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Artykuły w czasopismach na temat "ALS inhibitor resistance"
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Beckie, Hugh J., Suzanne I. Warwick i Connie A. Sauder. "Basis for Herbicide Resistance in Canadian Populations of Wild Oat (Avena fatua)". Weed Science 60, nr 1 (marzec 2012): 10–18. http://dx.doi.org/10.1614/ws-d-11-00110.1.
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Wild oat is the second-most abundant, but most economically important, weed across the Canadian Prairies of western Canada. Despite the serious economic effects of resistance to acetyl-CoA carboxylase (ACC) or acetolactate synthase (ALS) inhibitors or both in this weed throughout the Northern Great Plains of North America, little research has examined the basis for herbicide resistance. We investigated target-site and nontarget-site mechanisms conferring ACC- and ALS-inhibitor resistance in 16 wild oat populations from across western Canada (four ACC-inhibitor resistant, four ALS-inhibitor resistant, and eight ACC- and ALS-inhibitor resistant). TheACC1mutations were found in 8 of the 12 ACC inhibitor-resistant populations. The Ile1781Leu mutation was detected in three populations, the Trp2027Cys and Asp2078Gly mutations were in two populations each, and the Trp1999Cys, Ile2041Asn, Cys2088Arg, and Gly2096Ser substitutions were in one population each. Three populations had twoACC1mutations. Only 2 of the 12 ALS inhibitor-resistant populations had anALStarget-site mutation—Ser653Thr and Ser653Asn substitutions. This is the first global report ofALStarget-site mutations inAvenaspp. and four previously undocumentedACC1mutations in wild oat. Based on these molecular analyses, seedlings of five ACC + ALS inhibitor-resistant populations (one with anACC1mutation; four with noACCorALSmutations) were treated with malathion, a known cytochrome P450 monooxygenase inhibitor, followed by application of one of four ACC- or ALS-inhibiting herbicides. Malathion treatment often resulted in control or suppression of these populations, suggesting involvement of this enzyme system in contributing to resistance to both ACC and ALS inhibitors.
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Eberlein, Charlotte V., Mary J. Guttieri, Philip H. Berger, John K. Fellman, Carol A. Mallory-Smith, Donn C. Thill, Roger J. Baerg i William R. Belknap. "Physiological consequences of mutation for ALS-inhibitor resistance". Weed Science 47, nr 4 (sierpień 1999): 383–92. http://dx.doi.org/10.1017/s0043174500091967.
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Biochemical and physiological effects of target site resistance to herbicides inhibiting acetolactate synthase (ALS) were evaluated using sulfonylurea-resistant (R) and -susceptible (S) near isonuclearLactuca sativa‘Bibb’ lines derived by backcrossing the resistance allele fromLactuca serriolaL. intoL. sativa.Sequence data suggest that resistance inL. sativais conferred by a single-point mutation that encodes a proline197to histidine substitution in Domain A of the ALS protein; this is the same substitution observed in RL. serriola. Kmapp(pyruvate) values for ALS isolated from R and SL. sativawere 7.3 and 11.1 mM, respectively, suggesting that the resistance allele did not alter the pyruvate binding domain on the ALS enzyme. Both R and S ALS had greater affinity for 2-oxobutyrate than for pyruvate at the second substrate site. Ratios of acetohydroxybutyrate: acetolactate produced by R ALS across a range of 2-oxobutyrate concentrations were similar to acetohydroxybutyrate: acetolactate ratios produced by S ALS. Specific activity of ALS from RL. sativawas 46% of the specific activity from SL. sativa, suggesting that the resistance allele has detrimental effects on enzyme function, expression, or stability. ALS activity from R plants was less sensitive to feedback inhibition by valine, leucine, and isoleucine than ALS from S plants. Valine, leucine, and isoleucine concentrations were about 1.5 times higher in R seed than in S seed on a per gram of seed basis, and concentrations of valine and leucine were 1.3 and 1.6 times higher, respectively, in R leaves than in S leaves. Findings suggest that the mutation for resistance results in altered regulation of branched-chain amino acid synthesis.
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Guo, Jiaqi, Chance W. Riggins, Nicholas E. Hausman, Aaron G. Hager, Dean E. Riechers, Adam S. Davis i Patrick J. Tranel. "Nontarget-Site Resistance to ALS Inhibitors in Waterhemp (Amaranthus tuberculatus)". Weed Science 63, nr 2 (czerwiec 2015): 399–407. http://dx.doi.org/10.1614/ws-d-14-00139.1.
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A waterhemp population (MCR) previously characterized as resistant to 4-hydroxyphenylpyruvate dioxygenase and photosystem II inhibitors demonstrated both moderate and high levels of resistance to acetolactate synthase (ALS) inhibitors. Plants from the MCR population exhibiting high resistance to ALS inhibitors contained the commonly found Trp574Leu ALS amino acid substitution, whereas plants with only moderate resistance did not have this substitution. A subpopulation (JG11) was derived from the MCR population in which the moderate-resistance trait was isolated from the Trp574Leu mutation. Results from DNA sequencing and ALS enzyme assays demonstrated that resistance to ALS inhibitors in the JG11 population was not due to an altered site of action. This nontarget-site ALS-inhibitor resistance was characterized with whole-plant dose–response experiments using herbicides from each of the five commercialized families of ALS-inhibiting herbicides. Resistance ratios ranging from 3 to 90 were obtained from the seven herbicides evaluated. Nontarget-site resistance to ALS has been rarely documented in eudicot weeds, and adds to the growing list of resistance traits evolved in waterhemp.
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Beckie, Hugh J., Linda M. Hall, Scott Meers, James J. Laslo i F. Craig Stevenson. "Management Practices Influencing Herbicide Resistance in Wild Oat". Weed Technology 18, nr 3 (wrzesień 2004): 853–59. http://dx.doi.org/10.1614/wt-03-124r.
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A 3-yr study was conducted in Wheatland County, Alberta to determine if agronomic practices of growers influenced the occurrence of herbicide resistance in wild oat. Wild oat seeds were collected in 33 fields in 1997 and in 31 fields in each of 1998 and 1999 (one field per grower). Seedlings were screened for resistance to two acetyl-CoA carboxylase (ACCase) inhibitors, imazamethabenz, an acetolactate synthase (ALS) inhibitor, and triallate, a thiocarbamate herbicide. A questionnaire on herbicide resistance awareness and management practices was completed by each grower. Both ACCase and ALS inhibitor resistance in wild oat were linked to a lack of crop rotation diversity. In addition, ALS inhibitor–resistant wild oat was associated with conservation-tillage systems and recent use of herbicides with that mode of action. Results of this study suggest that timely tillage and inclusion of fall-seeded and perennial forage crops in rotations will effectively slow the selection of resistance in this grass species.
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Varanasi, Vijay K., Jason K. Norsworthy, Chad Brabham i Robert C. Scott. "Characterization of Acetolactate Synthase (ALS)-Inhibitor Resistance in Pennsylvania smartweed (Persicaria pensylvanica)". Weed Science 66, nr 6 (21.09.2018): 710–14. http://dx.doi.org/10.1017/wsc.2018.44.
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AbstractPennsylvania smartweed [Persicaria pensylvanica(L.) M. Gómez] is a common weed of rice (Oryza sativaL.) in the midsouthern United States and has recently become a concern for farmers because of reduced tillage systems. Acetolactate synthase (ALS) inhibitors have been extensively used for controlling smartweeds in imidazolinone-resistant and conventional rice. In the present study, we confirmed resistance to commonly used ALS inhibitors in rice and characterized the underlying resistance mechanism in aP. pensylvanicabiotype from southeast Missouri. A dose–response experiment was conducted in the greenhouse using bensulfuron-methyl, imazethapyr, and bispyribac-sodium to determine the resistance index (resistance/susceptibility [R/S]) based on GR50estimates. The target-siteALSgene was amplified from R and S plants, and sequences were analyzed for mutations known to confer ALS-inhibitor resistance. TheP. pensylvanicabiotype in question was found to be resistant to bensulfuron-methyl (R/S=2,330), imazethapyr (R/S=12), and bispyribac-sodium (R/S=6). Sequencing of theALSgene from R plants revealed two previously known mutations (Pro-197-Ser, Ala-122-Ser) conferring resistance to sulfonylureas and imidazolinones. This is the first report of ALS-inhibitor resistance inP. pensylvanica.
