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BACKGROUND Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.

Objective A high rate of cerebral aneurysm recurrence following endovascular coiling has prompted the use of digital subtraction angiography (DSA) for interval follow-up. However, the utility of skull x-rays as an alternative screening method for aneurysm recurrence is unproperly characterized. Methods Retrospective review of a prospective registry of ruptured and unruptured cerebral aneurysms. Anteroposterior and lateral skull x-rays were obtained immediately at the end of the procedure and at 6-month follow-up. Aneurysm recurrence was defined by comparing post-procedure and 6-month DSA imaging. A true positive was defined as a change in coil mass morphology on at least one projection with aneurysm recurrence on DSA, and a true negative defined as a stable coil mass on both projections and no recurrence on DSA. Receiver operating characteristic area under the curve (AUC) statistics was used to assess the performance of skull x-rays in identifying aneurysm recurrence. Results A total of 118 cerebral aneurysms were evaluated with DSA imaging and skull x-rays. A change in coil mass morphology on one projection of skull x-rays correctly detected all true recurrences with a sensitivity of 100% (95% confidence interval [CI], 91-100%). Skull x-rays failed to identify a stable aneurysm coil mass in 15 cases, with a specificity of 79% (68-88%). Skull x-rays performed with AUC 0.8958 (95% CI, 0.8490-0.9431) in identifying aneurysm recurrence. Conclusions The findings of our study suggest that skull x-rays may represent a low-cost, non-invasive screening tool to rule out aneurysm recurrence, which can potentially aid in decreasing the utilization of DSA in the follow-up of patients with coiled cerebral aneurysms.

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009–2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm(3) and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

PURPOSE IDH wild-type (WT) glioblastoma (GBM) is an aggressive tumor with poor survival despite current therapies. The aim of this study was to characterize its genomic profile and determine whether a particular molecular signature is associated with improved survival outcomes. PATIENTS AND METHODS Tumor samples from 232 patients with IDH-WT GBM were sequenced, and the landscape of genomic alterations was fully delineated. Genomics data from The Cancer Genome Atlas (TCGA) cohort were analyzed for confirmation. Association of alterations with survival was evaluated in both univariable and multivariable approaches. RESULTS The genomic landscape of IDH-WT GBM revealed a high frequency of CDKN2A/B loss, TERT promoter mutations, PTEN loss, EGFR alteration, and TP53 mutations. Novel variants or gene mutations, such as ARID1B and MLL2, were identified. To better understand synergistic effects and facilitate decision making for precision medicine, we identified 11 pairs of gene alterations that tended to co-occur or were mutually exclusive, which were confirmed in the TCGA cohort. Survival analysis showed that genomic alterations in TP53 were associated with worse overall survival (OS). However, alterations in PI3K class I genes were associated with significantly better OS (univariable analysis: P = .002; multivariable analysis: hazard ratio [HR], 0.5785; P = .00162) and longer progression-free survival (univariable analysis: P = .0043; multivariable analysis: HR, 0.6228; P = .00913). CONCLUSION Genomic alterations in PI3K class I are a favorable prognostic factor in IDH-WT GBM. This new prognostic biomarker may facilitate risk stratification of patients, assist in clinical trial enrollment, and provide potential therapeutic targets

Patients with cerebral vasospasm caused by aneurysmal subarachnoid hemorrhage (aSAH) are often treated with intra-arterial (IA) vasodilator infusion. However, the optimal drug regimen is yet to be elucidated. A retrospective review of patients with aSAH and cerebral vasospasm treated with IA vasodilator infusion was performed. Patients in group 1 (2008–2011) were treated with a single agent, either nicardipine or verapamil, and patients in group 2 (2010–2016) were treated with a regimen of nitroglycerin, verapamil, and nicardipine. The post-infusion improvement ratio (PIIR) was compared between groups. Adjusted multivariate logistic regression models were utilized to determine whether patients treated with multiple vasodilators had an improved functional outcome, defined by the modified Rankin Scale, at discharge and 90-day follow-up. Among 116 patients from group 1 (N = 47) and group 2 (N = 69), the median age was 54.5 years [IQR, 46–53 years] and 78% were female. Use of multiple-agent therapy resulted in a 24.36% improvement in vessel diameter over single-agent therapy (median PIIR: group 1, 10.5% [IQR, 5.3–21.1%] vs group 2, 34.9% [IQR, 21.4–66.0%]; p < 0.0001). In the adjusted multivariate logistic regression, the use of multiple-agent therapy was associated with a better functional outcome at discharge (OR 0.15, 95% CI [0.04–0.55]; p < 0.01) and at 90-day follow-up (OR 0.20, 95% CI [0.05–0.77]; p < 0.05) when compared to single-agent therapy. In this study, we found that patients treated for cerebral vasospasm with IA infusion of multiple vasodilators had an increased vessel response and better functional outcomes compared to those treated with a single agent.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high‐ (>median, N=31) and low‐NOS2 (inducible nitric oxide synthase) (•(nitric oxide)‐mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (N=63,P= 0.01). Gene expression analysis in PDAC tumors (N=63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine‐2,3‐dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)‐target genes includingNFE2L2(NRF2),SERPINB2, IL1b,IL6andIL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO•donor induced IDO1, kynurenine production, and the expression of AHR‐target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO•‐induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.

Background: Cancer-associated adipocytes (CAAs) have been suggested to promote tumor progression. Yet, the role of CAAs in triple-negative breast cancer (TNBC) is poorly investigated. Methods: We compared the expression of secretory protein-encoding genes in CAAs and control adipocytes. The effect of key secretory protein(s) on TNBC cell behaviors was explored. Results: CAAs expressed and secreted FUCA2 at greater levels than control adipocytes. When FUCA2 activity was blocked with a neutralizing antibody, TNBC cell proliferation and migration induced by CAA conditioned medium was impaired. In contrast, supplement of exogenous FUCA2 protein reinforced the proliferation, colony formation, and migration of TNBC cells. In vivo studies confirmed that FUCA2 exposure enhanced tumorigenesis and metastasis of TNBC cells. Mechanistic investigation revealed that FUCA2 induced TNBC aggressiveness through TM9SF3-dependent signaling. Depletion of TM9SF3 blocked CAA- and FUCA2-induced TNBC cell proliferation and migration. Compared to adjacent breast tissues, TNBC tissues had increased expression of TM9SF3. Moreover, high TM9SF3 expression was associated with advanced TNM stage, lymph node metastasis, and shorter overall survival of TNBC patients. Conclusions: Altogether, CAAs secrete FUCA2 to promote TNBC growth and metastasis through interaction with TM9SF3. Inhibition of TM9SF3 may represent a potential therapeutic strategy in the treatment of TNBC.

