Journal articles on the topic 'Ai toxicity'
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Henry, Norah Lynn, Todd C. Skaar, Jessica Dantzer, Lang Li, Anne T. Nguyen, James M. Rae, Zeruesenay Desta, et al. "Genetic variants associated with toxicity-related discontinuation of adjuvant aromatase inhibitor (AI) therapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 525. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.525.
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525 Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003. Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in ESR1, which encodes estrogen receptor (ER) alpha, and one in CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity. Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy. [Table: see text]
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Helson, B. V., P. de Groot, J. J. Turgeon, and E. G. Kettela. "TOXICITY OF INSECTICIDES TO FIRST-INSTAR LARVAE OF THE SPRUCE BUDMOTH, ZEIRAPHERA CANADENSIS MUT. AND FREE. (LEPIDOPTERA: TORTRICIDAE): LABORATORY AND FIELD STUDIES." Canadian Entomologist 121, no. 1 (January 1989): 81–91. http://dx.doi.org/10.4039/ent12181-1.
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AbstractLaboratory tests with selected carbamate, organophosphorus, and pyrethroid insecticides demonstrated that the pyrethroid permethrin has the best potential for controlling newly hatched larvae of Zeiraphera canadensis Mut. and Free. Permethrin possessed high crawling contact toxicity (toxicity of insecticide deposits on foliage when contacted by crawling larvae) and direct contact toxicity to first-instar larvae and exhibited long residual effectiveness on potted, white spruce trees. Chlorpyrifos, fenitrothion, mexacarbate, and methomyl had high crawling contact toxicity but short residual activity. Azinphos-methyl appeared to possess long residual effectiveness but relatively low crawling contact toxicity. Aminocarb and thiodicarb exhibited short residual effectiveness and relatively low toxicity. In field trials, an aerial application of permethrin (70 g/ha) at egg hatch resulted in an 81% population reduction and limited the destruction of tree leaders to 9%. Leader destruction was greater than 19% after treatments of permethrin at 35 g AI/ha or aminocarb at 180 g AI/ha or aminocarb twice at 90 g AI/ha. Leader destruction in an untreated plantation was 51%.
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Ban, Choongjin, Joon-Bum Park, Sora Cho, Hye Rin Kim, Yong Joon Kim, Hyungjin Bae, Chinhan Kim, et al. "Characterization of Ginkgo biloba Leaf Flavonoids as Neuroexocytosis Regulators." Molecules 25, no. 8 (April 17, 2020): 1829. http://dx.doi.org/10.3390/molecules25081829.
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Ginkgo biloba leaf (GBL) is known as a potential source of bioactive flavonoids, such as quercetin, arresting the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-zippering. Here, the GBL flavonoids were isolated in two different manners and then examined for their bioactivity, physicochemical stability, and biocompatibility. The majority of flavonoids in the non-hydrolyzed and acidolyzed isolates, termed non-hydrolyzed isolate (NI) and acidolyzed isolate (AI) hereafter, were rich in flavonol glycosides and aglycones, respectively. Glycosidic/aglyconic quercetin and kaempferol were abundant in both NI and AI, whereas a little of apigenin, luteolin, and isorhamnetin were found in AI. NI was more thermostable in all pH ranges than quercetin, kaempferol, and AI. NI and AI both inhibited neurotransmitter release from differentiated neuronal PC-12 cells. NI and AI showed 1/2–1/3 lower EC50/CC50 values than quercetin and kaempferol. The NI and AI exhibited no toxicity assessed by the tests on chorioallantoic membranes of hen’s eggs, removing toxicological concerns of irritation potential. Moreover, GBL isolates, particularly AI, showed antioxidant and anti-inflammatory activities in the use below the CC50 levels. Taken together, these results suggest that GBL isolates that are rich in antioxidant flavonoids are effective anti-neuroexocytotic agents with high stability and low toxicity.
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Alford, Adam, Thomas P. Kuhar, George C. Hamilton, Peter Jentsch, Grzgorz Krawczyk, James F. Walgenbach, and Celeste Welty. "Baseline Toxicity of the Insecticides Bifenthrin and Thiamethoxam on Halyomorpha halys (Hemiptera: Pentatomidae) Collected From the Eastern United States." Journal of Economic Entomology 113, no. 2 (January 6, 2020): 1043–46. http://dx.doi.org/10.1093/jee/toz361.
