Search

Pesticides exert a wide variety of functions for controlling pests. At low doses the pests are not much affected and parallel to that a chance of tolerance has been expected. In this study a population of fruit flies Drosophila melanogaster was grown under various doses of insecticide Malathion and herbicide Paraquat. Lower than the sub-lethal doses (0.2 micromolar), various biomolecular alterations in terms of protein oxidation (Advanced Oxidation Protein Products, AOPP), lipid peroxidation (Malondialdehyde, MDA), sialic acids, total thiols, Cupric Ion Reducing Antioxidant Capacity (CUPRAC) and 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radical scavenging activity have been observed. Positive alteration in AOPP for both Malathion and Paraquat treated fruit flies as well as increased MDA content in Paraquat treated flies are the alterations in the fruit fly population because of oxidative stress. The unaffected MDA, sialic acid content and CUPRAC antioxidant capacity for Malathion treated flies demonstrates the diminished effects of oxidative stress exerted through Malathion. There is increase sialic acid and CUPRAC antioxidant capacity after treatment of Paraquat. There is also an increase in total thiols and ABTS cation radical scavenging activity after treatment of both Malathion and Paraquat. These results evidently show that improved antioxidant mechanisms effectively alleviate the oxidative stress exerted by pesticides. This study is clearly reflecting that oxidative stress generated by the sub lethal doses of pesticides can be diminished and certain tolerance level is also achieved by the insects in terms of increased antioxidant defence and longevity.

Bu calismada cagri merkezlerinde kullanilan otomatik konusma tanima sisteminde Turkce ve yabanci kokenli sozeukleri taniyabilen bir yapidan bahsedilmektedir. Cagri merkezlerinin farkli sektor ve alanlara hizmet vermesinden kaynakli Turkce kokenli konusmalarin yani sira bircok yabanci kokenli kelimelerin gectigi konusmalara da sahiptir. Sadece Turkce icin gelistirilen konusma tanima sistemleri bu merkezlerin ihtiyaeini tam anlamiyla karsilayamadigi icin, Turkce ve yabanci kelimelerin bir arada yer aldigi hibrit bir yapi olusturulmustur. Bu yapida seslere karsilik gelen metinler okunuldugu gibi yazilmak yerine, okunusun duzgun soylendigi varsayilarak yazilmistir. Boylelikle metine cevrilen konusmanin anlamlandirilmasindaki gecen zaman azalmistir. Soyleyis sozlugunde duzgun soylemlerin karsisina okunus varyasyonlari eklenerek degisik agizdaki konusmalarin ve yabanci kokenli kelimelerin taninmasi saglanmistir. Gerceklestirilen calisma sonueunda uygulanan yontemler sayesinde oneeki sisteme gore basarim oramnin arttigi gozlemlenmistir.

The Gram-negative (−) bacterium Helicobacter pylori colonizes in the mucus gel layer above the gastric epithelium and has been considered to be a major etiologic factor in several gastric health complications including peptic ulcers, gastric MALT, gastritis, and gastric cancer in approximately 50% of the world’s population. Besides inducing colon carcinogenesis, the bacterium shows to be associated with different extragastric disorders. Eradication of H. pylori is reported to reduce 33–47% of gastric cancer; however, treatment of H. pylori against colon cancer is less effective in older people. Several targets of H. pylori to induce colorectal carcinogenesis have been hypothesized, and an association of gastric H. pylori with colorectal adenomatous polyps (CAPs) has been experimentally revealed. CAPs are precancerous lesions of epithelial cells and lead to colorectal cancer (CRC) from the adenomatous stage. Pathway analysis decrypts the cascade mechanism of CAPs via inducing matrix metalloproteinase (MMP), prostaglandin-endoperoxide synthase, and mucin with other molecular targets. Several therapeutic approaches have been established to eradicate H. pylori before inoculation and during histologic progression in early stages. This book chapter explains the impact and molecular mechanism of H. pylori in colon carcinogenesis and methods of therapeutic approaches.

