Dissertations / Theses on the topic 'ALS inhibitor resistance'
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Iwakami, Satoshi. "Molecular mechanism of resistance in a multiple-herbicide resistant Echinochloa phyllopogon." Kyoto University, 2013. http://hdl.handle.net/2433/180368.
Full text0048
新制・課程博士
博士(農学)
甲第17830号
農博第2015号
新制||農||1016(附属図書館)
学位論文||H25||N4787(農学部図書室)
30645
京都大学大学院農学研究科農学専攻
(主査)教授 稲村 達也, 教授 冨永 達, 教授 奥本 裕
学位規則第4条第1項該当
Friesen, Lincoln Jacob Shane. "Identification of the mechanisms of wild radish herbicide resistance to PSII inhibitors, auxinics, and AHAS inhibitors." University of Western Australia. School of Plant Biology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0106.
Full textFerguson, Gabrielle Mary. "ALS-inhibitor resistance in populations of Amaranthus powellii S. Wats. and Amaranthus retroflexus L." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0023/MQ51062.pdf.
Full textWeerasooriya, Dilooshi Kumari. "Genetic analysis of interveinal chlorosis and reduced seedling vigor as related to agronomic performance in sorghum resistant to ALS inhibitor herbicides." Diss., Kansas State University, 2016. http://hdl.handle.net/2097/32896.
Full textDepartment of Agronomy
Tesfaye T. Tesso
The lack of effective post-emergence weed control options is often highlighted as one of the major factors behind dwindling acreage under sorghum (Sorghum bicolor (L.) Moench) in the United States. The discovery of herbicide resistance sources in wild sorghum population and subsequent efforts to incorporate them into cultivated sorghum was received with much optimism to change weed management practices in sorghum. As the development of the technology advances, especially of the Acetolactate synthase (ALS) resistance, concerns over the temporary interveinal chlorosis and reduced seedling vigor in some of the resistant families became heightened. This thesis research is designed to shed light on the genetic basis of seedling chlorosis and assess its impacts on yield potential. The study has three parts; the first part is focused on identifying the genetic causes and plant mechanisms associated with the chlorotic phenotype. ALS herbicide resistant sister-lines expressing normal and chlorotic phenotypes were analyzed via RNA sequencing at four time points during seedling growth. The study identified several variants of genes coding chloroplast precursors and those that cause epigenetic modifications. Once confirmed, genetic markers can be developed to track these gene variants in the breeding population and eliminate segregates genetically prone to chlorosis/yellowing. The second part of the study focuses on assessing the effect of ALS resistance associated chlorosis on agronomic and nutritional parameters of sorghum inbred lines. A set of ALS resistant lines expressing different levels of the chlorotic phenotype were evaluated in replicated field trials and laboratory methods. Results showed that interveinal chlorosis delays flowering but does not have negative effect on yield and nutritional parameters with and without herbicide treatment. The last part addresses whether there is any yield drag that may be associated with herbicide resistance traits and foliar interveinal chlorosis. For this, we synthesized a large set (182) of hybrids from ALS resistant, ACCase resistant and regular (susceptible) seed and pollinator parents. The hybrids were then evaluated in three sets at multiple locations during the 2014 and 2015 crop seasons along with commercial checks. The results revealed that resistance to both herbicides do not cause any drag to grain yield. The traits also do not have any negative impact on grain and nutritional quality of resistant hybrids.
Castel, Morales Pau. "Molecular mechanisms of resistance to PI3K inhibitors." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396640.