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Abstract Brown marmorated stink bug, Halyomorpha halys (Stål), is an invasive species in the United States that attacks a wide variety of agricultural commodities including fruits, vegetables, agronomic crops, and ornamental plants. Populations of H. halys adults were collected from four and six states in 2017 and 2018, respectively, and tested using topical applications to establish baseline levels of susceptibility to two commonly used insecticides, bifenthrin and thiamethoxam. A Probit-estimated (95% fiducial limits) LD50 and LD99 of 2.64 g AI/L (1.2–3.84 g AI/L) and 84.96 g AI/L (35.76–716.16 g AI/L) for bifenthrin, and a LD50 and LD99 of 0.05 g AI/liter (1.14E-5–0.27 g AI/L) and 150.11 g AI/L (27.35–761,867 g AI/L) for thiamethoxam, respectively. These baseline levels can be used for future insecticide resistance monitoring in H. halys.
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Kuhar, Thomas P., Helene B. Doughty, Erin M. Hitchner, and Anna V. Chapman. "Toxicity and Field Efficacy of Acetamiprid on Asparagus Beetle." Plant Health Progress 7, no. 1 (January 2006): 17. http://dx.doi.org/10.1094/php-2006-0818-01-rs.
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The asparagus beetle, Crioceris asparagi L., is a major pest of asparagus in the United States. Commercial growers typically apply a foliar insecticide in the spring to kill adults before they can oviposit on asparagus spears. However, very few new insecticides have been registered on the crop in the last twenty years, and many chemicals have lost their registrations due to enactment of the Food Quality Protection Act. Laboratory and field experiments were conducted to evaluate the efficacy of a novel neonicotinoid insecticide, acetamiprid, to control all life stages of the asparagus beetle. Laboratory toxicity assays revealed that acetamiprid is highly toxic to asparagus beetle eggs and larvae. LC50 levels were 8.95 mg ai/liter for eggs and 0.012 mg ai/liter for larvae. Field efficacy trials in Virginia showed that acetamiprid applied at 0.112 kg ai/ha significantly reduced the numbers of asparagus beetle adults, eggs, and larvae on asparagus equal to or greater than that of the insecticide standard, methomyl. Acetamiprid also provided excellent control of aphids on spears, equal to or greater than that of methomyl. Accepted for publication 3 May 2006. Published 18 August 2006.
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Truong, D. H., M. J. Rieder, and W. Dantor. "Artificial intelligence (AI) in prediction of beta-lactam antibiotic toxicity." Clinical Pharmacology & Therapeutics 73, no. 2 (February 2003): P10. http://dx.doi.org/10.1016/s0009-9236(03)90392-4.
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Greenlees, Matthew, and Richard Shine. "Ontogenetic shift in toxicity of invasive cane toads facilitates learned avoidance by native predators." Aquatic Invasions 14, no. 3 (2019): 458–64. http://dx.doi.org/10.3391/ai.2019.14.3.05.
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Goldvaser, Hadar, Domen Ribnikar, Tristan Alexandra Barnes, David W. Cescon, Alberto Ocana, and Eitan Amir. "Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 549. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.549.
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549 Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P < 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P < 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.
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Arumugam, Saranya, and Ramanathan Thiruganasambantham. "STANDARDIZED SUPERCRITICAL CO2 EXTRACT OF ACANTHUS ILICIFOLIUS (LINN.) LEAVES INHIBITS THE PRO-INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-Α IN LIPOPOLYSACCHARIDE-ACTIVATED MURINE RAW 264.7 MACROPHAGE CELLS." Asian Journal of Pharmaceutical and Clinical Research 11, no. 7 (July 7, 2018): 193. http://dx.doi.org/10.22159/ajpcr.2018.v11i7.25230.