Aging, in a large measure, has long been defined as the resultant of oxidative stress acting on the cells. The cellular machinery eventually malfunctions at the basic level by the damage from the processes of oxidation and the system starts slowing down because of intrinsic eroding. To understand the initial destruction at the cellular level spreading outward to affect tissues, organs and the organism, the relationship between molecular damage and oxidative stress is required to understand. Retarding the aging process is a matter of cumulatively decreasing the rate of oxidative damage to the cellular machinery. Along with the genetic reasons, the decrease of oxidative stress is somehow a matter of lifestyle and importantly of diet. In the current review, the theories of aging and the understanding of various levels of molecular damage by oxidative stress have been emphasized. A broader understanding of mechanisms of aging have been elaborated in terms of effects of oxidative at molecular, mitochondrial, cellular and organ levels. The antioxidants supplementation, hormesis and calorie restriction as the prominent anti-aging strategies have also been discussed. The relevance and the efficacy of the antiaging strategies at system level have also been presented.

Today, as a civilization we produce an unprecedented amount of data, in the form of audio, images, video and so forth. One application of this data-driven approach is autonomous vehicles. The current technologies have made it possible to happen. The top car companies like Hyundai, Kia, Ford motors, Tesla motors have been working on the self-driving cars projects and they have achieved it to some extent. But self-autonomous vehicles are not only limited to the self-driving cars, but the UAVs (Unmanned Aerial Vehicles) are also part of it. While the applications of the self-driving cars are somewhat limited to the usage of normal public, the UAVs have applications that vary from surveillance to patrol to enemy reconnaissance, in short, the UAVs have more applications for the military than the normal public. These autonomous vehicles require an understanding of the environment they operate in. As these vehicles are used to travel in cities (in case of self-driving cars) and also might be used in forests or mountains (in case of UAV use by for reconnaissance), they require to detect obstacles in order to avoid them. This is often achieved through scene depth estimation, by various means. We propose an approach which not only requires a minimum amount of space but also consumes far less power. Our approach is based on Obstacle Detection and calculating distance using the disparity estimated. These represent highly desirable features, especially for micro aerial vehicles.

Background: Endocrine therapy (ET) and mTOR inhibition are important treatment strategies in ER-positive breast cancer, but no specific genomic alterations reliably predict benefit. Because tumors are tested pretreatment, we hypothesized that this may not capture tumor interaction with therapy. Methods: We studied tumors from protocol NCT00570921 using fulvestrant and everolimus for metastatic ER-positive breast cancer after aromatase inhibitor (AI) failure. DNA from FFPE tumor tissue was subjected to next-generation genomic profiling using the FoundationOne® assay and alterations were then compared between available paired samples: primary/metastatic, before/after everolimus, and upon progression on everolimus. Results: The most common alterations encountered were in the PI3K/AKT/mTOR pathway with increased frequency of PIK3CA in endocrine-sensitive disease but no specific association with everolimus benefit (Massarweh et al, ASCO 2015). One patient with lobular carcinoma relapse on ET and a new contralateral primary, had PIK3CA, CDH1, and MAP3K1 in both tumors with no new alterations detected. Her disease was everolimus sensitive. Another patient with PIK3CA at baseline acquired a CTNNA1 mutation upon relapse with no everolimus benefit. Interestingly, one patient with liver metastasis and complete response to everolimus lasting 3 years had no known alterations reported in the primary tumor but had a PIK3CA mutation in one of two simultaneous biopsies of separate liver lesions. Another patient with liver metastasis and a GATA3 mutation at baseline had response to everolimus lasting 18 months, then developed a PIK3R2_c.1936A>T mutation on progression reported as a variant of unknown significance (VUS). Another patient with metastatic lobular carcinoma to skin and bone had PIK3CA, CDH1, and ERBB2 mutations at baseline, and acquired KRAS and MCL1 amplification on two sequential skin biopsies in the first month on everolimus. She remained on therapy for 1 year. One patient with locally advanced disease and de novo bone metastasis had TP53 and GATA3 mutations at baseline with resistance to multiple chemotherapy and endocrine treatments. Upon progression on AI, her tumor acquired PDGFRA and SMAD4, detected on day 1 biopsy of everolimus treatment. Repeat biopsy on day 28 revealed loss of PDGFRA and SMAD4 with emergence of PIK3CA and MLL2 mutations and loss of STK11. After 1 year on everolimus her tumor progressed and repeat breast biopsy revealed loss of the PIK3CA, STK11, and MLL2 events, with appearance of AKT1 and NF1 mutations. Interestingly, her tumor also acquired ESR1_c.1607T>G, MTOR_c.6104C>T, and NSD1_c.5938G>A mutations, all classified as VUS but were not previously encountered in her course. Further analysis and biologic relevance of these changes will be presented. Conclusion: This small study suggests that ER-positive breast cancer is a dynamic disease with genomic evolution on endocrine therapy and mTOR inhibition. In some patients, this change occurs early on therapy, possibly through clonal selection, but may also be related to tumor heterogeneity. The significance of this change is not fully understood, but study of early on-treatment biopsies may help us better understand tumor response to therapy. Citation Format: Massarweh S, Romond E, Stewart R, Sun J, Chmielecki J, Mehdi M, Black EP. Evolution of genomic alterations on endocrine therapy and mTOR inhibition in estrogen receptor (ER)-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-06.