Full textEl desenvolupament de noves tècniques de seqüenciació massiva ha fomentat l’estudi d’un gran nombre de mostres de diversos tipus tumorals. Els resultats d’aquests estudis genòmics exhaustius ha revelat els gens que es troben mutats en major prevalença, contribuint a una millor comprensió dels processos de patogènesis, classificació molecular i estratègies terapèutiques per a aquesta malaltia. PIK3CA, el gen que codifica per a la isoforma PI3Kα, es troba entre els gens mes freqüentment mutats en el carcinoma de mama, cap i coll, colorectal, pulmó, entre d’altres. Les mutacions activadores a PIK3CA promouen la hiperactivació de la via de senyalització de PI3K/AKT, donant lloc a un increment en la proliferació, la supervivència, i el metabolisme de les cèl·lules tumorals. Els esforços actuals es centren en el desenvolupament d’inhibidors de l’enzim PI3K com a una possible teràpia efectiva en tumors que presenten mutacions a PIK3CA. Tot i que els assajos clínics inicials son prometedors, l’emergència de resistència a aquestes teràpies és una clara limitació. En aquesta tesis doctoral s’han explorat els possibles mecanismes de resistència per intentar entendre com els tumors evolucionen enfront d’aquest fàrmacs, poder definir les subpoblacions de pacients que respondran als inhibidors de PI3K i proporcionar noves combinacions farmacològiques per combatre el fenomen de la resistència. Hem demostrat que la pèrdua del supressor tumoral PTEN juga un paper important en la resistència als inhibidors de PI3Kα, tant en models preclínics com en pacients, mitjançant la reactivació de la via de PI3K/AKT que és resultat d’un increment en la dependència de la isoforma PI3Kβ. El nostre treball també ha evidenciat la noció d’evolució tumoral i ha demostrat el concepte d’evolució convergent fenotípica en resposta a la pressió terapèutica. També s’ha demostrat que la resistència intrínseca als inhibidors de PI3Kα es pot donar com a resultat d’una inhibició incompleta del complex 1 de mTOR (mTORC1), un efector clau de la via de PI3K/AKT. Cèl·lules resistents a inhibidors de PI3Kα es van poder sensibilitzar amb el bloqueig genètic o farmacològic de PDK1, una quinasa constitutivament activa. Experiments addicionals van poder demostrar que l’efector molecular de PDK1 era la quinasa SGK1, la qual promou la supervivència cel·lular a través de la fosforilació de proteïnes clau com FOXO3 i TSC2. El fenotip resistent es va poder revertir mitjançant la inhibició farmacològica d’aquesta proteïna, una aproximació terapèutica que ha revelat un rol interessant en la biologia tumoral. Els models murins modificats genèticament representen una eina segura per a l’estudi de la etiologia, biologia i progressió de malalties humanes, així com per explorar noves aproximacions terapèutiques. Com a resultat d’un descobriment imprevist, també hem pogut revelar el rol de les mutacions de PIK3CA en la formació de malformacions venoses, una aberració del desenvolupament normal de les venes que actualment no tenen un tractament específic. El nostre model animal de malformació venosa recapitula les característiques histopatològigues de la malaltia i proporciona una plataforma experimental única per a l’estudi de noves teràpies. En aquests models animals, els inhibidors de PI3Kα han demostrat ser efectius en la reducció de la morbiditat de les malformacions venoses.
Recondo, Gonzalo. "Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.
Full textThe molecular study and classification of lung adenocarcinomas has led to the development of selective targeted therapies aiming to improve disease control and survival in patients. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor from the insulin tyrosine kinase receptor family, with a physiologic role in neural development. Gene rearrangements involving the ALK kinase domain occur in ~3-6% of patients with lung adenocarcinoma. The fusion protein dimerizes leading to transactivation of the ALK kinase domain in a ligand-independent and constitutive manner. Lorlatinib is a third generation ALK inhibitor with high potency and selectivity for this kinase in vitro and in vivo, and elevated penetrance in the central nervous system. Lorlatinib can overcome resistance mediated by over 16 secondary kinase domain mutations occurring in 13 residues upon progression to first - and second - generation ALK TKI. In addition, treatment with lorlatinib is effective for patients who have been previously treated with a first and a second generation or a second generation ALK TKI upfront and is currently approved for this indication. The full spectrum of biological mechanisms driving lorlatinib resistance in patients remains to be elucidated. It has been recently reported that the sequential acquisition of two or more mutations in the kinase domain, also referred as compound mutations, is responsible for disease progression in about 35% of patients treated with lorlatinib, mainly by impairing its binding to the ALK kinase domain. However, the effect of these compound mutations on the sensitivity to the repertoire of ALK inhibitors can vary, and other resistance mechanisms occurring in most patients are unknown. My PhD thesis aimed at exploring resistance to lorlatinib in patients with ALK-rearranged lung cancer through spatial and temporal tumor biopsies and development of patient-derived models. Within the institutional MATCH-R study (NCT02517892), we performed high-throughput whole exome, RNA and targeted next-generation sequencing, together with plasma sequencing to identify putative genomic