Background Inflammatory and immune responses triggered by brain ischemia worsen clinical outcomes of stroke and contribute to hemorrhagic transformation, massive edema and reperfusion injury associated with intravenous alteplase. We assessed whether a combination of the immune-modulator fingolimod and alteplase is safe and effective in attenuating reperfusion injury in patients with acute ischemic stroke (AIS) treated within the first 4.5 hours of symptom onset. Methods and Results In this multi-center trial, we randomly assigned 25 eligible patients with hemispheric ischemic stroke stemming from anterior or middle cerebral arterial occlusion to receive alteplase alone or 22 patients to receive alteplase plus oral fingolimod 0.5 mg daily for three consecutive days within 4.5 hours of the onset of ischemic stroke. Compared with patients who received alteplase alone or patients who received combination of fingolimod with alteplase exhibited lower circulating lymphocytes, smaller lesion volumes (10.1 vs 34.3 ml, P = 0.04), less hemorrhage (1.2 vs 4.4 ml, p = 0.01) and attenuated neurodeficits in National Institute of Health Stroke Scales (4 vs 2, P =0.02) at day 1. Furthermore, restrained lesion growth from day 1 to day 7 (−2.3 vs 12.1 ml, P < 0.01) with a better recovery at day 90 (modified Rankin Scale 0-1, 73% vs 32%, P < 0.01) was evident in patients given fingolimod and alteplase. No serious adverse events were recorded in all patients. Conclusions In this pilot study, combination therapy of fingolimod and alteplase was well tolerated, attenuated reperfusion injury and improved clinical outcomes in AIS patients. These findings need to be tested in further clinical trials.

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Myasthenia gravis (MG) is a chronic humoral immunity-mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4(+)CXCR5(+)PD-1(+) Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti-acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling-dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.

Noise equivalent count rate (NECR) and image noise are two different but related metrics that have been used to predict and assess image quality, respectively. The aim of this study is to investigate, using patient studies, the relationships between injected dose (ID), body mass index (BMI) and scanner type on NECR and image noise measurements in PET imaging. Two groups of 90 patients each were imaged on a GE DSTE and a DRX PET/CT scanner, respectively. The patients in each group were divided into nine subgroups according to three BMI (20-24.9, 25-29.9, 30-45 kg m(-2)) and three ID (296-444, 444-555, 555-740 MBq) ranges, resulting in ten patients/subgroup. All PET data were acquired in 3D mode and reconstructed using the VuePoint HD® fully 3D OSEM algorithm (2 iterations, 21(DRX) or 20 (DSTE) subsets). NECR and image noise measurements for bed positions covering the liver were calculated for each patient. NECR was calculated from the trues, randoms and scatter events recorded in the DICOM header of each patient study, while image noise was determined as the standard deviation of 50 non-neighboring voxels in the liver of each patient. A t-test compared the NECR and image noise for different scanners but with the same BMI and ID. An ANOVA test on the other hand was used to compare the results of patients with different BMI but the same ID and scanner type as well as different ID but the same BMI and scanner type. As expected the t-test showed a significant difference in NECR between the two scanners for all BMI and ID subgroups. However, contrary to what is expected no such findings were observed for image noise measurement. The ANOVA results showed a statistically significant difference in both NECR and image noise among the different BMI for each ID and scanner subgroup. However, there was no statistically significant difference in NECR and image noise across different ID for each BMI and scanner subgroup. Although the GE DRX PET/CT scanner has better count rate performance than the GE DSTE PET/CT scanner, this improvement does not translate to a lower image noise when using OSEM reconstruction. Our results show that patients with larger BMI consistently generate poorer image quality. Dose reduction from>555 to 296-444 MBq has minimal impact on image quality independent of the scanner used. A reduction in ID decreases patient and technologist exposure and can potentially reduce the overall cost of the study.

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Amplitude gating techniques have recently been shown to be better at suppressing respiratory motion artifacts than phase gating. However, most commercial PET/CT scanners are equipped with phase gating capabilities only. The objective of this article was to propose and evaluate using patient studies an automated respiratory amplitude gating technique that could be implemented on current whole-body PET/CT scanners. A primary design feature of the proposed technique is to automatically match the respiratory amplitude captured during the CT scan with a corresponding amplitude during the PET scan. Methods The proposed amplitude gating technique consists of a CT scan, followed by a list-mode PET scan. The CT scan was acquired while the patient’s respiratory motion was recorded by a monitoring device that determined the respiratory motion amplitude captured during the CT scan. A program was designed to inject triggers into the PET list stream whenever the patient’s respiration crossed a preset amplitude range determined by the captured amplitude during CT. To implement this proposed amplitude gating technique in whole-body PET/CT, a PET-first protocol was necessary to minimize the respiratory baseline drift between the CT and PET scans. In this implementation, a regular PET scan was first acquired over the patient’s whole body but excluding the bed position that covered the lesion of interest. The whole-body CT scan was then acquired, followed by a list-mode PET acquisition over the bed position that covered the area of interest (lesion). The proposed amplitude gating technique was tested using 13 patients with 21 lung or thoracic tumors. Results In the patient studies, the gated images—when compared with the ungated images—showed statistically significant improvements, with an average 27% and 28% increase in maximum and mean standardized uptake value, respectively, for all lesions. Furthermore, the tumors in the gated images showed better contrast using visual inspection and line profiles. Conclusion The implementation of the proposed respiratory amplitude gating technique on current PET/ CT scanners is feasible, and amplitude-matched CT and PET data can be automatically generated using our proposed procedures without requiring patients to hold their breath or increase their radiation exposure.

Wnt/b-catenin signaling activates the transcription of target genes to regulate stem cells and cancer development. However, the contribution of epigenetic regulation to this process is unknown.Here, we report that Wnt activation stabilizes the epigenetic regulator KDM4C that promotes tumorigenesis and survival of human glioblastoma cells by epigenetically activating the transcription of Wnt target genes. KDM4C protein expression was upregulated in human glioblastomas, and its expression directly correlated with Wnt activity and Wnt target gene expression. KDM4C was essential for Wnt-induced gene expression and tumorigenesis of glioblastoma cells. In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degrada-tion. Wnt3a stabilized KDM4C through inhibition of GSK3-dependent protein kinase R activity. Stabilized KDM4C accumulated in the nucleus and bound to and demethylated TCF4-associated histone H3K9 by interacting with b-catenin, promoting HP1g removal and transcriptional activation. These findings reveal that Wnt-KDM4C-b-catenin signaling represents a novel mechanism for the transcription of Wnt target genes and regulation of tumorigenesis, with important clinical implications.Significance: These findings identify the Wnt-KDM4C-bcatenin signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.