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Purpose: Ceritinib is an orally bioavailable, small-molecule inhibitor of anaplastic lympoma kinase (ALK), insulin-like growth factor 1 receptor (IGFR1), and focal adhesion kinase (FAK), which are highly expressed in glioblastoma and many brain metastases. Preclinical and clinical studies indicate that ceritinib has antitumor activity in central nervous system (CNS) malignancies. This phase 0 trial measured the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in patients with brain metastasis or recurrent glioblastoma. Patients and Methods: Preoperative patients with brain tumors demonstrating high expression of pSTAT5b/pFAK/pIGFR1 were administered ceritinib for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at predefined timepoints following the final dose. Total and unbound drug concentrations were determined using LC-MS/MS. In treated tumor and matched archival tissues, tumor PD was quantified through IHC analysis of pALK, pSTAT5b, pFAK, pIGFR1, and pIRS1. Results: Ten patients (3 brain metastasis, 7 glioblastoma) were enrolled and no dose-limiting toxicities were observed. Ceritinib was highly bound to human plasma protein [median fraction unbound (Fu), 1.4%] and to brain tumor tissue (median Fu, 0.051% and 0.045% in gadolinium-enhancing and -nonenhancing regions respectively). Median unbound concentrations in enhancing and nonenhancing tumor were 0.048 and 0.006 μmol/L, respectively. Median unbound tumor-to-plasma ratios were 2.86 and 0.33 in enhancing and nonenhancing tumor, respectively. No changes in PD biomarkers were observed in the treated tumor samples as compared to matched archival tumor tissue. Conclusions: Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastases and patients with recurrent glioblastoma were insufficient for target modulation.

Suicide is commonly found in patients with major depressive disorder (MDD), while the associations among depressive symptoms and their relationships with suicidal risk remain unclear. This study identified the symptoms associated with suicidal risk and the most central symptoms in the MDD networks based on both self-reported and clinical-interview scales. A total of 446 outpatients with MDD were recruited. The Mini International Neuropsychiatric Interview (MINI) was used to assess the suicidal risk. The 13-item Beck Depression Inventory (BDI-13) and 17-item Hamilton Depression Rating Scale (HAMD-17) were used to measure the depressive symptoms. Network analysis was used to estimate the network models. Ten symptoms in the BDI-13 network were related to suicidal risk, among which sadness had the strongest association. Among the six symptoms in the HAMD-17 network that were associated with suicidal risk, guilty feeling was the strongest. Sense of failure was the most central symptom in the BDI-13 network, while depressed mood had the highest centrality in the HAMD-17 network. The depressive symptoms related to suicide risk and the clinical features of MDD showed different characteristics based on different assessment types. Combining self-reported and clinician-rated assessments in future studies and clinical practice might lead to some new findings.

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is a leading cause of blindness worldwide. Activated macrophages recruited to the injured eyes greatly contribute to the pathogenesis of choroidal neovascularization (CNV) in exudative AMD (wet AMD). This study describes the effects of cyclooxygenase-2 (COX2)/prostaglandin E2 (PGE2) signalling on the M2 macrophage recruitment and CNV formation of wet AMD. In a mouse model of laser-induced wet AMD, the mice received an intravitreal injection of celecoxib (a selective COX2 inhibitor). Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), choroidal histology of the CNV lesions, and biochemical markers were assessed. The level of PGE2 expression was high in the laser-induced CNV lesions. M2 polarization and CNV development were significantly less after celecoxib treatment. E-prostanoid1 receptor (EP1R)/protein kinase C (PKC) signalling was involved in M2 polarization and interleukin-10 (IL-10) production of bone marrow-derived macrophages (BMDMs) in vitro. In addition, IL-10 was found to induce the proliferation and migration of human choroidal microvascular endothelial cells (HCECs). Thus, the PGE2/EP1R signalling network serves as a potential therapeutic target for CNV of the wet-type AMD.

