Evaluation of living bacterial therapy assisted by pH/reactive oxygen species dual-responsive sodium alginate-based hydrogel for wound infections.

The enhancement of antimicrobial wound dressings is of utmost importance in light of the escalating risk of antibiotic resistance caused by excessive antibiotic usage. Conventional antimicrobial materials eradicate pathogenic bacteria while impeding the proliferation of beneficial bacteria during the management of wound infections, thereby disturbing the equilibrium of the skin micro-ecosystem and engendering recurrent cutaneous complications. Lactobacillus rhamnosus (L.rha) is a probiotic that can inhibit the growth of certain pathogenic bacteria by secreting a large number of metabolites. In this paper, we synthesized a cross-linker (SPBA) with a boric acid molecule from succinic acid and 4-(bromomethyl)phenylboronic acid, which formed a boric acid ester bond with a diol on the natural polysaccharide sodium alginate (SA), and obtained a pH/reactive oxygen species (ROS) dual-responsive hydrogel (SA-SPBA) for loading L.rha to treat wound infections. The SA-SPBA@L.rha hydrogel improves the survival of L.rha during storage and has good injectability as well as self-healing properties. The hydrogel showed good biocompatibility, the antimicrobial effect increases in a dose-dependent manner, and it has a certain antioxidant and anti-inflammatory capacity, accelerating wound repair. The use of SA-SPBA@L.rha hydrogel provides a safe and effective strategy for the repair of skin wound infections.

Inorganic catalase-powered nanomotors with hyaluronic acid coating for pneumonia therapy.

Clinical therapy for widespread infections caused by Streptococcus pneumoniae (S. pneumoniae), such as community-acquired pneumonia, is highly challenging. As an important bacterial toxin, hydrogen peroxide (H2O2) secreted by S. pneumoniae can suppress the host's immune system and cause more severe disease. To address this problem, a hyaluronic acid (HA)-coated inorganic catalase-driven Janus nanomotor was developed, which can cleverly utilize and decompose H2O2 to reduce the burden of bacterial infection, and have excellent drug loading capacity. HA coating prevents rapid leakage of loaded antibiotics and improves the biocompatibility of the nanomaterials. The Janus nanomotor converted H2O2 into oxygen (O2), gave itself the capacity to move actively, and encouraged widespread dispersion in the lesion site. Encouragingly, animal experiments demonstrated that the capability of the nanomotors to degrade H2O2 contributes to diminishing the proliferation of S. pneumoniae and lung tissue damage. This self-propelled drug delivery platform provides a new therapeutic strategy for infections with toxin-secreting bacteria.

pH-Responsive Co-Assembled Peptide Hydrogel to Inhibit Drug-Resistant Bacterial Infection and Promote Wound Healing.

Drug-resistant bacterial infection and biofilm formation are the key inhibitors of wound healing, and new strategies are urgently needed to address these issues. In this study, we designed a pH-responsive co-assembled peptide hydrogel to inhibit Methicillin-resistant Staphylococcus aureus (MRSA) infection and promote wound healing. We synthesized a cationic short peptide (Nap-FFKKK) and a co-assembled hydrogel with curcumin at pH ∼ 7.8. The loaded curcumin was continuously released in a weak acid environment (pH ∼ 5.5). The lysine-rich cationic peptide inhibited biofilm formation in MRSA via electrostatic interaction with the negatively charged bacterial cell surface and, thus, provided a reinforcing antibacterial effect with curcumin. In vitro antibacterial experiments showed that the co-assembled system considerably reduced the minimum inhibitory concentration of curcumin against MRSA by 10-fold and promoted wound healing in a mouse model of MRSA-infected wounds. This study provides a simple and promising strategy to treat drug-resistant bacterial infections in wounds.

Manipulation of Charge Dynamics for Efficient and Bright Blue Perovskite Light-Emitting Diodes with Chiral Ligands.

Perovskite light-emitting diodes (PeLEDs) emerge as a promising class of optoelectronic devices for next-generation displays and lighting technology. However, the performance of blue PeLEDs lags far behind that of their green and red counterparts, including the unachieved trade-off between high efficiency and high luminance, severe efficiency roll-off, and unsatisfactory power efficiency. Here, a multi-functional chiral ligand of L-phenylalanine methyl ester hydrochloride is strategically introduced into quasi-2D perovskites, which can effectively passivate defects, modulate the phase distribution, improve photoluminescence quantum yield, guarantee high-quality film morphology, and enhance charge transport. Furthermore, ladder-like hole transport layers are established, boosting charge injection and balance. The resultant sky-blue PeLEDs (the photoluminescence peak is 493 nm and the electroluminescence peak is 497 nm) exhibit an external quantum efficiency of 12.43% at 1000 cd m-2 and a record power efficiency of 18.42 lm W-1 , rendering that the performance is among the best blue PeLEDs.