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Objective: Acanthus ilicifolius Linn. (Acanthaceae) is a medicinal mangrove plant used in the treatment of inflammation. Previous phytochemical studies have identified 2-benzoxazolinone (BOA) from the leaves of A. ilicifolius. In the present study, we attempted to standardize the supercritical CO2 leaf extract of A. ilicifolius (SCFE-AI) for BOA content and investigate the tumor necrosis factor-α (TNF-α) inhibitory effect of SCFE-AI and BOA on the lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. The acute oral toxicity of SCFE-AI and BOA was also established.Methods: SCFE-AI was standardized for BOA content using high-performance thin-layer chromatography (HPTLC) method. The cytotoxicity of SCFE-AI and BOA was evaluated using MTS colorimetric method. The in vitro anti-inflammatory effect of SCFE-AI and BOA on TNF-α production in LPS-activated RAW 264.7 cells was quantified using ELISA method. Acute oral toxicity studies were performed following the Organization for Economic Co-operation and Development test guideline No. 423.Results: The amount of BOA was found 0.8% w/w of SCFE-AI. The RAW 264.7 cell viability was unaffected by SCFE-AI and BOA treatments within a concentration range <1000 mg/ml after 24 h incubation. SCFE-AI decreased the production of TNF-α in a dose-dependent manner compared to BOA. The LD50 value for SCFE-AI was found to be >2000 mg/kg and ranges from 300 to 2000 mg/kg with BOA.Conclusion: The HPTLC chromatogram could serve as an analytical tool for authentication and quantification of BOA content. The anti-inflammatory mechanism of A. ilicifolius might be through the inhibition of TNF-α production.
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Tal, Abraham, Yuval Benyamini, and Baruch Rubin. "Differential Toxicity of Tralkoxydim inHordeumSpecies." Weed Technology 7, no. 4 (December 1993): 946–48. http://dx.doi.org/10.1017/s0890037x00038057.
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In greenhouse studies, tralkoxydim applied POST at 100 to 300 g ai/ha during the three-to four-leaf stage of development were differentially toxic to threeHordeumspecies. Tralkoxydim severely injured wall barley by cessation of growth and death of the whole plant.Hordeum spontaneum, barley, and wheat were less affected by the herbicide in declining order, respectively. However, 4 wk after treatment, full recovery was observed in barley and wheat, but not inH. spontaneum, as reflected in the shoot fresh weight. Tralkoxydim could be considered as a selective herbicide in wheat and barley fields for the control of wall barley.
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Bich-Loan, Nguyen T., Kieu Trung Kien, Nguyen Lai Thanh, Nguyen T. Kim-Thanh, Nguyen Quang Huy, Pham The-Hai, Marc Muller, Amandine Nachtergael, Pierre Duez, and Nguyen Dinh Thang. "Toxicity and Anti-Proliferative Properties of Anisomeles indica Ethanol Extract on Cervical Cancer HeLa Cells and Zebrafish Embryos." Life 11, no. 3 (March 20, 2021): 257. http://dx.doi.org/10.3390/life11030257.
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In this study, we showed that crude extract of Anisomeles indica (AI-EtE) expressed its toxicity to HeLa cells with an IC50 dose of 38.8 µg/mL and to zebrafish embryos with malformations, lethality and hatching inhibition at 72-hpf at doses higher than 75 µg/mL. More interestingly, flow cytometry revealed that AI-EtE significantly promoted the number of cells entering apoptotic. Accordingly, the transcript levels of BAX, CASPASE-8, and CASPASE-3 in the cells treated with AI-EtE at IC50 dose were 1.55-, 1.62-, and 2.45-fold higher than those in the control cells, respectively. Moreover, treatment with AI-EtE caused cell cycle arrest at the G1 phase in a p53-independent manner. Particularly, percentages of AI-EtE-treated cells in G1, S, G2/M were, respectively 85%, 6.7% and 6.4%; while percentages of control cells in G1, S, G2/M were 64%, 15% and 19%, respectively. Consistent with cell cycle arrest, the expressions of CDKN1A and CDNK2A in AI-EtE-treated cells were up-regulated 1.9- and 1.64-fold, respectively. Significantly, treatment with AI-EtE also decreased anchorage-independent growth of HeLa cells. In conclusion, we suggest that Anisomeles indica can be considered as a medicinal plant with a possible use against cervical cancer cells; however, the used dose should be carefully monitored, especially when applying to pregnant women.
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Ivey, P. W., S. J. Johnson, and Richard Story. "Toxicity of Three Formulations of Bacillus Thuringiensis Against Diamondback Moth, 1996." Arthropod Management Tests 23, no. 1 (January 1, 1998): 369. http://dx.doi.org/10.1093/amt/23.1.369.
