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1.  The effect of a virtual ward program on emergency services utilization and quality of life in frail elderly patients after discharge: a pilot study 
Attendance at emergency departments and unplanned hospital readmissions are common for frail older patients after discharge from hospitals. A virtual ward service was piloted to deliver “hospital-at-home” services by community nurses and geriatricians to frail older patients immediately after their discharge from hospital to reduce emergency services utilization.
This study examined the impacts of the virtual ward service on changes in the patients’ emergency attendance and medical readmissions, and their quality of life (QOL).
A matched-control quasi-experimental study was conducted at four hospitals, with three providing the virtual ward service (intervention) and one providing the usual community nursing care (control). Subjects in the intervention group were those who are at high risk of readmission and who are supported by home carers recruited from the three hospitals providing the virtual ward service. Matched control patients were those recruited from the hospital providing usual care. Outcome measures include emergency attendance and medical readmission in the past 90 days as identified from medical records, and patient-reported QOL as measured by the modified Quality-of-Life Concerns in the End of Life Questionnaire (Chinese version). Wilcoxon signed-rank tests compared the changes in the outcome variables between groups.
A total of 39 patients in each of the two groups were recruited. The virtual ward group showed a greater significant reduction in the number of unplanned emergency hospital readmissions (−1.41±1.23 versus −0.77±1.31; P=0.049) and a significant improvement in their overall QOL (n=18; 0.60±0.56 versus 0.07±0.56; P=0.02), but there was no significant difference in the number of emergency attendances (−1.51±1.25 versus −1.08±1.48; P=0.29).
The study results support the effectiveness of the virtual ward service in reducing unplanned emergency medical readmissions and in improving the QOL in frail older patients after discharge.
PMCID: PMC4322950
elderly; emergency attendance; emergency medical readmission; emergency services utilization; quality of life; virtual ward
2.  Seroprevalence and risk factors of Chlamydia abortus infection in free-ranging white yaks in China 
Chlamydia is gram-negative obligate bacteria which causes a wide variety of diseases in humans and animals. To date, there are a few reports about the seroprevalence of Chlamydia and the risk factors associated with Chlamydia infection in yaks in the world. In this study, 974 blood samples were collected from white yaks (Bos grunniens) in Tianzhu Tibetan Autonomous County, Gansu province, northwest China from June 2013 to April 2014.
Antibodies against Chlamydia abortus were examined by the indirect hemagglutination (IHA) test, and 158 of 974 (16.22%) white yaks were seropositive for C. abortus antibodies at the cut-off of 1:16. The risk factors associated with seroprevalence were evaluated by a multivariate logistic regression analysis. Region, gender and age of white yak were left out of the final model, due to its insignificance in the logistic regression analysis (P > 0.05). However, season was considered as a major risk factor associated with C. abortus infection in white yaks.
To our knowledge, this is the first survey of C. abortus seroprevalence in white yaks in China, which extends the host range for C. abortus and has important implications for public health and the local Tibetan economy.
PMCID: PMC4308933  PMID: 25601354
Chlamydia abortus; White yaks; Seroprevalence; Tibetans; China
3.  Metformin Is Associated With Survival Benefit in Cancer Patients With Concurrent Type 2 Diabetes: A Systematic Review and Meta-Analysis 
The Oncologist  2013;18(12):1248-1255.
Patients with type 2 diabetes have increased cancer risk and cancer-related mortality, which can be reduced by metformin treatment. However, it is unclear whether metformin can modulate clinical outcomes in patients with cancer and concurrent type 2 diabetes. We found that there was a relative survival benefit associated with metformin treatment compared with treatment with other glucose-lowering medications in both overall survival and cancer-specific survival. This benefit was also observed in subgroups by cancer type and country.
Learning Objectives
Describe the influences of different types of glucose-lowering medications on therapeutic outcomes of cancer patients who received standard anticancer treatment.Compare the survival associated with metformin treatment with survival in treatment with other glucose-lowering medications.
Patients with type 2 diabetes have increased cancer risk and cancer-related mortality, which can be reduced by metformin treatment. However, it is unclear whether metformin can also modulate clinical outcomes in patients with cancer and concurrent type 2 diabetes.
Patients and Methods.
A meta-analysis of 20 publications that included 13,008 subjects was performed to investigate the association between metformin and overall survival (OS) as well as cancer-specific survival (CSS) in patients with cancer and concurrent type 2 diabetes.