ROS-responsive hyaluronic acid hydrogel for targeted delivery of probiotics to relieve colitis.

Probiotics are generally used as therapeutic intervention in inflammatory bowel disease. However, the low survival rate in harsh gastrointestinal environment and limited retention in intestine greatly restrict their health benefits. To address this problem, a ROS-responsive hydrogel based on hyaluronic acid (HA) was developed for encapsulation and targeted delivery of probiotics. The hydrogel was prepared facilely by physiological crosslink with methacrylated HA and thiolated thioketal. As a model probiotic, Lactobacillu reuteri showed a significantly increased survival rate in simulated digestive conditions after encapsulated in hydrogel. The negative properties conferred the hydrogel preferential adhesions to inflammation sites. Meanwhile, the excess reactive oxygen species (ROS) produced by inflamed colon tissues selectively cleaved thioketal linkages resulted in hydrogel degradation and local probiotics release. Furthermore, the hydrogel exerted an appropriate ROS-scavenge capacity and protected HT-29 cells from oxidative damage. Animal experiments indicated that hydrogel-encapsulated L. reuteri could remarkably alleviate the symptoms and improve the survival rate of mice with dextran sulfate sodium (DSS)-induced colitis. These results suggested that the biocompatible hydrogel may be a delivery platform to target inflamed intestines and expand the application of probiotics as pharmaceuticals.

High-Performance Deep Red Colloidal Quantum Well Light-Emitting Diodes Enabled by the Understanding of Charge Dynamics.

Colloidal quantum wells (CQWs) have emerged as a promising family of two-dimensional (2D) optoelectronic materials with outstanding properties, including ultranarrow luminescence emission, nearly unity quantum yield, and large extinction coefficient. However, the performance of CQWs-based light-emitting diodes (CQW-LEDs) is far from satisfactory, particularly for deep red emissions (≥660 nm). Herein, high efficiency, ultra-low-efficiency roll-off, high luminance, and extremely saturated deep red CQW-LEDs are reported. A key feature for the high performance is the understanding of charge dynamics achieved by introducing an efficient electron transport layer, ZnMgO, which enables balanced charge injection, reduced nonradiative channels, and smooth films. The CQW-LEDs based on (CdSe/CdS)@(CdS/CdZnS) ((core/crown)@(colloidal atomic layer deposition shell/hot injection shell)) show an external quantum efficiency of 9.89%, which is a record value for 2D nanocrystal LEDs with deep red emissions. The device also exhibits an ultra-low-efficiency roll-off and a high luminance of 3853 cd m-2. Additionally, an exceptional color purity with the CIE coordinates of (0.719, 0.278) is obtained, indicating that the color gamut covers 102% of the International Telecommunication Union Recommendation BT 2020 (Rec. 2020) standard in the CIE 1931 color space, which is the best for CQW-LEDs. Furthermore, an active-matrix CQW-LED pixel circuit is demonstrated. The findings imply that the understanding of charge dynamics not only enables high-performance CQW-LEDs and can be further applied to other kinds of nanocrystal LEDs but also is beneficial to the development of CQW-LEDs-based display technology and related integrated optoelectronics.

In situ integration of Te/Si 2D/3D heterojunction photodetectors toward UV-vis-IR ultra-broadband photoelectric technologies.