and bypass mechanisms of resistance. We developed patient-derived cell lines and characterized novel mechanisms of resistance and personalized treatment strategies in vitro and in vivo. We characterized three mechanisms of resistance in four patients with paired biopsies. We studied the induction of epithelial-mesenchymal transition (EMT) by SRC activation in a patient-derived cell line exposed to lorlatinib. Mesenchymal cells were sensitive to combined SRC and ALK co-inhibition, showing that even in the presence of an aggressive and challenging phenotype, combination strategies can overcome ALK resistance. We identified two novel ALK kinase domain compound mutations, F1174L/G1202R, C1156Y/G1269A, occurring in two patients treated with lorlatinib. We developed Ba/F3 cell models harboring single and compound mutations to study the differential effect of these mutations on lorlatinib resistance. Finally, we characterized a novel mechanism of resistance caused by NF2 loss of function at the time of lorlatinib progression through the development of patients derived PDX and cell lines, and in vitro validation of NF2 knock-out with CRISPR/CAS9 gene editing. Downstream activation of mTOR was found to drive lorlatinib resistance by NF2 loss of function and was overcome by providing treatment with mTOR inhibitors.This study shows that mechanisms of resistance to lorlatinib are more diverse and complex than anticipated. Our findings also emphasize how longitudinal studies of tumor dynamics allow deciphering TKI resistance and identifying reversing strategies
Miller, David James. "Phosphinic acids as inhibitors of D-Ala-D-Ala adding enzyme." Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242865.
Full textLee, Liam Changwoo. "Functional identification of molecular oncotargets associated with the resistance to ALK inhibition in neuroblastoma via genome-wide CRISPR-Cas9 screens." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267921.
Full textRandhawa, Ranjeet Singh. "Characterization and Management of Acetolactate Synthase Inhibiting Herbicide Resistant Mouse-Ear Cress (Arabidopsis thaliana) in Winter Wheat." Thesis, Virginia Tech, 2017. http://hdl.handle.net/10919/79370.
Full textMaster of Science in Life Sciences
Llibre, Codina Josep Maria. "Clinical impact of HIV-1 resistance against nonnucleoside analogue reverse transcriptase Inhibitors. Impacte clínic de la resistència del VIH-1 als inhibidors de la transcriptassa inversa no anàlegs de nucleòsids." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/322789.
Full textNon-nucleoside reverse transcriptase inhibitors (NNRTIs) are popular components of antiretroviral therapy due to their efficacy and simplicity. Resistance is caused only by specific mutations at drug-resistance positions. Despite its proven efficacy, the clinical use of first-generation NNRTIs (nevirapine and efavirenz) has been limited by side effects and low barrier to resistance. To overcome these limitations, a second-generation of NNRTIs has been developed including etravirine and rilpivirine, both recently approved. Rilpivirine also depicts a low barrier to resistance development. Like nevirapine and efavirenz, complete drug resistance can arise with only one or two resistance-associated mutations (RAMs). In addition, there is a considerable degree of class cross-resistance among all NNRTIs, nearly complete between nevirapine and efavirenz, and more limited from first to second generation NNRTIs. Therefore, the knowledge of RAMs selected by first-generation NNRTIs that have a potential to impact both rilpivirine or etravirine in subsequent treatments is of paramount importance. Genotypic scores are now fully developed for all these drugs, therefore allowing resistance analyses in clinical samples and offering a unique opportunity to investigate the clinical impact of HIV-1 resistance on treatment response both in initial, salvage or simplification treatment. In this PhD thesis, we discuss the relevance of RAMs on treatment response; we pinpoint the patterns of RAMs selected at virologic failure (VF) with specific NNRTIs, and the consequent risk of failure to salvage or simplification with NNRTIs. The first chapter evaluates the effectiveness of etravirine in salvage regimens in VF recruited at four acute-care University hospitals in Barcelona. These regimens were generally well tolerated and achieved rates of virological suppression that exceed those observed in etravirine’s pivotal clinical trials, probably due to the inclusion of a higher number of active drugs in the regimens. We identified baseline CD4+ T cell count >200 cells/mm3 and use of raltegravir and darunavir as factors associated with lower treatment failure rates using a multivariate analysis. We found no relationship between prior interruption or VF with nevirapine or efavirenz and response to etravirine. The second chapter assesses the RAMs selected in subjects failing NNRTI-based treatments (with nevirapine, efavirenz or etravirine) at 22 clinics in Spain and the potential impact on rilpivirine’s activity. Rilpivirine resistance was recognized in 20% of these patients, more commonly following etravirine or nevirapine failures than efavirenz. The most prevalent rilpivirine RAMs in subjects failing other NNRTIs were Y181C, K101E/P, H221Y and E138A/G/K. E138K/M184I, the most frequently selected combination in initial treatment with rilpivirine, was absent in this treatment-experienced population. L100I and V108I were significantly more frequent in efavirenz failures. Conversely, Y181C/I, V106A, H221Y