We found that there was a relative survival benefit associated with metformin treatment compared with treatment with other glucose-lowering medications in both OS and CSS (hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.55–0.79 and HR = 0.62; 95% CI: 0.46–0.84, respectively). These associations were also observed in subgroups by cancer type and country.
These results suggest that metformin is the drug of choice in the treatment of patients with cancer and concurrent type 2 diabetes.
PMCID: PMC3868417  PMID: 24258613
Metformin; Cancer; Diabetes; Survival; Meta-Analysis
4.  Examination of Physiological Function and Biochemical Disorders in a Rat Model of Prolonged Asphyxia-Induced Cardiac Arrest followed by Cardio Pulmonary Bypass Resuscitation 
PLoS ONE  2014;9(11):e112012.
Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion.
A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition.
After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue.
The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.
PMCID: PMC4226499  PMID: 25383962
5.  Agx@WO3 core-shell nanostructure for LSP enhanced chemical sensors 
Scientific Reports  2014;4:6745.
Exceptional properties of graphene have triggered intensive research on other 2D materials. Surface plasmon is another subject being actively explored for many applications. Herein we report a new class of core-shell nanostructure in which the shell is made of a 2D material for effective plasmonic propagation. We have designed a much enhanced chemical sensor made of plasmonic Agx@(2D-WO3) that combines above advantages. Specifically, the sensor response increases from 38 for Agx-WO3 mixture to 217 for the Agx@(2D-WO3) core-shell structure; response and recovery time are shortened considerably to 2 and 5 seconds; and optimum sensor working temperature is lowered from 370°C to 340°C. Light irradiation is found to increase the Agx@(2D-WO3) sensor response, particularly at blue wavelength where it resonates with the absorption of Ag nanoparticles. Raman scattering shows significantly enhanced intensity for both the 2D-WO3 shell and surface adsorbates. Both the resonance sensor enhancement and the Raman suggest that the improved sensor performance is due to nanoplasmonic mechanism. It is demonstrated that (1) 2D material can be used as the shell component of a core-shell nanostructure, and (2) surface plasmon can effectively boost sensor performance.
PMCID: PMC4206871  PMID: 25339285
6.  Seroprevalence and Risk Factors of Chlamydia abortus Infection in Tibetan Sheep in Gansu Province, Northwest China 
The Scientific World Journal  2014;2014:193464.
Chlamydia abortus, an important pathogen in a variety of animals, is associated with abortion in sheep. In the present study, 1732 blood samples, collected from Tibetan sheep between June 2013 and April 2014, were examined by the indirect hemagglutination (IHA) test, aiming to evaluate the seroprevalence and risk factors of C. abortus infection in Tibetan sheep. 323 of 1732 (18.65%) samples were seropositive for C. abortus antibodies at the cut-off of 1 : 16. A multivariate logistic regression analysis was used to evaluate the risk factors associated with seroprevalence, which could provide foundation to prevent and control C. abortus infection in Tibetan sheep. Gender of Tibetan sheep was left out of the final model because it is not significant in the logistic regression analysis (P > 0.05). Region, season, and age were considered as major risk factors associated with C. abortus infection in Tibetan sheep. Our study revealed a widespread and high prevalence of C. abortus infection in Tibetan sheep in Gansu province, northwest China, with higher exposure risk in different seasons and ages and distinct geographical distribution.
PMCID: PMC4226191  PMID: 25401129
7.  Characterization of the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound, in vitro and in vivo 
Acta Pharmacologica Sinica  2014;35(10):1302-1310.
To investigate the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound in vitro and in vivo.
The anti-proliferative action of S115 was analyzed in 12 human and mouse cancer cell lines using MTT assay. Autograft and xenograft cancer models were made by subcutaneous inoculation of cancer cells into mice or nude mice. The mice were orally treated with S115 (2, 8, 32 mg·kg−1·d−1) for 7 d, and the tumor size was measured every 3 d. Cell apoptosis and cell cycle distribution were examined using flow cytometry, gene expression profile analyses, Western blots and RT-PCR.
