as a small decrease in Ktrans predicting improved OS.

Exploring the relationship between perceived social support and college students' autonomous fitness behavior: Chain mediating effect test.

Objective: This study aims to explore the effect of perceived social support on college students' autonomous fitness behavior, and the mediating role of mental toughness and exercise self-efficacy. Methodology: A survey participated by 985 college Students (average age, 19.55) was conducted by applying the following scales: The Perceived Social Support Scale, the Adolescent Self-Government Behavior Scale, the Mental Toughness Scale, and the Exercise Self-efficacy Scale (ESES). Results: (1) Perceived social support can directly and positively predict autonomous fitness behavior, mental toughness, and exercise self-efficacy; mental toughness can directly and positively predict exercise self-efficacy. Likewise, perceived social support, mental toughness, and exercise self-efficacy can positively predict autonomous fitness behavior. (2) The indirect effect of the path with mental toughness as the mediating variable is 0.078, the indirect effect of the path with exercise self-efficacy as the mediating variable is 0.122, and the indirect effect of the path with mental toughness and exercise self-efficacy as the mediating variable is 0.082. (3) The total of all indirect effects is 0.282, and the effects of the three indirect pathways account for 18.25, 28.62, and 19.37% of the total, respectively. Conclusion: The perceived social support can indirectly predict college students' autonomous fitness behavior through the independent mediating effect of mental toughness and self-efficacy, as well as the chain mediating effect of the two. The claim that mental toughness and exercise self-efficacy perform a chain-mediate role in the positive effect brought by perceived social support on autonomous fitness behavior has been supported. This study revealed the relationship and mechanism between perceived social support and college students' autonomous fitness behavior and further improved the research on the impact of perceived social support on college students' autonomous fitness behavior.

18F-RGD PET/CT imaging reveals characteristics of angiogenesis in non-small cell lung cancer.

BACKGROUND: The objective of this study was to explore the benefit of 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (denoted as 18F-RGD PET/CT) imaging for determining the clinical pathologic features of non-small cell lung cancer (NSCLC). METHODS: Seventy-two patients with NSCLC (37 cases of adenocarcinoma and 35 cases of squamous carcinoma) were enrolled to receive 18F-RGD PET/CT scanning pretreatment. The peak standard uptake value (SUVpeak), mean standard uptake value (SUVmean), angiogenic tumor volume (ATV) and total lesion angiogenesis (TLA) of tumors were determined using an automated contouring program. Cases were classified according to the tumor, lymph node, metastasis (TNM) stage. RESULTS: Significant differences in ATV and TLA were observed among T1, T2, T3 and T4 cases (ATV, P=0.000; TLA, P=0.000). ATV and TLA also differed significantly among cases of clinical stage I, II, III and IV (ATV, P=0.002; TLA, P=0.011). However, no significant differences in any values were observed between stage III and IV NSCLC cases (SUVpeak, P=0.675; SUVmean, P=0.668; ATV, P=0.52; TLA, P=0.634). All assessed values were higher in squamous cell carcinoma cases than in adenocarcinoma cases (SUVpeak, P=0.045; SUVmean, P=0.014; ATV, P=0.003; TLA, P=0.001). For clinical stage III and IV cases specifically, SUVpeak, SUVmean, and TLA were higher for squamous cell carcinoma than for adenocarcinoma (SUVpeak, P=0.015; SUVmean, P=0.009; TLA, P=0.036).Conclusions: 18F-RGD PET/CT imaging revealed the presence of increased angiogenesis in the tumor microenvironment of NSCLC, especially squamous cell carcinoma, and thus may be valuable in planning therapeutic regimens for individual patients.

Correlation of hypoxia as measured by fluorine-18 fluoroerythronitroimidazole (18F-FETNIM) PET/CT and overall survival in glioma patients.