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Beckie, H. J., L. M. Hall, F. J. Tardif i G. Séguin-Swartz. "Acetolactate synthase inhibitor-resistant stinkweed (Thlaspi arvense L.) in Alberta". Canadian Journal of Plant Science 87, nr 4 (1.10.2007): 965–72. http://dx.doi.org/10.4141/cjps06019.
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Two stinkweed populations from southern and central Alberta were not controlled by acetolactate synthase (ALS)-inhibiting herbicides in 2000. This study reports on their cross-resistance to ALS-inhibiting herbicides, molecular basis of resistance, and inheritance of resistance. Both putative herbicide-resistant biotypes responded similarly to increasing doses of the herbicides. The biotypes were highly resistant to ethametsulfuron and exhibited a low level of resistance to metsulfuron and imazethapyr. However, both biotypes were not resistant to florasulam, a triazolopyrimidine ALS inhibitor, or sulfometuron, a non-selective sulfonylurea ALS inhibitor. The cross-resistance pattern was consistent with the confirmed target-site mutation. Sequence analysis of the ALS gene detected a Pro197Leu mutation in both biotypes. Similar to many other ALS inhibitor-resistant weed biotypes, resistance was conferred by a single dominant gene. This study confirms the first global occurrence of herbicide resistance in this species. Key words: ALS-inhibitor resistance, ALS sequence, herbicide resistance, target-site mutation
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Tranel, Patrick J., Chenxi Wu i Ahmed Sadeque. "Target-Site Resistances to ALS and PPO Inhibitors Are Linked in Waterhemp (Amaranthus tuberculatus)". Weed Science 65, nr 1 (13.12.2016): 4–8. http://dx.doi.org/10.1614/ws-d-16-00090.1.
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It is generally expected that, in the case of multiple herbicide resistance, different resistance mechanisms within a weed will follow Mendel’s law of independent assortment. Research was conducted to investigate anecdotal observations suggesting that target site–based resistances to inhibitors of acetolactate synthase (ALS) and protoporphyrinogen oxidase (PPO) did not follow independent assortment in common waterhemp. Cosegregation of the two resistances was observed in backcross lines (population sensitive to both herbicides as recurrent parent). Specifically, whereas 52% of backcross plants were resistant to a PPO inhibitor, this percentage increased to 92% when the backcross plants were preselected for resistance to an ALS inhibitor. Molecular marker analysis confirmed that the corresponding genes (ALSandPPX2) were genetically linked. When data from all plants analyzed were pooled, the genetic distance between the two genes was calculated to be 7.5 cM. The two genes were found to be about 195 kb apart in the recently published grain amaranth genome, explaining the observed genetic linkage. There is likely enough recombination that occurs between the linked genes to prevent the linkage from having significant implications in terms of resistance evolution. Nevertheless, documentation of the happenstance linkage between target-site genes for resistance to ALS and PPO inhibitors in waterhemp is a reminder that one should not assume distinct resistance mechanism will independently assort.
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Beckie, Hugh J., i Xavier Reboud. "Selecting for Weed Resistance: Herbicide Rotation and Mixture". Weed Technology 23, nr 3 (wrzesień 2009): 363–70. http://dx.doi.org/10.1614/wt-09-008.1.
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Herbicide rotations and mixtures are widely recommended to manage herbicide resistance. However, little research has quantified how these practices actually affect the selection of herbicide resistance in weeds. A 4-yr experiment was conducted in western Canada from 2004 to 2007 to examine the impact of herbicide rotation and mixture in selecting for acetolactate synthase (ALS) inhibitor resistance in the annual broadleaf weed, field pennycress, co-occurring in wheat. Treatments consisted of the ALS-inhibitor herbicide, ethametsulfuron, applied in a mixture with bromoxynil/MCPA formulated herbicide (photosystem-II inhibitor/synthetic auxin), or in rotation with the non-ALS inhibitor at an ALS-inhibitor application frequency of 0, 25, 50, 75, and 100% (i.e., zero to four applications, respectively) over the 4-yr period. The field pennycress seed bank at the start of the experiment contained 5% ethametsulfuron-resistant seed. Although weed control was only marginally reduced, resistance frequency of progeny of survivors increased markedly after one ALS-inhibitor application. At the end of the experiment, the level of resistance in the seed bank was buffered by susceptible seed, increasing from 29% of recruited seedlings after one application to 85% after four applications of the ALS inhibitor. The level of resistance in the seed bank for the mixture treatment after 4 yr remained similar to that of the nontreated (weedy) control or 0% ALS-inhibitor rotation frequency treatment. The results of this study demonstrate how rapidly ALS-inhibitor resistance can evolve as a consequence of repeated application of herbicides with this site of action, and supports epidemiological information from farmer questionnaire surveys and modeling simulations that mixtures are more effective than rotations in mitigating resistance evolution through herbicide selection.
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Tseng, Te-Ming, Swati Shrestha, James D. McCurdy, Erin Wilson i Gourav Sharma. "Target-site Mutation and Fitness Cost of Acetolactate Synthase Inhibitor-resistant Annual Bluegrass". HortScience 54, nr 4 (kwiecień 2019): 701–5. http://dx.doi.org/10.21273/hortsci13512-18.
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Annual bluegrass (Poa annua L.) is an annual weed that is particularly troublesome in managed turfgrass. It has been controlled conventionally with herbicides, including acetolactate synthase (ALS) inhibitors. However, resistance to ALS inhibitors has been documented throughout the southeastern United States since 2012. A rate–response trial was conducted to confirm and determine the resistance level of suspected resistant P. annua biotypes from Mississippi (Reunion), followed by DNA sequencing to determine whether the mechanism of resistance is a target-site mutatio n. In addition, a fitness assay was conducted together with a susceptible biotype to determine whether resistance to ALS inhibitors is associated with decreased fitness. Reunion was at least 45 times more resistant to foramsulfuron than the standard susceptible biotype based on I50 estimates [I50 is the rate of herbicide giving a 50% response (50% visual necrosis)], requiring a predicted 331 g a.i./ha foramsulfuron for 50% control. DNA sequencing results identified a Trp574-to-Leu mutation in the ALS gene of the Reunion biotype, which has been shown by other studies to confer resistance to ALS inhibitors. Measurement of fitness parameters among the Reunion and susceptible biotypes demonstrated reduced seed yield, tillering, and flowering time in the resistant Reunion biotype, suggesting that ALS inhibitor resistance is possibly correlated to decreased fitness in P. annua. Alternative methods to control P. annua need to be considered as a result of the evolution of herbicide-resistant biotypes. An integrated management strategy to control P. annua weeds will help prevent further evolution of resistance. Because this study evaluated only the target-site mechanism of resistance, it is also necessary to determine whether the resistant biotype has reduced uptake, translocation, or enhanced metabolism as additional mechanisms of resistance. Consequently, a fitness study encompassing a more comprehensive list of plant parameters will provide conclusions of the fitness costs associated with ALS inhibitor resistance in P. annua. Chemical names: Foramsulfuron {1-(4,6-dimethoxypyrimidin-2-yl)-3-[2-(dimethylcarbamoyl)-5-formamidophenylsulfonyl] urea}.
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Molin, William T., Vijay K. Nandula, Alice A. Wright i Jason A. Bond. "Transfer and Expression of ALS Inhibitor Resistance from Palmer Amaranth (Amaranthus palmeri) to anA. spinosus×A. palmeriHybrid". Weed Science 64, nr 2 (czerwiec 2016): 240–47. http://dx.doi.org/10.1614/ws-d-15-00172.1.
