Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
We performed an ...analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval CI:=1.70–2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36–2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50–2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01–3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78–7.17, p=0.13).
Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
This large Mendelian randomization study utilizes a risk score of telomere length associated genetic variants to demonstrate a strong association between longer predicted leukocyte telomere length and increased risk of developing common subtypes of renal cell carcinoma.
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► The resistance of E. connexa to lambda-cyhalothrin is autosomally inherited and incompletely dominant. ► It is estimated 54.5 generations of successive selections to increase the ...initial LD50 10-fold. ► The resistance in E. connexa varies from functionally dominant to functionally recessive depending on the dose used.
Lambda-cyhalothrin is a pyrethroid insecticide widely used to control pests in various crop ecosystems, in which the lady beetle occurs naturally. Therefore, lady beetle populations are exposed to lambda-cyhalothrin sprays that may foster tolerance to this insecticide. This study was conducted to confirm the occurrence of resistance in the lady beetle Eriopis connexa (Germar) (Coleoptera: Coccinellidae) to lambda-cyhalothrin and to characterize the inheritance of resistance after eight progressive selection with insecticide dosages based on the LD50 determined for the F1 generation. Dose–mortality curves were determined for parental populations, F1 hybrids and backcross progenies. Parameters regarding the heritability of resistance to lambda-cyhalothrin in E. connexa allow estimating 10-fold increase in the initial LD50 after 54.5 generations of successive selections. The resistance of E. connexa to lambda-cyhalothrin was characterized as autosomally inherited and incompletely dominant, and influenced by a major gene with possible influence of secondary genes. Additionally, the resistance in E. connexa varies from functionally dominant to functionally recessive depending on the dose used. These findings indicate that insecticide resistance in E. connexa can be selected in the field as determined for field-collected individuals, and subsequently enhanced under laboratory conditions. Its characterization presented here is an important step toward linking biological and chemical control within pest management regarding the lady beetle and lambda-cyhalothrin targeting different pest groups.
Historical ecology draws on a broad range of information sources and methods to provide insight into ecological and social change, especially over the past ∼12000 yr. While its results are often ...relevant to conservation and restoration, insights from its diverse disciplines, environments, and geographies have frequently remained siloed or underrepresented, restricting their full potential. Here, scholars and practitioners working in marine, freshwater, and terrestrial environments on 6 continents and various archipelagoes synthesize knowledge from the fields of history, anthropology, paleontology, and ecology with the goal of describing global research priorities for historical ecology to influence conservation. We used a structured decision-making process to identify and address questions in 4 key priority areas: (1) methods and concepts, (2) knowledge co-production and community engagement, (3) policy and management, and (4) climate change impacts. This work highlights the ways that historical ecology has developed and matured in its use of novel information sources, efforts to move beyond extractive research practices and toward knowledge co-production, and application to management challenges including climate change. We demonstrate the ways that this field has brought together researchers across disciplines, connected academics to practitioners, and engaged communities to create and apply knowledge of the past to address the challenges of our shared future.
Abstract
Background: Effective treatment options for triple-negative inflammatory breast cancer (TN-IBC), the most aggressive form of breast cancer, are currently lacking. We previously reported that ...mediators of inflammation promote the growth of TN-IBC xenografts. Eicosapentaenoic acid (EPA), an omega-3 fatty acid (fish oil) with anti-inflammatory properties, is an emerging FDA-approved therapeutic with a favorable toxicology profile. Here we aimed to develop a novel approach to enhance EPA efficacy against TN-IBC by identifying a kinase inhibitor that synergizes with EPA's antitumor activity.
Methods and Results: Using a high-throughput siRNA screen in the TN-IBC cell line SUM149PT, we identified inhibition of ephrin type-A receptor 2 (EPHA2), an oncogenic receptor tyrosine kinase, as a target that sensitizes TN-IBC cells to EPA therapy. To determine the clinical relevance of EPHA2, we investigated a meta-analysis of breast cancer mRNA expression data sets and found that high EPHA2 tumor expression, compared with low expressing, correlated significantly with poor overall survival in TN-IBC patients (P = 0.01), while not with other subtypes. Similar findings were observed in vitro, were EPHA2 protein and mRNA overexpression occurred predominantly in the TN subtypes among 49 and 51 breast cancer cell lines (63% and 47%, respectively), highlighting EPHA2 translational potential. Functional expression studies using proliferation and apoptosis assays in vitro, and xenografts in vivo, were performed in two EPHA2-expressing TN-IBC cell lines, SUM149PT and BCX010, to validate EPHA2 as a synergistic combinational target with EPA. EPHA2 gene silencing in combination with EPA significantly reduced cell growth, and enhanced apoptosis, compared with untreated and monotherapy in vitro (P < 0.05), and in vivo (P < 0.001). To translate our findings to the clinic, we validated dasatinib, an FDA-approved small molecule inhibitor of EPHA2, in combination to EPA to significantly enhance apoptosis of TN-IBC cells in vitro (P < 0.05) and in vivo (P < 0.05), compared with untreated and monotherapies. Using membrane fluidity assessment and cholesterol quantification we determined that apoptosis induction after combination therapy was due to increased membrane rigidity and cholesterol concentrations in the plasma membrane of TN-IBC cells (P < 0.05, compared with monotherapies). Finally, we discovered by western blot and gain/loss-of-expression studies that combination therapy inhibited the cholesterol efflux protein ATP-binding cassette sub-family A member 1 (ABCA1), which plays a significant role mediating increased cellular cholesterol (P < 0.05), cell membrane rigidity (P < 0.05), and induction of apoptosis (P < 0.05) in TN-IBC after EPA and EPHA2-targeting combination therapy.