Objective: Current guidelines recommend active surveillance with serial magnetic resonance angiography (MRA) for management of small, asymptomatic unruptured anterior circulation aneurysms (UIAs). We sought to determine the cost-effectiveness of active surveillance compared to immediate surgery. Methods: We developed a Markov cost-effectiveness model simulating patients with small (Results: Immediate surgical treatment was the most cost-effective management strategy for small UIAs with ICER of USD 45,772 relative to active surveillance. Sensitivity analysis demonstrated immediate surgery was the preferred strategy, if rupture rate was >0.1%/year and if the diagnosis age was 11%. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay of USD 100,000/QALY, immediate surgical treatment was the most cost-effective strategy in 64% of iterations. Conclusion: Immediate surgical treatment is a cost-effective strategy for initial management of small UIAs in patients

BACKGROUND: Early diagnosis of Alzheimer’s disease (AD) remains challenging. It is speculated that structural atrophy in white matter tracts commences prior to the onset of AD symptoms. OBJECTIVE: We hypothesize that disruptions in white matter tract connectivity precedes the onset of AD symptoms and these disruptions could be leveraged for early prediction of AD. METHODS: Diffusion tensor images (DTI) from 52 subjects with mild cognitive impairment (MCI) were selected. Subjects were dichotomized into two age and gender matched groups; the MCI-AD group (22 subjects who progressed to develop AD) and the MCI-control group (who did not develop AD). DTI images were anatomically parcellated into 90 distinct regions ROIs followed by tractography methods to obtain different biophysical networks. Features extracted from these networks were used to train predictive algorithms with the objective of discriminating the MCI-AD and MCI-control groups. Model performance and best features are reported. RESULTS: Up to 80% prediction accuracy was achieved using a combination of features from the ‘right anterior cingulum’ and ‘right frontal superior medial’. Additionally, local network features were more useful than global in improving the model’s performance. CONCLUSION: Connectivity-based characterization of white matter tracts offers potential for early detection of MCI-AD and in the discovery of novel imaging biomarkers.

Aims The relationship between high-density lipoprotein cholesterol and the severity of coronary artery disease beyond low-density lipoprotein cholesterol, the primary target of cholesterol-lowering therapy, remains uncertain. We evaluated the association between high-density lipoprotein cholesterol and obstructive coronary artery disease using parameters of any obstructive plaque, obstructive plaque in the left main coronary artery or proximal left anterior descending artery, and obstructive plaque in multi-vessels, according to low-density lipoprotein cholesterol levels. Methods and results We analyzed 5130 asymptomatic non-diabetics who underwent coronary computed tomography angiography for general health examination. Obstructive plaque was defined as a plaque with ≥50% luminal diameter stenosis. The participants were divided into three groups based on low-density lipoprotein cholesterol levels of ≤129, 130–159, and ≥160 mg/dl. The prevalence of any obstructive plaque (5.9% vs 6.4% vs 10.6%) and obstructive plaque in the left main coronary artery or proximal left anterior descending artery (2.1% vs 2.1% vs 4.3%) significantly increased with low-density lipoprotein cholesterol category (all p Conclusion Increased high-density lipoprotein cholesterol levels were independently associated with a lower risk of obstructive coronary artery disease in asymptomatic non-diabetics with low low-density lipoprotein cholesterol levels.

Background Unregulated inflammatory and thrombotic responses have been proposed to be important causes of early brain injury and worse clinical outcomes after subarachnoid hemorrhage (SAH). Objective We hypothesize that SAH is characterized by an increased inflammatory and thrombotic state and disruption of associations between these states. Methods This is a retrospective cohort study of 60 patients with SAH. 23 patients with unruptured aneurysms (UA) and 77 patients with traumatic brain injury (TBI) were chosen as controls. Plasma cytokine levels were measured using a 41-plex human immunoassay kit, and cytokine patterns associated with SAH, UA and TBI were identified using statistical and informatics methods. Results SAH was characterized by an increase in several cytokines and chemokines, platelet-derived factors, and growth factors. Cluster analysis identified several cytokine clusters common in SAH, UA and TBI groups – generally grouped as platelet-derived, vascular and pro-inflammatory clusters. In the UA group, the platelet-derived cluster had an inverse relationship with the inflammatory cluster which was absent in SAH. Additionally, a cluster comprising of growth and colony stimulating factors was unique to SAH. Conclusions A cluster of cytokines involved in growth and colony stimulation was unique to SAH. Negative associations between the thrombotic and inflammatory molecules were observed in UA but not in SAH. Further studies to examine the pathophysiology behind the cluster unique to SAH and the associations between the thrombotic and inflammatory cytokines are required.

Background: This study aimed to investigate the morphological features and 2D/3D coverage parameters of the true acetabulum of Crowe type IV hips and to identify the optimal component center of standard-sized cup implantation.Methods: A total of 42 Crowe IV hips in 37 patients and 36 normal hips were included in the present study. Based on 3D reconstruction, anatomy and volume of the true acetabulum were measured quantitatively. Through simulated implantation, the feasibility of standard-sized cup implantation was evaluated by cup-based morphological assessments and coverage parameters. Eventually, bony landmarks for optimal component center location were determined. Mean follow-up was 4.7 years (1.2 to 6.3 years).Results: All the dysplastic hips were placed with standard-size acetabular implant (44.67mm, 44 to 48mm) successfully, with no acetabular implant loosening during the follow-up period. Compared with control group, the dysplastic acetabulum was more anteverted and abductive, with a thicker medial wall. According to the true acetabulum, bone stock is relatively sufficient in the posterior direction and prominently deficient in the anterosuperior and superior direction. Average 3D component coverage can reach 79.89% by standard-sized cup implantation at the true acetabulum. Regarding the component opening plane, the optimal component center located at the midpoint between the superolateral and posteroinferior point of the true acetabulum. Conclusion: Standard cup implantation is feasible and available in Crowe IV hip at the true acetabulum. The optimal component center was determined to be relatively constant based on the useful bony landmarks.Level of evidence: Therapeutic Level 3b.

