Realtime assessment of vascular occlusion and reperfusion in animal models of intraoperative imaging - a pilot study.

Objectives: Intraoperative monitoring of blood flow (BF) remains vital to guiding surgical decisions. Here, we report the use of SurgeON™ Blood Flow Monitor (BFM), a prototype system that attaches to surgical microscopes and implements laser speckle contrast imaging (LSCI) to noninvasively obtain and present vascular BF information in real-time within the microscope's eyepiece. Methods: The ability of SurgeON BFM to monitor BF status during reversible vascular occlusion procedures was investigated in two large animal models: occlusion of saphenous veins in six NZW rabbit hindlimbs and clipping of middle cerebral artery (MCA) branches in four Dorset sheep brain hemispheres. SurgeON BFM acquired, presented, and stored LSCI-based blood flow velocity index (BFVi) data and performed indocyanine green video angiography (ICG-VA) for corroboration. Results: Stored BFVi data were analyzed for each phase: pre-occlusion (baseline), with the vessel occluded (occlusion), and after reversal of occlusion (re-perfusion). In saphenous veins, BFVi relative to baseline reduced to 5.2±3.7 % during occlusion and returned to 102.9±14.9 % during re-perfusion. Unlike ICG-VA, SurgeON BFM was able to monitor reduced BFVi and characterize re-perfusion robustly during five serial occlusion procedures conducted 2-5 min apart on the same vessel. Across four sheep MCA vessels, BFVi reduced to 18.6±7.7 % and returned to 120.1±27.8 % of baseline during occlusion and re-perfusion phases, respectively. Conclusions: SurgeON BFM can noninvasively monitor vascular occlusion status and provide intuitive visualization of BF information in real-time to an operating surgeon. This technology may find application in vascular, plastic, and neurovascular surgery.

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation.

Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on tissue oxygenation following hemorrhage and resuscitation in specialized animal models that challenge their resuscitative capabilities. Pre-existing conditions that compromise the vasculature and end organs, such as the liver, may limit the effectiveness of resuscitation and exacerbate the toxicity of these molecules, which is an important but minimally explored therapeutic dimension. In this study, we compared the effective oxygen delivery of intermediate molecular weight PolyhHb (PolyhHb-B3; 500-750 kDa) to high molecular weight PolyhHb (PolyhHb-B4; 750 kDa-0.2 µm) for resuscitative effectiveness in guinea pig models subjected to hemorrhagic shock. We evaluated how the size of PolyhHb impacts hemodynamics and tissue oxygenation in normal guinea pigs and guinea pigs on an atherogenic diet. We observed that while PolyhHb-B3 and -B4 equivalently restore hemodynamic parameters of normal-dieted guinea pigs, high-fat-dieted guinea pigs resuscitated with PolyhHb-B4 have lower mean arterial pressures, impaired tissue oxygenation, and higher plasma lactate levels than those receiving PolyhHb-B3. We characterized the plasma of these animals following resuscitation and found that despite similar oxygen delivery kinetics, circulating PolyhHb-B3 and -B4 demonstrated a size-dependent increase in the plasma viscosity, consistent with impaired perfusion in the PolyhHb-B4 transfusion group. We conclude that intermediate-sized PolyhHbs (such as -B3) are ideal for further research given the effective resuscitation of hemorrhagic shock based on tissue oxygenation in hypercholesterolemic guinea pigs.

EDIRNet: an unsupervised deformable registration model for X-ray and neutron images.

For high-precision industrial non-destructive testing, multimodal image registration technology can be employed to register X-ray and neutron images. X-ray and neutron image registration algorithms usually use conventional methods through iterative optimization. These methods will increase the cost of registration time and require more initialization parameters. The imaging results of internal sample structures can suffer from edge blurring due to the influence of a neutron beam collimator aperture, X-ray focal point, and imaging angles. We present an unsupervised learning model, EDIRNet, based on deep learning for deformable registration of X-ray and neutron images. We define the registration process as a function capable of estimating the flow field from input images. By leveraging deep learning techniques, we effectively parameterize this function. Consequently, given a registration image, our optimized network parameters enable rapid and direct estimation of the flow field between the images. We design an attention-based edge enhancement module to enhance the edge features of the image. For evaluating our presented network model, we utilize a dataset including 552 pairs of X-ray and neutron images. The experimental results show that the registration accuracy of EDIRNet reaches 93.09%. Compared with traditional algorithms, the accuracy of EDIRNet is improved by 3.17%, and the registration time is reduced by 28.75 s.