PURPOSE: Hypoxia is important in the biology of glioma in humans. Positron emission tomography/computed tomography (PET/CT) with a hypoxia tracer offers a noninvasive method to differentiate individual tumor biology and potentially modify treatment for patients with malignancies. The purpose of this study was to determine whether hypoxia, as measured by fluorine-18 fluoroerythronitroimidazole (18F-FETNIM) PET/CT, was associated with tumor grade, overall survival (OS), and immunohistochemical features related to hypoxia, proliferation, angiogenesis, and the invasion of gliomas. PROCEDURES: Twenty-five patients with gliomas in whom gross maximal resection could be safely attempted were analyzed. All patients underwent 18F-FETNIM PET/CT studies before surgery. The maximum standardized uptake value (SUVmax) was obtained from the PET images of tumor tissues. Tumor specimens were stereotactically obtained for the immunohistochemical staining of hypoxia-inducible factor-1 alpha (HIF-1α), Ki-67, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9). RESULTS: A correlation between the SUVmax and glioma grade was found (r = 0.881, P < 0.001). The SUVmax was significantly correlated with the expression of HIF-1α, Ki-67, VEGF, and MMP-9 (r = 0.820, 0.747, 0.606, and 0.727; all P < 0.001). Patients with a high SUVmax had significantly worse 3-year OS than those with a low SUVmax (24.4% vs. 82.1%, P = 0.003). CONCLUSIONS: 18F-FETNIM PET/CT provides an excellent noninvasive assessment of hypoxia in glioma. It can be used to understand the mechanisms by which hypoxia affects the OS of glioma patients.

[Effects of different intensity interval exercise of 6 weeks on body composition of obese rats].

OBJECTIVE: To investigate the effects of different intensity intermittent exercise on the body function of obese rats, and to provide basis for the prevention and treatment of obesity. METHODS: Eighty SD rats were randomly divided into normal diet group (n=20) and high-fat diet group (n=60). After adaptive feeding for 8 weeks, 8 normal diet rats and 32 high-fat obese rats were selected for follow-up experiments. The experimental rats were randomly divided into 5 groups (n=8): control diet-sedentary (CS),with ordinary feed and without any exercise; high diet-sedentary (HS), with high-fat feed feeding and without any exercise; high diet-continual exercise(HC), 60 min/day,5 days/week with 6 weeks; high diet-long time-low frequency interval exercise(HLL), 30 min/time,twice/day (intermittent 6 h), 5 days/week with 6 weeks; high diet-short time-high frequency interval exercise(HSH), 20 min/ time, 3 times/d (intermittent 3 h), 5 days/week with 6 weeks. The training intensity of rats in each exercise group was 25 m/min. After 6 weeks, rats in each groups were weighed, and resting metabolic rate(RMR), fasting blood glucose(FBG), triglyceride(TG) and other biochemical indexes were detected, and fat and muscle weight were measured. RESULTS: Before experiment, there were no significant differences in RMR, FBG and TG in each groups(P＞0.05).The body weight of HSH, HLL, HC and HS groups was higher than that of CS group (P＜0.05). After the experiment, RMR of the HSH,HLL and HC groups was significantly higher than that of HS and CS groups (P＜0.05), but without significant difference among the HSH,HLL and HC groups (P＞0.05).The body weight of HSH, HLL and HC groups was significantly lower than that of HS group (P＜0.05), but the three groups was not significant (P＞0.05); perirenal fat(PF), idymis fat(EF), perirenal fat/weight(PF/W) and epididymis fat/weight(EF/W) of HSH, HLL, HC group were significantly lower than those of HS group (P＜0.01), while there was no statistical difference among the three groups (P＞0.05). There was no significant difference in gastrocnemius(GM) and quadricep(QF) of each group (P＞0.05), gastrocnemius/weight(GM/W) and quadriceps/weight (QF/W) in HSH,HLL and HC groups were higher than those of HS group (P＜0.05),while there was no significant difference among HSH,HLL and HC groups (P＞0.05);FEB,TG of HSH,HLL,HC group were lower than those of CS and HS group (P＜0.05),but the difference with HS group was more significant (P＜0.01),there was no significant difference among training groups(P＞0.05). CONCLUSION: 6 weeks of intermittent exercise of different intensity had a good intervention effect on the body composition of obese rats, and high diet-short time-high frequency interval exercise (HSH) may be more effective.