Background Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Background: COVID-19 nucleic acid swab tests have a high false positive rate; therefore, diagnosing COVID-19 pneumonia and predicting prognosis by CT scan are very important. Methods: In this retrospective single-centre study, we included consecutive suspected critical COVID-19 pneumonia cases in the intensive care unit of Wuhan Third Hospital from January 31, 2020, to March 16, 2020. 204 cases were confirmed by real-time RT-PCR, and all patients were evaluated with CT, cut-off values were obtained according to the Youden index and were divided into a high CT score group and a low CT score group. Epidemiological, demographic, clinical, and laboratory data were collected. Finally, Through multi-factor logistic regression model, a prediction model based on multiple prediction indicators was formed, and new joint predictive factors were calculated. The prediction model of mortality in COVID-19 pneumonia based on CT score and lymphocyte count was constructed through data processing analysis. Results: The major imaging feature of COVID-19 pneumonia is Ground Glass Opacities (GGOs). Multivariate regression analysis found that the CT score and absolute lymphocyte count were independent risk factors for death and that the CT score predicted mortality (AUC-ROC =0.7, cut-off=1.45). When the absolute lymphocyte count was lower, the patient’s CT score was also lower. Based on this, a prediction model was established. The prediction model was: In [P/(1-P)]=0.667*gender+0.057*age-0.086CT score-0.831 lymphocyte count-3.91, the goodness of fit test of the model was P=0.041, and the area under the curve of the ROC curve of the model was 0.779. Conclusion: CT score and absolute lymphocyte count are independent risk factors for mortality, and patients with a high CT score may have a worse prognosis. A lower absolute lymphocyte count may indicate that the patient’s CT score is also reduced. The model established by combining CT scores and lymphocyte count showed a good degree of calibration and differentiation.

SUMMARY Spinal cord injury (SCI) is one of the most devastating neural injuries without effective therapeutic solutions. Astrocytes are the predominant component of the scar. Understanding the complex contributions of reactive astrocytes to SCI pathophysiologies is fundamentally important for developing therapeutic strategies. We have studied the molecular changes in the injury environment and the astrocyte-specific responses by astrocyte purification from injured spinal cords from acute to chronic stages. In addition to protein-coding genes, we have systematically analyzed the expression profiles of long non-coding RNAs (lncRNAs) (>200 bp), which are regulatory RNAs that play important roles in the CNS. We have identified a highly conserved lncRNA, Zeb2os, and demonstrated using functional assays that it plays an important role in reactive astrogliosis through the Zeb2os/Zeb2/Stat3 axis. These studies provide valuable insights into the molecular basis of reactive astrogliosis and fill the knowledge gap regarding the function(s) of lncRNAs in astrogliosis and SCI., Graphical Abstract, In Brief Wei et al. comprehensively investigate the coding and long non-coding gene expression changes and astrocyte-specific responses in injured spinal cord tissue and purified astrocytes from acute to chronic stages. Bioinformatic and functional analysis identify a conserved lncRNA Zeb2os that plays an essential role in reactive astrogliosis through the Zeb2os/Zeb2/Stat3 axis.

Cancer and organ injury-such as that occurring in the perioperative period, including acute lung injury, myocardial infarction, and acute gut injury-are among the leading causes of death in the United States and impose a significant impact on quality of life. MicroRNAs (miRNAs) have been studied extensively during the last two decades for their role as regulators of gene expression, their translational application as diagnostic markers, and their potential as therapeutic targets for disease treatment. Despite promising preclinical outcomes implicating miRNA targets in disease treatment, only a few miRNAs have reached clinical trials. This likely relates to difficulties in the delivery of miRNA drugs to their targets to achieve efficient inhibition or overexpression. Therefore, understanding how to efficiently deliver miRNAs into diseased tissues and specific cell types in patients is critical. This review summarizes current knowledge on various approaches to deliver therapeutic miRNAs or miRNA inhibitors and highlights current progress in miRNA-based disease therapy that has reached clinical trials. Based on ongoing advances in miRNA delivery, we believe that additional therapeutic approaches to modulate miRNA function will soon enter routine medical treatment of human disease, particularly for cancer or perioperative organ injury. SIGNIFICANCE STATEMENT: MicroRNAs have been studied extensively during the last two decades in cancer and organ injury, including acute lung injury, myocardial infarction, and acute gut injury, for their regulation of gene expression, application as diagnostic markers, and therapeutic potentials. In this review, we specifically emphasize the pros and cons of different delivery approaches to modulate microRNAs, as well as the most recent exciting progress in the field of therapeutic targeting of microRNAs for disease treatment in patients.

Introduction: Prior studies suggest that patients with large vessel occlusion (LVO) who undergo endovascular stroke therapy (EST) after inter-hospital transfer (IHT) have worse outcomes than those who present directly to EST centers. However, these studies were largely derived from clinical trials or registries and may not be representative of real-world clinical practice. Methods: We performed a multicenter, observational cohort study on acute ischemic stroke (AIS) patients with LVO that presented to EST-capable centers directly (LVO-D) or after IHT (LVO-T) between 1/1/2018 to 2/1/2019. The study included 11 hospitals in the Houston area, of which 4 are EST-capable. Clinical data were collected using our cerebrovascular data registry. All transfers were from non-EST capable hospitals to EST-capable hospitals. Logistic regression adjusted for age, NIHSS, occlusion location and direct vs transfer arrival was used to assess the likelihood of good outcome, defined as discharge to home or rehabilitation. Results are given as median [IQR] and OR [95% CI]. Results: Among 4,313 patients with AIS, 772 (18%) patients had LVO. Among LVO patients, median age was 68 [59-79], 47% were female, 51% were white, 378 (49%) were LVO-D and 394 (51%) were LVO-T. Median IHT time was 152 min [114-198]. LVO-D patients arrived at EST-treating hospitals with superior ASPECTS compared to LVO-T (9 [7-10] vs 7 [6-9], p Conclusion: In this real-world cohort of a multi-center stroke network, IHT was not associated with worse outcomes for patients with LVO, for both patients who did receive EST and those that did not.