Conclusions: This is the first study demonstrating that EPA can enhance conventional targeted therapy against breast cancer. Our study provides molecular and preclinical evidence to support the development of an EPA/EPHA2-inhibition–based phase I clinical trial for patients with EPHA2-positive TN-IBC; our study further suggests the use of EPHA2 and ABCA1 protein expression as biomarkers for patient selection and therapeutic response.
Citation Format: Torres-Adorno AM, Vitrac H, Qi Y, Tan L, Levental KR, Fan Y-Y, Yang P, Chapkin RS, Eckhardt BL, Ueno NT. EPHA2-targeting enhances eicosapentaenoic acid cytotoxicity against triple-negative inflammatory breast cancer via ABCA1 inhibition–mediated membrane rigidity abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-09.
Background Parasympathetic dysautonomia is an established feature of advanced Chagas cardiomyopathy. However, in the absence of cardiac involvement, the presence of vagal dysfunction remains ...controversial. In a cross-sectional study, we compared patients with Chagas disease without cardiac involvement and healthy individuals by three different methods to determine whether vagal dysfunction is present in the early phase of Chagas disease. Methods Sixty-one patients with Chagas disease without cardiac involvement and 38 controls were submitted to respiratory sinus arrhythmia test and 24-hour Holter monitoring. Vagal heart influences were assessed by the expiratory/inspiratory (E/I) ratio, time-domain indexes of heart rate variability (HRV), and by the quantification of a 3-dimensional return map. Results The two groups were comparable in terms of left ventricular ejection fraction and left ventricular end-diastolic dimension. Compared with the control group, patients with Chagas disease had significantly lower values of the E/I ratio (mean ± SD: 1.38 ± 0.02 and 1.25 ± 0.02, P <.004) and short-term indexes of HRV (median interquartile range—rMSSD: 23 18-27 and 17 13-23, P =.00; pNN50: 11 7-17 and 6 2-12, P =.00). P3, a beat-to-beat HRV index derived from the 3-dimensional return map, also was significantly reduced in the Chagas disease group (mean ± SD: 118 ± 5 vs 100 ± 4, P =.00). None of these indexes of vagal heart control were significantly correlated with left ventricular function or to the presence of esophageal radiologic abnormalities. Conclusion Parasympathetic dysautonomia is an independent and early phenomenon in Chagas disease and may precede left ventricular systolic dysfunction. (Am Heart J 2001;141:260-5.)
Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis, a disease that affects 10 million individuals in Latin America. This report depicts the results of the analysis of ...6,022 assembled groups from mycelium and yeast phase expressed sequence tags, covering about 80% of the estimated genome of this dimorphic, thermo-regulated fungus. The data provide a comprehensive view of the fungal metabolism, including overexpressed transcripts, stage-specific genes, and also those that are up- or down-regulated as assessed by in silico electronic subtraction and cDNA microarrays. Also, a significant differential expression pattern in mycelium and yeast cells was detected, which was confirmed by Northern blot analysis, providing insights into differential metabolic adaptations. The overall transcriptome analysis provided information about sequences related to the cell cycle, stress response, drug resistance, and signal transduction pathways of the pathogen. Novel P. brasiliensis genes have been identified, probably corresponding to proteins that should be addressed as virulence factor candidates and potential new drug targets.
Dr. Sinatra is Professor, Department of Anesthesiology, Yale University School of Medicine, New Haven, CT. Dr. Torres is Resident, Department of Anesthesiology, Yale University School of Medicine. ...Dr. Bustos is Resident, Department of Anesthesiology, Yale University School of Medicine.
Reprint requests: Dr. Sinatra, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8051.
Several recently developed analgesic techniques effectively control pain after major orthopaedic surgery. Neuraxial analgesia provided by epidural and spinal administration of local anesthetics and opioids provides the highest level of pain control; however, such therapy is highly invasive and labor intensive. Neuraxial analgesia is contraindicated in patients receiving low-molecular-weight heparin. Continuous plexus and peripheral neural blockades offer excellent analgesia without the side effects associated with neuraxial and parenteral opioids. Intravenous patient-controlled analgesia allows patients to titrate analgesics in amounts proportional to perceived pain stimulus and provide improved analgesic uniformity. Oral sustained-release opioids offer superior pain control and greater convenience than short-duration agents provide. Opioid dose requirements may be reduced by coadministration of COX-2type nonsteroidal analgesics.
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