Hypoxia with 18F-fluoroerythronitroimidazole integrated positron emission tomography and computed tomography (18F-FETNIM PET/CT) in locoregionally advanced head and neck cancer: Hypoxia changes during chemoradiotherapy and impact on clinical outcome.

Hypoxia is a well-recognized biological characteristic to therapy resistance and negative prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC). This study aims to investigate the changes of hypoxia measured by F-fluoroerythronitroimidazole (FETNIM) uptake on integrated positron emission tomography and computed tomography (PET/CT) during chemoradiotherapy and its prognostic value of clinical outcome in locoregionally advanced HNSCC.Thirty-two patients with locoregionally advanced HNSCC who received definitive treatment with concurrent chemoradiotherapy underwent FETNIM PET/CT scans before and after 5 weeks of treatment. The intensity of hypoxia using the maximum standardized uptake value (SUVmax) was evaluated both on primary lesion and metastatic lymph node (MLN). The pre-SUVmax and mid-SUVmax were defined as SUVmax on pre- and mid-FETNIM PET/CT. The local control (LC), regional control (RC), distant metastatic-free survival (DMFS), and overall survival (OS) were collected in patient follow-ups.Mid-SUVmax decreased significantly both in the primary tumor (t = 8.083, P < .001) and MLN (t = 6.808, P < .001) compared to pre-SUVmax. With a median follow-up of 54 months, the 5-year LC, RC, DMFS, and OS rates were 55%, 66.7%, 64.7%, and 55%, respectively, for all of the patients. On univariate analysis, patients with high pre-SUVmax in primary tumor had significantly worse LC (56.3% vs 87.5%, P = .046) and OS (43.8% vs 87.5%, P = .023) than other patients. Patients with high mid-SUVmax had significantly worse DMFS (50% vs 84.6%, P = .049) and OS (33.3% vs 73.1%, P = .028) than other patients. The tumor grade and mid-SUVmax were the significant predictors of OS on multivariate analysis.In this study, hypoxia in tumor significantly decreased during chemoradiotherapy. The persistent hypoxia predicted poor OS. The data provided evidence that FETNIM PET/CT could be used dynamically for selecting appropriate patients and optimal timing of hypoxia-adapted therapeutic regimens.

To Explore a Representative Hypoxic Parameter to Predict the Treatment Response and Prognosis Obtained by [18F]FMISO-PET in Patients with Non-small Cell Lung Cancer.

PURPOSE: To explore a representative hypoxic parameter to predict the treatment response and prognosis for [18F]fluoromisonidazole ([18F]FMISO) positron emission tomography (PET)/X-ray computed tomography (CT) in patients with non-small cell lung cancer (NSCLC). PROCEDURES: Twenty-nine patients with NSCLC underwent FMISO-PET scans before chemoradiotherapy (CRT). The maximum standard uptake values (SUVmax) in the tumor, normal lung, aortic arch, and vertical ridge muscle were measured, and the tumor-to-lung (T/L) ratios, tumor-to-blood (T/B) ratios, ands tumor-to-muscle (T/M) ratios were calculated and analyzed. Fractional hypoxic volume (FHV) was expressed as percentage of hypoxic volume. RESULTS: SUVmax, T/L ratio, T/B ratio, and FHV were all significantly different between the responders and the non-responders (SUVmax, 2.07 ± 0.53 vs. 2.61 ± 0.69, P = 0.026; T/L ratio, 3.16 ± 0.85 vs. 4.09 ± 1.46, P = 0.047; T/B ratio, 1.27 ± 0.20 vs. 1.48 ± 0.32, P = 0.042; 38.92 ± 18.47 vs. 52.91 ± 11.29 %, P = 0.020). However, the T/M ratio was not significantly different between the two populations (1.46 ± 0.31 vs. 1.67 ± 0.33, P = 0.098). The correlation ratio between hypoxic parameters and treatment responses ranged from high to low as FHV (r = 0.412); SUVmax (r = 0.400); T/L ratio (r = 0.379), P < 0.05; and T/B ratio (r = 0.355), P = 0.059. According to the area under curve (AUC) to predict response, the hypoxic parameters were arranged as FHV (AUC = 0.748), SUVmax (AUC = 0.731), T/L ratio (AUC = 0.719), and T/B ratio (AUC = 0.705). Binary logistic regression analyses showed that FHV was the only independent predictor for treatment response with the P value of 0.038. In the progression-free survival (PFS) prediction, both FHV and SUVmax reached statistical significance by Kaplan-Meier plots (FHV, 46.99 %, P = 0.010; SUVmax, 1.99, P = 0.046) while only FHV was the independent prognostic factor in multivariate analysis by Cox proportional hazard model (P = 0.037). CONCLUSION: FHV may be a representative hypoxic parameter to predict the CRT response and PFS in patients with NSCLC.

