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1.
J Neural Eng ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578409

RESUMO

OBJECTIVE: Established guidelines for safe levels of electrical stimulation for neural prostheses are based on a limited range of the stimulus parameters used clinically. Recent studies have reported particulate platinum (Pt) associated with long-term clinical use of these devices, highlighting the need for more carefully defined safety limits. We previously reported no adverse effects of Pt corrosion products in the cochleae of guinea pigs following 4 weeks of electrical stimulation using charge densities far greater than the published safe limits for cochlear implants. The present study examines the histopathological effects of Pt within the cochlea following continuous stimulation at a charge density well above the defined safe limits for periods up to 6 months. APPROACH: Six cats were bilaterally implanted with Pt electrode arrays and unilaterally stimulated using charge balanced current pulses at a charge density of 267 C/cm2/phase using a tripolar electrode configuration. Electrochemical measurements were made throughout the implant duration and evoked potentials recorded at the outset and on completion of the stimulation program. Cochleae were examined histologically for particulate Pt, tissue response, and auditory nerve survival; electrodes were examined for surface corrosion; and cochlea, brain, kidney, and liver tissue analysed for trace levels of Pt. MAIN RESULTS: Chronic stimulation resulted in both a significant increase in tissue response and particulate Pt within the tissue capsule surrounding the electrode array compared with implanted, unstimulated control cochleae. Importantly, there was no stimulus-induced loss of auditory neurons or increase in evoked potential thresholds. Stimulated electrodes were significantly more corroded compared with unstimulated electrodes. Trace analysis revealed Pt in both stimulated and control cochleae although significantly greater levels were detected within stimulated cochleae. There was no evidence of Pt in brain or liver; however, trace levels of Pt were recorded in the kidneys of two animals. Finally, increased charge storage capacity and charge injection limit reflected the more extensive electrode corrosion associated with stimulated electrodes. SIGNIFICANCE: Long-term electrical stimulation of Pt electrodes at a charge density well above existing safety limits and nearly an order of magnitude higher than levels used clinically, does not adversely affect the auditory neuron population or reduce neural function, despite a stimulus-induced tissue response and the accumulation of Pt corrosion product. The mechanism resulting in Pt within the unstimulated cochlea is unclear, while the level of Pt observed systemically following stimulation at these very high charge densities does not appear to be of clinical significance.

2.
Glob Chang Biol ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33609326

RESUMO

Increasing temperatures in the U.S. Midwest are projected to reduce maize yields because warmer temperatures hasten reproductive development and, as a result, shorten the grain fill period. However, there is widespread expectation that farmers will mitigate projected yield losses by planting longer season hybrids that lengthen the grain fill period. Here, we ask: a) how current hybrid maturity length relates to thermal availability of the local climate, and b) if farmers are shifting to longer season hybrids in response to a warming climate. To address these questions, we used county-level Pioneer brand hybrid sales (Corteva Agriscience) across 17 years and 650 counties in 10 Midwest states (IA, IL, IN, MI, MN, MO, ND, OH, SD, WI). Northern counties were shown to select hybrid maturities with growing degree day (GDD˚C) requirements more closely related to the environmentally available GDD compared to central and southern counties. This measure, termed "thermal overlap", ranged from complete (106%) in northern counties to a mere 63% in southern counties. The relationship between thermal overlap and latitude was fit using split-line regression and a break point of 42.8° N was identified. Over the 17-year, hybrid maturities shortened across the majority of the Midwest with only a minority of counties lengthening in select northern and southern areas. The annual change in maturity ranged from -5.4 to 4.1 GDD year-1 with a median of -0.9 GDD year-1 . The shortening of hybrid maturity contrasts with widespread expectations of hybrid maturity aligning with magnitude of warming. Factors other than thermal availability appear to more strongly impact farmer decision-making such as the benefit of shorter maturity hybrids on grain drying costs, direct delivery to ethanol biorefineries, field operability, labor constraints, and crop genetics availability. Prediction of hybrid choice under future climate scenarios must include climatic factors, physiological-genetic attributes, socio-economic, and operational constraints.