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Transfer of herbicide resistance among closely related weed species is a topic of growing concern. A spiny amaranth × Palmer amaranth hybrid was confirmed resistant to several acetolactate synthase (ALS) inhibitors including imazethapyr, nicosulfuron, pyrithiobac, and trifloxysulfuron. Enzyme assays indicated that the ALS enzyme was insensitive to pyrithiobac and sequencing revealed the presence of a known resistance conferring point mutation, Trp574Leu. Alignment of the ALS gene for Palmer amaranth, spiny amaranth, and putative hybrids revealed the presence of Palmer amaranth ALS sequence in the hybrids rather than spiny amaranth ALS sequences. In addition, sequence upstream of the ALS in the hybrids matched Palmer amaranth and not spiny amaranth. The potential for transfer of ALS inhibitor resistance by hybridization has been demonstrated in the greenhouse and in field experiments. This is the first report of gene transfer for ALS inhibitor resistance documented to occur in the field without artificial/human intervention. These results highlight the need to control related species in both field and surrounding noncrop areas to avoid interspecific transfer of resistance genes.
Rozprawy doktorskie na temat "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.
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Kyoto University (京都大学)0048
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
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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.
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The objective of this Ph.D. research was to identify new and novel mechanisms of wild radish (Raphanus raphanistrum L.) resistance to photosystem II (PSII) inhibitors, auxinics, and acetohydroxyacid synthase (AHAS) inhibitors. PSIIinhibitor resistance was demonstrated to be target-site based, and conferred by a Ser264 to Gly substitution of the D1 protein. Auxinic resistance was associated with reduced herbicide translocation to the meristematic regions of resistant wild radish plants. Two new resistance mutations of wild radish AHAS were discovered, including one encoding the globally rare Asp376 to Glu substitution, and another encoding an Ala122 to Tyr substitution, which has never been identified or assessed for resistance in plants previously. Characterization of the frequency and distribution of AHAS resistance mutations in wild radish from the WA wheatbelt revealed that Glu376 was widespread, and that some mutations of AHAS are more common than others. Computer simulation was used to examine the molecular basis of resistance-endowing AHAS target-site mutations. Furthermore, through the computer-aided analysis, residues were identified with the potential to confer resistance upon substitution, but which have not previously been assessed for this possibility. Results from this Ph.D. research demonstrate that diverse, unrelated mechanisms of resistance to PSII inhibitors, auxinics, and AHAS inhibitors have evolved in wild radish of the WA wheatbelt, and that these mechanisms have accumulated in some populations.
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Ferguson, 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.
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Weerasooriya, 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.
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Doctor of PhilosophyDepartment 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.
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Castel, Morales Pau. "Molecular mechanisms of resistance to PI3K inhibitors". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396640.
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The development of high-throughput sequencing technologies has prompted the evaluation of large cohorts of different tumor types. The results from these comprehensive genomic studies have revealed the most commonly mutated genes across human cancers, providing further understanding of the pathogenesis, molecular classification, and therapeutic strategies for this disease.
PIK3CA, the gene encoding the PI3Kα isoform, is among the most frequently mutated genes in breast, head and neck, colorectal, and lung cancer, among others. Activating mutations in PIK3CA promote hyperactivation of the PI3K/AKT pathway, leading to increased proliferation, cell growth, survival, and metabolism.
Current efforts are aimed to develop PI3K inhibitors as an effective therapy for PIK3CA mutated cancers and, despite promising clinical responses, the emergence of drug resistance is a clear limitation. In this doctoral thesis, we have explored these mechanisms of resistance in order to provide a better understanding of tumor evolution upon therapy, define subpopulations of patients that are likely to respond to PI3K inhibitors, and provide novel pharmacological combinations to overcome therapy refractoriness.
The loss of the tumor suppressor PTEN was found to play an important role in the resistance of PI3Kα inhibitors in preclinical models and patients, mainly by reactivating the PI3K/AKT pathway as a result of an increased dependency on the PI3Kβ isoform. Our work also demonstrated the notion of tumor evolution and phenotypic convergent evolution in response to therapeutic pressure.
Moreover, we have established that intrinsic resistance to PI3Kα inhibitors occurs as a result of incomplete inhibition of the mammalian target of rapamycin complex 1 (mTORC1), a downstream effector of the PI3K/AKT pathway. PI3Kα inhibitor-resistant cells could be re-sensitized through the blockade of phosphoinositide-dependent kinase (PDK1), a constitutively active kinase, using genetic or pharmacologic inhibition. Further experiments showed that the downstream effector of PDK1 is the serum and glucocorticoid-induced kinase 1 (SGK1), which promotes cell survival through the
phosphorylation of key proteins such as FOXO3 and TSC2. Accordingly, the resistant phenotype could be also reverted by inhibiting SGK1, a novel pharmacological approach that has revealed interesting roles of this kinase in tumor biology.
Genetically engineered mouse models represent reliable tools for investigating the etiology, biology, and progression of human diseases, as well as for exploring novel therapeutic approaches. By serendipity, we discovered the role of PIK3CA mutations in the genesis of venous malformations, an aberration of normal venous development that currently lacks effective treatments. Our mouse models recapitulated the histopathologic features of the disease and provided an experimental platform to test novel pharmacological approaches. PI3Kα inhibitors were effective at reducing the morbidity and mortality of mice carrying venous malformations.
The results from this thesis highlight the importance of defining the molecular determinants of sensitivity and resistance to PI3K inhibitors, a therapy that will most likely benefit PIK3CA mutant patients.El 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.
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Recondo, Gonzalo. "Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.
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Les analyses moléculaires et la classification des adénocarcinomes bronchiques ont conduit au développement de thérapies ciblées sélectives visant à améliorer le contrôle de la maladie et la survie des patients. ALK (anaplastic lymphoma kinase) est un récepteur tyrosine kinase de la famille des récepteurs de l'insuline. Des réarrangements chromosomiques impliquant le domaine kinase d’ALK sont présents dans environ 3 à 6% des patients atteints d'un adénocarcinome bronchique. La protéine de fusion provoque une activation du domaine kinase de manière constitutive et indépendante du ligand. Lorlatinib est un inhibiteur d’ALK de troisième génération avec une efficacité et une sélectivité optimale, ainsi qu’une pénétration élevée vers le système nerveux central. Lorlatinib peut vaincre la résistance induite par plus de 16 mutations secondaires dans le domaine kinase d’ALK acquises lors de la progression aux ALK TKI de première et deuxième générations. Le traitement par lorlatinib est donc efficace chez les patients préalablement traités par un ALK TKI de première ou deuxième génération, et est actuellement approuvé pour cette indication. Le spectre complet de mécanismes de résistance au lorlatinib chez les patients reste à élucider. Il a récemment été rapporté que l'acquisition séquentielle de deux mutations ou plus dans le domaine kinase, également appelées mutations composées, est responsable de la progression de la maladie chez environ 35% des patients traités par le lorlatinib, principalement en altérant sa liaison au domaine kinase d’ALK. Cependant, l’effet de ces mutations sur la sensibilité aux différents inhibiteurs d’ALK peut varier, et les autres mécanismes de résistance survenant chez la plupart des patients restent inconnus. Mon travail de thèse avait pour but d’explorer la résistance au lorlatinib chez des patients atteints d'un cancer du poumon ALK réarrangé par la mise en œuvre de biopsies spatiales et temporelles et le développement de modèles dérivés de patients. Dans le cadre de l’étude institutionnelle MATCH-R (NCT02517892), nous avons effectué un séquençage à haut débit de l’exome, de l’ARN et ciblé, ainsi qu’un séquençage des ctDNA afin d’identifier les mécanismes de résistance. Nous avons établi des lignées cellulaires dérivées de patients et caractérisé de nouveaux mécanismes de résistance et identifiés de nouvelles stratégies thérapeutiques in vitro et in vivo. Nous avons identifié trois mécanismes de résistance chez quatre patients avec des biopsies appariées. Nous avons étudié l'induction de la transition épithélio-mésenchymateuse (EMT) par l'activation de SRC dans une lignée cellulaire, dérivée d’un patient, exposée au lorlatinib. Les cellules mésenchymateuses étaient sensibles à l’inhibition combinée de SRC et d'ALK, montrant que même en présence d'un phénotype agressif, des stratégies de combinaison peuvent surmonter la résistance aux ALK TKI. Nous avons identifié deux nouvelles mutations composées du domaine kinase d’ALK, F1174L / G1202R, C1156Y / G1269A survenues chez deux patients traités par le lorlatinib. Nous avons développé des modèles de cellules Ba / F3 exprimant les mutations simples et composées pour étudier leur effet sur la résistance au lorlatinib. Enfin, nous avons caractérisé un nouveau mécanisme de résistance provoqué par la perte de fonction de NF2 au moment de la progression du lorlatinib par l’utilisation de PDX et de lignées cellulaires dérivées de patients, et par CRISPR / CAS9 knock-out de NF2. Nous avons constaté que l'activation de mTOR par la perte de fonction de NF2 provoquait la résistance au lorlatinib et qu'elle pouvait être surmontée par le traitement avec des inhibiteurs de mTOR.Cette étude montre que les mécanismes de résistance au lorlatinib sont plus divers et complexes que prévu. Nos résultats démontrent également comment les études longitudinales de la dynamique tumorale permettent de déchiffrer la résistance aux TKI et d'identifier des stratégies thérapeutiquesThe 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
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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.
