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.
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.
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.
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.
hemolysis; hemolytic anemia; malignancy; cancer
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.
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).
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.
Hermetical seal; implantable device; inductive power; neural recording; wireless transmission
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.
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.
SNP; NTCP; biomarker; non-small cell lung cancer
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.
melanoma; nucleotide excision repair; survival; association
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.
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
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.
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
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.
Frequency shift keying; implantable microelectronic devices; neural interfacing; pulse width modulation; telemetry; time division multiplexing
Lysine acetyltransferases (KATs) play a unique role in regulating gene transcription as well as maintaining the epigenetic state of the cell. KATs such as Gcn5 and p300/CBP can modify multiple residues on a single histone; however, order and specificity of acetylation can be altered by factors such as histone chaperones, subunit proteins or external stimulus. While the importance of acetylation is well documented, it has been difficult to quantitatively measure the specificity and selectivity of acetylation at different residues within a histone. In this paper, we demonstrate a label-free quantitative high throughput mass spectrometry-based assay capable of quantitatively monitoring all known acetylation sites of H3 simultaneously. Using this assay, we are able to analyze the steady-state enzyme kinetics of Gcn5, an evolutionarily conserved KAT. In doing so, we measured Gcn5-mediated acetylation at six residues (K14>K9 ≈ K23> K18> K27 ≈ K36) and the catalytic efficiency (kcat/Km) for K9, K14, K18, and K23 as well as the nonenzymatic acetylation rate. We observed selectivity differences of up to −4 kcal/mol between K14 and K18, the highest and lowest measurable kcat/Km. These data provide a first look at quantitating the specificity and selectivity of multiple lysines on a single substrate (H3) by Gcn5.
We present a 32-channel wireless implantable neural recording system-on-a-chip (SoC) that operates based on time division multiplexing (TDM) of pulse width modulated (PWM) samples with minimal substrate noise and interference. We have utilized analog-to-time conversion (ATC) on the transmitter and time-to-digital conversion (TDC) on the receiver to reduce the size and power consumption of the implantable unit by moving the digitization circuitry to the external unit. We have managed the TDM switching times such that no switching occurs during sensitive sampling onsets. The chip has been implemented in the AMI 0.5-μm standard CMOS process, occupying 3.3 × 3.0 mm2 and consuming 5.6 mW at ±1.5 V when all channels are active. The measured input referred noise for the entire system, including the receiver at 1 m distance, is only 4.9 μVrms from 1 Hz~10 kHz. Finally, in vivo testing results on rats have been presented to validate the full functionality of the system.
This experiment aimed to investigate the effects of the chitosan (CTS) and water-soluble chitosan (WSC) microspheres on plasma lipids in male Sprague-Dawley rats fed with high-fat diets. CTS microspheres and WSC microspheres were prepared by the spray-drying technique. Scanning electron microscopy (SEM) micrographs showed that the microspheres were nearly spherical in shape. The mean size of CTS microspheres was 4.07 μm (varying from 1.50 to 7.21 μm) and of WSC microspheres was 2.00 μm (varying from 0.85 to 3.58 μm). The rats were classified into eight groups (n = 8) and were fed with high-fat diets for two weeks to establish the hyperlipidemic condition and were then treated with CTS microspheres and WSC microspheres, CTS and WSC for four weeks. The results showed that CTS and WSC microspheres reduced blood lipids and plasma viscosity and increased the serum superoxide dismutase (SOD) levels significantly. This study is the first report of the lipid-lowering effects of CTS and WSC microspheres. CTS and WSC microspheres were found to be more effective in improving hyperlipidemia in rats than common CTS and WSC.
chitosan; water-soluble chitosan; microsphere; lower lipids; hyperlipidemia
Non-homologous end joining (NHEJ) is a pathway that repairs DNA double-strand breaks (DSBs) to maintain genomic stability in response to irradiation. We hypothesized that single nucleotide polymorphisms (SNPs) in NHEJ repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy.