Over the past decade, 2D elemental semiconductors have emerged as an ever-increasingly important group in the 2D material family due to their simple crystal structures and compositions, and versatile physical properties. Taking advantage of the relatively small bandgap, outstanding carrier mobility, high air-stability and strong interactions with light, 2D tellurium (Te) has emerged as a compelling candidate for use in ultra-broadband photoelectric technologies. In this study, high-quality centimeter-scale Te nanofilms have been successfully produced by exploiting pulsed-laser deposition (PLD). By performing deposition on pre-patterned SiO2/Si substrates, a Te/Si 2D/3D heterojunction array is formed in situ. To our delight, taking advantage of the relatively small bandgap of Te, the Te/Si photodetectors demonstrate an ultra-broadband photoresponse from ultraviolet to near-infrared (370.6 nm to 2240 nm), enabling them to serve as important alternatives to conventional 2D materials such as MoS2. In addition, an outstanding on/off ratio of ∼108 and a fast response rate (a response/recovery time of 3.7 ms/4.4 ms) are achieved, which is associated with the large band offset and strong interfacial built-in electric field that contribute to suppressing the dark current and separating photocarriers. Beyond these, a 35 × 35 matrix array has been successfully constructed, where the devices exhibit comparable properties, with a production yield of 100% for 100 randomly tested devices. The average responsivity, external quantum efficiency and detectivity reach 249 A W-1, 76 350% and 1.15 × 1011 Jones, respectively, making the Te/Si devices among the best-performing 2D/3D heterojunction photodetectors. On the whole, this study has established that PLD is a promising technique for producing high-quality Te nanofilms with good scalability, and the Te/Si 2D/3D heterojunction provides a promising platform for implementing high-performance ultra-broadband photoelectronic technologies.

Testing calibration of phenotyping models using positive-only electronic health record data.

Validation of phenotyping models using Electronic Health Records (EHRs) data conventionally requires gold-standard case and control labels. The labeling process requires clinical experts to retrospectively review patients' medical charts, therefore is labor intensive and time consuming. For some disease conditions, it is prohibitive to identify the gold-standard controls because routine clinical assessments are performed for selective patients who are deemed to possibly have the condition. To build a model for phenotyping patients in EHRs, the most readily accessible data are often for a cohort consisting of a set of gold-standard cases and a large number of unlabeled patients. Hereby, we propose methods for assessing model calibration and discrimination using such "positive-only" EHR data that does not require gold-standard controls, provided that the labeled cases are representative of all cases. For model calibration, we propose a novel statistic that aggregates differences between model-free and model-based estimated numbers of cases across risk subgroups, which asymptotically follows a Chi-squared distribution. We additionally demonstrate that the calibration slope can also be estimated using such "positive-only" data. We propose consistent estimators for discrimination measures and derive their large sample properties. We demonstrate performances of the proposed methods through extensive simulation studies and apply them to Penn Medicine EHRs to validate two preliminary models for predicting the risk of primary aldosteronism.

Construction of Schottky contact by modification with Pt particles to enhance the performance of ultra-long V2O5 nanobelt photodetectors.

Schottky-contacted nanosensors have attracted extensive attention due to their high sensitivity and fast response time. In this article, we proved that the construction of Schottky contact by Pt nanoparticles (NPs) decoration can effectively improve the performance of V2O5 nanobelts photodetectors. After modified by Pt NPs, the photocurrent of V2O5 nanobelts is increased by more than two orders of magnitude, and the photoresponse speed is improved by at least three orders of magnitude. Detailed studies have shown that the performance enhancement is attributed to the formation of the Schottky contact at the electrode-semiconductor interface due to the decrease of surface gas adsorption and the increase of V2O5 work function after Pt NPs modification. The strong built-in field in the Schottky barrier region will quickly separate photogenerated carriers, thereby reducing the electron-hole recombination rate, resulting in the fast response time and an increase in the free carrier density. Moreover, it is found that this enhancement effect can be regulated by controlling the pressure to modulating the Schottky barrier height at the interface. Overall, the Pt NPs-modified V2O5 nanobelts photodetector exhibits a broad response spectrum (visible to near infrared), fast rise/fall response time (less than 6.12/6.15 ms), high responsivity (5.6 A/W), and high specific detectivity (6.9 × 108 Jones). This study demonstrates the feasibility of building a Schottky barrier to enhance the photodetection performance, which provides a general and effective strategy towards the construction and its practical application of supersensitive and fast-response nanosensors.

Penetrance of Breast and Ovarian Cancer in Women Who Carry a BRCA1/2 Mutation and Do Not Use Risk-Reducing Salpingo-Oophorectomy: An Updated Meta-Analysis.