The α1-adrenergic receptor is involved in hepcidin upregulation induced by adrenaline and norepinephrine via the STAT3 pathway.

Elevated body iron stores are associated with hypertension progression, while hypertension is associated with elevated plasma catecholamine levels in patients. However, there is a gap in our understanding of the connection between catecholamines and iron regulation. Hepcidin is a key iron-regulatory hormone, which maintains body iron balance. In the present study, we investigated the effects of adrenaline (AD) and norepinephrine (NE) on hepatic hepcidin regulation. Mice were treated with AD, NE, phenylephrine (PE, α1-adrenergic receptor agonist), prazosin (PZ, α1-adrenergic receptor antagonist), and/or propranolol (Pro, ß-adrenergic receptor antagonist). The levels of hepcidin, as well as signal transducer and activator of transcription 3 (STAT3), ferroportin 1 (FPN1), and ferritin-light (Ft-L) protein in the liver or spleen, were assessed. Six hours after AD, NE, or PE treatment, hepatic hepcidin mRNA levels increased. Pretreatment with PZ, but not Pro, abolished the effects of AD or NE on STAT3 phosphorylation and hepatic hepcidin expression. When mice were treated with AD or NE continuously for 7 days, an increase in hepatic hepcidin mRNA levels and serum hepcidin concentration was also observed. Meanwhile, the expected downstream effects of elevated hepcidin, namely decreased FPN1 expression and increased Ft-L protein and non-heme iron concentrations in the spleen, were observed after the continuous AD or NE treatments. Taken together, we found that AD or NE increase hepatic hepcidin expression via the α1-adrenergic receptor and STAT3 pathways in mice. The elevated hepatic hepcidin decreased FPN1 levels in the spleen, likely causing the increased iron accumulation in the spleen.

A novel molecular agent for glioma angiogenesis imaging.

BACKGROUND: Gliomas are rich in blood vessels and are the most primary and malignant type of brain tumor affecting the central nervous system. A few fluorine-18 (F)-labeled imaging agents can be used for imaging of tumor angiogenesis. In the current study, F-labeled recombinant human endostatin (rh-endostatin) was developed and evaluated as a probe for PET imaging of tumor angiogenesis. MATERIALS AND METHODS: F-fluorobenzoyl-endostatin (F-FB-endostatin) was synthesized from radiolabeling of rh-endostatin with N-succinimidyl-4-F-fluorobenzoate produced by a facile module-assisted radiosynthesis procedure. Blocking studies were used to measure the relative affinities of F-FB-endostatin to human glioblastoma U87MG cells in tumor tissues rich with vessels. In addition, biodistribution, metabolic stability, and small-animal PET imaging studies were carried out with F-FB-endostatin using Institute of Cancer Research and U87MG tumor-bearing mice. RESULTS: Noninvasive small-animal PET imaging indicated that F-FB-endostatin showed rapid and good tumor uptake. The probe was rapidly cleared from the blood and most organs, resulting in excellent tumor-to-normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Metabolite assays showed that the probe was highly stable, making it suitable for in-vivo applications. CONCLUSION: F-FB-endostatin shows promising in-vivo properties. Therefore, the promising properties of F-FB-endostatin indicate that this probe can be a powerful tool to evaluate the antiangiogenic therapy for gliomas and thus warrants further investigation as a novel PET probe for imaging of tumor angiogenesis.