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Lee, 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.
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Recent whole-exome sequencing studies of hundreds of high-risk neuroblastoma (hNB) patients have identified Anaplastic Lymphoma Kinase (ALK) as the only directly ‘druggable’ target with a significant mutation rate (9%). ALK is a receptor tyrosine kinase whose dysregulation has been implicated as the driver lesion in a variety of cancer types, including Non-Small Cell Lung Cancer (NSCLC) and various paediatric malignancies. As a kinase normally only expressed during early development in the foetal brain, ALK is an ideal therapeutic target and it has proven relatively simple to target therapeutically. However, resistance to ALK-targeted therapy, particularly in ALK+ NSCLC patients has frequently been observed. The majority of the acquired resistance mechanisms noted in NSCLC patients rely on bypass signalling pathways, which are tissue-context dependent. To proactively identify and develop strategies to counter these varied yet expected resistance mechanisms in other ALK-driven tumours, we must gain a better insight of the bypass-track mechanism(s) in a tumour-specific manner. The present study aimed to functionally identify putative resistance mechanisms against ALK inhibitors via extensive CRISPR/Cas9-based genome-wide knockout (GeCKO) or overexpression screens (SAM) in the human neuroblastoma cell line, SHSY-5Y, to develop novel therapeutic strategies for ALK mutant NBs. The GeCKO screen identified a total of 39 genes and miRNAs, and the SAM overexpression screen identified 25 genes that induce resistance to ALK inhibitors. These putative resistance-inducing candidates were then aligned with a publicly available expression dataset of hNB patients (n = 476) to identify those with prognostic significance (Kaplan-Meier event-free survival analysis), specifically those that are indicative of relapse risk. Furthermore, all candidates identified from the screen were individually validated in vitro. Two of the candidates, one from each of the knockout and overexpression screens, were further investigated. Inhibition of hsa-miR-1304-5p, identified from GeCKO screen, induced resistance to ALK inhibitors. Interestingly, interference of has-miR-1304-5p, in the absence of ALK inhibitors, also enabled enhanced cell viability whilst the transfection of its mimic led to a significant reduction of viability across 17 distinct NB cell lines. Through genome-wide cDNA microarrays, in silico predictions, and UTR-luciferase assays, this study identified hsa-miR-1304-5p to be a major regulator of the Ras/MAP Kinase pathway. Overexpression of PIM1, identified from the SAM screen, in NB cell lines induced resistance to ALK inhibitors and this phenotype could be reversed on transducing cells with RNAi against PIM1. Interestingly, inhibition of PIM1 in wild-type cell lines via RNAi or pharmacological compounds led to substantially enhanced potency of ALK inhibitors suggesting PIM1 inhibitors as combinatorial agents with ALK inhibitors for the therapy of treatment-naive hNB. Through protein analysis of all identified downstream targets of PIM1, this study revealed NB-specific actions of the PIM1 oncoprotein that include the inactivation of the pro-apoptotic protein BAD. In summary, this study has identified mechanisms of resistance to ALK inhibitors as well as novel front-line therapeutic strategies for hNB patients that should be implemented clinically.
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Randhawa, 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.
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The first case of field evolved acetolactate synthase (ALS) inhibiting herbicide resistance in the model plant, mouse-ear cress, was reported in winter wheat fields in Westmoreland County, Virginia. A putative resistant (R) mouse-ear population was assessed for ALS resistance relative to a putative susceptible (S) and a susceptible lab population Columbia (C). Results indicated that the R population needed 23 to >2400 fold rate of thifensulfuron relative to S or C population, and it has evolved cross-resistance to sulfonylureas (SU), triazolopyrimidine sulfonanilides (TP), and sulfonylaminocarbonyltriazolinones (SCT). Further studies sequenced the whole genome for four field populations, representing two locations and two resistance levels (high and low) per location, to characterize the genetic mechanism of ALS resistance. The results revealed that all populations contained mutations in the ALS gene at the Pro197 site, although the Pro was substituted by Phe in one location and Thr in the other. Also, both high- and low-level resistant plants at one location had additional mutations (Trp574Leu or Asp376Glu) known to confer resistance to ALS inhibiting herbicides. Patterns of herbicide cross-resistance also varied among the populations. Additionally, research was conducted to assess preemergent (PRE) and postemergent (POST) alternative herbicide options for control of ALS resistant mouse-ear cress and its interference with winter wheat. Results indicate flumioxazin, pyroxasulfone, and metribuzin can be used for effective PRE control whereas 2,4-D, dicamba, and metribuzin can be effective post control options. No mouse-ear cress interference with winter wheat was observed at density of more than 300 plants m-2.Master of Science in Life Sciences
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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.
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Els inhibidors de la transcriptassa inversa no anàlegs de nucleòsids (ITINAN) s’utilitzen sovint en el tractament antiretroviral (TAR) per la seva eficàcia i simplicitat. La resistència està causada per mutacions específiques a posicions de resistència. L’ús clínic dels ITINAN de primera generació (nevirapina i efavirenz) s’ha vist limitat pels efectes adversos, i la baixa barrera en front a la resistència, pel que s’han desenvolupat ITINAN de segona generació (etravirina i rilpivirina), ambdós recentment aprovats.
Rilpivirina mostra també una baixa barrera a la resistència. Al igual que nevirapina o efavirenz, pot perdre l’activitat amb només una o dues mutacions. Hi ha un elevat grau de resistència creuada entre tots els ITINAN, pràcticament complerta entre nevirapina i efavirenz, i més limitada entre els ITINAN de primera i segona generació. Per tant, el coneixement del impacte de les mutacions de resistència seleccionades per ITINAN de primera generació sobre els de segona generació té una importància cabdal.
Els llistats de mutacions de resistència front als ITINAN estan ja ben definits a l’actualitat, permetent el seu anàlisi en mostres clíniques, oferint una oportunitat única per a la investigació del impacte de la resistència del VIH-1 en la resposta al TAR de inici, rescat o simplificació.
En aquesta tesi es discuteix la rellevància de les mutacions de resistència sobre la resposta al tractament, s’identifiquen les mutacions i patrons de mutacions seleccionades en el fracàs virològic (FV) amb determinats ITINAN, i s’analitza el risc de FV posterior a tractaments basats en ITINAN.