Introduction: In patients with advanced-stage ovarian cancer, FDA has recently granted approval of treatment with PARP inhibitors (PARPi) in patients harboring deleterious BRCA mutations (~25% of population). However, there is clear evidence of “BRCA-like” patients who respond to PARPi without BRCA mutations. To identify such patients, it has been shown that deficiency in homologous recombination repair leads to a common phenotype of genome-wide loss of heterozygosity (LOH). Depending on the cutoff employed, genomic LOH could identify more than twice the number of ovarian cancer patients who could benefit from PARPi than measuring BRCA alone. We present here an NGS-based platform developed and performed in compliance with FDA 21 CFR part 820. The assay provides a tumor measurement of BRCA1/2 (FDA-approved as FoundationFocus CDx BRCA) as well as genomic LOH, and is on the same platform as the comprehensive FoundationOne CDx, which interrogates 324 genes. Methods: DNA extracted from FFPE tumor tissue underwent whole-genome shotgun library construction and hybridization-based capture, followed by sequencing using Illumina HiSeq 4000. Sequence data were processed using a proprietary analysis pipeline designed to detect base substitutions, indels, copy number alterations (CNA), genomic rearrangements, microsatellite instability (MSI), and tumor mutational burden (TMB). A genome-wide LOH profile based on SNPs is measured as part of the CNA pipeline, and is summarized as the percentage of the tumor genome displaying LOH (scored from 0-100%), with ≥16% being considered LOH high based on clinical data derived from ARIEL2 Part 1, a phase II study of the PARPi rucaparib for the treatment of platinum-sensitive ovarian cancer (ARIEL2; NCT01891344) Results: For analytical validity, BRCA limit of detection (LoD) was at allele frequency 5.9% for substitutions and non-repetitive indels, and 30% tumor content for LOH. Overall percent agreement with comparator NGS assay was 97.3% for BRCA. No orthogonal platform concordance was established for LOH as no validated test exists. Within-assay reproducibility was measured with overall concordance of 100% for BRCA, and 98% for LOH. Conclusion: We developed a novel diagnostic assay (in compliance with FDA 21 CFR part 820) that can measure BRCA and genomic LOH simultaneously, and established robust analytical validation data. Citation Format: James X. Sun, Kevin Lin, Yali Li, Kyle Gowen, Yuting He, Coren Milbury, Christine Burns, Jun Luo, Steve Roels, Murtaza Mehdi, John Truesdell, Pei Ma, Lakshman Ramamurthy, Christine Vietz, Jeri Beltman, Thomas Harding, Doron Lipson, Jeffrey Ross, Vincent Miller, Philip Stephens, Michael Doherty, Julia Elvin. A validated diagnostic assay for identifying ovarian cancer patients with deleterious BRCA mutations and high genomic loss of heterozygosity (LOH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4544.

