High Inflammatory Tendency Induced by Malignant Stimulation Through Imbalance of CD28 and CTLA-4/PD-1 Contributes to Dopamine Neuron Injury.

BACKGROUND: Parkinson's disease is a common neurodegenerative disease in the elderly. The incidence of various cancers in Parkinson's disease patients is significantly lower than in healthy people. Parkinson's disease patients are individuals with a high tendency for inflammation, whose peripheral immune system is represented in an activated state. We hypothesized that the hyperinflammatory predisposition of Parkinson's disease patients is pathogenic. METHODS: DBA/1 mice were used to simulate "highly inflammatory individuals", and the carcinogen DEN was used to induce malignancy. Hematoxylin & eosin (H&E) staining was used to observe the formation of lung tumors. Apoptosis of neurons was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Immunohistochemistry and flow cytometry were used to observe CD4, CD28, major histocompatibility complex II (MHCII), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed death 1 (PD-1). The ionized calcium binding adaptor molecule-1 (IBA-1) + inducible nitric oxide synthase (iNOS) was used to label M1 microglia, and IBA-1 + arginase 1 (Arg1) was used to label M2 microglia by immunofluorescence. The expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and anti-inflammatory cytokines IL-10 and IL-4 was detected by ELISA. RESULTS: DBA/1 mice with high inflammatory tendency showed a continuous increase of peripheral inflammation, promoting intracranial inflammation, decreasing the tumor incidence and increasing the neurodegeneration under induction of malignant change. CD28 and CTLA-4/PD-1 reduced the T-cell-dominated inflammatory response, reduced the intracerebral inflammatory response, protected from neurodegeneration, and increased the incidence of tumor. Combination of CTLA-4 and PD-1 blocker can overactivate T cells, worsen peripheral and intracranial inflammation, reduce the incidence of tumor, cause damage to dopamine neurons, and promote the occurrence of neurodegeneration. CONCLUSION: High inflammatory tendency induced by malignant stimulation through the imbalance of CD28 and CTLA-4/PD-1 leads to dopamine neuron injury.

A preliminary study of imaging paclitaxel-induced tumor apoptosis with (99)Tc(m)-His10-Annexin V.

BACKGROUND: In tumors the process of apoptosis occurs over an interval of time after chemotherapy. It is important to determine the best time for detecting apoptosis by in vivo imaging. In this study, we evaluated the dynamics and feasibility of imaging non-small cell lung cancer (NSCLC) apoptosis induced by paclitaxel treatment using a (99)Tc(m)-labeled Annexin V recombinant with ten consecutive histidines (His10-Annexin V) in a mouse model. METHODS: (99)Tc(m)-His10-Annexin V was prepared by one step direct labeling; radio-chemical purity (RCP) and radio-stability was tested. The binding of (99)Tc(m)-His10-Annexin V to apoptotic cells was validated in vitro using camptothecin-induced Jurkat cells. In vivo bio-distribution was determined in mice by dissection. The human H460 NSCLC tumor cell line (H460) tumor-bearing mice were treated with intravenous paclitaxel 24, 48 and 72 hours later. (99)Tc(m)-His10-Annexin V was injected intravenously, and planar images were acquired at 2, 4 and 6 hours post-injection on a dual-head gamma camera fitted with a pinhole collimator. Tumor-to-normal tissue ratios (T/NT) were calculated by ROI analysis and they reflected specific binding of (99)Tc(m)-His10-Annexin V. Mice were sacrificed after imaging. Caspase-3, as the apoptosis detector, was determined by flow cytometry, and DNA fragmentation was analyzed by the terminal deoxynucleotidytransferase mediated dUTP nick-end labeling (TUNEL) assay. Nonspecific accumulation of protein was estimated using bovine serum albumin (BSA). The imaging data were correlated with TUNEL-positive nuclei and caspase-3 activity. RESULTS: (99)Tc(m)-His10-Annexin V had a RCP > 98% and high stability 2 hours after radio-labeling, and it could bind to apoptotic cells with high affinity. Bio-distribution of (99)Tc(m)-His10-Annexin V showed predominant uptake in kidney, relatively low uptake in myocardium, liver and gastrointestinal tract, and rapid clearance from blood and kidney was observed. The T/NT was significantly increased after paclitaxel treatment, whereas it was low in untreated tumors (T/NT = 1.43 ± 0.18). The %ID/g activity in Group 2 (24 hours), Group 3 (48 hours) and Group 4 (72 hours) after treatment was 2.55 ± 0.73, 3.35 ± 1.10, and 3.4 ± 0.96, respectively. Whereas in the non-treated group, Group 1, %ID/g was 1.10 ± 0.18. The radiotracer uptake was positively correlated to the apoptotic index (r = 0.852, P < 0.01), as well as caspase-3 activity (r = 0.816, P < 0.01). CONCLUSION: This study addresses the dynamics and feasibility of imaging non-small cell lung tumor apoptosis using (99)Tc(m)- His10-Annexin V.

[A comparison of ventilation/perfusion single photon emission CT and CT pulmonary angiography for diagnosis of pulmonary embolism].

OBJECTIVE: To assess the diagnostic accuracy of ventilation/perfusion (V/Q) single photon emission CT (SPECT) as compared to computed tomographic pulmonary angiography (CTPA) for pulmonary embolism (PE). METHODS: In this prospective multicenter study, 111 patients in whom acute or sub-acute PE was clinically confirmed or suspected were enrolled. The patients underwent one-day method V/Q lung scan (including SPECT and planar imaging) within 3 days before and after completion of CTPA. The European Association of Nuclear Medicine (EANM) guidelines for ventilation/perfusion scintigraphy (2009) reference was used as the evaluation criteria of V/Q SPECT imaging. The refined modified prospective investigation of pulmonary embolism diagnosis (RM-PIOPED) criteria was used for evaluation of planar imaging. According to the direct and indirect signs of PE, the imaging of CTPA was evaluated. All patients were followed for at least 6 months. A diagnosis was finally made by consensus of respiratory physicians, radiologists and nuclear medicine physicians based on the clinical data, laboratory tests, imaging features and follow-up results. The difference among diagnostic methods was evaluated for significance using chi-square test. The receiver operator characteristic (ROC) curve was drawn according to the results of the 3 diagnostic tests. The area under ROC curve (AUC) was calculated and compared. P < 0.05 was considered statistically significant. RESULTS: Among the 111 patients, PE was confirmed in 80, and excluded in 31. The diagnostic sensitivity/specificity/accuracy of V/Q SPECT, planar imaging, and CTPA were 85.9%/93.5%/88.1%, 75.7%/92.9%/81.4%, and 85.5%/90.0%/86.8%, respectively. By ROC curve analysis, the AUC values of V/Q SPECT, planar imaging and CTPA were 0.898, 0.838, and 0.877, respectively; with 95% confidence intervals [CI] 0.831 to 0.966, 0.759 to 0.917, and 0.801 to 0.954, respectively. The area of the fitted smooth ROC curve was statistically significant (P < 0.05) as compared with the area under the reference line. CONCLUSION: The results indicate that SPECT V/Q imaging is superior to V/Q planar scan and CTPA in the diagnosis of PE.