Modern cancer treatment techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), have greatly increased the demand for more accurate treatment planning (structure definition, dose calculation, etc) and dose delivery. The ability to use fast and accurate Monte Carlo (MC)-based dose calculations within a commercial treatment planning system (TPS) in the clinical setting is now becoming more of a reality. This study describes the dosimetric verification and initial clinical evaluation of a new commercial MC-based photon beam dose calculation algorithm, within the iPlan v.4.1 TPS (BrainLAB AG, Feldkirchen, Germany). Experimental verification of the MC photon beam model was performed with film and ionization chambers in water phantoms and in heterogeneous solid-water slabs containing bone and lung-equivalent materials for a 6 MV photon beam from a Novalis (BrainLAB) linear accelerator (linac) with a micro-multileaf collimator (m(3) MLC). The agreement between calculated and measured dose distributions in the water phantom verification tests was, on average, within 2%/1 mm (high dose/high gradient) and was within +/-4%/2 mm in the heterogeneous slab geometries. Example treatment plans in the lung show significant differences between the MC and one-dimensional pencil beam (PB) algorithms within iPlan, especially for small lesions in the lung, where electronic disequilibrium effects are emphasized. Other user-specific features in the iPlan system, such as options to select dose to water or dose to medium, and the mean variance level, have been investigated. Timing results for typical lung treatment plans show the total computation time (including that for processing and I/O) to be less than 10 min for 1-2% mean variance (running on a single PC with 8 Intel Xeon X5355 CPUs, 2.66 GHz). Overall, the iPlan MC algorithm is demonstrated to be an accurate and efficient dose algorithm, incorporating robust tools for MC-based SBRT treatment planning in the routine clinical setting.

Background and Purpose: Symptomatic intracranial hemorrhage (sICH), potentially associated with poor prognosis, is a major complication of endovascular thrombectomy (EVT) for ischemic stroke patients. We aimed to develop and validate a risk model for predicting sICH after EVT in Chinese patients due to large-artery occlusions in the anterior circulation. Methods: The derivation cohort recruited patients with EVT from the Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke Registry in China. sICH was diagnosed according to the Heidelberg Bleeding Classification within 24 hours of EVT. Stepwise logistic regression was performed to derive the predictive model. The discrimination and calibration of the risk model were assessed using the C index and the calibration plot. An additional cohort of 503 patients from 2 stroke centers was prospectively enrolled to validate the new model. Results: We enrolled 629 patients who underwent EVT as the derivation cohort, among whom 87 developed sICH (13.8%). In the multivariate adjustment, Alberta Stroke Program Early CT Score (odds ratio [OR], 0.85; P =0.005), baseline glucose (OR, 1.13; P =0.001), poor collateral circulation (OR, 3.06; P =0.001), passes with retriever (OR, 1.52; P =0.001), and onset-to-groin puncture time (OR, 1.79; P =0.024) were independent factors of sICH and were incorporated as the Alberta Stroke Program Early CT Score, Baseline Glucose, Poor Collateral Circulation, Passes With Retriever, and Onset-to-Groin Puncture Time (ASIAN) score. The ASIAN score demonstrated good discrimination in the derivation cohort (C index, 0.771 [95% CI, 0.716–0.826]), as well as the validation cohort (C index, 0.758 [95% CI, 0.691–0.825]). Conclusions: The ASIAN score reliably predicts the risk of sICH in Chinese ischemic stroke patients treated by EVT.

Background and Purpose In acute arterial occlusion, FLAIR vascular hyperintensity (FVH) has been linked to slow flow in leptomeningeal collaterals and cerebral hypoperfusion, but the impact on clinical outcome is still controversial. In this study, we aimed to investigate the association between FVH topography or FVH-ASPECTS pattern and outcome in acute M1-MCA occlusion patients with endovascular treatment. Methods We included acute M1-MCA occlusion patients treated with endovascular therapy. All patients had DWI and FLAIR before endovascular therapy. Distal FVH ASPECT score was evaluated according to distal MCA-ASPECT area (M1–M6) and acute DWI lesion was also reviewed. Presence of FVH inside and outside DWI positive lesions was separately analyzed. Clinical outcome after endovascular therapy was analyzed with respect to different distal FVH-ASPECTS topography. Results Among 101 patients that met inclusion criteria for the study, mean age was 66.2±17.8 and median NIHSS was 17.0 (IQR 12.0–21.0). FVH-ASPECTS measured outside of the DWI lesion was significantly higher in patients with good outcome (mRS 0–2), (8.0 vs 4.0, p<0.001). Logistic regression demonstrated that FVH-ASPECTS outside of the DWI lesion was independently associated with clinical outcome of these patients (OR 1.3; 95% CI, 1.06 to 1.68; p=0.013). FVH-ASPECTS inside the DWI lesion was associated with hemorrhagic transformation (OR 1.3; 95% CI, 1.04 to 1.51; p=0.019). Conclusions Higher FVH-ASPECTS measured outside the DWI lesion is associated with good clinical outcomes in patients undergoing endovascular therapy. FVH-ASPECTS measured inside the DWI lesion was predictive of hemorrhagic transformation. The FVH pattern, not number, can serve as an imaging selection marker for endovascular therapy in acute middle cerebral artery occlusion.