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Abstract A leaf-dip assay was used to test three commercial formulations of B. thuringiensis Berliner: Agree 50 WP, Dipel ES, and XenTari AS, against diamondback moth. Concentrations ([AI]/liter) were based on dilution series using the recommended “field” rates of the three formulations of B. thuringiensis. Dipel and Xen-Tari were tested at concentrations of 2.5, 0.25, 0.025, 0.0025, and 0.00025 [ml (AI)/liter]; Agree was tested at concentrations of 3.0, 0.3, 0.03, 0.003, and 0.0003 [g(AI)/liter]. Disks (20 mm diam) were cut from leaves of the above cabbage cultivar. Each disk was dipped into each test solution and hung vertically to dry at room temperature for about 1 h and then placed in petri dishes (100 X 15 mm) on top of a moistened filter peper (90 mm diameter). Five third instars were placed on each leaf disk in each petri dish and allowed to feed for 96 h, after which mortality was recorded. A larva was considered dead if it did not move when prodded with forceps. Tests with each concentration and the untreated control (distilled water) were replicated five times.
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Cao, Chuan-Wang, Fang Niu, Xiao-Peng Li, Shi-Lin Ge, and Zhi-Ying Wang. "Acute and joint toxicity of twelve substituted benzene compounds to Propsilocerus akamusi Tokunaga." Open Life Sciences 9, no. 5 (May 1, 2014): 550–58. http://dx.doi.org/10.2478/s11535-014-0289-y.
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AbstractThis study investigated the toxic effects of 12 substituted benzenes exposed to Propsilocerus akamusi larvae singly and as mixtures. Their toxicities were quantified in terms of median effective concentration (EC50) killing 50% of the larvae. For individual substituted benzenes to 4th-instar P. akamusi larvae, the toxicity was in decreasing order of p-chlorophenol > nitrobenzene > phenol > 1,2-dimethylbenzene > 1,3-dimethylbenzene > chlorobenzene > p-phenylenediamine > 1,4-dimethylbenzene > m-phenylenediamine > methylbenzene > benzene > aniline. The order of toxicity among three isomers of dimethylbenzene was 1,2-dimethylbenzene > 1,3-dimethylbenzene > 1,4-dimethylbenzene while p-phenylenediamine > m-phenylenediamine. The binary substituted benzene compounds’ toxicities were evaluated by toxic unit (TU), additive index (AI), mixture toxicity index (MTI) and similarity parameter index (λ). The evaluation results of TU and MTI for 9 substituted benzene compounds were completely consistent while the results of AI were the same as the results of λ based on 24 h EC50 of binary substituted benzenes. The evaluation results of 10 substituted benzene compounds were consistent using TU, MTI, AI and λ evaluation methods. 52.63% and 47.37% of binary substituted benzene tests on P. akamusi larvae showed synergism and partial addition/antagonism, respectively, under mixtures of equal proportions. These results suggest that substituted benzenes indicate acute and binary joint toxicity to P. akamusi.
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Dent, Susan Faye, Michelle M. Campbell, Freya Crawley, Mark J. Clemons, and Xinni Song. "Endocrine therapy in early breast cancer: Encouraging observations in a nontrial setting." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 587. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.587.
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587 Background: Poor adherence to adjuvant endocrine therapy (ET) in women with hormone receptor positive (HR +) early breast cancer (EBC) is well documented. Given the availability of multiple ET strategies [aromatase inhibitor (AI) upfront, tamoxifen (TAM) to AI, AI after 5 years TAM], we evaluated the delivery of ET in a non-trial setting. Methods: Post-menopausal women with HR + EBC treated with ET (that included an AI) at The Ottawa Hospital Cancer Center between 01/99 and 12/06 were included. Data was retrospectively collected and included: demographics, choice/duration of ET, adherence and toxicities. Results: In 626 patients (pts), median age 59 years (r: 30-92) with stage I (195 pts; 31 %), stage II (339 pts; 54 %) and stage III (88 pts; 14 %) EBC. Treatment strategies included: AI (s) only (251 pts; 40 %); TAM followed by AI (s) (323 pts; 51.6 %); AI (s) followed by TAM (16 pts; 2.6 %); TAM-AI (s)-TAM (24 pts; 3.8 %) and unknown (12 pts; 1.9 %). Prescribed AI therapy (upfront or sequential) was discontinued in 39 % of cases mainly due to toxicity (62.5 %) after median of 6, 9, or 12 months (ms) on exemestane, anastrazole and letrozole respectively. Common toxicities included: arthralgias (40.6 %), hot flushes (34 %), fatigue (25 %), myalgias (24.7 %) and osteoporosis (22.5%). In cases (177) where AI therapy was discontinued due to toxicity: 98 received no further ET, 29 TAM and 50 another AI. The majority of pts received at least 5 years of ET (79 %; median duration 64 ms; r 1-156 ms) and 376 pts (60 %) completed at least 5 years of AI therapy (median duration 59 ms; r: 1-124 ms). 9.9 % of pts are still receiving ET. Conclusions: This is one of the first non-clinical trial studies to demonstrate, that despite poor adherence to initial ET, the majority of women are able to complete five years of treatment (79 %). These results are encouraging and reflect the practical use of mutilple endorcrine strategies that have been shown to be efficacious in this pt population.