Background This study sought to evaluate the effect of tumor-infiltrating lymphocyte (TIL) density and programmed death ligand 1 (PD-L1) expression on the prognosis of esophageal cancer. Methods Banked tissue specimens from 53 patients who underwent esophagectomies for malignancy at a single institution over a 6-year period were stained for cluster of differentiation 3 (CD3), CD8, and PD-L1. Tumors were characterized as staining high or low density for CD3 and CD8, as well as positive or negative for PD-L1. TIL density and PD-L1 expression were analyzed in the context of survival, recurrence, and perioperative characteristics. Results Median follow-up was 823 days, with 92.5% survival and 26.8% recurrence rates. All tumors were adenocarcinomas. Neoadjuvant chemotherapy was given in 56.6% of cases, and neoadjuvant radiotherapy was given in 37.7%. High CD3 density was found in 83%, whereas high CD8 density was found in 56.6%. A total of 18.9% of the tumors stained positive for PD-L1. Survival was significantly shorter in Kaplan-Meier analysis for patients with primary tumors staining positive for PD-L1 (log rank: p = 0.05). Multivariable analysis controlling for neoadjuvant therapy, TIL markers, PD-L1, age, and sex found no significant difference in recurrence or survival. Conclusions Positive staining for PD-L1 may be a prognostic marker for decreased survival in esophageal adenocarcinoma. Additional TIL cell types should be investigated for creation of an esophageal cancer Immunoscore. PD-L1 has potential as a therapeutic target.

Background Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. Methods Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods ( Results Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. Conclusions Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.

Background Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is an important determinant of clinical outcomes. However, a major hindrance to studies of EBI is the lack of radiographic surrogate marker. Objective To propose a scoring system based on early changes in clinically obtained computed tomography (CT), called the Subarachnoid hemorrhage Early Brain Edema Score (SEBES). Methods Patients with spontaneous aneurysmal SAH and a CT within 24 h of ictus were included. We defined SEBES as a scale of 0 to 4 points according to the (1) absence of visible sulci caused by effacement of sulci or (2) absence of visible sulci with disruption of the gray-white matter junction at 2 predetermined levels in each hemisphere. Prognostic value of the SEBES grade for the prediction of delayed cerebral ischemia (DCI) and unfavorable outcomes was assessed. A separate cohort of patients was used as a validation cohort. Results Of the 164 subjects in our study, high-grade SEBES (3 or 4 points) was identified in 48 patients (29.3%). CT interobserver reliability of SEBES grades was high with a Kappa value of 0.89. After adjusting for covariables, SEBES was identified as an independent predictor of DCI (OR = 2.24, 95% CI: 1.58-3.17) and unfavorable outcome (OR = 3.45, 95% CI: 1.95-6.07). In our validation cohort, 84 subjects showed similar predictive power of SEBES for a prediction of DCI and unfavorable long-term outcome. Conclusion SEBES may be a surrogate marker of EBI and predicts DCI and clinical outcomes after SAH.

As a potentially unlimited autologous cell source, patient induced pluripotent stem cells (iPSCs) provide great capability for tissue regeneration, particularly in spinal cord injury (SCI). However, despite significant progress made in translation of iPSC-derived neural progenitor cells (NPCs) to clinical settings, a few hurdles remain. Among them, non-invasive approach to obtain source cells in a timely manner, safer integration-free delivery of reprogramming factors, and purification of NPCs before transplantation are top priorities to overcome. In this study, we developed a safe and cost-effective pipeline to generate clinically relevant NPCs. We first isolated cells from patients’ urine and reprogrammed them into iPSCs by non-integrating Sendai viral vectors, and carried out experiments on neural differentiation. NPCs were purified by A2B5, an antibody specifically recognizing a glycoganglioside on the cell surface of neural lineage cells, via fluorescence activated cell sorting. Upon further in vitro induction, NPCs were able to give rise to neurons, oligodendrocytes and astrocytes. To test the functionality of the A2B5+ NPCs, we grafted them into the contused mouse thoracic spinal cord. Eight weeks after transplantation, the grafted cells survived, integrated into the injured spinal cord, and differentiated into neurons and glia. Our specific focus on cell source, reprogramming, differentiation and purification method purposely addresses timing and safety issues of transplantation to SCI models. It is our belief that this work takes one step closer on using human iPSC derivatives to SCI clinical settings.

Contains fulltext : 169736.pdf (Publisher’s version ) (Closed access) Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-beta-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

Background and Purpose— A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease. Methods— More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses and functional studies performed using an in vitro endothelial cell model. Results— A nonsense mutation in THSD1 was identified that segregated with the 9 affected (3 suffered subarachnoid hemorrhage and 6 had unruptured IA) and was absent in 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered subarachnoid hemorrhage (1.6% [95% confidence interval, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89 040 chromosomes in Exome Aggregation Consortium (ExAC) database ( P THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions— This report identifies THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

Objective: The safety and effect of intra-arterial (IA) tirofiban, a glycoprotein IIb/IIIa inhibitor, during the stent retriever mechanical thrombectomy (MT) was investigated. Methods: From January 2015 to May 2019, a total of 327 patients underwent mechanical thrombectomy of large artery occlusions (LAO). Patients were classified into two groups: MT with IA tirofiban (MTT) group and MT only (MTO, without IA tirofiban) group. Clinical outcomes, radiological results, and various complications, such as post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding, and hemorrhagic transformation of infarct were evaluated by comparing the MTT group and MTO group. In addition, subgroup analysis was performed for patients who underwent MT with prior intravenous (IV) tissue plasminogen activator (t-PA). Results: The MTT group needed a lower mean number of stent passes and showed a re-occlusion rate as compared with the MTO group (P=0.038 and 0.022, respectively). Between the two groups, there were no statistically significant differences in post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding complications, or hemorrhagic transformation of infarct (P = 0.511, 0.397, 0.429, and 0.355, respectively). In the subgroup analysis, similar findings were observed. Conclusion: The use of IA tirofiban during MT seems to be safe and potentially more effective than only MT without IA tirofiban, even in patients who used IV t-PA before MT.