The IC50 values of S115 against 12 human and mouse cancer cell lines ranged from 0.3 to 6.6 μmol/L. The tumor growth inhibition rate caused by oral administration of S115 (32 mg·kg−1·d−1) were 89.7%, 81.7%, 78.4% and 77.8%, respectively, in mouse model of B16 melanoma, mouse model of Colon26 colon cancer, nude mouse model of A549 lung cancer and nude mouse model of SK-OV-3 ovarian cancer. Furthermore, oral administration of S115 (7.5 mg·kg−1·d−1) synergistically enhanced the anticancer effects of cyclophosphamide, cisplatin, or 5-fluorouracil in mouse model of S180 sarcoma. Treatment of A549 human lung cancer cells with S115 (1.5 μmol/L) induced G0/G1 cell cycle arrest, and increased apoptosis. Furthermore, S115 downregulated the level of ubiquitin, and upregulated the level of Tob2 in A549 cells.
S115 exerts anticancer effects against a variety of cancer cells in vitro and in grafted cancer models by inducing apoptosis, downregulating ubiquitin and upregulating Tob2.
PMCID: PMC4186988  PMID: 25220642
anticancer drug; thiourea; thiosemicarbazone; melanoma; colon cancer; human lung cancer; ovarian cancer; cell cycle arrest; apoptosis; ubiquitin; Tob2
8.  A Wideband Dual-Antenna Receiver for Wireless Recording From Animals Behaving in Large Arenas 
A low-noise wideband receiver (Rx) is presented for a multichannel wireless implantable neural recording (WINeR) system that utilizes time-division multiplexing of pulse width modulated (PWM) samples. The WINeR-6 Rx consists of four parts: 1) RF front end; 2) signal conditioning; 3) analog output (AO); and 4) field-programmable gate array (FPGA) back end. The RF front end receives RF-modulated neural signals in the 403–490 MHz band with a wide bandwidth of 18 MHz. The frequency-shift keying (FSK) PWM demodulator in the FPGA is a time-to-digital converter with 304 ps resolution, which converts the analog pulse width information to 16-bit digital samples. Automated frequency tracking has been implemented in the Rx to lock onto the free-running voltage-controlled oscillator in the transmitter (Tx). Two antennas and two parallel RF paths are used to increase the wireless coverage area. BCI-2000 graphical user interface has been adopted and modified to acquire, visualize, and record the recovered neural signals in real time. The AO module picks three demultiplexed channels and converts them into analog signals for direct observation on an oscilloscope. One of these signals is further amplified to generate an audio output, offering users the ability to listen to ongoing neural activity. Bench-top testing of the Rx performance with a 32-channel WINeR-6 Tx showed that the input referred noise of the entire system at a Tx–Rx distance of 1.5 m was 4.58 μVrms with 8-bit resolution at 640 kSps. In an in vivo experiment, location-specific receptive fields of hippocampal place cells were mapped during a behavioral experiment in which a rat completed 40 laps in a large circular track. Results were compared against those acquired from the same animal and the same set of electrodes by a commercial hardwired recording system to validate the wirelessly recorded signals.
PMCID: PMC3925346  PMID: 23428612
Behavioral neuroscience; in vivo; neural prosthesis; neural recording; pulse width modulation (PWM); wideband receiver
9.  Cell-based assays for Parkinson's disease using differentiated human LUHMES cells 
Acta Pharmacologica Sinica  2014;35(7):945-956.
Lund human mesencephalic (LUHMES) cells can be differentiated to post-mitotic cells with biochemical, morphological and functional features of dopaminergic (DAergic) neurons. Given the limited scale of primary DAergic neuron culture, we developed differentiated LUHMES cell-based cytotoxicity assays for identifying neuroprotective agents for Parkinson's disease (PD).
LUHMES cells were incubated in a differentiation medium containing cAMP and GDNF for 6 d, and then differentiated cells were treated with MPP+ or infected with baculovirus containing α-synuclein. Cytotoxicity was determined by measuring intracellular ATP levels and caspase 3/7 activity in the cells. DAergic neuron-specific marker protein and mRNA levels in the cells were analyzed using Western blotting and RT-PCR, respectively.