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Gui, Yu, Xiujing He, Jing Yu, and Jing Jing. "Artificial Intelligence-Assisted Transcriptomic Analysis to Advance Cancer Immunotherapy." Journal of Clinical Medicine 12, no. 4 (February 6, 2023): 1279. http://dx.doi.org/10.3390/jcm12041279.
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The emergence of immunotherapy has dramatically changed the cancer treatment paradigm and generated tremendous promise in precision medicine. However, cancer immunotherapy is greatly limited by its low response rates and immune-related adverse events. Transcriptomics technology is a promising tool for deciphering the molecular underpinnings of immunotherapy response and therapeutic toxicity. In particular, applying single-cell RNA-seq (scRNA-seq) has deepened our understanding of tumor heterogeneity and the microenvironment, providing powerful help for developing new immunotherapy strategies. Artificial intelligence (AI) technology in transcriptome analysis meets the need for efficient handling and robust results. Specifically, it further extends the application scope of transcriptomic technologies in cancer research. AI-assisted transcriptomic analysis has performed well in exploring the underlying mechanisms of drug resistance and immunotherapy toxicity and predicting therapeutic response, with profound significance in cancer treatment. In this review, we summarized emerging AI-assisted transcriptomic technologies. We then highlighted new insights into cancer immunotherapy based on AI-assisted transcriptomic analysis, focusing on tumor heterogeneity, the tumor microenvironment, immune-related adverse event pathogenesis, drug resistance, and new target discovery. This review summarizes solid evidence for immunotherapy research, which might help the cancer research community overcome the challenges faced by immunotherapy.
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Crowley, Fionnuala, Karen Anne Cadoo, Sarah Chiang, Jennifer Jean Mueller, Martee Leigh Hensley, and Roisin Eilish O'Cearbhaill. "Evaluating the role of aromatase inhibitors (AIs) in the treatment of endometrial stromal sarcomas (ESS)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5575. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5575.
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5575 Background: Endometrial stromal sarcomas (ESS) account for < 20% of uterine sarcomas. They usually express estrogen and progesterone receptors (ER/PR) and are considered hormone sensitive. Due to the rarity of these tumors, large clinical trials studying optimal treatment have not been possible. This study represents the largest retrospective study of ESS treated with AI. Methods: The clinicopathological variables and outcomes of patients (pts) with pathologically confirmed low grade ESS treated with AI at our institution between 1998-2020 were recorded. Results: 48 pts with ESS treated with AI were identified. They had a median age of 54 years (range 23-84) and BMI of 27 (range 20-50). 79% were white. 6 (12%), 9 (19%), 14 (29%) and 19 pts (40%) had stage 1,2,3,4 ESS, respectively. 37 (77%) were ER+/PR+; 2 (4%) ER+/PR- and 9 pts (19%) had unknown ER/PR status. All pts were postmenopausal at AI initiation. 12 pts (25%) had a synchronous cancer (5 of these had breast cancer {3 of the 5 presented post tamoxifen}). 23 pts (48%) received megestrol acetate and 25 (52%) an AI as first line hormonal manipulation. During their disease course, 35 pts (73%) received letrozole, 21 (44%) anastrozole and 19 (39.6%) exemestane. 22 pts (46%) were treated with more than one AI. 28 pts (58%) reported side-effects; arthralgia (33%) being the most common. 10 pts (21%) discontinued AI due to toxicity; 12 pts (25%) switched AI for toxicity (with improved tolerance in 67% of these pts). Among the 24 pts (50%) with measurable disease there were 2 partial responses (objective response rate of 8.3%). 1-year disease control rate (DCR) was (79%) for all pts and 58% in stage 4 disease. Median PFS for 1st line AI was 161.6 months (95% CI 48.5 to 274.7). Conclusions: This study represents the largest study of AI use in ESS to date. We found the ORR to be more modest than previously reported. The majority of pts had prolonged stable disease with a DCR of 58% even in stage 4 disease. Pts who progress on one AI may benefit from trial of a 2nd AI. A phase 2 study of interruption versus maintenance AI in locally advanced/metastatic ESS is currently underway (NCT03624244).