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2–5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

BACKGROUND: Perioperative corticosteroid use may reduce acute kidney injury. We sought to test whether methylprednisolone reduces the risk of acute kidney injury after cardiac surgery. METHODS: We conducted a prespecified substudy of a randomized controlled trial involving patients undergoing cardiac surgery with cardiopulmonary bypass (2007-2014); patients were recruited from 79 centres in 18 countries. Eligibility criteria included a moderate-to-high risk of perioperative death based on a preoperative score of 6 or greater on the European System for Cardiac Operative Risk Evaluation I. Patients (n = 7286) were randomly assigned (1:1) to receive intravenous methylprednisolone (250 mg at anesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients, caregivers, data collectors and outcome adjudicators were unaware of the assigned intervention. The primary outcome was postoperative acute kidney injury, defined as an increase in the serum creatinine concentration (from the preoperative value) of 0.3 mg/dL or greater (≥ 26.5 μmol/L) or 50% or greater in the 14-day period after surgery, or use of dialysis within 30 days after surgery. RESULTS: Acute kidney injury occurred in 1479/3647 patients (40.6%) in the methylprednisolone group and in 1426/3639 patients (39.2%) in the placebo group (adjusted relative risk 1.04, 95% confidence interval 0.96 to 1.11). Results were consistent across several definitions of acute kidney injury and in patients with preoperative chronic kidney disease. INTERPRETATION: Intraoperative corticosteroid use did not reduce the risk of acute kidney injury in patients with a moderate-to-high risk of perioperative death who had cardiac surgery with cardiopulmonary bypass. Our results do not support the prophylactic use of steroids during cardiopulmonary bypass surgery. Trial registration: ClinicalTrials.gov, no. NCT00427388. ispartof: CANADIAN MEDICAL ASSOCIATION JOURNAL vol:191 issue:9 pages:E247-E256 ispartof: location:Canada status: published

The objective of this study is to investigate whether central sensitization (CS) was associated with patient dissatisfaction after revision total knee arthroplasty (TKA).Between 2012 and 2016, 68 cases (68 patients) of revision TKA performed by a single surgeon were included in this study with a minimum follow-up of 2 years. Patients were categorized into 2 groups by 40-point preoperative Central Sensitization Inventory (CSI) scores. The control group consisted of 48 patients (48 knees) with CSI scores of less than 40 points, while the CS group consisted of 20 patients (20 knees) with CSI scores of 40 points or more. Clinical outcomes were evaluated using an 11-point visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index scores. Patient satisfaction was evaluated using the satisfaction items of the new Knee Society Scores, where scores ≥20 indicated satisfaction.Higher preoperative pain VAS scores in the CS group were maintained 3, 6, 12, and 24 months postoperatively (all P.05). The CS group showed significantly worse pain, function subscores, and total scores of the Western Ontario and McMaster Universities Osteoarthritis Index preoperatively and at 2 years postoperatively. Forty-four (91.7%) patients in the control group and 3 (15.0%) patients in the CS group were satisfied with their revision TKAs (P.001). Multivariate logistic regression analysis demonstrated that the odds of dissatisfaction after revision TKAs were increased 39.081 times (95% confidence interval 6.926-220.504, P.001) in patients with CSI scores ≥40. Higher VAS intensity 2 years postoperatively also predicted dissatisfaction following revision TKA (odds ratio 1.864, 95% confidence interval 1.086-3.199, P = .024).CS is a risk factor for persistent postoperative pain and dissatisfaction in patients undergoing revision TKAs.III.

Background The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Fibronectin containing the ED-A domain is currently being used as drug delivery target in the development of anti-inflammatory drugs (e.g. Dekavil). Methods In this study, samples of synovial membrane were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A fibronectin and the myofibroblast marker alpha smooth muscle actin (αSMA) was performed on fibroblast-like synovial cells (FLS) and synovial membranes. RAW 264.7 macrophages were incubated with recombinant ED-A fibronectin. Results The staining of ED-A fibronectin in OA FLS was increased by TGFβ but not by TNFα, lipopolysaccharide, or IL-6 (n = 3). ED-A fibronectin co-stained with the myofibroblast marker αSMA in both the OA FLS (n = 3) and in the OA synovial membranes (n = 8). ED-A fibronectin staining was associated with both number of lining layer cells (rho = 0.85 and p = 0.011) and sublining cells (rho = 0.88 and p = 0.007) in the OA synovium (n = 8), and co-distributed with TNFα (n = 5). Recombinant ED-A fibronectin increased the production of TNFα by RAW 264.7 macrophages (n = 3). Conclusions The disease process in OA shares features with the chronic wound healing response. Our findings support utilizing ED-A fibronectin for drug delivery or therapeutic targeting to reduce pro-inflammatory responses in OA.

// Seung Ho Yang 1, 2, 3, * , Shenglan Li 1, 3, * , Guangrong Lu 1 , Haipeng Xue 1, 3 , Dong H. Kim 1, 3 , Jay-Jiguang Zhu 1, ** , Ying Liu 1, 3, ** 1 Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA 2 Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea 3 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA * These authors contributed equally to this work ** These authors contributed equally to this work Correspondence to: Jay-Jiguang Zhu, email: jay.jiguang.zhu@uth.tmc.edu Ying Liu, email: ying.liu@uth.tmc.edu Keywords: glioblastoma, metformin, temozolomide resistance, SOX2, global gene expression Received: September 07, 2016 Accepted: October 14, 2016 Published: October 24, 2016 ABSTRACT It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo . Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.

Several antecedent studies had reported close relationship between low body weight and Parkinson's disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.

Background Cost-effectiveness analyses for the treatment of aneurysmal subarachnoid hemorrhage are necessary to determine health policy, treatment guidelines, and screening protocols for cerebral aneurysms. To perform these modeling studies, detailed cost data are necessary and are currently lacking. Objective The goal of this study was to determine detailed inpatient cost of aneurysmal subarachnoid hemorrhage. Methods A retrospective review of our ruptured subarachnoid hemorrhage database was performed to identify consecutive patients between January 2013 and December 2015. Patients were searched by International Classification of Disease 9 diagnosis and procedure codes. Patient demographics and clinical characteristics were acquired. The cost breakdown was compiled into a comprehensive itemized list encompassing all aspects of hospitalization. A mean cost based on resource used per patient was obtained. Results There were 269 patients treated, 209 were coiled and 60 were clipped. Mean age in the clipping group was 49 years and 55 years in the coil group (P = 0.006). Other patient demographics and clinical characteristics were found to be statistically similar for both groups. Total cost per patient for treatment and hospital stay was $74,192 for clipping and $85,553 for coiling (P = 0.06). Cost amplified with increasing Hunt and Hess grade in both clipping and coiling groups. Conclusions The detailed cost information reported in this article can be used to help establish appropriate, standardized costs nationally by improving transparency. It can also help provide critical information necessary to develop cost-effective treatment algorithms and screening protocols.