El primer capítol avalua la efectivitat de etravirina en el rescat de FV atesos a 4 hospitals de referència de Barcelona. Els tractaments van ser ben tolerats i assolir taxes de supressió virològica superiors a les observades en els seus assaigs clínics de registre, probablement degut a la inclusió de un nombre més elevat de fàrmacs actius als règims. Hem identificat l’associació de recomptes de cèl·lules CD4+ >200 cèls/mm3 i l’ús de raltegravir i darunavir a taxes menors de FV en l’anàlisi multivariant. No hem trobat relació entre interrupció o FV previs a nevirapina o efavirenz, i resposta a etravirina.
El segon capítol analitza el impacte sobre rilpivirina de mutacions de resistència seleccionades en FV als altres ITINAN (nevirapina, efavirenz o etravirina) a 22 centres hospitalaris de España. Es va demostrar resistència a rilpivirina en el 20% de FV a ITINAN, més freqüent en FV a etravirina i nevirapina que a efavirenz. Les mutacions de resistència a rilpivirina més freqüents van ser Y181C, K101E/P, H221Y i E138A/G/K. E138K/M184I, la combinació mes freqüentment seleccionada amb rilpivirina en naives, va estar absent en aquesta població pretractada. L100I i V108I van ser significativament més freqüents en fracassos a efavirenz. Contràriament, Y181C/I, V106A, H221Y i F227L ho van ser amb nevirapina.
Finalment el tercer capítol estima la eficàcia de un règim de simplificació de TAR amb nevirapina, tenofovir i emtricitabina/lamivudina, realitzat a la nostra Unitat a Barcelona. No es van aïllar patrons de mutacions inesperats en els FV. A les 48 setmanes el 90% de malalts tenien una càrrega viral < 50 còpies/mL, el FV va ser infreqüent, i 25 (7.4%) pacients van suspendre el tractament per toxicitat. Els factors associats amb FV a l’anàlisi multivariant van ser drogadicció intravenosa, temps amb càrrega viral indetectable abans de la simplificació, nombre de NRTIs i NNRTIs rebuts, i les interrupcions no programades de tractaments previs amb nevirapina o efavirenz. En base a aquestes dades s’hauria de desaconsellar el reinici del TAR amb nevirapina, tenofovir i emtricitabina/lamivudina en interrupcions no programades del TAR, encara que la càrrega viral sigui indetectable al moment de la suspensió.
Inesperadament, hem trobat una taxa significativament més elevada de FV amb lamivudina que amb emtricitabina amb aquesta combinació, així com una major selecció de M184V. Aquests resultats suggereixen precaució en la substitució de emtricitabina per lamivudina, al menys en règims basats en nevirapina i tenofovir.Non-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.
Książki na temat "ALS inhibitor resistance"
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Gilbert, Paul, i Jennifer S. Mascaro. Compassion Fears, Blocks and Resistances. Redaktorzy Emma M. Seppälä, Emiliana Simon-Thomas, Stephanie L. Brown, Monica C. Worline, C. Daryl Cameron i James R. Doty. Oxford University Press, 2017. http://dx.doi.org/10.1093/oxfordhb/9780190464684.013.29.
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While there is increasing research on the benefits and facilitators of compassion, as with all motives, there are inhibitors. This chapter will not cover the benefits of compassion, explored in other chapters, but instead considers its inhibitors: the fears, blocks, and resistances (FBRs) to compassion and their evolutionary and psychosocial origins. We begin with an explication of a model for compassion, and show how compassion rests on discrete components and competencies that can be differentially inhibited. Next, we utilize Ernst Mayr’s (1961) classic heuristic to understand compassion inhibition; namely, the “ultimate” and “proximate” analysis. We conclude with an exploration of the antidotes to these inhibitors. Greater research into the nature of compassion inhibitors and insights on how to address them could increase the use of compassion in different domains of life.
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Tobon, Amalia Londono, i Hanna E. Stevens. Adolescents with SSRI-Resistant Depression. Redaktorzy Ish P. Bhalla, Rajesh R. Tampi, Vinod H. Srihari i Michael E. Hochman. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190625085.003.0008.
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This chapter provides a summary of a landmark study in child and adolescent psychiatry addressing the common clinical experience of an adolescent that does not respond to initial antidepressant treatment. Should adolescents with selective serotonin reuptake inhibitor (SSRI) resistant depression be switched to another SSRI or to venlafaxine with or without cognitive behavioral therapy? Starting with that question, it describes the basics of the study, including funding, study locations, who was studied, how many patients, study design, study interventions, follow-up, endpoints, results, and criticism and limitations. This chapter also briefly reviews other relevant studies and information, discusses implications of the findings, and concludes with a relevant clinical case scenario and suggested management for the case.
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Wong, Han Hsi, Basma Greef i Tim Eisen. Treatment of metastatic renal cancer. Redaktor James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0089.
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Metastatic renal cancer is resistant to standard chemotherapy. Although some patients with indolent disease can be initially managed with observation, the majority of patients will require aggressive treatment soon after diagnosis. Options include cytoreductive nephrectomy, resection of a solitary metastasis in highly selected cases, or systemic therapy options. The TKIs sunitinib and pazopanib are currently the first-line treatments of choice. Whilst axitinib and cabozantinib have important roles in the second line the PD-1 checkpoint inhibitor, nivolumab, is now established as standard second line therapy. Inhibitors of the mammalian target of rapamycin (mTOR) pathway, everolimus and temsirolimus, interleukin-2 as well as the anti-angiogenic antibody bevacizumab have also been shown to be effective. The treatment paradigm of metastatic renal cancer is constantly changing as evidence from clinical trials continues to emerge. With the development of agents addressing novel targets such as T-cell regulation, the future certainly looks brighter for patients diagnosed with this disease.
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Mukherji, Deborah, Aurelius Omlin, Carmel Pezaro i Johann De Bono. Novel therapies and emerging strategies for the treatment of patients with castration-resistant prostate cancer. Redaktor James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0069.
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Castration-resistant prostate cancer (CRPC) represents a final stage of this malignancy for many men and is defined as the progression of prostate cancer despite castrate levels of testosterone. CRPC may present as a rising PSA, the development of new metastases, or worsening of known metastases. Recent advances have resulted in five new treatments for CRPC: the immunotherapy sipuleucel-T; the cytotoxic cabazitaxel; the androgen biosynthesis inhibitor abiraterone acetate; the radioisotope radium-223; and the antiandrogen enzalutamide. These have all improved overall survival in randomized phase III studies for patients with metastatic CRPC. Furthermore, multiple agents and combinations are currently in late-stage clinical testing. Men with advanced prostate cancer represent an important population for clinical and translational research and clinical trial participation should be considered as part of standard care.
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Ewald, Paul W. Evolutionary control of infectious disease in low-income countries. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198789833.003.0009.
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An evolutionary suggests that health interventions can reduce not only the frequency of infectious disease but also the harmfulness of the causal organisms. Interventions that may accomplish this dual goal include hygienic investments such as vector proofing of housing, provisioning of safe water supplies, infrastructure that blocks transmission of durable propagules, the prevention of attendant-borne transmission in hospitals and reductions in the potential for sexual transmission. Vaccines can also reduce the frequency of infection and the harmfulness of the target organisms if they are designed to inhibit selectively the harmful variants in the target population. These approaches should help suppress the evolution of antimicrobial resistance because benign variants causing mild or asymptomatic infections will be less exposed to antimicrobial treatment, reducing the strength of selection for antimicrobial resistance. The interventions should improve health at low cost, which would be especially important for low-income populations.
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Barnard, Matthew, i Nicola Jones. Intensive care management after cardiothoracic surgery. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0368.