and F227L were more prevalent in nevirapine ones. Finally, the third chapter estimates the effectiveness of a nevirapine-based switch regimen in subjects with suppressed viremia, combined with tenofovir and emtricitabine (or lamivudine). The analysis has been done in our clinic in Barcelona. No unexpected RAMs or patterns of RAMs were selected in treatment failures to this regimen. At week 48, nearly 90% of the subjects had HIV-1 RNA <50 copies/mL, VF was uncommon, and 25 (7.4%) subjects discontinued the treatment due to toxicity. Factors independently associated with VF in multivariate analysis were intravenous drug use, time with undetectable viral load before the switch, number of prior NRTIs or NNRTIs, and previous nevirapine or efavirenz unscheduled interruptions. Reinitiation of nevirapine plus tenofovir plus emtricitabine (or lamivudine) should be discouraged in subjects experiencing unplanned treatment interruptions, even with an undetectable plasma viral load at the time of treatment withdrawal. Unexpectedly, we found a significantly higher rate of VF with lamivudine instead of emtricitabine with this regimen, with a significantly higher selection of M184V as well. Our findings suggest caution against substituting emtricitabine for lamivudine, at least in nevirapine- and tenofovir-based regimens.
Herrmann, Johannes Verfasser], and Otto [Akademischer Betreuer] [Richter. "Analysis of the spatial and temporal dynamics of herbicide resistance to ACCase- and ALS-Inhibitors in Alopecurus myosuroides Huds. and their causes / Johannes Herrmann ; Betreuer: Otto Richter." Braunschweig : Technische Universität Braunschweig, 2017. http://d-nb.info/1175817872/34.
Full textMeyer, Lucie. "The annual ragweeds (Ambrosia artemisiifolia L. - Ambrosia trifida L.) : adaptive response to chemical weeding and population genetics in agricultural environments." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCK005.
Full textThe first aim of this work was to investigate the risk for the evolution of resistance to acetolactate synthase inhibitor (ALS) herbicides in the common ragweed (Ambrosia artemisiifolia L.) through four points: (i) the selection pressure (effectiveness of a range of ALS inhibitor herbicides), (ii) the adaptive response of Ambrosia artemisiifolia (recurrent selection experiment), (iii) a resistance monitoring in fields in France, and (iv) the investigation of the mechanisms underlying herbicide resistance (target-site (TSR) and non-target-site resistance (NTSR) using transcriptomic analyses). The second aim was to study the connectivity of A. artemisiifolia populations in agricultural landscapes using microsatellite markers developed during this work, to determine factors that could facilitate the spread of this invasive weed species and the spread of herbicide resistance.In regards to herbicide resistance:-The sensitivity of A. artemisiifolia to ALS-inhibiting herbicides is variable between active ingredients.-Plants that survived the French maximum authorized field rate and higher rates of metsulfuron were selected to implement a recurrent breeding program. After two selection cycles, the resistance level to metsulfuron increased and resistance to imazamox and tribenuron emerged.-Three cases of imazamox resistance were identified in the field, including two cases of pure NTSR and one case of TSR - NTSR coexistence.-A transcriptome for A. artemisiifolia, AMBELbase, was generated using the PacBio sequencing technology to search for genes involved in NTSR mechanisms (RNAseq approach). 62 candidate contigs were identified including ABC transporters, cytochromes P450 and glutathione S-transferases known to be involved in the degradation of herbicides.In regards to population connectivity:-26 microsatellite markers were developed and revealed high genetic variability. Genetic structuring has been studied on a large scale for populations of A. artemisiifolia from Europe (invasion range) and North America (native range).-On a finer scale (agricultural landscape), the genetic structure of populations was influenced by colonization events. Migration events detected among the areas colonized by A. artemisiifolia suggested moderate pollen/seed flows and connectivity at the farmland scale. In agricultural environments, herbicide resistant alleles could be easily spread among neighbouring populations via pollen flow, and also at longer distances via seed dispersal. Human-related activities play a major role in the dispersal of seeds (agricultural machinery, contaminated seed lots, etc.).-The mating system analysis confirmed that A. artemisiifolia is an obligate outcrossing species which leads to important intra- and inter-population gene flow.The knowledge acquired during this work may help to foster the development of better management strategies to effectively control A. artemisiifolia to limit its spread, such as:-Diversified weed control strategies: combination of mechanical (including false-seed) and chemical weeding (diversification of herbicide modes of action).-Longer diversified crop rotations including more winter crops and/or cover and competitive crops to break the life cycle of A. artemisiifolia.These knowledge may also be used to better control of another weed species of the genus Ambrosia, Ambrosia trifida L
Oliveras, Serrat Glòria. "Derivats del (-)3-galat d'epigalocatequina com a nous inhibidors de la sintasa d'àcids grassos amb efectes antitumorals en models cel•lulars i animals de càncer de mama." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/91282.