Comprehensive bioinformatic analysis of mind bomb 1 gene in stomach adenocarcinoma.

BACKGROUND: The carcinogenesis of stomach adenocarcinoma (STAD) involves many different molecules and multiple pathways, including the NOTCH signaling pathway. As a key factor that functions as a critical link in the NOTCH pathway, mind bomb 1 (MIB1) is upregulated in various tumors and has been reported to promote cell metastasis and invasion. However, studies on the role of MIB1 in STAD are limited. Here, we evaluated the prognostic value of MIB1 in STAD and its association with immune infiltration and copy number variation. AIM: To elucidate the relationship between MIB1 gene and gastric cancer (GC) and provide a new idea for the treatment of GC. METHODS: We identified mutations in the MIB1 gene by searching the cBioPortal database and then analyzed their relationship with the overall survival rate and disease-free survival rate using the Kaplan-Meier method. The Cancer Genome Atlas (TCGA) database provided transcript levels for MIB1 in STADs and normal tissues. As a method of distinguishing the STAD tissues from adjacent normal tissues, a receiver operating characteristic (ROC) curve was generated. Kaplan-Meier plotter was used to determine the effect of MIB1 expression on survival. Based on the LinkedOmics database, we were able to identify the coexpressed genes of the MIB1 gene, the top 50 positively correlated genes, and the top 50 negatively correlated genes. STRING was used to construct protein-protein interaction networks related to the MIB1 gene. An analysis of functional enrichment was carried out using the R package "Cluster Profiler". The relationships between mRNA expression of MIB1 and immune infiltrates were assessed by Tumor IMmune Estimation Resource (TIMER) and the "GSVA package" in R. RESULTS: According to the cBioPortal database, the MIB1 mutation rate in 287 patients in the TCGA dataset was approximately 6%. Kaplan-Meier survival analysis showed that patients with STAD in the mutated group had a worse prognosis than those in the unmutated group (P = 0.0156). There was a significant upregulation of MIB1 expression in STAD tissues compared to adjacent normal tissues. A high T stage was associated with increased MIB1 mRNA expression. The ROC curve analysis revealed 59.4% sensitivity and 85.6% specificity of MIB1 for differentiating STAD tissues from adjacent normal tissues at a truncation level of 2.248. Kaplan-Meier plotter indicated that patients with higher MIB1 levels had a worse prognosis than those with lower levels (26.4 mo vs 56.2 mo, P = 0.0330). A correlation analysis demonstrated an association between immune infiltrates and MIB1 mRNA expression. CONCLUSION: Upregulation of MIB1 expression is significantly associated with poor survival rate and immune infiltration in gastric adenocarcinoma. MIB1 may be a biomarker for the poor prognosis of STAD patients and a potential immunotherapeutic target.

Quantification of Cerebral Vascular Autoregulation Immediately Following Resuscitation from Cardiac Arrest.

Cerebral vascular autoregulation is impaired following resuscitation from cardiac arrest (CA), and its quantification may allow assessing CA-induced brain injury. However, hyperemia occurring immediately post-resuscitation limits the application of most metrics that quantify autoregulation. Therefore, to characterize autoregulation during this critical period, we developed three novel metrics based on how the cerebrovascular resistance (CVR) covaries with changes in cerebral perfusion pressure (CPP): (i) Î¸CVR, which quantifies the CVR vs CPP gradient, (ii) a CVR-based transfer function analysis, and (iii) CVRx, the correlation coefficient between CPP and CVR. We tested these metrics in a model of asphyxia induced CA and resuscitation using seven adult male Wistar rats. Mean arterial pressure (MAP) and cortical blood flow recorded for 30 min post-resuscitation via arterial cannulation and laser speckle contrast imaging, were used as surrogates of CPP and cerebral blood flow (CBF), while CVR was computed as the CPP/CBF ratio. Using our metrics, we found that the status of cerebral vascular autoregulation altered substantially during hyperemia, with changes spread throughout the 0-0.05 Hz frequency band. Our metrics push the boundary of how soon autoregulation can be assessed, and if validated against outcome markers, may help develop a reliable metric of brain injury post-resuscitation.