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Management of the post-cardiothoracic surgical patient follows general principles of intensive care, but incorporates certain unique considerations. In cardiac surgical patients peri-operative ischaemia, arrhythmias and ventricular dysfunction mandate specific monitoring requirements, and individual pharmacological and mechanical support. Suspicion of myocardial ischaemia should not only lead to pharmacological treatment, but also consideration of urgent angiography to exclude coronary graft occlusion. Ventricular dysfunction may be pre-existing or attributable to intra-operative myocardial ‘stunning’. Catecholamines and phosphodiesterase inhibitors are the mainstay of therapy. Rarely, intra-aortic balloon pumping or ventricular assist devices are required. Significant bleeding (with potential cardiac tamponade), respiratory compromise, acute kidney injury, neurological injury, and deep sternal wound infection each occur in ~2–3% of cardiac surgical patients. Each of these has individual risk factors and specific management considerations. General guidelines for patients who have undergone thoracic surgery include early extubation, fluid restriction, effective analgesia, and protective lung ventilation. Thoracic patients are at risk of atelectasis, respiratory infection, bronchial air leak, and right ventricular failure. Positive pressure ventilation is avoided whenever possible particularly after pneumonectomy, but is sometimes necessary in compromised patients. Air leaks are common. Alveolopleural fistulae usually improve with conservative management,whereas bronchopleural fistulae are more likely to require surgical intervention. Lung surgery is high risk for patients with ischaemic heart disease. Patients with pre-existing elevated pulmonary vascular resistance may exhibit right ventricular dysfunction and may fail to cope with a further increase in pulmonary vascular resistance consequent to lung resection. Lung collapse and infection are constant risks throughout the entire post-operative period.
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Macdougall, Iain C. Erythropoiesis-stimulating agents in chronic kidney disease. Redaktor David J. Goldsmith. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0124.
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The advent of recombinant human erythropoietin (epoetin) in the late 1980s transformed the management of renal anaemia, liberating many dialysis patients from lifelong regular blood transfusions, in turn causing severe iron overload and human leucocyte antigen sensitization. Epoetin can be administered either intravenously or subcutaneously, but the half-life of the drug is fairly short at around 6–8 hours, necessitating frequent injections. To circumvent this problem, two manipulations to the erythropoietin molecule were engineered. The first of these was to attach an extra two carbohydrate chains to the therapeutic protein hormone (to make darbepoetin alfa), and the second was to attach a large pegylation chain to make continuous erythropoietin receptor activator. Both of these strategies prolonged the circulating half-life of the erythropoietin analogue. The next erythropoietic agent to be produced was peginesatide, a peptide-based agent which had no structural homology with native or recombinant erythropoietin, but shared the same biological and functional characteristics. Future strategies include stabilization of hypoxia-inducible factor, by orally active inhibitors of the prolyl hydroxylase enzyme, and advanced clinical trials are underway. In the meantime, several large randomized controlled trials have highlighted the potential harm in targeting a near normal haemoglobin of 13–14 g/dL (with an increased risk of cardiovascular complications), and sub-normal correction of anaemia is now advised. Some patients may show mild or severe resistance to erythropoiesis-stimulating agent (ESA) therapy, and common causes include iron insufficiency, infection, and underlying inflammation. Very rarely, patients may produce antibodies against their ESA, which neutralize not only the ESA, but also endogenous erythropoietin, causing pure red cell aplasia.
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Whitworth, Caroline, i Stewart Fleming. Malignant hypertension. Redaktor Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0216.
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Malignant hypertension (MH) is recognized clinically by elevated blood pressure together with retinal haemorrhages or exudates with or without papilloedema (grades III or IV hypertensive retinopathy); and may constitute a hypertensive emergency or crisis when complicated by evidence of end-organ damage including microangiopathic haemolysis, encephalopathy, left ventricular failure, and renal failure. Though reversible, it remains a significant cause of end-stage renal failure, and of cardiovascular and cerebrovascular morbidity and mortality in developing countries.MH can complicate pre-existing hypertension arising from diverse aetiologies, but most commonly develops from essential hypertension. The absolute level of blood pressure appears not to be critical to the development of MH, but the rate of rise of blood pressure may well be relevant in the pathogenesis. The pathogenesis of this transformation remains unclear.The pathological hallmark of MH is the presence of fibrinoid necrosis (medial vascular smooth muscle cell necrosis and fibrin deposition within the intima) involving the resistance arterioles in many organs. Fibrinoid necrosis is not specific to MH and this appearance is seen in other conditions causing a thrombotic microangiopathy such as haemolytic uraemic syndrome, scleroderma renal crisis, antiphospholipid syndrome, and acute vascular rejection post transplant. MH can both cause a thrombotic microangiopathy (TMA) but can also complicate underlying conditions associated with TMA.The pathophysiological factors that interact to generate and sustain this condition remain poorly understood. Risk factors include Afro-Caribbean race, smoking history, younger age of onset of hypertension, previous pregnancy, and untreated hypertension associated with non-compliance or cessation of antihypertensive therapy.Evidence from clinical studies and animal models point to a central role for the intrarenal renin–angiotensin system (RAS) in MH; there is good evidence for renal vasoconstriction and activation of the renal paracrine RAS potentiating MH once established; however, there may also be a role in the predisposition of MH suggested by presence of increased risk conferred by an ACE gene polymorphism in humans and polymorphisms for both ACE and AT1 receptor in an animal model of spontaneous MH. Other vasoactive mediators such as the endothelin and the inflammatory response may be important contributing to and increasing endothelial damage. There have been no randomized controlled trials to define the best treatment approach, but progressive lowering of pressures over days is considered safest unless made more urgent by critical clinical state. It seems logical to introduce ACE inhibition cautiously and early, but in view of the risk of rapid pressure lowering some recommend delay.
Części książek na temat "ALS inhibitor resistance"
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Eberlein, C. V., M. J. Guttieri, C. A. Mallory-Smith i D. C. Thill. "Effects of Mutation for ALS-Inhibitor Resistance on ALS Activity in Resistant and Susceptible Near-Isonuclear Lactuca Lines". W Weed and Crop Resistance to Herbicides, 191–97. Dordrecht: Springer Netherlands, 1997. http://dx.doi.org/10.1007/978-94-011-5538-0_21.
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Simionato, Francesca, Carmine Carbone, Giampaolo Tortora i Davide Melisi. "Resistance to ALK Inhibitors". W Resistance to Targeted Anti-Cancer Therapeutics, 147–63. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-46091-8_5.
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Shibaike, Hiroyuki, Akira Uchino i Kazuyuki Itoh. "Molecular Characterization of Resistance to Acetolactate Synthase Inhibitors inLindernia micrantha: Origin and Expansion of Resistant Biotypes". W ACS Symposium Series, 244–54. Washington, DC: American Chemical Society, 2005. http://dx.doi.org/10.1021/bk-2005-0899.ch021.
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Müllner, H., P. Eckes i G. Donn. "Engineering Crop Resistance to the Naturally Occurring Glutamine Synthetase Inhibitor Phosphinothricin". W ACS Symposium Series, 38–47. Washington, DC: American Chemical Society, 1993. http://dx.doi.org/10.1021/bk-1993-0524.ch003.
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Shaner, D. L., i I. Heap. "Herbicide Resistance in North America: The Case for Resistance to ALS Inhibitors in the United States". W ACS Symposium Series, 161–67. Washington, DC: American Chemical Society, 2001. http://dx.doi.org/10.1021/bk-2002-0808.ch010.
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Mancini, Maicol, i Yosef Yarden. "Resistance of Lung Cancer to Kinase Inhibitors Specific to EGFR or ALK". W Resistance to Targeted Anti-Cancer Therapeutics, 29–49. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67932-7_2.
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Ishikawa, Toshihisa, Yutaka Inoue, Yoji Ikegami, Takahiro Fujishiro, Tomohiro Osaki, Yoshinaga Kajimoto, Shin-Ichi Miyatake i Toshihiko Kuroiwa. "A New Strategy of ALA-Photodynamic Cancer Therapy: Inhibition of ABC Transporter ABCG2". W Resistance to Targeted Anti-Cancer Therapeutics, 89–104. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-09801-2_4.