3.
BMC Med ; 18(1): 370, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33261611

RESUMO

BACKGROUND: Observational studies have shown that milk consumption is inversely associated with colorectal, bladder, and breast cancer risk, but positively associated with prostate cancer. However, whether the associations reflect causality remains debatable. We investigated the potential causal associations of milk consumption with the risk of colorectal, bladder, breast, and prostate cancer using a genetic variant near the LCT gene as proxy for milk consumption. METHODS: We obtained genetic association estimates for cancer from the UK Biobank (n = 367,643 women and men), FinnGen consortium (n = 135,638 women and men), Breast Cancer Association Consortium (n = 228,951 women), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254 men). Milk consumption was proxied by a genetic variant (rs4988235 or rs182549) upstream of the gene encoding lactase, which catalyzes the breakdown of lactose. RESULTS: Genetically proxied milk consumption was associated with a reduced risk of colorectal cancer. The odds ratio (OR) for each additional milk intake increasing allele was 0.95 (95% confidence interval [CI] 0.91-0.99; P = 0.009). There was no overall association of genetically predicted milk consumption with bladder (OR 0.99; 95% CI 0.94-1.05; P = 0.836), breast (OR 1.01; 95% CI 1.00-1.02; P = 0.113), and prostate cancer (OR 1.01; 95% CI 0.99-1.02; P = 0.389), but a positive association with prostate cancer was observed in the FinnGen consortium (OR 1.07; 95% CI 1.01-1.13; P = 0.026). CONCLUSIONS: Our findings strengthen the evidence for a protective role of milk consumption on colorectal cancer risk. There was no or limited evidence that milk consumption affects the risk of bladder, breast, and prostate cancer.

4.
Clin Nutr ; 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33199044

RESUMO

BACKGROUND & AIMS: Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers. METHODS: Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10-971] and rs16966952 in PDXDC1 [P = 2.4 × 10-10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453). RESULTS: Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10-8) for colorectal cancer and 1.07 (95%CI 1.05-1.10; P = 3.5 × 10-7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02-1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary. CONCLUSION: These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.

5.
PLoS One ; 15(10): e0241357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33108366

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a 'real world' cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1-1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0-4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0-1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8-4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD.

7.
Elife ; 92020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33046214

RESUMO

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

8.
Mol Ther Methods Clin Dev ; 19: 47-57, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-32995359

RESUMO

Stable suspension producer cell lines for the production of vesicular stomatitis virus envelope glycoprotein (VSVg)-pseudotyped lentiviral vectors represent an attractive alternative to current widely used production methods based on transient transfection of adherent 293T cells with multiple plasmids. We report here a method to rapidly generate such producer cell lines from 293T cells by stable transfection of a single DNA construct encoding all lentiviral vector components. The resulting suspension cell lines yield titers as high as can be achieved with transient transfection, can be readily scaled up in single-use stirred-tank bioreactors, and are genetically and functionally stable in extended cell culture. By removing the requirement for efficient transient transfection during upstream processing of lentiviral vectors and switching to an inherently scalable suspension cell culture format, we believe that this approach will result in significantly higher batch yields than are possible with current manufacturing processes and enable better patient access to medicines based on lentiviral vectors.

9.
J Neural Eng ; 17(5): 056009, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32916669

RESUMO

OBJECTIVE: Cochleae of long-term cochlear implant users have shown evidence of particulate platinum (Pt) corroded from the surface of Pt electrodes. The pathophysiological effect of Pt within the cochlea has not been extensively investigated. We previously evaluated the effects of Pt corrosion at high charge densities and reported negligible pathophysiological impact. The present study extends this work by examining techniques that may reduce Pt corrosion. APPROACH: Deafened guinea pigs were continuously stimulated for 28 d using biphasic current pulses at extreme charge densities using: (i) electrode shorting; (ii) electrode shorting with capacitive coupling (CC); or (iii) electrode shorting with alternating leading phase (AP). On completion of stimulation, cochleae were examined for corrosion product, tissue response, auditory nerve (AN) survival and trace levels of Pt; and electrodes examined for surface corrosion. MAIN RESULTS: Pt corrosion was evident at ≥200 µC cm-2 phase-1; the amount dependent on charge density (p< 0.01) and charge recovery technique (p < 0.01); reduced corrosion was apparent using CC. Tissue response increased with charge density (p< 0.007); cochleae stimulated at ≥200 µC cm-2 phase-1 exhibited a vigorous response including a focal region of necrosis and macrophages. Notably, tissue response was not dependent on the charge recovery technique (p = 0.56). Despite stimulation at high charge densities resulting in significant levels of Pt corrosion, there was no stimulus induced loss of ANs. SIGNIFICANCE: Significant increases in tissue response and Pt corrosion were observed following stimulation at high charge densities. Charge recovery using CC, and to a lesser extent AP, reduced the amount of Pt corrosion but not the tissue response. Stimulation at change densities an order of magnitude higher than those used when programming cochlear implant recipients in the clinic, produced a vigorous tissue response and corrosion products without evidence of neural loss.