LUHMES cells grew extensive neurites and became post-mitotic neuron-like cells during differentiation period, and three DAergic neuron markers TH, DAT and Nurr1 exhibited different expression profiles. MPP+ dose-dependently reduced ATP levels in the cells with an IC50 value of 65 μmol/L. MPP+ (80 μmol/L) significantly increased caspase 3/7 activity in the cells. Both the CDK inhibitor GW8510 and the GSK3β inhibitor SB216763 effectively rescued MPP+-induced reduction of ATP levels with EC50 values of 12 and 205 nmol/L, respectively. Overexpression of α-synuclein also significantly decreased intracellular ATP levels and increased caspase 3/7 activity in the cells. GW8510 and SB216763 effectively rescued α-synuclein overexpression-induced reduction of ATP levels, whereas GW8510, but not SB216763, ameliorated α-synuclein overexpression-induced increase of caspase 3/7 activity.
MPP+- and α-synuclein overexpression-induced cytotoxicity of differentiated LUHMES cells may serve as good alternative systems for identifying neuroprotective compounds for PD.
PMCID: PMC4088286  PMID: 24989254
LUHMES cell; dopaminergic neuron; cytotoxicity; MPP+; α-synuclein; GW8510; SB216763; cell-based assay; Parkinson's disease
10.  First report of Cryptosporidium spp. in white yaks in China 
Parasites & Vectors  2014;7:230.
Cryptosporidium is an enteric apicomplexan parasite, which can infect yaks, leading to reduction of milk production and poor weight gain. White yak (Bos grunniens) is a unique yak breed inhabiting only in Tianzhu Tibetan Autonomous County, Gansu province, northwestern China. The objective of the present study was to molecularly determine Cryptosporidium infection and species in white yaks.
Seventy-six fecal samples from white yaks in Tianzhu Tibetan Autonomous County, Gansu province were collected. The small subunit ribosomal RNA (SSU rRNA) gene of each sample was amplified using nested PCR and sequenced. The Cryptosporidium species was determined by comparison of the obtained sequences with that of corresponding Cryptosporidium sequences available in GenBank by BLAST ( and phylogenetic analysis with maximum likelihood (ML) using PAUP*. The overall prevalence of Cryptosporidium infection in white yak was 5.26% (4/76). Species identification showed C. andersoni in one sample (collected in September), and C. bovis in three samples (one collected in November and two collected in September).
The present investigation revealed the existence of Cryptosporidium infection in white yaks in China, for the first time, and two Cryptosporidium species, namely C. andersoni and C. bovis, were identified. These findings extend the host range for Cryptosporidium spp., and also provide base-line information for further studies of molecular epidemiology and control of Cryptosporidium infection in the unique white yaks.
PMCID: PMC4033679  PMID: 24885747
Cryptosporidium spp; Genetic characterization; Prevalence; White Yak; China
12.  An Implantable Wireless Neural Interface for Recording Cortical Circuit Dynamics in Moving Primates 
Journal of neural engineering  2013;10(2):026010.
Neural interface technology suitable for clinical translation has the potential to significantly impact the lives of amputees, spinal cord injury victims, and those living with severe neuromotor disease. Such systems must be chronically safe, durable, and effective.
We have designed and implemented a neural interface microsystem, housed in a compact, subcutaneous, and hermetically sealed titanium enclosure. The implanted device interfaces the brain with a 510k-approved, 100-element silicon-based MEA via a custom hermetic feedthrough design. Full spectrum neural signals were amplified (0.1Hz to 7.8kHz, ×200 gain) and multiplexed by a custom application specific integrated circuit, digitized, and then packaged for transmission. The neural data (24 Mbps) was transmitted by a wireless data link carried on an frequency shift key modulated signal at 3.2GHz and 3.8GHz to a receiver 1 meter away by design as a point-to-point communication link for human clinical use. The system was powered by an embedded medical grade rechargeable Li-ion battery for 7-hour continuous operation between recharge via an inductive transcutaneous wireless power link at 2MHz.
Main results
Device verification and early validation was performed in both swine and non-human primate freely-moving animal models and showed that the wireless implant was electrically stable, effective in capturing and delivering broadband neural data, and safe for over one year of testing. In addition, we have used the multichannel data from these mobile animal models to demonstrate the ability to decode neural population dynamics associated with motor activity.
We have developed an implanted wireless broadband neural recording device evaluated in non-human primate and swine. The use of this new implantable neural interface technology can provide insight on how to advance human neuroprostheses beyond the present early clinical trials. Further, such tools enable mobile patient use, have the potential for wider diagnosis of neurological conditions, and will advance brain research.