The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with varying degrees of mono- to trilineage cytopenias and bone marrow dysplasia. In recent years much progress has been made in the treatment of MDS and there are now several therapeutic compounds used with varying levels of success. These compounds typically cause side effects that make them unattractive for treatment of patients in the early stages of MDS. Naturally occurring compounds that are not toxic may provide a means to treat patients in the initial stages of disease. We conducted a pilot study to test the efficacy of coenzyme Q10 (coQ10) in MDS patients with low to intermediate-2 risk disease. A variety of responses were observed in 7 of 29 patients including two trilineage and two cytogenetic responses. Sequencing mitochondrial DNA (mtDNA) from pretreatment bone marrows showed multiple mutations, some resulting in amino acid changes, in 3/5 nonresponders, 1/4 responders and in two control samples. We conclude that coQ10 may be of clinical benefit in a subset of MDS patients, but responders cannot be easily pre-selected on the basis of either the conventional clinical and pathologic characteristics or mtDNA mutations.

Therapeutic options for the heterogeneous hematopoietic disorders grouped under the myelodysplastic syndromes (MDS) have been difficult to develop, even though the incidence of this disease is increasing because of the ageing population. Several drugs have now been shown to have therapeutic efficacy in subgroups of patients, but the main challenge is still the preselection of the patient for a given strategy. To state the problem simply, effective therapies may already exist for a substantial number of MDS patients, but we do not know how to match the right drug to the right patient. Cytogenetic abnormalities have provided some treatment guidance, however these are generally restricted to patients known to have a better prognosis. To develop reliable predictive assays in patients with complex or more advanced diseases, we will have to delve deeper than cytogenetics. This review summarizes what is known about the clinical and biological characteristics of various karyotypic subgroups of MDS, and proposes a roadmap for combining the bedside-to-bench approach with the use of DNA microarray analysis in developing expression profiles that can serve as a guide in the preselection of treatment options for individual MDS patients.

Background and Aims Oxidative stress is thought to play a major role in the development of several age-dependent diseases. Proteins are major targets for oxidative attack. Protein hydroperoxides are formed by hydroxyl and singlet oxygen attack on protein, forming relatively stable hydroperoxides on histidine, tyrosine and tryptophan residues. This study investigated the levels of plasma protein hydroperoxides and antioxidant potential of plasma during aging in humans. We correlated the protein hydroperoxide formation with plasma antioxidant potential, paraoxonase 1 (PON1) arylesterase activity and plasma total thiols. Methods The protein hydroperoxides and antioxidant potential were measured in plasma of human subjects aged between 20 and 81 years of both genders. Results Increase in plasma protein hydroperoxides and decrease in plasma antioxidant potential were observed as function of human age. Conclusion This study provides strong correlation between plasma protein hydroperoxides formation and decrease in plasma antioxidant potential during aging. PON1 arylesterase activity and plasma total thiols levels were also found to show significant correlation with increasing levels of plasma protein hydroperoxides during aging. The plasma protein hydroperoxides provide a reliable marker of long-term redox balance and degree of oxidative stress during aging process.

Background and Aims The role of free radicals has long been proposed as a cause for the aging process. Oxidative stress is considered a major factor for altering many physiological processes and enzymatic activities during aging and is also known to play a major role in the development of several age-dependent diseases. Paraoxonase 1 (PON1) is an anti-atherosclerotic enzyme that mainly prevents accumulation of lipoperoxides and inhibits the lipid oxidation in low-density lipoproteins (LDL). This study was undertaken to investigate the antioxidant behavior of PON1 by measuring its arylesterase activity. The susceptibility of LDL for oxidation and the radical scavenging activity of plasma were also measured during aging in humans. Methods Arylesterase activity of PON1 was measured in plasma of human subjects between 20 and 81 years of age of both genders. The susceptibility of LDL for oxidation and radical scavenging activity were measured in plasma. Results Decrease in plasma arylesterase activity of PON1, increase in susceptibility of LDL for oxidation and decrease in plasma radical scavenging activity were observed as a function of human age. Conclusions The study provides evidence of a relationship between PON1 activity, LDL oxidation and free radical scavenging activity of plasma. The present results emphasize the dependency of PON1 activity to prevailing oxidative stress during human aging. Our findings assume significance in view of the possible categorization of PON1 as a longevity gene.