Full textFatty Acid Synthase (FASN), an enzyme responsible for the de novo synthesis of fatty acids is overly manifested in certain types of cancer, especially in breast cancer, and it is associated with a poor diagnosis. Its regulation is associated with the signalling of HER2, a cellular receptor belonging to the human epidermal growth receptors family. However, the molecular mechanisms associated with this relationship are not well understood. FASN inhibitors, such as cerulenin or C75, offers low levels of stability and present side effects, like anorexia and weight loss, since they activate Carnitina Palmitoil Transferasa 1 (CPT1), a regulator enzyme of fatty acids’ β-oxidation. Previously our research group has proven that epigallocatechin 3-gallate (EGCG), a polyphenol present in green tea, inhibits FASN, has anti-tumoral effects and since it does not affect CPT1, is more selective than both cerulenin and C75. The therapeutic use of EGCG as an anti-tumoral agent is limited by its high IC50 value, as well as by its instability in physiological conditions. Following these results, a family of polyphenol compounds structurally related to EGCG has been designed with the goal of enhancing its anti-tumoral activity, its biodistribution and its stability. In vitro, we evaluated the biological and molecular activity of these compounds to assessing their specificity, their FASN-specific inhibiting capacity and their cytotoxic activity in different models of breast cancer. G28UCM shows a 90% inhibition of FASN activity and a high cytotoxicity levels in breast cancer cells (IC50= 30 9M). Also, G28UCM were analyzed in combination with already existing anti-HER therapies (trastuzumab, lapatinib, erlotinib, and cetuximab) in a cellular model of FASN/HER2- positive breast cancer. G28UCM shows synergysm with trastuzumab, lapatinib, and erlotinib, as opposed to EGCG, which only shows additivism with trastuzumab. Further, we also developed cellular models of breast cancer, which were resistant to trastuzumab, and lapatinib, and assessed whether G28UCM presents anti-tumoral activity in said cellular models. G28UCM presents cytotoxic activity with anti-HER2 drug resistant cells. In vivo, the tumoral activity and the toxicity profile of G28UCM were characterized in the murine model of FASN and HER2+ breast carcinoma. The results showed an inhibition of tumor growth in mice treated with a third G28UCM and any toxicity or weight loss. In summary, our findings provide the basis for the pre-clinical development of G28UCM.
Tanguy, Schmidt Aline. "Les leucémies aiguës lymphoblastiques en 2015 : contribution des facteurs de risque cytogénétiques et moléculaires à une thérapeutique adaptée." Thesis, Angers, 2015. http://www.theses.fr/2015ANGE0041/document.