Purpose: CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma. Patients and Methods: Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification were treated with ribociclib daily (900 mg) for 5 days before tumor resection. Blood, tumor, and cerebrospinal fluid (CSF) samples were collected, and total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared with matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled into the expansion cohort for preliminary assessment of progression-free survival (PFS). Results: Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, nonenhancing, and enhancing tumor regions were 0.374 μmol/L, 0.560, and 2.152 μmol/kg, respectively, which were more than 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 μmol/L). G1-to-S phase suppression was inferred by decreases in phosphorylation of RB (P < 0.01) and cellular proliferation (P < 0.05). Six of 12 patients were enrolled into the pharmacokinetic/pharmacodynamic-guided expansion cohort and demonstrated a median PFS of 9.7 weeks. Examination of recurrent tumors following monotherapy indicated upregulation of the PI3K/mTOR pathway. Conclusions: Ribociclib exhibited good CNS penetration, and target modulation was indicated by inhibition of RB phosphorylation and tumor proliferation. Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR inhibitors may be explored for treating recurrent glioblastoma.

A better understanding of the human central nervous system (CNS) pharmacokinetics is critical to the selection of the right drug and refinement of dosing regimen for more effective treatment of primary and metastatic brain cancer. Using the physiologically-based pharmacokinetic (PBPK) modeling approach, we systematically compared the CNS pharmacokinetics of three cyclin D-cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (ribociclib, palbociclib, and abemaciclib) in patients with cancer. A PBPK model platform was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration to the in vitro half-maximal inhibitory concentration (IC50 ) for CDK4/6 inhibition, was used as a crude predictor of efficacy. As compared with ribociclib and palbociclib, abemaciclib penetrated into the human brain to a larger extent, but at a slower rate, and was retained in the brain longer. Following the standard dosing regimens, the predicted CDK4/6 TERs were 26/5.2 for abemaciclib, 2.4/0.62 for ribociclib, and 0.36/0.27 for palbociclib. Simulations suggested that abemaciclib achieved comparable TERs following twice daily or daily dosing; ribociclib may sufficiently inhibit both CDK4 and CDK6 at the maximum tolerated dose; whereas, palbociclib achieved TERs < 0.5 even at a dose 50% higher than the standard dose. In conclusion, the PBPK modeling, supported by available preclinical and clinical evidence, suggests that abemaciclib is the best CDK4/6 inhibitor for brain cancer treatment, whereas palbociclib is not recommended. The model refined dosing regimen is 300 mg daily on a 4-weeks-on schedule for abemaciclib, and 900 mg daily on a 3-weeks-on/1-week-off schedule for ribociclib.

The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of RAD6-mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting RAD6 with a RAD6-selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity toward TNBC cells. Here, we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild-type and BRCA1-mutant TNBC xenograft models, and investigated the impact of RAD6 inhibition on TNBC metabolism by 1H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared with the unconjugated drug. Systemically administered SMI#9-GNP inhibited the TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP–treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP–treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild-type and BRCA1-mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy-mediated RAD6 inhibition offers a promising strategy for TNBC treatment.

In this network meta-analysis, we determined the optimal surgical method for treating unstable femoral intertrochanteric fractures. We searched the EMBASE, Cochrane Library and Medline databases for studies evaluating sliding hip screws (SHS), gamma nail (GN) or proximal femoral nail antirotation (PFNA) methods, and included nine randomized controlled trials that met the inclusion criteria. Our analysis showed no differences in the rates of complications between SHS and PFNA relative to GN (p > 0.05). However, the surface under the cumulative ranking curve (SUCRA) score for PFNA (77.6%) was higher than the SUCRA scores for GN (65%) and SHS (7.5%). This suggests PFNA is the better surgical method than GN or SHS for unstable femoral intertrochanteric fractures.

Although Butylphthalide (BP) has protective effects that reduce ischemia-induced brain damage and neuronal cell death, little is known about the precise mechanisms occurring during cerebral ischemia/reperfusion (I/R). Therefore, the aim of this study was to investigate the neuroprotective mechanisms of BP against ischemic brain injury induced by cerebral I/R through inhibition of the c-Jun N-terminal kinase (JNK)-Caspase3 signaling pathway. BP in distilled non-genetically modified Soybean oil was administered intragastrically three times a day at a dosage of 15 mg/(kg day) beginning at 20 min after I/R in Sprague-Dawley rats. Immunohistochemical staining and Western blotting were performed to examine the expression of related proteins, and TUNEL-staining was used to detect the percentage of neuronal apoptosis in the hippocampal CA1 region. The results showed that BP could significantly protect neurons against cerebral I/R-induced damage. Furthermore, the expression of p-JNK, p-Bcl2, p-c-Jun, FasL, and cleaved-caspase3 was also decreased in the rats treated with BP. In summary, our results imply that BP could remarkably improve the survival of CA1 pyramidal neurons in I/R-induced brain injury and inhibit the JNK-Caspase3 signaling pathway.