We genotyped five potentially functional SNPs (i.e., XRCC4 rs6869366 [-1394G>T] and rs28360071 [intron 3, del/ins], XRCC5 rs3835 [2408G>A], XRCC6 rs2267437 [-1310C>G] and LIG4 rs1805388 [T9I]) and estimated their associations with severe radiation pneumonitis (RP, ≥ grade 3) in 195 NSCLC patients.
We found a predictive role of LIG4 rs1805388 SNP in RP development (adjusted hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.04-4.12, P = 0.037 for CT/TT vs. CC). In addition, male patients with the TT genotype of XRCC4 rs6869366 SNP and female patients with AG/AA genotypes of XRCC5 rs3835 SNP were also at increased risk of severe RP development.
Our results suggest that NHEJ genetic polymorphisms, particularly LIG4 rs1805388, may modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings.
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
Poly(ADP-ribose) polymerase-1 (PARP-1 catalyzes poly(ADP-ribosyl)ation to various proteins involved in many cellular processes, including DNA damage detection and repair, and cell proliferation and death. PARP-1 has been implicated in human carcinogenesis, but the association between the most-studied PARP-1 V762A polymorphism (rs1136410) and risk of various cancers was reported with inconclusive results.
To assess the association between the PARP-1 V762A polymorphism and cancer risk.
A meta-analysis of 21 studies with 12027 cancer patients and 14106 cancer-free controls was conducted to evaluate the strength of the association using odds ratio (OR) with 95% confidence interval (CI).
Overall, no significant association was found between the PARP-1 V762A polymorphism and cancer risk. In the stratified analyses, however, it was found that the variant A allele of the PARP-1 V762A polymorphism was associated with an increased risk of cancer among Asian populations (VA+AA vs.VV: OR = 1.11, 95% CI: 1.01-1.23; Pheterogeneity = 0.210) but a decreased risk of cancer (VA+AA vs.VV: OR =0.89, 95% CI: 0.80-1.00; Pheterogeneity = 0.004), among Caucasian populations, especially for glioma risk (OR = 0.79, 95% CI: 0.69-0.90; Pheterogeneity = 0.800).
This meta-analysis found evidence for an association of the PARP-1 V 762A polymorphism with increased risk of cancer among Asians but decreased risk of cancer among Caucasians, particularly of glioma. Further well designed studies with large sample sizes of different ethnic populations and different cancer types are warranted to confirm these findings.
DNA repair; Case-control study; Meta-analysis; Polymorphism; Susceptibility
Embryonic hematopoiesis is a complex process. Elucidating the mechanism regulating hematopoietic differentiation from pluripotent stem cells would allow us to establish a strategy to efficiently generate hematopoietic cells. However, the mechanism governing the generation of hematopoietic progenitors from human embryonic stem cells (hESCs) remains unknown. Here, on the basis of the emergence of CD43+ hematopoietic cells from hemogenic endothelial (HE) cells, we demonstrated that VEGF was essential and sufficient, and that bFGF was synergistic with VEGF to specify the HE cells and the subsequent transition into CD43+ hematopoietic cells. Significantly, we identified TGFβ as a novel signal to regulate hematopoietic development, as the TGFβ inhibitor SB 431542 significantly promoted the transition from HE cells into CD43+ hematopoietic progenitor cells (HPCs) during hESC differentiation. By defining these critical signaling factors during hematopoietic differentiation, we can efficiently generate HPCs from hESCs. Our strategy could offer an in vitro model to study early human hematopoietic development.