Full textAcute leukemias are a heterogeneous groups of malignant hematological diseases due to the clonaloncogenic transformation of hematopoietic stem cells(HSTs). We distinguish acute myeloblastic leukaemiafrom acute lymphoblastic leukemia (ALL). ALLs are classified according to the type of lymphoid precursoraffected, its degree of maturity, and with associated cytogenetic abnormalities.Treatment incorporating induction therapy,consolidation, and intensification – delayedintensification or allogeneic stem cell transplantation(SCT) according to prognostic factors – enable 80 to 90% of complete remission (CR). Nevertheless, long-termoverall survival is only 40 to 50% because of relapseand treatment-related toxicity. Different prognosticgroups based on cytogenetic abnormalities andmolecular biology are emerging and patients from eachprognostic group can benefit from adapted therapies.In chromosome Philadelphia-positive ALL (Ph+ ALL) which used to be of particular bad prognosis, tyrosinekinase inhibitors (TKIs) enables 80% of CR but with ahigh-relapse risk. We demonstrated that high-dosetherapy followed by autologous SCT enables prolongedlong-term survival with less drug-related toxicity ascompared to allogeneic SCT in patients with undetectable minimal residual disease. By showing the implication of autotaxine in the resistance to TKIs inPh+ LAL, we enable the use of novel therapeutics inclinical practice.T-cell ALL is considered of poor prognosis as one thirdof patients relapse. In this group of patients we showedthat the absence of a Notch and/or a FBXW7 mutation or the presence of mutations in RAS or PTEN identified a subgroup of patients in whom the treatmentmust be intensified. Our research has contributed to the identification of prognostic groups in ALL and to theadjustment of treatment according to potential survival
Park, Kee-Woong. "ALS-inhibitor resistant downy brome (Bromus tectorum L.) biotypes in Oregon : mechanism of resistance, fitness, and competition." Thesis, 2003. http://hdl.handle.net/1957/30435.
Full text(6632369), Jodi E. Boe. "Establishing the Value of ALS-Inhibiting Herbicides in Fields with Confirmed Weed Resistance to ALS-Inhibiting Herbicides." Thesis, 2019.
Find full textAcetolactate synthase (ALS) inhibitors are a widely used class of selective herbicides used to control grass and broadleaf weeds. The repeated use of ALS-inhibiting herbicides has selected for biotypes of weeds resistant to ALS inhibitors, especially in the weeds most problematic to growers in the Midwest. While ALS inhibitor use seems futile, new mechanisms of herbicide action are not predicted to be commercialized in the near future to solve this problem. This leads to the main objective of this research, determining what value ALS inhibitors provide in controlling populations of weeds with resistance to ALS inhibitors.
Field experiments with soil-applied (PRE) applications of ALS inhibitors on horseweed (Erigeron canadensis) and tall waterhemp (Amaranthus tuberculatus var. rudis) exhibited higher efficacy than would be expected given the frequency of the ALS resistance trait in the population. Whereas control of these species with POST-applied applications was similar or less than the proportion of the population characterized as susceptible using molecular techniques. Soil-applied applications, therefore, resulted in relatively greater control than POST applications in populations with known ALS-inhibitor-resistance mechanisms.
Greenhouse experiments showed that overall resistance ratios were higher for PRE applications of ALS inhibitors in horseweed, tall waterhemp, and Palmer amaranth (Amaranthus palmeri). However, GR50 values decreased for both susceptible and resistant biotypes for the PRE applications compared to POST, suggesting the biologically effective dose of these herbicides is lower in soil residual applications. This research found that PRE applications of ALS inhibitors resulted in some level of control on horseweed and tall waterhemp classified as resistant to ALS inhibitors due to the higher efficacy of PRE herbicide applications.
Genetic analysis assessing the amino acid substitutions that confer resistance to ALS inhibitors in tall waterhemp confirmed a difference in selection pressure between PRE and POST applications and between ALS active ingredients in tall waterhemp. Applications of chlorimuron PRE at 11 g ai ha-1 selected for 35% homozygous W574L genotypes and at 44 g ha-1 selected for 70% homozygous W574L genotypes. An increase of homozygous W574L individuals along with a decrease in heterozygous individuals from 65 (11 g ha-1) to 29% (44 g ha-1) suggests that W574L is semi-dominant in tall waterhemp and that high labeled rates of chlorimuron applied PRE can partially overcome the heterozygous W574L-resistance mechanism. In horseweed, no difference in selection pressure was observed between application timing or between chlorimuron or cloransulam. A new mutation conferring ALS-inhibitor resistance in horseweed was discovered, a Pro197Leu amino acid substitution, with resistance ratios of 21X to chlorimuron and 8.6X to cloransulam. These resistance ratios are slightly less than those reported for the Pro197Ala and Pro197Ser amino acid substitutions in conferring ALS-inhibitor resistance in horseweed.