Aim To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. Materials and methods The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice. Results AJ5018 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance, as reflected by the lower brain/plasma concentration ratio and the attenuated centrally mediated neurobehavioural effects, compared with its brain-penetrant parent compound rimonabant. In DIO and db/db mice, AJ5018 exhibited comparable effects to rimonabant in improving metabolic abnormalities and suppressing macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines. Conclusions These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.

Currently, there is an incomplete understanding of the molecular pathogenesis of meningiomas, the most common primary brain tumor. Several familial syndromes are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes. For each of these syndromes, the diagnostic criteria, incidence in the population, and frequency of meningioma are presented to review the relevant clinical information for these conditions. The genetic mutations, molecular pathway derangements, and relationship to sporadic disease for each syndrome are described in detail to identify targets for further investigation. Familial syndromes characterized by meningiomas often affect genes and pathways that are also implicated in a subset of sporadic cases, suggesting key molecular targets for therapeutic intervention. Further studies are needed to resolve the functional relevance of specific genes whose significance in sporadic disease remains to be elucidated.

It has not been well established whether dietary folate intake reduces the risk of diabetes development. We aimed to clarify the prospective association between dietary folate intake and type 2 diabetes (T2D) risk among 7333 Korean adults aged 40 years or older who were included in the Multi-Rural Communities Cohort. Dietary folate intake was estimated from all 106 food items listed on a FFQ, not including folate intake from supplements. Two different measurements of dietary folate intake were used: the baseline consumption and the average consumption from baseline until just before the end of follow-up. The association between folate intake and T2D risk was determined through a modified Poisson regression model with a robust error estimator controlling for potential confounders. For 29 745 person years, 319 cases of diabetes were ascertained. In multivariable analyses, dietary folate intake was inversely associated with risk of T2D for women, not for men. For women, the incidence rate ratio of diabetes in the third tertile compared with the first tertile was 0·57 (95 % CI 0·38–0·87, Pfor trend=0·0085) in the baseline consumption model and 0·64 (95 % CI 0·43–0·95, Pfor trend=0·0244) in the average consumption model. These inverse associations was found in both normal fasting blood glucose group and impaired fasting glucose group among women. Among non-users of multinutrients and vitamin supplements, the significant inverse association remained. Thus, higher dietary intake of folate is prospectively associated with lower risk of diabetes for women.

Damage to peripheral nerves or the spinal cord is often accompanied by neuropathic pain, which is a complex, chronic pain state. Increasing evidence indicates that alterations in the expression and activity of gap junction channels in the spinal cord are involved in the development of neuropathic pain. Thus, this review briefly summarizes evidence that regulation of the expression, coupling, and activity of spinal gap junction channels modulates pain signals in neuropathic pain states induced by peripheral nerve or spinal cord injury. We particularly focus on connexin 43 and pannexin 1 because their regulation vastly attenuates symptoms of neuropathic pain. We hope that the study of gap junction channels eventually leads to the development of a suitable treatment tool for patients with neuropathic pain.

Purpose To report short-term surgical outcomes of single-stage simultaneous rescue and sutureless intrascleral fixation of dislocated intraocular lens (IOLs). Methods Sixteen eyes of 16 patients who underwent simultaneous rescue and intrascleral fixation of dislocated 3-piece IOLs were retrospectively evaluated. Partial thickness limbal-based scleral flaps (2.0 × 2.0 mm) were created, and a 22-gauge round needle was used to create a sclerotomy at 1.5 mm from the limbus under the previously created scleral flap, and a 23-gauge trans pars plana vitrectomy was performed. Bimanual maneuvers using two 23-gauge end-grasping forceps under chandelier illumination and a wide-angle viewing system enabled 1 step rescue of IOLs from the posterior vitreous cavity with 1 hand and simultaneous haptic externalization through sclerotomy with the other hand. An externalized haptic was placed into the 3-mm intrascleral tunnel created using a bent 26-gauge needle. Fibrin glue was used to fixate haptics and close the scleral flaps. Results Intraocular lenses were successfully rescued and sclera-fixated through intrascleral tunnels in all 16 eyes (mean age, 56.56 ± 19.89 years). The mean preoperative logarithm of the minimum angle of resolution best-corrected visual acuity was 0.92 ± 0.68, and this significantly improved at 6 months to 0.289 ± 0.36 (P = 0.003). During the follow-up period (10.1 ± 3.21 months), no significant change of endothelial cell count or central foveal thickness was noted postoperatively (P = 0.203 and P = 0.979, respectively). There were no significant postoperative complications such as IOL dislocation, IOL decentration, retinal detachment, endophthalmitis, or postoperative hypotony. Conclusion Simultaneous rescue and sutureless intrascleral haptic fixation of dislocated 3-piece IOLs using bimanual maneuvers is an effective, safe, and minimally invasive surgical method to rescue and fixate the dislocated IOL without further explant.

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) is defined as brain injury occurring within 72 h of aneurysmal rupture. Although EBI is the most significant predictor of outcomes after aSAH, its underlying pathophysiology is not well understood. We hypothesize that EBI after aSAH is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes in associations between cytokines. aSAH patients were enrolled into a prospective observational study and were assessed for markers of EBI: global cerebral edema (GCE), subarachnoid hemorrhage early brain edema score (SEBES), and Hunt–Hess grade. Serum samples collected at ≤ 48 h of admission were analyzed using multiplex bead-based assays to determine levels of 13 pro- and anti-inflammatory cytokines. Pairwise correlation coefficients between cytokines were represented as networks. Cytokine levels and differences in correlation networks were compared between EBI groups. Of the 71 patients enrolled in the study, 17 (24%) subjects had GCE, 31 (44%) subjects had SEBES ≥ 3, and 21 (29%) had HH ≥ 4. IL-6 was elevated in groups with GCE, SEBES ≥ 3, and HH ≥ 4. MIP1β was independently associated with high-grade SEBES. Correlation network analysis suggests higher systematic inflammation in subjects with SEBES ≥ 3. EBI after SAH is associated with increased levels of specific cytokines. Peripheral levels of IL-10, IL-6, and MIP1β may be important markers of EBI. Investigating systematic correlations in addition to expression levels of individual cytokines may offer deeper insight into the underlying mechanisms related to EBI.

Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.