10.
Nat Cancer ; : 1-3, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32838302

RESUMO

The COVID-19 pandemic has disrupted the spectrum of cancer care, including delaying diagnoses and treatment and halting clinical trials. In response, healthcare systems are rapidly reorganizing cancer services to ensure that patients continue to receive essential care while minimizing exposure to SARS-CoV-2 infection.

11.
EBioMedicine ; 59: 102956, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32805626

RESUMO

BACKGROUND: Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer. METHODS: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia. FINDINGS: Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94). INTERPRETATION: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.

12.
Cancer Med ; 9(18): 6836-6842, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32717139

RESUMO

Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we estimated genetic associations with 14 site-specific cancers in European-descent individuals in UK Biobank. Supplementary analyses were conducted for six site-specific cancers using summary-level data from the BioBank Japan Project. Genetically predicted serum IGF-1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF-1 levels was 1.11 (95% confidence interval [CI] 1.01-1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09-1.36; P = 3.9 × 10-4 ) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01-1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97-1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95-1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92-1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02-1.13; P = 4.4 × 10-3 ) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF-1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF-1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF-1 levels with prostate, breast, and other cancers.

13.
PLoS Med ; 17(7): e1003178, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701947

RESUMO

BACKGROUND: Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. METHODS AND FINDINGS: We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. CONCLUSIONS: Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Análise da Randomização Mendeliana/métodos , Neoplasias/etiologia , Fumar/genética , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Reino Unido
14.
Diabetes ; 69(7): 1588-1596, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32349989

RESUMO

We conducted a two-sample Mendelian randomization study to investigate the causal associations of type 2 diabetes mellitus (T2DM) with risk of overall cancer and 22 site-specific cancers. Summary-level data for cancer were extracted from the Breast Cancer Association Consortium and UK Biobank. Genetic predisposition to T2DM was associated with higher odds of pancreatic, kidney, uterine, and cervical cancer and lower odds of esophageal cancer and melanoma but not associated with 16 other site-specific cancers or overall cancer. The odds ratios (ORs) were 1.13 (95% CI 1.04, 1.22), 1.08 (1.00, 1.17), 1.08 (1.01, 1.15), 1.07 (1.01, 1.15), 0.89 (0.81, 0.98), and 0.93 (0.89, 0.97) for pancreatic, kidney, uterine, cervical, and esophageal cancer and melanoma, respectively. The association between T2DM and pancreatic cancer was also observed in a meta-analysis of this and a previous Mendelian randomization study (OR 1.08; 95% CI 1.02, 1.14; P = 0.009). There was limited evidence supporting causal associations between fasting glucose and cancer. Genetically predicted fasting insulin levels were positively associated with cancers of the uterus, kidney, pancreas, and lung. The current study found causal detrimental effects of T2DM on several cancers. We suggest reinforcing the cancer screening in T2DM patients to enable the early detection of cancer.