BACKGROUND: Use of risk-reducing Salpingo-oophorectomy (RRSO) substantially reduces the risk of ovarian and breast cancer for women who carry a BRCA1/2 mutation. It is important to adjust for RRSO use in the estimation of BRCA1/2 penetrance of breast and ovarian cancer. METHODS: We searched PubMed for penetrance estimates of breast and ovarian cancer from studies that genotyped individual patients and explicitly adjusted for RRSO use by censoring follow-up at the age of RRSO. We meta-analyzed penetrance estimates from 7 identified studies. We implemented the resulting penetrance estimates in a Mendelian risk prediction model as iplemented in the software package BRCAPRO, which we applied to estimate carrier probabilities in 2 BRCA cohorts. RESULTS: Penetrance estimates by age 70 years for breast cancer were 64.6% (95% confidence interval [CI] = 59.5% to 69.4%) for BRCA1 mutation carriers and 61.0% (95% CI = 48.1% to 72.5%) for BRCA2 mutation carriers, and for ovarian cancer they were 48.3% (95% CI = 38.8% to 57.9%) and 20.0% (95% CI = 13.3% to 29.0%), respectively. When integrated into BRCAPRO, our estimates led to good calibration and different estimates of carrier probabilities for some individuals when evaluating the models in 2 cohorts. CONCLUSIONS: The report updates penetrance estimates for BRCA1/2-associated cancer. We report higher estimates than previously reported, which did not adjust for RRSO. Differential use of RRSO may partially explain heterogeneity in the currently available penetrance estimates. For some individuals, using our estimates in BRCAPRO may result in changes in estimated carrier probabilities, which warrants validation in future studies.

Phenotyping issues for exploring electronic health records to design clinical trials.

For utilizing electronic health records to help design and conduct clinical trials, an essential first step is to select eligible patients from electronic health records, that is, electronic health record phenotyping. We present two novel statistical methods that can be used in the context of electronic health record phenotyping. One mitigates the requirement for gold-standard control patients in developing phenotyping algorithms, and the other effectively corrects for bias in downstream analysis introduced by study samples contaminated by ineligible subjects.

A maximum likelihood approach to electronic health record phenotyping using positive and unlabeled patients.

OBJECTIVE: Phenotyping patients using electronic health record (EHR) data conventionally requires labeled cases and controls. Assigning labels requires manual medical chart review and therefore is labor intensive. For some phenotypes, identifying gold-standard controls is prohibitive. We developed an accurate EHR phenotyping approach that does not require labeled controls. MATERIALS AND METHODS: Our framework relies on a random subset of cases, which can be specified using an anchor variable that has excellent positive predictive value and sensitivity independent of predictors. We proposed a maximum likelihood approach that efficiently leverages data from the specified cases and unlabeled patients to develop logistic regression phenotyping models, and compare model performance with existing algorithms. RESULTS: Our method outperformed the existing algorithms on predictive accuracy in Monte Carlo simulation studies, application to identify hypertension patients with hypokalemia requiring oral supplementation using a simulated anchor, and application to identify primary aldosteronism patients using real-world cases and anchor variables. Our method additionally generated consistent estimates of 2 important parameters, phenotype prevalence and the proportion of true cases that are labeled. DISCUSSION: Upon identification of an anchor variable that is scalable and transferable to different practices, our approach should facilitate development of scalable, transferable, and practice-specific phenotyping models. CONCLUSIONS: Our proposed approach enables accurate semiautomated EHR phenotyping with minimal manual labeling and therefore should greatly facilitate EHR clinical decision support and research.

Geographically Derived Socioeconomic Factors to Improve Risk Prediction in Patients Having Aortic Valve Replacement.

Socioeconomic status (SES) has been associated with adverse outcomes after cardiac surgery, but is not included in commonly applied risk adjustment models. This study evaluates whether inclusion of SES improves aortic valve replacement (AVR) risk prediction models, as this is the most common elective operation performed at our institution during the study period. All patients who underwent AVR at a single institution from 2005 to 2015 were evaluated. SES measures included unemployment, poverty, household income, home value, educational attainment, housing density, and a validated SES index score. The risk scores for mortality, complications, and increased length of stay were generated using models published by the Society for Thoracic Surgeons. Univariate models were fitted for each SES covariate and multivariable models for mortality, any complication, and prolonged length of stay (PLOS). A total of 1,386 patients underwent AVR with a 2.7% mortality, 15.1% complication rate, and 9.7% PLOS. In univariate models, higher education was associated with decreased mortality (odds ratio [OR] 0.96, p = 0.04) and complications (OR 0.97, p <0.01). Poverty was associated with increased length of stay (OR 1.02, p = 0.02). In the multivariable models, the inclusion of SES covariates increased the area under the curve for mortality (0.735 to 0.750, p = 0.14), for any complications (0.663 to 0.680, p <0.01), and for PLOS (0.749 to 0.751, p = 0.12). The inclusion of census-tract-level socioeconomic factors into the the Society of Thoracic Surgeons risk predication models is new and shows potential to improve risk prediction for outcomes after cardiac surgery. With the possibility of reimbursement and institutional ranking based on these outcomes, this study represents an improvement in risk prediction model.