PMCID: PMC3638022  PMID: 23428937
13.  A 32-channel fully implantable wireless neurosensor for simultaneous recording from two cortical regions 
We present a fully implantable, wireless, neurosensor for multiple-location neural interface applications. The device integrates two independent 16-channel intracortical microelectrode arrays and can simultaneously acquire 32 channels of broadband neural data from two separate cortical areas. The system-on-chip implantable sensor is built on a flexible Kapton polymer substrate and incorporates three very low power subunits: two cortical subunits connected to a common subcutaneous subunit. Each cortical subunit has an ultra-low power 16-channel preamplifier and multiplexer integrated onto a cortical microelectrode array. The subcutaneous epicranial unit has an inductively coupled power supply, two analog-to-digital converters, a low power digital controller chip, and microlaser-based infrared telemetry. The entire system is soft encapsulated with biocompatible flexible materials for in vivo applications. Broadband neural data is conditioned, amplified, and analog multiplexed by each of the cortical subunits and passed to the subcutaneous component, where it is digitized and combined with synchronization data and wirelessly transmitted transcutaneously using high speed infrared telemetry.
PMCID: PMC3925433  PMID: 22254801
14.  Isolated Hemolytic Anemia: An Unusual Manifestation of Occult Malignancy 
Hematology Reports  2014;6(1):5159.
Hemolysis is an uncommon and usually late complication of malignancy, and very rarely the presenting feature. Cancer-associated hemolysis may be immune-mediated, or may result from thrombotic microangiopathy accompanied by thrombocytopenia. We describe an unusual case of isolated hemolysis in the setting of occult metastatic breast cancer. The patient initially presented with symptomatic anemia, with evidence of hemolysis but with negative direct antiglobulin testing and a normal platelet count. Subsequent investigation discovered metastatic adenocarcinoma of the breast involving bone marrow. Hemolysis worsened despite initial treatment with cytotoxic chemotherapy and a trial of corticosteroids, but later resolved with aromatase inhibitor therapy.
PMCID: PMC3977155  PMID: 24711918
hemolysis; hemolytic anemia; malignancy; cancer
15.  Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system 
Scientific Reports  2014;4:3943.
Here, we report a convenient and efficient miRNA inhibition strategy employing the CRISPR system. Using specifically designed gRNAs, miRNA gene has been cut at a single site by Cas9, resulting in knockdown of the miRNA in murine cells. Using a modified CRISPR interference system (CRISPRi), inactive Cas9 can reversibly prevent the expression of both monocistronic miRNAs and polycistronic miRNA clusters. Furthermore, CRISPR/CRISPRi is also capable of suppressing genes in porcine cells.
PMCID: PMC3909901  PMID: 24487629
16.  Polymeric Packaging for Fully Implantable Wireless Neural Microsensors 
We present polymeric packaging methods used for subcutaneous, fully implantable, broadband, and wireless neurosensors. A new tool for accelerated testing and characterization of biocompatible polymeric packaging materials and processes is described along with specialized test units to simulate our fully implantable neurosensor components, materials and fabrication processes. A brief description of the implantable systems is presented along with their current encapsulation methods based on polydimethylsiloxane (PDMS). Results from in-vivo testing of multiple implanted neurosensors in swine and non-human primates are presented. Finally, a novel augmenting polymer thin film material to complement the currently employed PDMS is introduced. This thin layer coating material is based on the Plasma Enhanced Chemical Vapor Deposition (PECVD) process of Hexamethyldisiloxane (HMDSO) and Oxygen (O2).
PMCID: PMC3904293  PMID: 23365999
17.  A 100-Channel Hermetically Sealed Implantable Device for Chronic Wireless Neurosensing Applications 
A 100-channel fully implantable wireless broadband neural recording system was developed. It features 100 parallel broadband (0.1 Hz–7.8 kHz) neural recording channels, a medical grade 200 mAh Li-ion battery recharged inductively at 150 kHz, and data telemetry using 3.2 GHz to 3.8 GHz FSK modulated wireless link for 48 Mbps Manchester encoded data. All active electronics are hermetically sealed in a titanium enclosure with a sapphire window for electromagnetic transparency. A custom, high-density configuration of 100 individual hermetic feedthrough pins enable connection to an intracortical neural recording microelectrode array. A 100 MHz bandwidth custom receiver was built to remotely receive the FSK signal and achieved −77.7 dBm sensitivity with 10−8 BER at 48 Mbps data rate. ESD testing on all the electronic inputs and outputs has proven that the implantable device satisfies the HBM Class-1B ESD Standard. In addition, the evaluation of the worst-case charge density delivered to the tissue from each I/O pin verifies the patient safety of the device in the event of failure. Finally, the functionality and reliability of the complete device has been tested on-bench and further validated chronically in ongoing freely moving swine and monkey animal trials for more than one year to date.