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Ohta, Hiroki, Noburo Kyomura, Yoji Takahashi i Philip S. Magee. "Inhibition of Susceptible and Resistant Green Rice Leafhopper Acetylcholinesterase byN-Methylcarbamate and Oxadiazolone Insecticides". W ACS Symposium Series, 136–46. Washington, DC: American Chemical Society, 1989. http://dx.doi.org/10.1021/bk-1989-0413.ch009.
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Mitsuya, Hiroaki, i Arun K. Ghosh. "Development of HIV-1 Protease Inhibitors, Antiretroviral Resistance, and Current Challenges of HIV/AIDS Management". W Aspartic Acid Proteases as Therapeutic Targets, 245–62. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2011. http://dx.doi.org/10.1002/9783527630943.ch9.
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Xu, Feng, Benjamin D. Sherry i Timothy A. Blizzard. "Discovery and Chemical Development of Relebactam: A Potent β-Lactamase Inhibitor in Combination with Primaxin® for the Treatment of Serious and Antibiotic-Resistant Bacterial Infections". W ACS Symposium Series, 253–84. Washington, DC: American Chemical Society, 2020. http://dx.doi.org/10.1021/bk-2020-1369.ch008.
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Nawaz, Muddasir, Sehrish Habib, Adnan Khan, Abdul Shakoor i Ramazan Kahraman. "Cellulose microfibers (CMFs) reinforced smart self-healing polymeric composite coatings for corrosion protection of steel". W Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0003.
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The use of organic coating for the metals has been widely being used to protect the surface against corrosion. Polymeric coating incorporated with Nanocontainers loaded with inhibitor and self-healing provides better corrosion resistance. Cellulose microfibers (CMFs) used as smart carriers were synthesized and loaded with dodecylamine (DOC)-inhibitor and polyethyleneimine (PEI)-both inhibitor and self-healing agents. Smart polymeric coatings were developed by mixing CMF/DOC and CMFs/PEI into the epoxy matrix. Reference coatings (that has only CMFs) were also prepared for a compersion. Scanning electron microscope (SEM), X-ray diffraction spectroscopy (XRD), Fourier transform infrared spectroscopy (FTIR) and thermal gravitational analysis (TGA) were used to confirm the loading of DOC and PEI onto the CMFs. UV-vis analysis indicates that the self-release of inhibitor from CMFs is sensitive to pH of the solution and the immersion time. Recovery of controlled surface damage confirms the decent self-healing ability of the prepared smart coatings is due to the efficient release of inhibitor (DOC) and self-healing agent (PEI) in the damaged area leading to the formation of a protective film. Electrochemical impedance spectroscopy (EIS) results demonstrate that corrosion resistance of the smart coating increases with an increase in immersion time which is due to the progressive release of inhibitors from CMFs in response to the pH change. Therefore, smart coatings demonstrate superior properties as compared to the reference coatings. The study reveals the polymeric composite coatings have potential to inhibit the corrosion of steel for oil and gas industry.
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Baker, J. B., M. P. McGrogan, C. Simonsen, R. L. Gronke i B. W. Festoff. "STRUCTURE AND PROPERTIES OF PROTEASE NEXIN I". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644765.
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Human foreskin fibroblasts secrete several different serine protease inhibitors which differ in size and protease specificities. These proteins, called protease nexins (PNs) all form SDS-resistant complexes with their protease targets. Fibroblast surface receptors recognize the protease-PN complexes and mediate their delivery to lysosomes. PNI is a 45 kilodalton glycoprotein that rapidly inhibits several arg or lys-specific proteases including trypsin, thrombin, and urokinase (k assoc.∼ 4×l06,∼ 6×105 and ∼ 2×105, m−1s−1 respectively). Like antithrombin III, PNI binds heparin and inhibits thrombin at a vastly accelerated rate in the presence of this glycoaminoglycan. Immunofluorescence studies show that in addition to secreting PNI foreskin fibroblasts carry this inhibitor on their surfaces. PNI cDNA has been cloned and sequenced. A mixed oligonucleotide probe derived from PNI N-terminal sequence was used to probe a foreskin fibroblast cDNA library constructed with λGT10. Identification of PNI cDNAs has been verified by sequencing and by expressing active PNI protein in mammalian cells. The full amino acid sequence of PNI, deduced from cDNA sequencing, is 392 residues long and has 30% homology to antithrombin III. An arg-ser pair 32 residues from the C-terminus of the inhibitor is proposed as the reactive center P1-P1 residues. In the hinge region a lys residue is present in a position occupied by a ginor glu residue in other serpins. PNI mRNA exists in 2 slightly different forms:One (αPNI) yields a thr-arg-ser sequence wherethe other βPNI) yields a thr-thr-gly-ser sequence. The presence of the appropriate splice acceptor sites in the genome indicates that these forms are generated from a single gene by alternative splicing. Expressed aPNI and 0PNI proteins both bind thrombin and urokinase. In foreskin fibroblaststhe α form of PNI mRNA predominates over the β form by about 2:1. In foreskin fibroblast cultures secreted PNI inhibits the mitogenic response to thrombin and regulate secreted urokinase. Purified PNI added to human fibrosarcoma (HT1080) cells inhibitsthe tumor cell-mediated destruction of extracellular matrix and transiently, but dramatically, inhibits tumor cell growth. PNI or PNI-like inhibitors may function at multiple physiological sites. The β form of PNI is virtually identical to a glia-derived neurite promoting factor, the cDNA for which has been recently cloned and sequenced by Gloor et al (1). The neurite outgrowth activity of PNI may result from inhibition of a thrombin-like protease that is associated with neurons, since a number of thrombin inhibitors stimulate neurite extension. Recent immunofluoresence experiments, carried out with D. Hantai (Inserm; Paris) demonstrate that anti-PNI antibody intensely stains neuromuscular synapses. In addition, a PNI-like inhibitor is associated with platelets. At low (0.5 nM <) 125I-thrombin concentrations formation of 125I-thrombin-platelet PNI complexes accounts for most of the specific binding of 125I-thrombin to platelets (2). Although the platelet-associated form of PNI is electrophoretically and immunologically indistinguishable from fibroblast PNI, it does not bind urokinase, suggesting that it may be distinct.(1) Gloor, S., K. Odink, J. Guenther, H. Nick, and D. Monard. (1986) Cell 47:687-693.(2) Gronke, R.S., B.L. Bergman, and J.B. Baker. (1987) J. Biol. Chem. (in press)
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Dardaei, Leila, Hui Qin Wang, Manrose Singh, Paul Fordjour, Satoshi Yoda, Grainne Kerr, Jinsheng Liang i in. "Abstract A145: SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged NSCLC". W Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1535-7163.targ-17-a145.
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Liu, Jin-hua, Bin Gong, E. Jang, Wei-gang Ma, Ju-hua Wen i Yan-chun He. "Corrosion Inhibitor on Copper and Stainless Steel for Component Cooling Water System of NPP". W 2013 21st International Conference on Nuclear Engineering. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/icone21-16249.
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Based on the corrosion issues of component cooling water system (CCWs) in nuclear power plant (NPP), the corrosion inhibition properties and protection mechanism on copper and stainless steel was studied by using tests such as electrochemical method, immersion test and dynamic water simulation. Results show that the optimum inhibitor is the compound of tolyltriazole (TTA) and phosphate, which has an excellent corrosion inhibition efficiency on copper in either pure water or abnormal water. The inhibitor also elevated the pitting potential of stainless steel and contributed to the corrosion resistance.
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Griffith, T. M., D. H. Edwards, R. L. Davies, T. J. Harrison i K. L. Evans. "EDRF AND RESISTANCE VESSELS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643721.