Breast and ovarian cancer penetrance of BRCA1/2 mutations among Hong Kong women.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are associated with increased risk of breast and ovarian cancer. The penetrance of breast and ovarian cancer in BRCA1/2 mutation carriers has been well characterized in Caucasian but not in Asian. Two studies have investigated the breast cancer risk in Asian women with BRCA1/2 mutations, and no published estimates are available for ovarian cancer. Therefore, we estimated the age-specific cumulative risk of BRCA1/2-associated breast and ovarian cancer in Chinese women. From Jan 2007 to Nov 2015, the Hong Kong Hereditary Breast Cancer Family Registry identified 1635 families with hereditary breast-ovarian cancer. Among probands in these families, 66 had BRCA1 mutations, 84 had BRCA2 mutations, and 1,485 tested negative for BRCA1/2 mutations. Using the female first-degree relatives of these probands, we estimated the risk of breast and ovarian cancer using a modified marginal likelihood approach. Estimates of breast cancer penetrance by age 70 were 53.7% (95% CI 34.5-71.6%) for BRCA1 mutation carriers and 48.3% (95% CI 31.8-68.5%) for BRCA2. The estimated risk of ovarian cancer by age 70 was 21.5% and 7.3% for Chinese women carrying BRCA1 or BRCA2 mutation respectively. A meta-analysis of available studies in Asian women revealed pooled estimates of breast cancer risk by age 70 of 44.8% (95% CI 33-57.2%) and 40.7% (95% CI 31.3-50.9%) for BRCA1 and BRCA2 mutation carriers respectively. These data suggest that BRCA1/2-associated breast cancer risk for Chinese women is similar to that for Caucasian women, although BRCA1/2-associated ovarian cancer risks are lower for Chinese women.

Survival and complications of stereotactic radiosurgery: A systematic review of stereotactic radiosurgery for newly diagnosed and recurrent high-grade gliomas.

BACKGROUND: Utilization of stereotactic radiosurgery (SRS) for treatment of high-grade gliomas (HGGs) has been slowly increasing with variable reported success rates. OBJECTIVE: Systematic review of the available data to evaluate the efficacy of SRS as a treatment for HGG with regards to median overall survival (OS) and progression-free survival (PFS), in addition to ascertaining the rate of radiation necrosis and other SRS-related major neurological complications. METHODS: Literature searches were performed for publications from 1992 to 2016. The pooled estimates of median PFS and median OS were calculated as a weighted estimate of population medians. Meta-analyses of published rates of radiation necrosis and other major neurological complications were also performed. RESULTS: Twenty-nine studies reported the use of SRS for recurrent HGG, and 16 studies reported the use of SRS for newly diagnosed HGG. For recurrent HGG, the pooled estimates of median PFS and median OS were 5.42 months (3-16 months) and 20.19 months (9-65 months), respectively; the pooled radiation necrosis rate was 5.9% (0-44%); and the pooled estimates of major neurological complications rate was 3.3% (0-23%). For newly diagnosed HGG, the pooled estimates of median PFS and median OS were 7.89 months (5.5-11 months) and 16.87 months (9.5-33 months) respectively; the pooled radiation necrosis rate was 6.5% (0-33%); and the pooled estimates of other major neurological complications rate was 1.5% (0-25%). CONCLUSION: Our results suggest that SRS holds promise as a relatively safe treatment option for HGG. In terms of efficacy at this time, there are inadequate data to support routine utilization of SRS as the standard of care for newly diagnosed or recurrent HGG. Further studies should be pursued to define more clearly the therapeutic role of SRS.

CSF inflammatory response after intraventricular hemorrhage.

OBJECTIVE: To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH). METHODS: We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days. RESULTS: A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity. CONCLUSIONS: Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome. CLINICALTRIALSGOV IDENTIFIER: NCT00784134.

Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model.

