Abstract P3-09-02: Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers & are associated with increased oxidative stress and telomere length alterations

Abstract The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes. Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p &amp;lt; 0.0001). Correlation of serum 4-HNE levels with individual features of the MetS and related parameters revealed significant direct correlations with waist circumference (p = 0.02), number of features of MetS (p = 0.0007), insulin (p = 0.02) insulin resistance score (HOMA-IR) (p = 0.01), HBA1c (p = 0.006), glucose (p = 0.048) and triglycerides (p &amp;lt;0.0001). Age-adjusted telomere length was not influenced by anthropometric measurements or MetS status in this group. Moderate physical activity levels were inversely associated with age-adjusted telomere length; particularly, among post-menopausal participants (p =0.009). This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication.The lifetime-risk of breast-cancer is greatly increased in women carrying a deleterious mutation in the BRCA1 or BRCA2 genes. Recently, there has been increased penetrance of BRCA1 and BRCA2 mutations which may be due to lifestyle influences. There is a need to identify approaches to reduce the penetrance of BRCA 1/2 mutations. Understanding how modifiable lifestyle-factors affect cancer-risk in BRCA-mutation carriers may have implications for risk-reduction in this group. At the molecular level, oxidative-stress and telomere dysfunction are early events in cancer development and these processes may be considered surrogate markers of cancer-risk. It has been reported that BRCA-mutation carriers are more susceptible to these pro-carcinogenic processes that non-carriers. The aim of this pilot study was to objectively measure lifestyle factors in unaffected BRCA-mutation carriers and to assess the impact of these lifestyle-factors on oxidative-stress profiles and telomere length. Participants (n=75) were recruited from breast-cancer family-risk clinics and cancer-genetics clinics. Body-composition (BMI, waist-circumference), metabolic profiles and physical-activity (triaxial accelerometry) were measured for each participant. Serum levels of the oxidative-stress markers 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-DG) and 4-hydroxynonenal (4-HNE) were measured in a subset of participants (n=30) by ELISA. Telomere length was measured in a subset of participants (n=30) by quantitative PCR (qPCR). Participants demonstrated poor adherence to physical-activity guidelines with 94% not reaching physical-activity levels recommended by the American College of Sports Medicine. The majority of participants were overweight (39%) or obese (32%) with 73% exhibiting abdominal obesity. 21% of participants had the metabolic syndrome (MetS) at the time of study enrolment with the majority of participants (80%) presenting with at least one feature of the MetS. Circulating levels of 8-oxo-DG did not appear to be affected by body composition or MetS status, however, serum levels of the lipid peroxidation marker 4-HNE were significantly higher in participants with the MetS (p &amp;lt; 0.0001). Correlation of serum 4-HNE levels with individual features of the MetS and related parameters revealed significant direct correlations with waist circumference (p = 0.02), number of features of MetS (p = 0.0007), insulin (p = 0.02) insulin resistance score (HOMA-IR) (p = 0.01), HBA1c (p = 0.006), glucose (p = 0.048) and triglycerides (p &amp;lt;0.0001). Age-adjusted telomere length was not influenced by anthropometric measurements or MetS status in this group. Moderate physical activity levels were inversely associated with age-adjusted telomere length; particularly, among post-menopausal participants (p =0.009). This work has provided compelling evidence that in this cohort of BRCA-mutation carriers, unhealthy lifestyle-patterns are prevalent. In addition, these results suggest that the potential may exist to modify pro-carcinogenic processes in this cohort by modifying physical activity levels and targeting the metabolic syndrome and its component features lifestyle interventions and/or medication. Citation Format: McGarrigle SA, Guinan EM, Hussey J, O'Sullivan J, Boyle T, Hanhauser Y, Al-azawi D, Kennedy MJ, Gallagher DJ, Connolly EM. Unhealthy lifestyle patterns are prevalent in unaffected BRCA mutation carriers &amp; are associated with increased oxidative stress and telomere length alterations [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-02.</jats:p

Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE2RD) for diagnostics

Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes

Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE 2

Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients’ homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD’s broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients’ homes