Biophysical Analysis and Preclinical Pharmacokinetics-Pharmacodynamics of Tangential Flow Filtration Fractionated Polymerized Human Hemoglobin as a Red Blood Cell Substitute.

Red blood cell (RBC) substitutes tested in late-phase clinical trials contained low-molecular-weight hemoglobin species (<500 kDa), resulting in vasoconstriction, hypertension, and oxidative tissue injury; therefore, contributing to poor clinical outcomes. This work aims to improve the safety profile of the RBC substitute, polymerized human hemoglobin (PolyhHb), via in vitro and in vivo screening of PolyhHb fractionated into four molecular weight brackets (50-300 kDa [PolyhHb-B1]; 100-500 kDa [PolyhHb-B2]; 500-750 kDa [PolyhHb-B3]; and 750 kDa to 0.2 µm [PolyhHb-B4]) using a two-stage tangential flow filtration purification process. Analysis showed that PolyhHb's oxygen affinity, and haptoglobin binding kinetics decreased with increasing bracket size. A 25% blood-for-PolyhHb exchange transfusion guinea pig model suggests that hypertension and tissue extravasation decreased with increasing bracket size. PolyhHb-B3 demonstrated extended circulatory pharmacokinetics, no renal tissue distribution, no aberrant blood pressure, or cardiac conduction effects, and may therefore be appropriate material for further evaluation.

COVID-19 impairs oxygen delivery by altering red blood cell hematological, hemorheological, and oxygen transport properties.

Introduction: Coronavirus disease 2019 (COVID-19) is characterized by impaired oxygen (O2) homeostasis, including O2 sensing, uptake, transport/delivery, and consumption. Red blood cells (RBCs) are central to maintaining O2 homeostasis and undergo direct exposure to coronavirus in vivo. We thus hypothesized that COVID-19 alters RBC properties relevant to O2 homeostasis, including the hematological profile, Hb O2 transport characteristics, rheology, and the hypoxic vasodilatory (HVD) reflex. Methods: RBCs from 18 hospitalized COVID-19 subjects and 20 healthy controls were analyzed as follows: (i) clinical hematological parameters (complete blood count; hematology analyzer); (ii) O2 dissociation curves (p50, Hill number, and Bohr plot; Hemox-Analyzer); (iii) rheological properties (osmotic fragility, deformability, and aggregation; laser-assisted optical rotational cell analyzer (LORRCA) ektacytometry); and (iv) vasoactivity (the RBC HVD; vascular ring bioassay). Results: Compared to age- and gender-matched healthy controls, COVID-19 subjects demonstrated 1) significant hematological differences (increased WBC count-with a higher percentage of neutrophils); RBC distribution width (RDW); and reduced hematocrit (HCT), Hb concentration, mean corpuscular volume (MCV), and mean corpuscular hemoglobin concentration (MCHC); 2) impaired O2-carrying capacity and O2 capacitance (resulting from anemia) without difference in p50 or Hb-O2 cooperativity; 3) compromised regulation of RBC volume (altered osmotic fragility); 4) reduced RBC deformability; 5) accelerated RBC aggregation kinetics; and (6) no change in the RBC HVD reflex. Discussion: When considered collectively, homeostatic compensation for these RBC impairments requires that the cardiac output in the COVID cohort would need to increase by ∼135% to maintain O2 delivery similar to that in the control cohort. Additionally, the COVID-19 disease RBC properties were found to be exaggerated in blood-type O hospitalized COVID-19 subjects compared to blood-type A. These data indicate that altered RBC features in hospitalized COVID-19 subjects burden the cardiovascular system to maintain O2 delivery homeostasis, which appears exaggerated by blood type (more pronounced with blood-type O) and likely plays a role in disease pathogenesis.

Incidental finding of metastatic prostatic adenocarcinoma of cerebellopontine angle presenting as acoustic neuroma: A case report and review of literature.