Oncolytic virotherapy represents a promising alternative for cancer treatment; however, viral delivery to the tumor represents a major challenge. Mesenchymal stem cells (MSCs) chemotax to tumors, and can serve as a viral delivery tool. Previously, we demonstrated antitumor therapeutic efficacy for mesenchymal stem cells (MSCs) infected with the oncolytic human adenovirus ICOVIR5 (Celyvir) for treatment of neuroblastoma patients. Given the lack of suitable immunocompetent preclinical models, the mechanism underlying Celyvir antitumor activity remains unknown. In this study, we used the syngeneic murine CMT64 cell line as a human adenovirus-semi-permissive tumor model and demonstrate the homing capacity of mouse Celyvir (mCelyvir) to CMT64 tumors. We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t. ICOVIR5 alone. Interestingly, the superior therapeutic effect of the combined therapy was associated with a higher tumor infiltration of CD8+ and CD4+ T cells. Our findings suggest that the use of MSCs as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, not only by driving the adenovirus to tumors, but also through their potential to recruit T cells.

Demographic Risk Factors for Vascular Lesions as Etiology of Intraventricular Hemorrhage in Prospectively Screened Cases.

BACKGROUND: Spontaneous intraventricular hemorrhage (IVH) is associated with high rates of morbidity and mortality despite critical care and other advances. An important step in clinical management is to confirm/rule out an underlying vascular lesion, which influences further treatment, potential for further bleeding, and prognosis. Our aim is to compare demographic and clinical characteristics between IVH patients with and without an underlying vascular lesion, and among cohorts with different vascular lesions. METHODS: We analyzed prospectively collected data of IVH patients screened for eligibility as part of the Clot Lysis: Evaluation Accelerated Resolution of IVH Phase III (CLEAR III) clinical trial. The trial adopted a structured screening process to systematically exclude patients with an underlying vascular lesion as the etiology of IVH. We collected age, sex, ethnicity, and primary diagnosis on these cases and vascular lesions were categorized prospectively as aneurysm, vascular malformation (arteriovenous malformation, dural arteriovenous fistula, and cavernoma), Moyamoya disease, or other vascular lesion. We excluded cases <18 or >80 years of age. Baseline characteristics were compared between the CLEAR group (IVH screened without vascular lesion) and the group of IVH patients screened and excluded from CLEAR because of an identified vascular lesion. We further analyzed the differential demographic and clinical characteristics among subcohorts with different vascular lesions. RESULTS: A total of 10,538 consecutive IVH cases were prospectively screened for the trial between 2011 and 2015. Out of these, 496 cases (4.7%) screened negative for underlying vascular lesion, met the inclusion criteria, and were enrolled in the trial (no vascular etiology group); and 1,205 cases (11.4%) were concurrently screened and excluded from the trial because of a demonstrated underlying vascular lesion (vascular etiology group). Cases with vascular lesion were less likely to be >45 years of age (OR 0.28, 95% CI 0.20-0.40), African-American (OR 0.23, 95% CI 0.18-0.31), or male gender (OR 0.48, 95% CI 0.38-0.60), and more likely to present with primary IVH (OR 1.85, 95% CI 1.37-2.51) compared to those with no vascular etiology (p < 0.001). Other demographic factors were associated with specific vascular lesion etiologies. A combination of demographic features increases the association with the absence of vascular lesion, but not with absolute reliability (OR 0.1, 95% CI 0.06-0.17, p < 0.001). CONCLUSION: An underlying vascular lesion as etiology of IVH cannot be excluded solely by demographic parameters in any patient. Some form of vascular imaging is necessary in screening patients before contemplating interventions like intraventricular fibrinolysis, where safety may be impacted by the presence of vascular lesion.

RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations.

BACKGROUND AND PURPOSE: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. METHODS: Two heterozygous murine models, Ccm1+/-Msh2-/- and Ccm2+/-Trp53-/-, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity. RESULTS: Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/- mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/- mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/- mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/- mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/- mice alone, and Fasudil benefit seemed limited to males. CONCLUSIONS: ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.

Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model.

Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme. CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. To elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft glioblastoma recurrent models induced by anti-glioma chemotherapy, temozolomide. In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single-cell level, glioma stem cell (GSC)-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem-like state and that temozolomide therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy-induced hypoxia-inducible factors (HIF) 1α and HIF2α play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon temozolomide therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. On the basis of our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the glioblastoma multiforme cells that induces the formation of therapy-resistant GSCs responsible for recurrence. Mol Cancer Ther; 15(12); 3064-76. ©2016 AACR.