Finally, a survey of 42 populations of tall waterhemp in Indiana counties with confirmed ALS-inhibitor resistant populations of tall waterhemp found that all populations contained at least 16% individuals with the W574L amino acid substitution, 35 populations contained at least 1% individuals with the S653N substitution, and 9 populations contained at least 1% individuals with the S653T substitution. Taking into consideration the three mutations tested, 8 of the 42 populations tested contained <50% ALS-inhibitor resistant individuals within the population. Using the same tall waterhemp populations as collected in the survey, Next-Generation Sequencing was used to determine if other amino acid substitutions conferring resistance to ALS inhibitors existed. Results from WideSeq revealed that 10 other amino acid substitutions in the ALS protein may be conferring resistance in tall waterhemp in Indiana: A122T, A122N, A122S, P197T, P197L, P197H, D376E, and G654F. Further research from this survey also suggests that metabolic resistance to ALS inhibitors is likely a contributor to resistance in tall waterhemp in Indiana.
This research suggests that ALS-inhibiting herbicides, more specifically chlorimuron, would provide the greatest contribution to management of tall waterhemp. Chlorimuron would perform best when used in soil residual applications and in populations of tall waterhemp containing either individuals susceptible to chlorimuron or individuals heterozygous for ALS inhibitor resistance conferred by the W574L mutation. This research also demonstrates the specificity of the amino acid substitutions in the ALS protein and by weed species to realize the benefit of these herbicides for management of weeds resistant to ALS inhibitors. Molecular characterization of target site resistance to ALS inhibitors has traditionally been considered relatively simple. However, we found 11 new amino acid substitutions that confer resistance to ALS inhibitors in horseweed and tall waterhemp. The complexity of ALS inhibitor resistance calls for the use of methods such as NGS to detect all potential resistance mutations in a timely manner and for the use of tests detecting metabolic resistance. Overall, this research demonstrates that ALS inhibitors still provide some utility for management of weed populations classified as resistant to ALS inhibitors and that the resistance mechanisms in horseweed and tall waterhemp are more numerous than previously reported.
LI, YI-CHIA, and 李宜家. "Pterostilbene induced cell growth inhibition and cell death in cisplatin-resistance AGS gastric cancer cells." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/tvd6qq.
Full text大仁科技大學
藥學系碩士班
107
Pterostilbene is known to possess antioxidant activity and induces cell death in various types of cancer cells. Here, the effects of pterostilbene on cell viability in cisplatin-resistant AGS gastric cancer cells were investigated. This study demonstrated that pterostilbene was able to inhibit cell proliferation and induce cell death in concentration- and time-dependent manners. Pterostilbene-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation by TUNEL staining. The molecular mechanism of pterostilbene induced apoptosis was also investigated. The results show the caspase-9 and caspase-3 are activated, and using the pan-caspase inhibitor carbobenzoxyvalyl-alanyl-aspartyl fluoromethyl ketone by pterostilbene in cisplatin-resistant AGS gastric cancer cells. In summary, pterostilbene induced apoptosis in cisplatin-resistant AGS gastric cancer cells through activating the caspase cascade. The induction of apoptosis by pterostilbene may provide a pivotal mechanism of the anti-cancer effects and for treatment of human gastric cancer.
CHANG, KENG-MING, and 張耕銘. "Kaempferol Induced Cell Growth Inhibition and Cell Death in Cisplatin-resistance AGS Gastric Cancer Cells." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/6z752u.
Full text大仁科技大學
藥學系碩士班
107
Cisplatin is the leading therapeutic agent for gastric cancer therapy. In our study, Kaempferol suppressed cell viability in cisplatin-resistant AGS gastric cancer cells through inhibiting cell proliferation and causing cell death. The results demonstrated that cisplatin-resistant AGS gastric cancer cells exhibited marked cell shrinkage, cell membrane breakage and apoptotic bodies following treatment with kaempferol. Kaempferol also effectively suppressed cell confluence in a time- and concentration-dependent manner. The DAPI/TUNEL double staining determined that DNA condensation, a characteristic of apoptosis, was enhanced following treatment with kaempferol, which confirmed by the pan-caspase inhibitor. In addition, kaempferol increased caspase-3 and caspase-9 activities in cisplatin-resistant AGS gastric cancer cells. Overview, Kaempferol may elicit an anti-cancer response in cisplatin-resistant AGS gastric cancer cells and may have a good chemotherapeutic adjuvant to treat gastric cancer.