PMCID: PMC3904295  PMID: 23853294
Hermetical seal; implantable device; inductive power; neural recording; wireless transmission
18.  Developing Implantable Neuroprosthetics: a New Model in Pig 
A new model has been established in the domestic pig for neural prosthetic device development and testing. To this end, we report on a complete neural prosthetic developmental system using a wireless sensor as the implant, a pig as the animal model, and a novel data acquisition paradigm for actuator control. A new type of stereotactic frame with clinically-inspired fixations pins that place the pig brain in standard surgical plane was developed and tested with success during the implantation of the microsystem. The microsystem implanted was an ultralow power (12.5mW) 16-channel intracortical/epicranial device transmitting broadband (40kS/s) data over a wireless infrared telemetric link. Pigs were implanted and neural data was collected over a period of 5 weeks, clearly showing single unit spiking activity.
PMCID: PMC3902772  PMID: 22254977
To determine whether single nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor beta, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC).
Methods and Materials
Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFβ, TNFα, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiotherapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (Grade ≥3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate (MV) analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data.
Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFβ, VEGF, TNFα, XRCC1 and APEX1. With smoking status included in the MV model, the SNPs significantly associated with increased risk of RP were in genes for TGFβ, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often.
This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk versus <10% risk of RP when exposed to high MLDs.
PMCID: PMC3521878  PMID: 22541966
SNP; NTCP; biomarker; non-small cell lung cancer
20.  Polymorphisms of Nucleotide Excision Repair Genes Predict Melanoma Survival 
Melanoma is the most highly malignant skin cancer, and nucleotide excision repair (NER) is involved in melanoma susceptibility. In this analysis of 1042 melanoma patients, we evaluated whether genetic variants of NER genes may predict survival outcome of melanoma patients. We used genotyping data of 74 tagging single nucleotide polymorphisms (tagSNPs) in eight core NER genes from our genome-wide association study (including 2 in XPA, 14 in XPC, 3 in XPE, 4 in ERCC1, 10 in ERCC2, 8 in ERCC3, 14 in ERCC4, and 19 in ERCC5) and evaluated their associations with prognosis of melanoma patients. Using the Cox proportional hazards model and Kaplan-Meier analysis, we found a predictive role of XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871 SNPs in prognosis of melanoma patients (rs28720291: AG vs. GG, adjusted hazard ratio [adjHR] = 11.2, 95% confidence interval [CI] 3.04–40.9, P = 0.0003; rs4150314: AG vs. GG, adjHR = 4.76, 95% CI 1.09–20.8, P = 0.038; rs2470458: AA vs. AG/GG, adjHR = 2.11, 95% CI 1.03–4.33, P = 0.040; and rs50871: AA vs. AC/CC adjHR =2.27, 95% CI 1.18–4.35, P = 0.015). Patients with an increasing number of unfavorable genotypes had dramatically increased death risk. Genetic variants of NER genes, particularly XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871, may independently or jointly modulate survival outcome of melanoma patients. Because our results were based on a median follow-up of 3 years without multiple test corrections, additional large prospective studies are needed to confirm our findings.
PMCID: PMC3660504  PMID: 23407396
melanoma; nucleotide excision repair; survival; association
21.  Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer 
The Oncologist  2012;17(12):1551-1561.
Thirteen tag SNPs at the CASP8 and CASP10 loci in patients with advanced NSCLC were genotyped in a two-stage analysis consisting of a discovery set and an independent validation set. These SNPs were evaluated for their association with toxicity outcomes with platinum-based chemotherapy.
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens.
PMCID: PMC3528388  PMID: 22843554
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
22.  Correction: Quantitating the Specificity and Selectivity of Gcn5-Mediated Acetylation of Histone H3 
PLoS ONE  2013;8(10):10.1371/annotation/b2bf9c2e-90a9-4228-9b38-2f1bc977a437.
PMCID: PMC3806868  PMID: 24194813
23.  Differences in Specificity and Selectivity Between CBP and p300 Acetylation of Histone H3 and H3/H4 
Biochemistry  2013;52(34):5746-5759.