16.
IEEE Trans Biomed Eng ; 67(12): 3510-3520, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32340929

RESUMO

OBJECTIVE: This study evaluated subthreshold biphasic stimulation pulses as a strategy to stabilize electrode impedance via control of protein adsorption. Following implantation, cochlear electrodes undergo impedance fluctuations thought to be caused by protein adsorption and/or inflammatory responses. Impedance increases can impact device power consumption, safe charge injection limits, and long-term stability of electrodes. METHODS: Protein-mediated changes in polarization impedance (Zp) were measured by voltage transient responses to biphasic current pulses and electrochemical impedance spectroscopy, with and without protein solutions. Four subthreshold stimulation regimes were studied to assess their effects on protein adsorption and impedance; (1) symmetric charge-balanced pulses delivered continuously, (2) at 10% duty cycle, (3) at 1% duty cycle, and (4) an asymmetric charge balanced pulse delivered continuously with a cathodic phase twice as long as the anodic phase. RESULTS: The Zp of electrodes incubated in protein solutions without stimulation for 2 h increased by between ∼28% and ∼55%. Subthreshold stimulation reduced the rate at which impedance increased following exposure to all protein solutions. Decreases in Zp were dependent on the type of protein solution and the stimulation regime. Subthreshold stimulation pulses were more effective when delivered continuously compared to 1% and 10% duty cycles. CONCLUSION: These results support the potential of subthreshold stimulation pulses to mitigate protein-mediated increase in impedance. SIGNIFICANCE: This research highlights the potential of clinically translatable stimulation pulses to mitigate perilymph protein adsorption on cochlear electrodes, a key phenomenon precursor of the inflammatory response.

17.
Data Brief ; 30: 105435, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32274410

RESUMO

The data supplied in this work are related to the research article entitled "Characterization of Bispecific and Mispaired IgGs by Native Charge-Variant Mass Spectrometry" (Phung et al., 2019). This data article describes a powerful analytical platform using native weak cation exchange chromatography coupled to a high-resolution mass spectrometer, charge variant mass spectrometry (CV-MS), to characterize bispecific and mispaired antibody species. Elution order is investigated through analytical methods and molecular modeling in an effort to understand the intrinsic charge, size and shape differences of these molecules.

18.
Int J Cancer ; 147(7): 1895-1903, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32215913

RESUMO

Whether thyroid dysfunction plays a causal role in the development of cancer remains inconclusive. We conducted a two-sample Mendelian randomization study to investigate the associations between genetic predisposition to thyroid dysfunction and 22 site-specific cancers. Single-nucleotide polymorphisms associated with four traits of thyroid function were selected from a genome-wide association meta-analysis with up to 72,167 European-descent individuals. Summary-level data for breast cancer and 21 other cancers were extracted from the Breast Cancer Association Consortium (122,977 breast cancer cases and 105,974 controls) and UK Biobank (367,643 individuals). For breast cancer, a meta-analysis was performed using data from both sources. Genetically predicted thyroid dysfunction was associated with breast cancer, with similar patterns of associations in the Breast Cancer Association Consortium and UK Biobank. The combined odds ratios of breast cancer were 0.94 (0.91-0.98; p = 0.007) per genetically predicted one standard deviation increase in TSH levels, 0.96 (0.91-1.00; p = 0.053) for genetic predisposition to hypothyroidism, 1.04 (1.01-1.07; p = 0.005) for genetic predisposition to hyperthyroidism and 1.07 (1.02-1.12; p = 0.003) per genetically predicted one standard deviation increase in free thyroxine levels. Genetically predicted TSH levels and hypothyroidism were inversely with thyroid cancer; the odds ratios were 0.47 (0.30-0.73; p = 0.001) and 0.70 (0.51-0.98; p = 0.038), respectively. Our study provides evidence of a causal association between thyroid dysfunction and breast cancer (mainly ER-positive tumors) risk. The role of TSH and hypothyroidism for thyroid cancer and the associations between thyroid dysfunction and other cancers need further exploration.

19.
Nutrients ; 12(2)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092884

RESUMO

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10-5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

20.
Clin Cancer Res ; 26(1): 183-192, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31852830

RESUMO

PURPOSE: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer. EXPERIMENTAL DESIGN: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan-Meier method and Cox regression. RESULTS: ctDNA detection rates were: 74% (n = 35/47) pretreatment, 21% (n = 10/47) mid CRT, 21% (n = 10/47) after completing CRT, and 13% (n = 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P = 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4-21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2-11.7; P = 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3-40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of ≥0.07% mid CRT or ≥0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P = 0.001). CONCLUSIONS: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.


Assuntos
Biomarcadores Tumorais/genética , Quimiorradioterapia/métodos , DNA Tumoral Circulante/sangue , Imagem por Ressonância Magnética/métodos , Mutação , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/patologia , Adulto , Idoso , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Medicina de Precisão , Estudos Prospectivos , Neoplasias Retais/sangue , Neoplasias Retais/genética , Neoplasias Retais/terapia , Fatores de Risco , Resultado do Tratamento
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