A Pilot Study of 18F-Alfatide PET/CT Imaging for Detecting Lymph Node Metastases in Patients with Non-Small Cell Lung Cancer.

Angiogenesis plays a key role in tumor development and αvß3 integrin are overexpressed on the endothelial cell surface of newly forming vessels. 18F-Alfatide has favorable properties for αvß3 integrin targeting and showed potential for imaging angiogenesis with Positron Emission Tomography (PET)/computed tomography (CT). In this study, 13 patients with non-small cell lung cancer (NSCLC) who underwent 18F-Alfatide PET/CT before surgery were enrolled. The uptake of all dissected lymph nodes (LNs) of 18F-Alfatide were assessed visually and analyzed with a maximum and mean standard uptake value (SUVmax, SUVmean) and SUV ratios. LN metastases were pathologically confirmed and 20 of 196 LNs were malignant. All malignant LNs were successfully visualized on 18F-Alfatide PET/CT in patients and the sensitivity, specificity and accuracy was 100.0%, 94.9% and 95.4%, respectively. SUVmax, SUVmean and SUV ratios in malignant LNs were significantly higher than in benign LNs for NSCLC patients (P < 0.001). The same result was observed in patients with adenocarcinoma and squamous cell carcinoma (P < 0.001). The 18F-Alfatide parameter shows high sensitivity (83.9-100%), specificity (78.6-96.7%) and accuracy (81.7-96.9%) according to thresholds calculated from receiver operating characteristic curve. Our results suggest that 18F-Alfatide PET/CT is valuable in the diagnosis of metastatic LNs for NSCLC patients.

18F-deoxyglucose positron emission tomography/computed tomography to predict local failure in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) patients are at risk for local failure (LF) following treatment. Predicting tumor regions at high risk for local failure before radiotherapy may increase treatment efficacy by permitting an escalated radiation dose specifically to those regions critical for tumor control. Forty-one patients with non-resectable locally advanced ESCC underwent 18F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging before concurrent chemoradiotherapy (CCRT). After CCRT, a second (failure) FDG PET/CT was performed in cases of relapse. Failure FDG PET/CT scans were fused to pre-treatment scans to identify tumor regions at high risk for LF. Within a median follow-up time of 26 months, 20 patients (48.8%) had LF. In 19 patients, the failure occurred within a pre-treatment high FDG uptake region; the failure occurred outside these regions in only one patient. Pre-treatment metabolic tumor volume (MTV) was independently associated with LF (P<0.001, HR 1.128, 95% CI: 1.061-1.198). LF was more likely in patients with MTVs ≥27 cm3. In initial PET/CT images, when 50% maximum standardized uptake value (SUVmax) was used as the threshold, delineated subvolumes overlapped LF regions. These results confirm that LF occurs most commonly within pre-treatment high FDG uptake regions.

[Effects of 4 week hypoxic training on endurance capacity and T lymphocyteofmale football players].

OBJECTIVE: To investigate the effects of 4-week hypoxia training on index related to endurance capacity and lymphocyte sub-jects of male football players. METHODS: Football players from a sport university were evenly divided into 4 groups:training group, hypoxic group, hypoxia training group and control group. The control group completed a 4-week cycling training with the intensity of 65%~75% VO2max, while the hypoxia training group did the same training in hypoxia environment (14.7% oxygen concentration);Low oxygen groups for 4 weeks daily 60 min, 5 times a week in a low oxygen (14.7% oxygen concentration) environment, did not cycle training;the control group without any intervention. RESULTS: In hypoxia training group, the red blood cell count and hemoglobin were significantly higher than those of the control group, training group and hypoxia group(P < 0.05);there was significant difference in VO2max and the performance of 3 000 m running between hypoxia training group and other groups(P < 0.05); the number of CD3+ level in hypoxia training group was significantly higher than that of the control group and hypoxia group (P < 0.05). CONCLUSIONS: Compared to other methods environment, a hypoxia training program of 60 min/d, 5 d/w, 4 weeks in total contributed to improve the endurance capacity of male football players, and it's also probably beneficial for improvement of immunity.