Volatile organic compounds (VOCs) are important precursors of ozone (O3) and secondary organic aerosols (SOAs). Tracing VOC pollution sources is important for controlling VOC emissions and reducing O3 and SOAs. We built a novel mobile proton transfer reaction mass spectrometry (M-PTR-MS) instrument to image the distribution of VOCs and trace their emission sources in cities and industrial parks. The M-PTR-MS is composed of a vibration-resistant proton transfer reaction mass spectrometry (PTR-MS) with a global positioning system receiver, modified box vehicle, and geographic information system (GIS) software. The PTR-MS, mounted on a vehicle, sends VOC data and vehicle position information to the GIS software. These data are used to image the space distribution of VOCs in real time while the vehicle platform is in motion and the VOC sources are precisely traced using the GIS. The spatial data resolution of the M-PTR-MS is typically 0.8 m. The limits of detection, sensitivity, and repeatability of the M-PTR-MS are 43.5 ppt, 347 counts ppb−1, and 2.4% (RSD, n = 5), respectively. The intensity of reagent ions is stable over 8 h (RSD = 0.45%). Compared with commercial PTR-MS equipment, the M-PTR-MS demonstrated high consistency, with a correlation coefficient of 92.665%. Several field experiments were conducted in China using the M-PTR-MS. In one field experiment, the VOC distribution along three different routes was surveyed; the navigation monitoring lasted 1.8 h over a distance of 26.7 km at an average speed of 15 km h−1. The VOC sources in an industrial park were identified by analyzing the components near different factories. The main species from a VOC source in an underground garage was related to paint. The M-PTR-MS instrument can be used by environmental protection agencies to trace VOC pollution sources in real time, and by researchers to survey VOC emissions in regions of concern.

BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. MATERIAL AND METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory Phase 2 cohort. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an expansion cohort for preliminary assessment of progression-free survival. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At 14 months, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

Background New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. Methods Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04 µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory phase 2 cohort. Results The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. Conclusions Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted. Clinical trial identification NCT02933736. Legal entity responsible for the study The authors. Funding The Ben and Catherine Ivy Foundation. Disclosure All authors have declared no conflicts of interest.

Background Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical data suggest that ceritinib has activity in central nervous system (CNS) malignancies, but to date there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in recurrent glioblastoma and brain metastasis patients. Methods Three brain metastasis and 7 glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750 mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ∼ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. Results Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one patient with brain metastasis, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor concentration and CSF concentration as compared to those in glioblastoma patients. In all patients, no changes in PD markers were detected. Conclusions Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation. Clinical trial identification NCT02605746. Legal entity responsible for the study The authors. Funding The Ben and Catherine Ivy Foundation. Disclosure All authors have declared no conflicts of interest.

BACKGROUND Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical data suggest that ceritinib has activity in central nervous system (CNS) malignancies, but to date there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in recurrent glioblastoma and brain metastasis patients. MATERIALS AND METHODS Three brain metastasis and seven glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750 mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. RESULTS Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one patient with brain metastasis, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor concentration and CSF concentration as compared to those in glioblastoma patients. In all patients, no changes in PD markers were detected. CONCLUSION Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation.

With the rapid aging populations in developed and developing countries and the increase of non-communicable disease, the contradiction between increasing healthcare demands and the lack of medical specialists have become more and more serious. Wearable personal health devices (PHDs) provide a good solution of this problem. But due to the proprietary interface and protocol, the compatibility and extensibility problem among different PHD manufacturers strongly influenced the spread application of the wearable PHDs. So we design and develop a ubiquitous healthcare system for Android tablet, which can not only acquire and process the physiological signals from non-standard laboratory developed multifunction wearable sensors, but also acquire and process the physiological signals from standard PHDs comply with Continua Alliance or ISO/IEEE 11073 standards. The preliminary results demonstrate that this system can not only receive data from standard and non-standard PHDs, but also do the arrhythmia classification and heart rate analysis in real time.