INTRODUCTION: Brain metastases from carcinoma of prostate are rare and only few cases with brain metastases preceding the diagnosis of carcinoma of prostate have been reported in the literature. Lesions of brain metastasis from prostate cancer had a large variety of imaging presentations and it is very difficult to distinguish them from the other types of brain occupying lesions. We report one case of metastatic prostatic adenocarcinoma of cerebellopontine angle presenting as acoustic neuroma, as the first clinical evidence of metastatic carcinoma of the prostate. PRESENTATION OF CASE: The 57-year-old male presented to the neurology clinic complaining of dizziness accompanied by right tinnitus, he was proposed to be diagnosed with acoustic neuroma, and the tumor resection was performed later in our neurosurgery department. The postoperative histopathological and immunohistochemical (IHC) examinations revealed a cerebellar pontine angle metastatic adenocarcinoma, which was then confirmed as prostate cancer metastasis. The patient refused surgical castration and only agreed to conservative treatment. The patient's condition continued to deteriorate, and he died 12 months after the initial presentation. DISCUSSION: Brain metastasis is rare in prostate cancer, which accounts for only 0.2 % to 2 % of all brain metastases. Intracranial metastasis as the first clinical symptom of prostate cancer is extremely rare. In our article, we report the VIIIth and VIIth cranial nerves palsy for the first time, caused by brain metastases from prostate cancer, with symptoms similar to an acoustic neuroma. Prostate cancer most commonly spreads to the bones, including the skull, Cranial nerve palsy is caused by extensive invasion of the skull base. The serum PSA level is considered the most valuable tool to monitor the disease progression of patients with prostate cancer metastasis. A high PSA level significantly increases the tendency of prostate cancer to metastasize to the brain. A high Gleason score is believed to help determine the risk and likelihood of brain metastases in patients with prostatic carcinoma. CONCLUSION: In our case, we initially report the VIIIth and VIIth cranial nerve palsy, mimicking an acoustic neuroma, caused by metastatic prostate carcinoma. For early diagnosis, the prostate should not be neglected as a possible source of the metastases in male patients presenting with brain metastases. High prostate specific antigen (PSA) level and high Gleason score can be useful parameters for the prediction of brain metastasis from prostate cancer. The PSA should play a vital role in distinguishing metastatic prostate carcinoma in male patients.

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma.

Recently, increasing attention has been paid to the role of Squalene epoxidase (SQLE) in several types of cancers. However, its functional role in tumor progression of head and neck squamous cell carcinoma (HNSCC) is still unclear. We performed bioinformatic analyses and relative experiments to assess the potential mechanism of SQLE-mediated HNSCC malignancy. And the results showed that SQLE was significantly upregulated in tumor samples compared with peritumor samples. Mechanistically, miR-584-5p downregulation may lead to the upregulation of SQLE in HNSCC. Moreover, high SQLE expression in HNSCC was associated with TNM stage, distant metastasis, and poor survival, indicating that SQLE be involved in the progression of HNSCC. Furtherly, SQLE boosted proliferation, migration, invasion of HNSCC cells in vitro and in vivo. Bioinformatic studies showed that PI3K/Akt signaling participated in HNSCC progression mediated by SQLE overexpression, which is confirmed by in vitro and in vivo analysis. Particularly, treatment with terbinafine, an inhibitor of SQLE widely used in the treatment of fungal infections, showed a therapeutic influence on HNSCC. Our findings demonstrate that SQLE plays a vital role in HNSCC progression, providing research evidence for SQLE as a prospective HNSCC therapeutic target and for terbinafine as a candidate drug of HNSCC treatment in the future.

Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long-term mortality. Post-cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer-N-acetylcysteine conjugate (D-NAC), can target "activated" microglial cells following CA, leading to an improvement in post-CA survival rate compared to saline (86% vs. 45%). D-NAC treatment also significantly improved gross neurological score within 4 h of treatment (p < 0.05) and continued to show improvement at 48 h (p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D-NAC treatment (p < 0.05). D-NAC also mitigated hippocampal cell density loss seen post-CA in the CA1 and CA3 subregions (p < 0.001). These results demonstrate that early therapeutic intervention even with a single D-NAC bolus results in a robust sustainable improvement in long-term survival, short-term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post-CA syndrome.

Early Thalamocortical Reperfusion Leads to Neurologic Recovery in a Rodent Cardiac Arrest Model.