embryonic stem cells; hematopoietic progenitors; SB431542
A fiber-optic pH sensor based on a tilted fiber Bragg grating (TFBG) with electrostatic self-assembly multilayer sensing film is presented. The pH sensitive polymeric film, poly(diallyldimethylammonium chloride) (PDDA) and poly(acrylic acid) (PAA) was deposited on the circumference of the TFBG with the layer-by-layer (LbL) electrostatic self-assembly technique. The PDDA/PAA film exhibits a reduction in refractive index by swelling in different pH solutions. This effect results in wavelength shifts and transmission changes in the spectrum of the TFBG. The peak amplitude of the dominant spectral fringes over a certain window of the transmission spectrum, obtained by FFT analysis, has a near-linear pH sensitivity of 117 arbitrary unit (a.u.)/pH unit and an accuracy of ±1 a.u. (in the range of pH 4.66 to pH 6.02). The thickness and surface morphology of the sensing multilayer film were characterized to investigate their effects on the sensor's performance. The dynamic response of the sensor also has been studied (10 s rise time and 18 s fall time for a sensor with six bilayers of PDDA/PAA).
fiber-optic sensor; layer-by-layer self-assembly; multilayer film; pH sensor; tilted fiber Bragg grating
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.
We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.
We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39–1.00 and 0.59; 95% CI, 0.36–0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (Pint = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02–3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus–dosage manner (adjusted Ptrend = 0.003).
These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.
PI3K/PTEN/AKT/mTOR and RAS/RAF/MEK/ERK pathways; Polymorphisms; Endometrial cancer risk; Survival; Recurrence
Some common genetic variants of TERT-CLPTM1L gene, which encode key protein subunits of telomerase, have been suggested to play a crucial role in tumorigenesis. The TERT-CLPTM1L polymorphism rs401681 was of special interest for cancers risk but with inconclusive results.
We performed a comprehensive meta-analysis of 29 publications with a total of 91263 cases and 735952 controls. We assessed the strength of the association between rs401681 and overall cancers risk and performed subgroup analyses by cancer type, ethnicity, source of control, sample size and expected power. Rs401681 C allele was found to be associated with marginally increased cancers risk, with per allele OR of 1.04 (95%CI = 1.00–1.08, Pheterogeneity<0.001) and an expected power of 1.000. Following further stratified analyses, the increased cancers risk were discovered in subgroups of lung, bladder, prostate, basal cell carcinomas and Asians, while a declined risk of pancreatic cancer and melanoma were detected.
These findings suggested that rs401681 C allele was a low-penetrance risk allele for the development of cancers of lung, bladder, prostate and basal cell carcinoma, but a potential protective allele for melanoma and pancreatic cancer.
To explore if functional single nucleotide polymorphisms (SNPs) of base-excision repair genes are predictors of radiation treatment-related pneumonitis (RP), we investigated associations between functional SNPs of ADPRT, APEX1, and XRCC1 and RP development.
Methods and Materials
We genotyped SNPs of ADPRT (rs1136410 [V762A]), XRCC1 (rs1799782 [R194W], rs25489 [R280H], and rs25487 [Q399R]), and APEX1 (rs1130409 [D148E]) in 165 patients with non-small cell lung cancer (NSCLC) who received definitive chemo-radiation therapy. Results were assessed by both Logistic and Cox regression models for RP risk. Kaplan-Meier curves were generated for the cumulative RP probability by the genotypes.
We found that SNPs of XRCC1 Q399R and APEX1 D148E each had a significant effect on the development of grade ≥2 RP (XRCC1: AA vs. GG, adjusted hazard ratio [HR] = 0.48, 95% confidence interval [CI] 0.24–0.97; APEX1: GG vs. TT, adjusted HR = 3.61, 95% CI 1.64–7.93) in an allele-dose response manner (Trend tests: P = 0.040 and 0.001, respectively). The number of the combined protective XRCC1 A or APEX1 T alleles (from 0 to 4) also showed a significant trend of predicting RP risk (P = 0.001).
SNPs of the base-excision repair genes may be biomarkers for susceptibility to RP. Larger prospective studies are needed to validate our findings.
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy.
Patients and Methods
All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy.
We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma.
We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy.
Excision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.
In this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50–0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58–1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40–0.92 for rs2276466; OR = 0.69, 95% CI: 0.48–0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.
These results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.