Introduction: Pipeline embolization devices (PED) have become an essential tool in the endovascular treatment of complex intracranial aneurysms. A high-density stent like device, the PED functions to redirect blood flow and facilitate the growth and remodeling of the artery. Postoperative ischemic stroke proves to be the most common neurological complication associated with treatment, ranging from about 3-6% with most occurring within 30 days. Transcranial Doppler (TCD) monitoring has been used in the past to evaluate similar procedures by measuring the occurrence of microembolic signals (MES). Due to the delivery and manipulation of the PED and its thrombotic nature, microembolic events have been postulated to form during device placement and contribute to thromboembolism. Our initial study is the first to detect and measure MES during a PED procedure. Methods: Patients undergoing endovascular PED treatment were simultaneously monitored with TCD. MES were detected, separated from artifacts, and counted for each step. Results: Embolic signals were detected in all patients and were highest during deployment. With 3 PED deployments in the paraophthalmic ICA of 2 patients, the mean MES during PED deployment was 515 +/- 46. Average emboli per second during deployment was 1.62 +/- 0.59 verses 0.30 +/- 0.12 emboli per second observed prior to microcatheter insertion and manipulation. Conclusion: A very high incidence of MES was observed during the procedure and PED deployment. The little success thus far in elucidating a possible mechanism to account for PED’s associated complications warrants more investigation. Determining the occurrence of MES might reveal insight into the relative safety of each step and on the formation of distal thromboembolisms.

Spinal cord injury (SCI) remains one of the most debilitating neurological disorders and the majority of SCI patients are in the chronic phase. Previous studies of SCI have usually focused on few genes and pathways at a time. In particular, the biological roles of long non-coding RNAs (lncRNAs) have never been characterized in SCI. Our study is the first to comprehensively investigate alterations in the expression of both coding and long non-coding genes in the sub-chronic and chronic stages of SCI using RNA-Sequencing. Through pathway analysis and network construction, the functions of differentially expressed genes were analyzed systematically. Furthermore, we predicted the potential regulatory function of non-coding transcripts, revealed enriched motifs of transcription factors in the upstream regulatory regions of differentially expressed lncRNAs, and identified differentially expressed lncRNAs homologous to human genomic regions which contain single-nucleotide polymorphisms associated with diseases. Overall, these results revealed critical pathways and networks that exhibit sustained alterations at the sub-chronic and chronic stages of SCI, highlighting the temporal regulation of pathological processes including astrogliosis. This study also provided an unprecedented resource and a new catalogue of lncRNAs potentially involved in the regulation and progression of SCI.

Unilateral laparoscopic ovariectomy was attempted in a red fox (Vulpes vulpes) with an ovarian cyst through single portal access. The ovarian cyst was resistant to conservative therapy using gonadotropin-releasing hormone. A 10-mm laparoscope with an operating channel was introduced into the abdomen via a 12-mm umbilical portal. The left ovary and cyst (34.1 × 30.8 mm) were fixed to the left abdominal wall by a transabdominal suspension suture. The ovarian pedicles and ligaments were progressively cauterized and transected with a multifunction bipolar electrocoagulation forceps. The resected cystic ovary was exteriorized through the umbilical portal site. The surgical time was 42 min, and no intra- and postoperative complications were encountered. Two months after the surgery mating was observed, and the fox gave birth to three healthy cubs 56 days after the mating. This is the first report of using laparoscopy in the red fox with an ovarian cyst.

To examine the relationship between dark adaptation (DA) and optical coherence tomography (OCT)-based macular morphology in age-related macular degeneration (AMD).Prospective, cross-sectional study.Patients with AMD and a comparison group (50 years) without any vitreoretinal disease.All participants were imaged with spectral-domain OCT and color fundus photographs, and then staged for AMD (Age-related Eye Disease Study system). Both eyes were tested with the AdaptDx (MacuLogix, Middletown, PA) DA extended protocol (20 minutes). A software program was developed to map the DA testing spot (2° circle, 5° superior to the fovea) to the OCT B-scans. Two independent graders evaluated the B-scans within this testing spot, as well as the entire macula, recording the presence of several AMD-associated abnormalities. Multilevel mixed-effects models (accounting for correlated outcomes between 2 eyes) were used for analyses.The primary outcome was rod-intercept time (RIT), defined in minutes, as a continuous variable. For subjects unable to reach RIT within the 20 minutes of testing, the value of 20 was assigned.We included 137 eyes (n = 77 subjects), 72.3% (n = 99 eyes) with AMD and the remainder belonging to the comparison group. Multivariable analysis revealed that even after adjusting for age and AMD stage, the presence of any abnormalities within the DA testing spot (ß = 4.8, P0.001), as well as any abnormalities in the macula (ß = 2.4, P = 0.047), were significantly associated with delayed RITs and therefore impaired DA. In eyes with no structural changes within the DA testing spot (n = 76, 55.5%), the presence of any abnormalities in the remaining macula was still associated with delayed RITs (ß = 2.00, P = 0.046). Presence of subretinal drusenoid deposits and ellipsoid zone disruption were a consistent predictor of RIT, whether located within the DA testing spot (P = 0.001 for both) or anywhere in the macula (P0.001 for both). Within the testing spot, the presence of classic drusen or serous pigment epithelium detachment was also significantly associated with impairments in DA (P ≤ 0.018).Our results suggest a significant association between macular morphology evaluated by OCT and time to dark-adapt. Subretinal drusenoid deposits and ellipsoid zone changes seem to be strongly associated with impaired dark adaptation.

Background Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). Objective To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. Methods Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. Results Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. Conclusion A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Objective: To (i) test whether atomoxetine is non-inferior to methylphenidate in treating symptoms of attention deficit hyperactivity disorder (ADHD) in paediatric patients; and (ii) determine the tolerability of the two drugs. Method: This double-blind study was conducted in 6- to 16-year-old outpatients with ADHD (DSM-IV) in China, Korea and Mexico (January–October 2004). Patients were randomly assigned to once-daily atomoxetine (0.8–1.8 mg kg−1 day−1; n = 164) or twice-daily methylphenidate (0.2–0.6 mg kg−1 day−1; n = 166) for ∼8 weeks. Primary efficacy assessment was the comparison of response rates (≥40% reduction from baseline to end point in total score) on the Attention Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and -Scored. Tolerability measures included, but were not limited to, the assessment of treatment-emergent adverse events (TEAEs) and weight. Results: Atomoxetine was non-inferior to methylphenidate in improving ADHD symptoms based on response rates (atomoxetine, 77.4%; methylphenidate, 81.5%; one-sided 95% lower confidence limit = −11.7%, p = 0.404). Treatment-emergent adverse effects experienced significantly more frequently in the atomoxetine group, compared with the methylphenidate group, included anorexia (37.2% vs. 25.3%; p = 0.024), nausea (20.1% vs. 10.2%; p = 0.014), somnolence (26.2% vs. 3.6%; p Conclusions: This study suggests that atomoxetine is non-inferior to methylphenidate in the improvement of ADHD symptoms in paediatric outpatients. Although both of the drugs were well tolerated, atomoxetine was associated with a higher incidence of TEAEs than methylphenidate.