BACKGROUND: Cerebral blood flow (CBF) plays an important role in neurological recovery after cardiac arrest (CA) resuscitation. However, the variations of CBF recovery in distinct brain regions and its correlation with neurologic recovery after return of spontaneous circulation (ROSC) have not been characterized. This study aimed to investigate the characteristics of regional cerebral reperfusion following resuscitation in predicting neurological recovery. METHODS: Twelve adult male Wistar rats were studied, ten resuscitated from 7-min asphyxial CA and two uninjured rats, which were designated as healthy controls (HCs). Dynamic changes in CBF in the cerebral cortex, hippocampus, thalamus, brainstem, and cerebellum were assessed by pseudocontinuous arterial spin labeling magnetic resonance imaging, starting at 60 min after ROSC to 156 min (or time to spontaneous arousal). Neurologic outcomes were evaluated by the neurologic deficit scale at 24 h post-ROSC in a blinded manner. Correlations between regional CBF (rCBF) and neurological recovery were undertaken. RESULTS: All post-CA animals were found to be nonresponsive during the 60-156 min post ROSC, with reductions in rCBF by 24-42% compared with HC. Analyses of rCBF during the post-ROSC time window from 60 to 156 min showed the rCBF recovery of hippocampus and thalamus were positively associated with better neurological outcomes (rs = 0.82, p = 0.004 and rs = 0.73, p < 0.001, respectively). During 96 min before arousal, thalamic and cortical rCBF exhibited positive correlations with neurological recovery (rs = 0.80, p < 0.001 and rs = 0.65, p < 0.001, respectively); for predicting a favorable neurological outcome, the thalamic rCBF threshold was above 50.84 ml/100 g/min (34% of HC) (area under the curve of 0.96), whereas the cortical rCBF threshold was above 60.43 ml/100 g/min (38% of HC) (area under the curve of 0.88). CONCLUSIONS: Early magnetic resonance imaging analyses showed early rCBF recovery in thalamus, hippocampus, and cortex post ROSC was positively correlated with neurological outcomes at 24 h. Our findings suggest new translational insights into the regional reperfusion and the time window that may be critical in neurological recovery and warrant further validation.

Intranasal Orexin After Cardiac Arrest Leads to Increased Electroencephalographic Gamma Activity and Enhanced Neurologic Recovery in Rats.

OBJECTIVES: Prolonged cardiac arrest is known to cause global ischemic brain injury and functional impairment. Upon resuscitation, electroencephalographic recordings of brain activity begin to resume and can potentially be used to monitor neurologic recovery. We have previously shown that intrathecal orexin shows promise as a restorative drug and arousal agent in rodents. Our goal is to determine the electrophysiology effects of orexin in a rodent model of asphyxial cardiac arrest, focusing on the electroencephalographic activity in the gamma and super-gamma bands (indicative of return of higher brain function). DESIGN: Experimental animal study. SETTING: University-based animal research laboratory. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: In an established model of asphyxial cardiac arrest (n = 24), we treated half of Wistar rats with orexin administered intranasally by atomizer 30 minutes post return of spontaneous circulation in one of two dose levels (10 and 50 µM); the rest were treated with saline as control. Continuous electroencephalographic recording was obtained and quantitatively analyzed for the gamma fraction. Gamma and high-frequency super-gamma band measures were compared against clinical recovery according to Neuro-Deficit Score. MEASUREMENTS AND MAIN RESULTS: Compared with the control cohort, the high-dose orexin cohort showed significantly better Neuro-Deficit Score 4 hours after return of spontaneous circulation (55.17 vs 47.58; p < 0.02) and significantly higher mean gamma fraction (0.251 vs 0.177; p < 0.02) in cerebral regions surveyed by rostral electrodes for the first 170 minutes after administration of orexin. CONCLUSIONS: Our findings support early and continuous monitoring of electroencephalography-based gamma activity as a marker of better functional recovery after intranasal administration of orexin as measured by Neuro-Deficit Score in an established animal model of asphyxial cardiac arrest.

Acute-stage MRI cerebral oxygen consumption biomarkers predict 24-hour neurological outcome in a rat cardiac arrest model.