Previous studies have indicated that the main molecular characteristic of aging is the progressive accumulation of oxidative damages in cellular macromolecules. Proteins are one of the main molecular targets of age-related oxidative stress, which have been observed during aging process in cellular systems. Reactive oxygen species (ROS) can lead to oxidation of amino acid side chains, formation of protein-protein cross-linkages, and oxidation of the peptide backbones. In the present study, we report the age-dependent oxidative alterations in biomarkers of plasma protein oxidation: protein carbonyls (PCO), advanced oxidation protein products (AOPPs) and plasma total thiol groups (T-SH) in the Indian population and also correlate these parameters with total plasma antioxidant potential. We show an age dependent decrease in T-SH levels and increase in PCO and AOPPs level. The alterations in the levels of these parameters correlated significantly with the total antioxidant capacity of the plasma. The levels of oxidized proteins in plasma provide an excellent biomarker of oxidative stress due to the relative long half-life of such oxidized proteins.

BACKGROUND. The treatment of myelodysplastic syndromes (MDS) remains a challenge to the clinician despite recent advances. Many patients will either not respond or will have only limited and/or brief responses to single-agent therapy. Eventually, 30% of patients with MDS will progress and develop acute myeloid leukemia (AML). New strategies are needed for these patients. METHODS. 5-Azacytidine (AZA) and thalidomide were administered to 40 patients with MDS or AML. AZA was given at a dose of 75 mg/m2 subcutaneously for 5 of 28 days together with thalidomide starting at a dose of 50 mg per day and increasing to 100 mg per. Six patients had refractory anemia (RA), 2 patients had RA with ringed sideroblasts, 10 patients had RA with excess blasts (RAEB), 1 patient had RAEB in transformation, 4 patients had chronic myelomonocytic leukemia, 1 patient had chronic idiopathic myelofibrosis, and 16 patients had AML. Thirty-six patients were evaluable for outcome. RESULTS. A hematologic improvement (HI) was observed in 15 of 36 patients (42%), stable disease was observed in 5 of 36 patients (14%), and 10 of 36 patients (28%) had disease progression. Six patients experienced complete remission (CR), 2 patients experienced an erythroid HI (HI-E), 1 patient experience an absolute neutrophil count HI (HI-ANC), 5 patients experienced a platelet HI (HI-P), and 7 patients had bilineage HI (HI-P and HI-ANC or an HI-E and HI-ANC). It was noteworthy that 9 of 14 patients with AML had a history of prior MDS, 2 of 9 patients achieved a CR, 4 of 9 patients had HI (HI-E and bilineage HI), and 1 patient had stable disease and was continuing treatment. DNA microarray analysis of 8 responders and 4 nonresponders revealed that the genes associated with cellular proliferation had higher expression levels in nonresponders. CONCLUSIONS. The current findings indicated that a combination of low-dose AZA and thalidomide was well tolerated and was effective therapy for the treatment of patients with MDS and AML arising from prior MDS. Cancer 2008. © 2008 American Cancer Society.