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The influence of endothelium on vasomotionin resistance vessels was studied in an isolated, buffer-perfused rabbit ear preparation using novel microangiographic techniques and haemoglobin as a specific inhibitor of EDRF. In constricted preparations acetylcholine and Substance P, whose action is EDRF-dependent in large vessels, induceddilatation in vessels down to 25um in diameter which was inhibited by haemoglobin. Log (IC50>q) values calculated from diameter changes were the same in the central artery, GO, and its first three generations of branch vessels Gl, G2 and G3 (ie down to 7Oum) being -7.7 and -9.8 respectively. Consistent with this, almost identical valueswere derived from the pressure responses of the intact network. Such spatial homogeneity has not been found when the same vessels are studied in isolation. In contrast,constrictor responses to 5HT or histamine exhibited spatial heterogeneity (in the rank order G0>G1>G2>G3) which was exaggerated by inhibition of basal EDRF activity. Inerms of normalised diameter changes EDRF and its analogue GTN were equipotent in reversing these constrictor responses in GO to G3. Interms of hydraulic resistance however, dilator responses paralleled relative changesn resistance induced by the constrictor agents. EDRF and GTN thus appear more potentin vessels exhibiting high degrees of tone.In control preparations (i.e. in the absence of pharmacological constriction) basal EDRF activity was found to exert maximal influence in vessels in which calculatedshear stress and hydraulic resistance werehighest, and continuously inhibited myogenic tope in Gl and to a lesser extent G2 and G3. In the absence of haemoglobin, diameter and flow were related by the expression QÒaD4+b in GO, Gl and G2 over an 8-fold range of flow rates. In the high-flow limit this implies constancyof pressure gradient and pressure drop inthese vessels so that the energy expended in delivering a given volume of perfusate to the terminal elements of the bed would be effectively independent of flow rate, rather than directly proportional to it as in a rigid tube.Basal EDRF activity also conferred identical flow-related distensibility in G0 through G3 in control and partially constricted preparations over the samerange of flow rates. This implies independence of flow distribution from flowrate. Flow dependent release of EDRF may provide a mechanism which links network topography with vessel function, thus optimising perfusion characteristics.
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Cortelazzo, S., D. Castagna, M. Galli, T. Barbui i G. de Gaetano. "INCREASED RESPONSE TO ARACHIDONIC ACID AND U-46619 AND RESISTANCE TO INHIBITORY PR0STAGLANDING IN PATIENTS WITH CHRONIC MYELOPROLIFE RATIVE DISORDERS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643381.
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The potency of prostaglandins (PGs) D2, I2 and as inhibitors of platelet aggregation induced by threshold aggregating concentration (TAC) of arachidonic acid (AA) and U-46619 was determined in platelet rich plasma from 20 normal subjects and 20 patients with thrombocytosis (≥500×l09 platelets/L) secondary to myeloproliferative disorders. Patients had a significantly increased response to both AA and U-46619 (p< 0.02) than the control group (i.e. TAC for AA, mean+SD, was 0.41±0.10 mM vs 0.48±0.12 mM ; TAC for U-46619 was 220±155 nM vs 375±102 nM). In contrast, platelet sensitivity to all three inhibitoty PGs was significantly lower in patients than in normal subjects. Indeed the threshold inhibiting concentrations (nM) of PGs against AA were the following: PGD2 20.33±4.16 vs 7.00±2.62 (p< 0.001), PGI2 0.76±0.46 vs 0.34±0.22 (p< 0.01) and PGE1 11.83±3.97 vs 6.50±2.22 (p<0.001). The corresponding inhibitory concentrations (nM) against U-46619 were the following: PGD2 4.67±4.24 vs 0.76±0.30 (p< 0.02), PGI2 1.15±0.96 vs 0.03±0.01 (p< 0.0001) and PGE1 21.12±15.27 vs 0.68± 0.30 (p< 0.0001). Selective pharmacologic inhibition of TxA2 sinthase by 40 μM dazoxiben resulted in 6 out of 11 “responders” in patients and 7 out of 10 in normal subjects, a difference not statistically significant. Serum TxB2 was slightly, but not significantly lower in patients than in controls (360±143 ng vs 390±155 ng/3×109 platelets/mL). It is suggested that in patients with myeloproliferative disorders platelet arachidonate metabolism is normal, but the functional response to aggregating and antiag-gregating prostanoids is altered towards a potential hyperaggrega bility. The relevanbe of this “in vitro” finding to thrombotic or haemorragic complications in these patients remains to be establi shed.
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Katayama, Ryohei, Noriko Yanagitani, Sumie Koike, Takuya Sakashita, Satoru Kitazono, Makoto Nishio, Yasushi Okuno, Jeffrey A. Engelman, Alice T. Shaw i Naoya Fujita. "Abstract 3590: Resistance mechanisms to ALK inhibitors". W Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3590.
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Kim, Soyeon, Tae Min Kim, Yong-Oon Ahn, Bhumsuk Keam, Se-Hoon Lee, Dae Seog Heo i Dong-Wan Kim. "Abstract 1842: Synergistic inhibition of ALK inhibitor-resistant lung cancer cells by dual-targetingEGFRandALKpathways". W Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1842.
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Zhai, Dayong, Wei Deng, Zhongdong Huang, Evan Rogers i J. Jean Cui. "Abstract 2132: The novel, rationally-designed, ALK/SRC inhibitor TPX-0005 overcomes multiple acquired resistance mechanisms to current ALK inhibitors". W Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2132.
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Al-Jaber, Hend Sultan, Layla Jadea Al-Mansoori i Mohamed Aghar Elrayess. "The Role of GATA3 in Adipogenesis & Insulin Resistance". W Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0143.
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Background: Impaired adipogenesis plays an important role in the development of obesityassociated insulin resistance and type 2 diabetes. Adipose tissue inflammation is a crucial mediator of this process. In hyperglycemia, immune system is activated partially through upregulation of GATA3, causing exacerbation of the inflammatory state associated with obesity. GATA3 also plays a role as a gatekeeper of terminal adipocyte differentiation. Here we are examining the impact of GATA3 inhibition in adipose tissue on restoring adipogenesis, reversing insulin resistance and potentially lowering the risk of type 2 diabetes. Results: GATA-3 expression was higher in insulin resistant obese individuals compared to their insulin sensitive counterparts. Targeting GATA-3 with GATA-3 specific inhibitors reversed impaired adipogenesis and induced changes in the expression of a number insulin signaling-related genes, including up-regulation of insulin sensitivity-related gene and down-regulation of insulin resistance-related genes. Conclusion: GATA3 expression is higher in differentiating adipocytes from obese insulin resistant. Inhibiting GATA3 improves adipocytes differentiation and rescues insulin sensitivity in insulin resistant cells
Raporty organizacyjne na temat "ALS inhibitor resistance"
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Lance, Richard, i Xin Guan. Variation in inhibitor effects on qPCR assays and implications for eDNA surveys. Engineer Research and Development Center (U.S.), sierpień 2021. http://dx.doi.org/10.21079/11681/41740.
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Aquatic environmental DNA (eDNA) surveys are sometimes impacted by polymerase chain reaction (PCR) inhibitors. We tested varying concentrations of different inhibitors (humic, phytic, and tannic acids; crude leaf extracts) for impacts on quantitative PCR (qPCR) assays designed for eDNA surveys of bighead and silver carp (Hypophthalmichthys nobilis and Hypophthalmichthys molitrix). We also tested for inhibition by high concentrations of exogenous DNA, hypothesizing that DNA from increasingly closely related species would be increasingly inhibitory. All tested inhibitors impacted qPCR, though only at very high concentrations — likely a function, in part, of having used an inhibitor-resistant qPCR solution. Closer phylogenetic relatedness resulted in inhibition at lower exogenous DNA concentrations, but not at relatively close phylogenetic scales. Inhibition was also influenced by the qPCR reporter dye used. Importantly, different qPCR assays responded differently to the same inhibitor concentrations. Implications of these results are that the inclusion of more than one assay for the same target taxa in an eDNA survey may be an important countermeasure against false negatives and that internal positive controls may not, in the absence of efforts to maximize inhibition compatibility, provide useful information about the inhibition of an eDNA assay.