Brain injury following cardiac arrest (CA) is thought to be caused by a sudden loss of blood flow resulting in disruption in oxygen delivery, neural function and metabolism. However, temporal trajectories of the brain's physiology in the first few hours following CA have not been fully characterized. Furthermore, the extent to which these early measures can predict future neurological outcomes has not been determined. The present study sought to perform dynamic measurements of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) with MRI in the first 3 hours following the return of spontaneous circulation (ROSC) in a rat CA model. It was found that CBF, OEF and CMRO2 all revealed a time-dependent increase during the first 3 hours after the ROSC. Furthermore, the temporal trajectories of CBF and CMRO2 , but not OEF, were different across rats and related to neurologic outcomes at a later time (24 hours after the ROSC) (P < .001). Rats who manifested better outcomes revealed faster increases in CBF and CMRO2 during the acute stage. When investigating physiological parameters measured at a single time point, CBF (ρ = 0.82, P = .004) and CMRO2 (ρ = 0.80, P = .006) measured at ~ 3 hours post-ROSC were positively associated with neurologic outcome scores at 24 hours. These findings shed light on brain physiological changes following CA, and suggest that MRI measures of brain perfusion and metabolism may provide a potential biomarker to guide post-CA management.

Integrin ß1 in Adipose-Derived Stem Cells Accelerates Wound Healing via Activating PI3K/AKT Pathway.

BACKGROUND: This study aims to investigate the effect of integrin ß1 on wound healing induced by adipose-derived stem cells (ADSCs), as well as the corresponding mechanism. METHODS: Integrin ß1 was overexpressed in ADSCs. Thereafter, flow cytometry and transwell chambers technology were used to measure the endothelial-like differentiation (CD31 as a biomarker of endothelial cell) and cell migration, respectively. Western blot was used to detect the activation of PI3K/AKT, NF-κB and ERK signaling pathways. The effects of integrin ß1 overexpression on healing time, healing rate and fibroblast number were further evaluated in the rat models of chronic refractory wound. RESULTS: The overexpression of integrin ß1 increased CD31+ endothelial-like cells (about 3.6-fold), promoted cell migration (about 1.9-fold) and enhanced the activation of PI3K (p-PI3K; about 2.1-fold) and AKT (p-AKT; about 2.2-fold). These effects were all weakened when PI3K/AKT pathway was inhibited by LY294002 treatment. In addition, the experiments in rat wound models showed that integrin ß1 overexpression obviously shortened healing time (approximately 0.41-fold), increased healing rate (about 2.7-fold, 2.8-fold and 1.6-fold at day 7, 14 and 21) and increased the number of fibroblasts (approximately 3.1-fold at day 21). All of the above differences were statistically significant (p < 0.05). CONCLUSION: Integrin ß1 can promote the migration and endothelial-like differentiation of ADSCs by activating PI3K/AKT pathway and then enhance the function of ADSCs in promoting wound healing.

Osteopontin accelerates the development and metastasis of bladder cancer via activating JAK1/STAT1 pathway.

BACKGROUND: Bladder cancer is the 10th common cancer worldwide. Osteopontin has been found to enhance cell proliferation, metastasis and invasion in various human tumors. OBJECTIVE: To investigate the roles of osteopontin in bladder cancer. METHODS: The RNA interference and overexpression of osteopontin were performed in bladder cancer cell lines (T24 and SCaBER). Cell proliferation and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. Cell invasion was determined using transwell assay. RESULTS: Osteopontin was highly expressed in bladder cancer tissues in comparison with the adjacent normal tissues. Its high expression significantly correlated with high histologic grade, high TNM stage (III and IV) and poor prognosis. For T24 cells with osteopontin interference and SCaBER cells with osteopontin overexpression, cell proliferation was significantly inhibited (3.58-fold vs. 5.62-fold) and enhanced (7.81-fold vs. 5.29-fold), respectively. The apoptosis portion of T24 cells significantly increased from 4.48 to 10.75%, and that of SCaBER cells significantly declined from 7.33 to 4.01%. The invaded T24 and SCaBER cells significantly decreased to 52.0% and increased to 2.0-fold, respectively. Osteopontin overexpression enhanced the expression (1.54-fold and 2.39-fold; 2.33-fold and 2.05-fold) and activation (1.80-fold and 1.96-fold; 2.00-fold and 2.59-fold) of JAK1 and STAT1 in two cell lines of bladder cancer. CONCLUSION: Osteopontin might enhance proliferation, inhibit apoptosis and accelerate invasion and thus promote the development and metastasis of bladder cancer, and osteopontin's functions might be mediated by activating JAK1/STAT1 signaling pathway.