Purpose Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. Methods and Materials A 3-step strategy for the determination of CRT sensitivity is proposed based on ( 1 ) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); ( 2 ) clinical association analysis of 113 patients treated with preoperative CRT; and ( 3 ) a cell-based functional assay for biological validation. Results Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele ( C ) of the SNP CORO2A rs1985859 than in those with the substitution allele ( T ) ( P =.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% ( P =.048) and 39% ( P =.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells ( P =.034 and .015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells ( P =.047), and it enhanced colony formation in RKO cells ( P =.001) and COLO320DM cells ( P =.002). Conclusion CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts.

Zinc is an essential trace element in human body and a cofactor for many enzymes.1 Zinc-binding proteins account for more than half of the transcription regulatory proteins in human body.2 Zinc plays a critical role in many basic biological processes, such as the metabolism of nucleic acids, proteins, carbohydrates, and lipids, as well as the regulation of gene transcription, cell growth, development, and differentiation.3 Zinc deficiency often leads to growth retardation, reduced food intake, impaired immune activity, and diminished brain function.4 As part of the catalytic center of over 300 metalloenzymes, such as DNA and RNA polymerases, carbonic anhydrase, and matrix metalloproteinase (MMP), zinc is highly involved in hypoxia, angiogenesis, cell proliferation, and metastasis of cancer. Zinc depletion causes increased oxidative stress and induces programmed cell death in many cells. However, excessive zinc can also be cytotoxic.5 Therefore, a complex zinc transport network has evolved to maintain the balance of zinc uptake, intracellular storage, and efflux.6 Zinc is the second most abundant trace element in brain after iron.7,8 Maternal zinc deficiency has been linked to congenital malformations of the central nervous system.9 Impaired brain development due to zinc deficiency was also observed in rats.10,11 Because it is critical to maintain a redox state, the concentration of zinc in the brain is tightly regulated.12–15 In the SPECT imaging performed in rats, it has been shown that zinc uptake in glioma xenografts was 3–10 times higher than that in the normal brain.16 Zinc cannot diffuse freely through the cell membrane; therefore, it uses membrane proteins as a way to cross membrane to maintain zinc homeostasis and keep a balance between apoptosis and cell growth. Two solute-linked carrier (SLC) gene families were identified in zinc transport, the ZIP (ZRT, IRT-like protein, encoded by SLC39) family and ZnT (Zinc Transporter, encoded by SLC30) family. They appear to have opposite roles in cellular zinc homeostasis. ZIP transporters increase intracellular zinc concentration by transporting zinc into cytosol either from extracellular space or from the lumen of intracellular compartments. Conversely, ZnTs efflux zinc ions and store excessive zinc in intracellular compartments.17 Aberrant zinc transporter expression has been observed in several cancers, such as breast and pancreatic cancer.18–20 Many zinc transporters are expressed in brain tissues.21 Alterations of zinc and zinc transporters have been reported in certain pathological conditions, such as Alzheimer's disease,22 Parkinson's disease,23 and epilepsy.24 Many of these studies focus on the zinc expression in neurons; however, glial cells that typically give rise to primary intrinsic brain tumors seem to react differently to changes of these elements.25 Abnormal activation of intracellular pathways has different effects on neurons, and glial cells in brain may be explained by the fact that neurons are terminally differentiated cells and astrocytes retain the ability to self-renew and proliferate, which could potentially lead to either cancer or neurodegenerative disorders, depending on the cells affected.26 Diffuse astrocytomas are the most common glioma, and are often resistant to standard treatment, such as radiation or chemotherapy. The median survival times for grade II and grade III gliomas are 5–8 years and 2–3 years, respectively.27 Grade IV astrocytomas (GBM) represent the most frequent and malignant form of astrocytomas, with a median survival time of only 14.6 months and a two-year survival rate of 5%–10%.28 The mechanisms underlying gliomagenesis remain largely unknown, and the limited choices of reliable biomarkers for early detection and the lack of curative treatment contribute to its poor prognosis. Because dysregulated zinc and zinc transporters are implicated in different types of cancers that show distinctive expression pattern of zinc transporters, we investigated whether altered expression profile of zinc transporters contributes to glioma pathogenesis and progression. In this study, we examined the expression profile of 24 zinc transporters (14 ZIPs and 10 ZnTs) in human glioma tissues from 3 independent cohorts of patients with glioma and studied their associations with tumor grade and patient overall survival time.

The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated.Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests.IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors.IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.

The transplantation of neural stem/progenitor cells is a promising therapeutic strategy for spinal cord injury (SCI). In this study, we tested whether combination of neurotrophic factors and transplantation of glial-restricted precursor (GRPs)-derived astrocytes (GDAs) could decrease the injury and promote functional recovery after SCI. We developed a protocol to quickly produce a sufficiently large, homogenous population of young astrocytes from GRPs, the earliest arising progenitor cell population restricted to the generation of glia. GDAs expressed the axonal regeneration promoting substrates, laminin and fibronectin, but not the inhibitory chondroitin sulfate proteoglycans (CSPGs). Importantly, GDAs or its conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons in vitro. GDAs were infected with retroviruses expressing EGFP or multi-neurotrophin D15A and transplanted into the contused adult thoracic spinal cord at 8 days post-injury. Eight weeks after transplantation, the grafted GDAs survived and integrated into the injured spinal cord. Grafted GDAs expressed GFAP, suggesting they remained astrocyte lineage in the injured spinal cord. But it did not express CSPG. Robust axonal regeneration along the grafted GDAs was observed. Furthermore, transplantation of D15A-GDAs significantly increased the spared white matter and decreased the injury size compared to other control groups. More importantly, transplantation of D15A-GDAs significantly improved the locomotion function recovery shown by BBB locomotion scores and Tredscan footprint analyses. However, this combinatorial strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. These results demonstrate that transplantation of D15A-expressing GDAs promotes anatomical and locomotion recovery after SCI, suggesting it may be an effective therapeutic approach for SCI.