A Comparative Study of Noninvasive Hypoxia Imaging with 18F-Fluoroerythronitroimidazole and 18F-Fluoromisonidazole PET/CT in Patients with Lung Cancer.

PURPOSE: This is a clinical study to compare noninvasive hypoxia imaging using 18F-fluoroerythronitroimidazole (18F-FETNIM) and 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT) in patients with inoperable stages III-IV lung cancer. METHODS: A total of forty-two patients with inoperable stages III-IV lung cancer underwent 18F-FETNIM PET/CT (n = 18) and 18F-FMISO PET/CT (n = 24) before chemo/radiation therapy. The standard uptake values (SUVs) of malignant and normal tissues depict 18F-FETNIM PET/CT and 18F-FMISO PET/CT uptake. Tumor-to-blood ratios (T/B) were used to quantify hypoxia. RESULTS: All patients with lung cancer underwent 18F-FETNIM PET/CT and 18F-FMISO PET/CT successfully. Compared to 18F-FMISO, 18F-FETNIM showed similar uptake in muscle, thyroid, spleen, pancreas, heart, lung and different uptake in blood, liver, and kidney. Significantly higher SUV and T/B ratio with 18F-FMISO (2.56±0.77, 1.98±0.54), as compared to 18F-FETNIM (2.12±0.56, 1.42±0.33) were seen in tumor, P = 0.022, <0.001. For the patients with different histopathological subtypes, no significant difference of SUV (or T/B ratio) was observed both in 18F-FMISO and 18F-FETNIM in tumor. A significantly different SUV (or T/B ratio) was detected between < = 2cm, 2~5cm, and >5cm groups in 18F-FMISO PET/CT, P = 0.015 (or P = 0.029), whereas no difference was detected in 18F-FMISO PET/CT, P = 0.446 (or P = 0.707). Both 18F-FETNIM and 18F-FMISO showed significantly higher SUVs (or T/B ratios) in stage IV than stage III, P = 0.021, 0.013 (or P = 0.032, 0.02). CONCLUSION: 18F-FMISO showed significantly higher uptake than 18F-FETNIM in tumor/non-tumor ratio and might be a better hypoxia tracer in lung cancer.

A pilot study imaging integrin αvß3 with RGD PET/CT in suspected lung cancer patients.

PURPOSE: Angiogenesis is an essential step in tumour development and metastasis. Integrin αvß3 plays a major role in angiogenesis, tumour growth and progression. A new tracer, (18)F-AL-NOTA-PRGD2, denoted as (18)F-alfatide, has been developed for positron emission tomography (PET) imaging of integrin αvß3. This is a pilot study to test the safety and diagnostic value of (18)F- arginine-glycine-aspartic acid (RGD) PET/computed tomography (CT) in suspected lung cancer patients. METHODS: Twenty-six patients with suspected lung cancer on enhanced CT underwent (18)F-alfatide RGD PET/CT examination before surgery and puncture biopsy. Standard uptake values (SUVs) and the tumour-to-blood ratios were measured, and diagnoses were pathologically confirmed. RESULTS: RGD PET/CT with (18)F-alfatide was performed successfully in all patients and no clinically significant adverse events were observed. The (18)F-alfatide RGD PET/CT analysis correctly recognized 17 patients with lung cancer, 4 patients (hamartoma) as true negative, and 5 patients (4 chronic inflammation and 1 inflammatory pseudotumour) as false positive. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of (18)F-alfatide RGD PET/CT for the diagnosis of suspected lung cancer patients was 100, 44.44, 80.77, 77.27, and 100%, respectively. The area under a receiver operating characteristic (ROC) curve was 0.75 (P = 0.038), and ROC analysis suggested an SUVmax cut-off value of 2.65 to differentiate between malignant lesions and benign lesions. The SUV for malignant lesions was 5.37 ± 2.17, significantly higher than that for hamartomas (1.60 ± 0.11; P < 0.001). The difference between the tumour-to-blood ratio for malignant lesions (4.13 ± 0.91) and tissue of interest-to-blood ratio for hamartomas (1.56 ± 0.24) was also statistically significant (P < 0.001). Neither the SUVmax nor the tumour-to-blood ratio was significantly different between malignant lesions and inflammatory lesions or inflammatory pseudotumours (P > 0.05). Sixteen of 26 patients later underwent successful surgery, and pathologic examination confirmed nodes positive for metastasis in 14 of 152 lymph nodes. The sensitivity, specificity, accuracy, PPV, and NPV of PET/CT for lymph nodes was 92.86, 95.65, 95.40, 61.90, and 99.25%, respectively. CONCLUSION: Our results suggest that RGD PET/CT with the new tracer (18)F-alfatide is safe and potentially effective in the diagnosis of non-small cell lung cancer. It may be used in the diagnosis of lung cancer, successfully distinguishing malignant lesions from hamartoma. However, it is difficult to clearly differentiate inflammatory or inflammatory pseudotumours from malignant lesions. Additional studies with a larger number of patients are needed to validate our findings.