The Microbead: A 0.009 mm3 Implantable Wireless Neural Stimulator.

Wirelessly powered implants are increasingly being developed to interface with neurons in the brain. They often rely on microelectrode arrays, which are limited by their ability to cover large cortical surface areas and long-term stability because of their physical size and rigid configuration. Yet some clinical and research applications prioritize a distributed neural interface over one that offers high channel count. One solution to make large scale, fully specifiable, electrical stimulation/recording possible, is to disconnect the electrodes from the base, so that they can be arbitrarily placed freely in the nervous system. In this work, a wirelessly powered stimulating implant is miniaturized using a novel electrode integration technique, and its implanted depth maximized using new optimization design methods for the transmitter and receiver coils. The stimulating device is implemented in a 130 nm CMOS technology with the following characteristics: 300 µm × 300 µm × 80 µm size; optimized two-coil inductive link; and integrated circuit, electrodes and coil. The wireless and stimulation capability of the implant is demonstrated in a conductive medium, as well as in-vivo. To the best of our knowledge, the fabricated free-floating miniaturized implant has the best depth-to-volume ratio making it an excellent tool for minimally-invasive distributed neural interface, and thus could eventually complement or replace the rigid arrays that are currently the state-of-the-art in brain set-ups.

A miniature multi-contrast microscope for functional imaging in freely behaving animals.

Neurovascular coupling, cerebrovascular remodeling and hemodynamic changes are critical to brain function, and dysregulated in neuropathologies such as brain tumors. Interrogating these phenomena in freely behaving animals requires a portable microscope with multiple optical contrast mechanisms. Therefore, we developed a miniaturized microscope with: a fluorescence (FL) channel for imaging neural activity (e.g., GCaMP) or fluorescent cancer cells (e.g., 9L-GFP); an intrinsic optical signal (IOS) channel for imaging hemoglobin absorption (i.e., cerebral blood volume); and a laser speckle contrast (LSC) channel for imaging perfusion (i.e., cerebral blood flow). Following extensive validation, we demonstrate the microscope's capabilities via experiments in unanesthetized murine brains that include: (i) multi-contrast imaging of neurovascular changes following auditory stimulation; (ii) wide-area tonotopic mapping; (iii) EEG-synchronized imaging during anesthesia recovery; and (iv) microvascular connectivity mapping over the life-cycle of a brain tumor. This affordable, flexible, plug-and-play microscope heralds a new era in functional imaging of freely behaving animals.

Therapeutic hypothermia promotes cerebral blood flow recovery and brain homeostasis after resuscitation from cardiac arrest in a rat model.

Laboratory and clinical studies have demonstrated that therapeutic hypothermia (TH), when applied as soon as possible after resuscitation from cardiac arrest (CA), results in better neurological outcome. This study tested the hypothesis that TH would promote cerebral blood flow (CBF) restoration and its maintenance after return of spontaneous circulation (ROSC) from CA. Twelve Wistar rats resuscitated from 7-min asphyxial CA were randomized into two groups: hypothermia group (7 H, n = 6), treated with mild TH (33-34℃) immediately after ROSC and normothermia group (7 N, n = 6,37.0 ± 0.5℃). Multiple parameters including mean arterial pressure, CBF, electroencephalogram (EEG) were recorded. The neurological outcomes were evaluated using electrophysiological (information quantity, IQ, of EEG) methods and a comprehensive behavior examination (neurological deficit score, NDS). TH consistently promoted better CBF restoration approaching the baseline levels in the 7 H group as compared with the 7 N group. CBF during the first 5-30 min post ROSC of the two groups was 7 H:90.5% ± 3.4% versus 7 N:76.7% ± 3.5% (P < 0.01). Subjects in the 7 H group showed significantly better IQ scores after ROSC and better NDS scores at 4 and 24 h. Early application of TH facilitates restoration of CBF back to baseline levels after CA, which in turn results in the restoration of brain electrical activity and improved neurological outcome.