With the growth of aging populations in both developed and developing countries and the increase of noncommunicable disease, the contradiction between increasing healthcare demands and the shortage of medical specialists have become more and more serious. Wearable personal health devices (PHDs) provide a good solution to this problem. But due to the proprietary interface and data protocol, the compatibility and extensibility problem among different PHDs producers strongly influenced the spread adoption of the wearable PHDs in the field of telemedicine. So we designed and implemented a ubiquitous health monitoring system based on Android tablet, which can not only acquire and process the physiological signals from non-standard laboratory developed multi-function wearable health monitoring sensors, but also acquire and process the physiological signals from standard PHDs comply with Continua Alliance or/and ISO/IEEE 11073 standards. The preliminary results demonstrate that this system can not only receive data from standard and non-standard PHDs, but also do the arrhythmia classification and heart rate variability analysis in real time.

Accuracy of independent GPS navigation systems is tied to the map-matching algorithm, which overcomes GPS error and traffic map error to map vehicle GPS tracks onto corresponding roads. The paper proposed an improved map-matching algorithm in which an intersection-based dynamic parallelogram criterion is used to improve the accuracy of navigation systems greatly.

BACKGROUND: CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma patients. We conducted a Phase 0/2 clinical trial (NCT02933736) of ribociclib, a selective CDK4/6-inhibitor, to examine the plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD) of recurrent glioblastoma. METHODS: Eligible patients with intact RB expression and CDKN2A deletion or CDK4/6 amplification were enrolled into the Phase 0 component to receive ribociclib (900mg daily) for 5 days prior to tumor resection. Plasma, tumor, and CSF samples were collected to determine drug concentrations using validated LC-MS/MS methods. PD effects, including RB and FoxM1 phosphorylation, were compared to archival tissue. Patients with favorable PK and PD outcomes were transitioned into the Phase 2 component. RESULTS: Twelve patients were enrolled into three presurgical time-escalation groups (2-hours, 8-hours, 24-hours). Ribociclib penetrated both enhancing and non-enhancing regions of the tumor. In non-enhancing tissue, median unbound brain-to-plasma ratio was 1.78 and median ribociclib concentration was 0.54 nmol/mL, exceeding the in vitro IC50 for CDK4/6 (0.04 nmol/mL). Suppression of G1-to-S phase was inferred by a decrease in RB phosphorylation (p

BACKGROUND CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma (GBM) patients and novel CDK4/6 inhibitors have shown anti-tumor activity in animal models. To explore the utility of ribociclib, a selective CDK4/6-inhibitor, in treating recurrent GBM patients, we conducted a phase 0/II clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT02933736","term_id":"NCT02933736"}}NCT02933736) to examine plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD).

In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved-caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2 % for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion.

Accuracy of independent GPS navigation systems is tied to the map-matching (MM) algorithm, which overcomes GPS error and traffic map error to map ve-hicle GPS tracks onto corresponding roads. This paper presents a map-matching process compatible with junction adjusting. An innovative idea is expressed in pa-per to improve the accuracy of intersection node at vector map by utilizing the large amounts of GPS trajectory data, which come from map-matching procedure. With the adaptively corrected digital map, the simulation result gave better map-matching effect, and showed the effectiveness of map-matching compatible with junction adjusting.

Annual Average Daily Traffic (AADT) and Vehicle Miles Traveled (VMT) of traffic network are very important data for the plan and decision making. How to estimate AADT and VMT on local area roads is a long-time existing problem due to lack of traffic monitor counts. This paper presents a novel approach to the community area AADT and VMT estimation by developing circuit network model and simulation to solve this difficult problem for community local traffic network roads. The circuit network model is developed based on the community traffic network, and has three sub-models combined by the least squares method (LSM). These sub-models respectively represent even, local and separate distributions of the entrance traffic flows among households in a community. The method is well validated by sampled measurement data and circuit network simulation results. In addition, it is discovered that the total entrance traffic amount is strongly related to the total number of households in communities. Thus, it makes the new method feasible to estimate the AADT and VMT on community local area roads even without any measurement in future. The proposed method not only can provide accurate estimate, but also can dramatically reduce the labor load and cost of traffic counts.