Extending the serum half-life of G-CSF via fusion with the domain III of human serum albumin.

Protein fusion technology is one of the most commonly used methods to extend the half-life of therapeutic proteins. In this study, in order to prolong the half-life of Granulocyte colony stimulating factor (G-CSF), the domain III of human serum albumin (3DHSA) was genetically fused to the N-terminal of G-CSF. The 3DHSA-G-CSF fusion gene was cloned into pPICZ α A along with the open reading frame of the α -factor signal under the control of the AOX1 promoter. The recombinant expression vector was transformed into Pichia pastoris GS115, and the recombinant strains were screened by SDS-PAGE. As expected, the 3DHSA-G-CSF showed high binding affinity with HSA antibody and G-CSF antibody, and the natural N-terminal of 3DHSA was detected by N-terminal sequencing. The bioactivity and pharmacokinetic studies of 3DHSA-G-CSF were respectively determined using neutropenia model mice and human G-CSF ELISA kit. The results demonstrated that 3DHSA-G-CSF has the ability to increase the peripheral white blood cell (WBC) counts of neutropenia model mice, and the half-life of 3DHSA-G-CSF is longer than that of native G-CSF. In conclusion, 3DHSA can be used to extend the half-life of G-CSF.

Noninvasive evaluation of microscopic tumor extensions using standardized uptake value and metabolic tumor volume in non-small-cell lung cancer.

PURPOSE: To prospectively evaluate whether maximal microscopic extensions (MEmax) correlate with maximal standardized uptake value (SUVmax) and metabolic tumor volume (MTV) at 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images in non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Thirty-nine patients with Stage I-IIIA NSCLC underwent surgery after FDG-PET/CT scanning. SUVmax and MTV were calculated on the PET/CT images. The maximum linear distance from the tumor margin to the farthest extent of the tumor in every dimension was measured at the tumor section. The correlations among MEmax, SUVmax, MTV and other clinical pathologic parameters were analyzed. RESULTS: MEmax for all patients had a significant correlation with SUVmax (r = 0.777, p = 0.008) and MTV (r = 0.724, p < 0.001). When expressed in terms of the probability of covering ME with respect to a given margin, we suggested that margins of 1.93 mm, 3.90 mm, and 9.60 mm for SUVmax ≤ 5, 5-10, and >10 added to the gross tumor volume would be adequate to cover 95% of ME. CONCLUSIONS: This study demonstrated that tumors with high SUVmax and MTV have more MEmax and would therefore require more margin expansion from gross tumor volume to clinical target volume. FDG-PET/CT, especially for SUVmax, is promising and effective and merits additional study in noninvasive delimiting of the clinical target volume margin for NSCLC.