Background: Genomic studies suggest that ∼50% of high-grade serous ovarian cancers (OC) have homologous recombination deficiency (HRD). Germline BRCA1/2 mutations (gBRCAmut) are expected to account for 1/3 of HRD in OC, and identification of non-gBRCAmut HRD tumors likely to respond to PARP inhibitors (PARPi) remains a challenge. Using comprehensive next generation sequencing (NGS)-based tumor genomic profiling, we developed a companion diagnostic HRD assay to predict sensitivity to the PARP inhibitor rucaparib by combining tumor BRCA1/2 status (germline and somatic) and genomic loss of heterozygosity (LOH). The HRD assay is being validated in a Phase 2 study (ARIEL2) and will be prospectively applied to the primary analysis of the ongoing Phase 3 study (ARIEL3) of rucaparib. Methods: The HRD assay uses 50-200ng of DNA from tumor FFPE specimens, which undergoes sequencing library construction and hybrid-capture of all coding exons from 100s of cancer-related genes. Libraries are sequenced to high, uniform depth (>500× unique coverage, Illumina® HiSeq) and data are processed by a customized pipeline that accurately detects all classes of genomic alterations, including BRCA1/2 base substitutions, indels, and homozygous deletions. Genomic LOH is assessed by a CGH-like analysis of sequencing coverage and >3,500 genome-wide SNPs and a tumor is classified as HRD with either BRCA1/2 alteration or high genomic LOH (LOH+). Somatic/germline status of discovered BRCA1/2 alterations is assessed by a previously-presented computational approach (“SGZ”, AACR 2014 abstract #1893), and verified against medical records where available. ARIEL2 is an ongoing single-arm (n = 180), open-label study of rucaparib in recurrent, platinum-sensitive OC patients. The primary objective is to evaluate clinical activity of rucaparib among 3 prospectively defined subgroups: tumor BRCAmut, BRCAwt/LOH+ (“BRCAness”) and BRCAwt/LOH-. Response is determined by RECIST and/or GCIG-CA125 criteria. Results: The HRD assay was performed on tumors from 121 patients, of whom 25% were found to be BRCA mutant (17 germline/12 somatic), 42% had the BRCAness signature (BRCAwt/LOH+), and 33% were biomarker negative (BRCAwt/LOH-). Efficacy data available for 61 patients revealed objective response rates (combined RECIST/CA125 criteria) at 70%, 40% and 8%, respectively. Responses were observed for all classes of genomic alterations, and in gBRCAmut and non-gBRCAmut tumors. Conclusions: Preliminary clinical data indicates that the HRD assay identifies OC patients likely to respond to rucaparib and highlights the potential for innovative companion diagnostics enabled by comprehensive genomic profiling based on NGS. Citation Format: James Sun, Iain McNeish, Robert L. Coleman, Amit Oza, Clare Scott, David M. O'Malley, Kevin K. Lin, Christine Burns, Christine Vietz, Philip J. Stephens, Murtaza Mehdi, Matthew Hawryluk, Heidi Giordano, Mitch Raponi, Lindsey Rolfe, Jeff Isaacson, Vincent A. Miller, Andrew Allen, Elizabeth Swisher, Roman Yelensky. A novel companion diagnostic predicts response to the PARP inhibitor rucaparib in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4670. doi:10.1158/1538-7445.AM2015-4670

532 Background: Aberrations of the PI3K/AKT/mTOR pathway are common in ER-positive breast cancer and may be associated with endocrine-resistance. We hypothesized that, since the majority of ER-posi...

530 Background: Everolimus, which inhibits mTOR, is used to treat metastatic ER-positive breast cancer after aromatase inhibitor failure. Because not all patients benefit and toxicity can be prohib...

5539 Background: Molecular profiling of tissue obtained with a biopsy aids detection of predictive and pharmacodynamic biomarkers to guide patient (pt) selection and treatment. This study assesses ...

18009 Background: MDS and myeloma patients respond to many of the same therapeutic agents, suggesting a possible pathologic mechanism for both diseases. C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes in response to tissue damage and inflammation under the transcriptional control of cytokines IL-6 and IL-1. Plasma CRP levels are a sensitive marker of inflammatory processes and are increased in patients with various cancers. CRP has been shown to bind and protect multiple myeloma cells from dexamethasone-induced apoptosis both in vitro and in vivo. CRP acts independently but in synergy with IL6, to promote survival and proliferation of myeloma. Increased expression of IL6 may be found in some patients with MDS suggesting that CRP may be a target of therapy in both diseases. We measured the serum concentrations of CRP in 94 MDS patients and 12 normal volunteers to see if levels correlated with clinical subtype as an initial step in exploring a common link between the two diseases....