Although p300 and CBP lysine acetyltransferases are often treated interchangeably, the inability of one enzyme to compensate for the loss of the other suggests unique roles for each. As these deficiencies coincide with aberrant levels of histone acetylation, we hypothesized that the key difference between p300 and CBP activity is differences in their specificity/selectivity for lysines within the histones. Utilizing a label-free, quantitative mass spectrometry based technique, we determined the kinetic parameters of both CBP and p300 at each lysine of H3 and H4, under conditions we would expect to encounter in the cell (either limiting acetyl-CoA or histone). Our results show that while p300 and CBP acetylate many common residues on H3 and H4, they do in fact possess very different specificities, and these specificities are dependent on whether histone or acetyl-CoA is limiting. Steady-state experiments with limiting H3 demonstrate that both CBP and p300 acetylate H3K14, H3K18, H3K23, with p300 having specificities up to 1010-fold higher than CBP. Utilizing tetramer as a substrate, both enzymes also acetylate H4K5, H4K8, H4K12, and H4K16. With limiting tetramer, CBP displays higher specificities, especially at H3K18, where CBP specificity is 1032-fold higher than p300. With limiting acetyl-CoA, p300 has the highest specificity at H4K16, where specificity is 1018-fold higher than CBP. This discovery of unique specificity for targets of CBP- vs p300-mediated acetylation of histone lysine residues presents a new model for understanding their respective biological roles and possibly an opportunity for selective therapeutic intervention.
PMCID: PMC3756530  PMID: 23862699
24.  Polymorphisms of the VEGF Gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy 
Cancer Science  2012;103(5):945-950.
Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and lung cancer progression. We hypothesized that VEGF polymorphisms may modulate the risk of radiation pneumonitis (RP) in non-small cell lung cancer (NSCLC) patients treated with definitive radiotherapy. We genotyped three potentially functional VEGF SNPs [−460 T>C (rs833061), −634 G>C (rs2010963), and +936 C >T (rs3025039)] and estimated the associations of their genotypes and haplotypes with severe radiation pneumonitis (RP ≥ grade 3) in 195 NSCLC patients. We found that the VEGF genotypes of rs2010963 and rs3025039 SNPs as well as the −460C/−634G/+936C haplotype were predictors of RP development (adjusted hazard ratio [adjHR] = 2.33, 95% confidence interval [CI], 1.01–5.37, P = 0.047 for CC vs. GG genotypes; adjHR = 28.13, 95% CI, 5.24–151.02, P < 0.001 for TT vs. CC genotypes; and adjHR = 2.51, 95% CI, 1.27–4.98, P = 0.008 for T-C-T vs. C-G-C halotypes). In addition, there was a trend towards reduced RP risk in patients carrying an increased number of protective VEGF genotypes. Our data suggest that VEGF polymorphisms can modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radiotherapy. Large and independent studies are needed to confirm our findings.
PMCID: PMC3337362  PMID: 22320189
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
25.  Using Pulse Width Modulation for Wireless Transmission of Neural Signals in Multichannel Neural Recording Systems 
We have used a well-known technique in wireless communication, pulse width modulation (PWM) of time division multiplexed (TDM) signals, within the architecture of a novel wireless integrated neural recording (WINeR) system. We have evaluated the performance of the PWM-based architecture and indicated its accuracy and potential sources of error through detailed theoretical analysis, simulations, and measurements on a setup consisting of a 15-channel WINeR prototype as the transmitter and two types of receivers; an Agilent 89600 vector signal analyzer and a custom wideband receiver, with 36 and 75 MHz of maximum bandwidth, respectively. Furthermore, we present simulation results from a realistic MATLAB-Simulink model of the entire WINeR system to observe the system behavior in response to changes in various parameters. We have concluded that the 15-ch WINeR prototype, which is fabricated in a 0.5-μm standard CMOS process and consumes 4.5 mW from ±1.5 V supplies, can acquire and wirelessly transmit up to 320 k-samples/s to a 75-MHz receiver with 8.4 bits of resolution, which is equivalent to a wireless data rate of ~ 2.26 Mb/s.
PMCID: PMC3579626  PMID: 19497823
Frequency shift keying; implantable microelectronic devices; neural interfacing; pulse width modulation; telemetry; time division multiplexing

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