Nerve growth factor (NGF) has been proved with the potential of promoting neurogenesis in adult mammalians. This study was aimed to investigate the effect of intranasal (IN) NGF on striatal neurogenesis and functional recovery in adult rats with focal cerebral ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h, and then reperfused. NGF or vehicle was intranasally administered 24 h after cerebral reperfusion, and the treatments continued for 6 consecutive days there after. All animals were injected with 5-bromodeoxyuridine (BrdU) twice daily for 5-7 days after MCAO, and sacrificed 1 day and 28 days, respectively, after the last BrdU injection. Neural cell proliferation and survival in different brain regions were analyzed. Functional tests and immunohistochemical staining were also performed. The results showed that treatment with IN NGF failed to increase cell proliferation but improved survival of newly generated cells in ipsilateral striatum and subventricular zones (SVZ). Double immunofluorescence with BrdU and neuronal nuclei protein, a mature neuronal marker, were increased in striatum and SVZ in rats treated with IN NGF. The functional recovery was also observed at time of neurogenesis enhancement in striate. In conclusion, IN NGF may enhance neurogenesis and survival of newly generated cells, which may result in improved functional recovery after cerebral ischemia.

Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN-β. Further analyses identified histidine 862 as a critical residue for USP15’s catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-β promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms.

Background The trajectory of ischemic stroke patients attributable to large vessel occlusion is fundamentally altered by endovascular thrombectomy. This study aimed to develop a nomogram for predicting 3‐month mortality risk in patients with ischemic stroke attributed to artery occlusion in anterior circulation who received successful endovascular thrombectomy treatment. Methods and Results Patients with successful endovascular thrombectomy (modified Thrombolysis in Cerebral Infarction IIb or III) were enrolled from a multicenter registry as the training cohort. Step‐wise logistic regression with Akaike information criterion was utilized to establish the best‐fit nomogram. The discriminative value of the nomogram was tested by concordance index. An additional 224 patients from 2 comprehensive stroke centers were prospectively recruited as the test cohort for validating the new nomogram. Altogether, 417 patients were enrolled in the training cohort. Age (odds ratio [OR], 1.07; 95% CI, 1.03−1.10), poor pretreatment collateral status (OR, 2.13; 95% CI, 1.18−3.85), baseline blood glucose level (OR, 1.12; 95% CI, 1.04−1.21), symptomatic intracranial hemorrhage (OR, 9.51; 95% CI, 4.54−19.92), and baseline National Institutes of Health Stroke Scale score (OR, 1.08; 95% CI, 1.03−1.12) were associated with mortality and were incorporated in the nomogram. The c‐index of the nomogram was 0.835 (95% CI, 0.785–0.885) in the training cohort and 0.758 (95% CI, 0.667–0.849) in the test cohort. Conclusions The nomogram, composed of age, pretreatment collateral status, baseline blood glucose level, symptomatic intracranial hemorrhage, and baseline National Institutes of Health Stroke Scale score, may predict risk of mortality in patients with ischemic stroke and treated successfully with endovascular thrombectomy.

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BackgroundMany studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk of ischemic stroke. However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous populations. To shed light on these inconclusive findings, we conducted a large meta-analysis of studies relating the ACE I/D polymorphism to the risk of ischemic stroke.MethodsRelevant studies were identified by searching PubMed and Embase through February 2012 and by reviewing the references of retrieved articles. We included studies that reported odds ratio (OR) with 95% confidence interval (CI) for the association between this polymorphism and ischemic stroke risk.ResultsFifty independent publications, with 10 070 stroke cases and 22 103 controls, were included. The results indicated that the DD homozygote carriers had a 37% higher risk of ischemic stroke when compared with the homozygotes II and heterozygote ID [odds ratio (OR) = 1.37, 95% confidence interval (CI): 1.22–1.53]. Subgroup analyses indicated that this higher risk was more pronounced among Asians, hospital-based studies, and small vessel disease (SVD). Potential publication bias may exist, but correction for this bias using a formal statistical method did not materially alter the combined risk estimate.ConclusionThe results of our meta-analysis indicate that the D allele of ACE I/D polymorphism is a low-penetrance susceptibility marker of ischemic stroke.