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Yevtushenko, A. V., O. S. Sirenko, V. S. Boyko, and M. E. Romanko. "Study of acute and subacute toxicity parameters of “Rybokhin” biological product on the model of carp." Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies 21, no. 94 (July 30, 2019): 25–32. http://dx.doi.org/10.32718/nvlvet9405.
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The goal of the work was to study of acute and subacute toxicity parameters of “Rybokhin” biological product (AI – chloroquine refer to derivatives 4-aminohinolines) on the model of carp. This drug is effective in the treatment of diseases caused by parasitic Protozoa and Monogenea. Carp scales of two years old were used in experiments. To determine acute toxicity, the fish were prescribed with chloroquine (by AI) in doses of 100; 200; 300; 400; 500; 600; 800; 1000 mg/kg of live weight. Two experimental and control fish groups of 30 individuals each were formed to determine subacute toxicity of “Rybokhin”. Experimental groups of fish were prescribed with “Rybokhin” in a dose (by AI) of 50 mg/kg and 10 mg/kg for two consecutive days. Blood samples were collected from six fish species from each group for clinical and biochemical indicators after 48 hours, 7, 14, 21 and 28 days. The hemoglobin content, number of red blood cells and leukocytes blood were determined. The intensity of peroxide oxidation of lipids (PОL), catalase activity, level of total antioxidant capacity (TAC), total proteins, albumin, globulins and glucose, circulating immune complexes (CІC) and seromucoids concentration, level of enzymatic activity: aspartate transaminase (АSТ), alanine transaminase (АLТ), ά-amylase blood plasma were determined. According to the research results, indicators of acute toxicity for carp were determined, namely LD50 of chloroquine is 528.66 ± 68.01 mg/kg; LD16 – 224.512 mg/kg; LD84 – 832.81 mg/kg; LD100 – 984.89 mg/kg, which indicate that the drug is low-toxic to fish (belongs to the fourth group of toxicity). When administrating of 50.0 mg/kg of “Rybokhin” (by AI) twice a day, the most expressed metabolic changes in fish body were observed on 21 day after its last administration. Thus, the drug’s toxic impact is in proteinogram alteration, transamination processes and in decreasing of fish immune reactivity. It points to the prevalence of catalytic processes over anabolic. Metabolic alterations are obviously directed to the activation of detoxication processes with increased energy use in fish body after getting of higher dosage of the product. So, on 28 day of experiment, the major part of studied parameters retrieved to control level. It was found that when the product was administrated twice a day in the dosage 10.0 mg/kg (by AI), which is used for treatment of parasitic diseases, no reliable changes of clinical and biochemical indices were detected in fish blood during the experiment.
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Michelson, Matthew, Tiffany Chow, Neil A. Martin, Mike Ross, Amelia Tee Qiao Ying, and Steven Minton. "Artificial Intelligence for Rapid Meta-Analysis: Case Study on Ocular Toxicity of Hydroxychloroquine." Journal of Medical Internet Research 22, no. 8 (August 17, 2020): e20007. http://dx.doi.org/10.2196/20007.
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Background Rapid access to evidence is crucial in times of an evolving clinical crisis. To that end, we propose a novel approach to answer clinical queries, termed rapid meta-analysis (RMA). Unlike traditional meta-analysis, RMA balances a quick time to production with reasonable data quality assurances, leveraging artificial intelligence (AI) to strike this balance. Objective We aimed to evaluate whether RMA can generate meaningful clinical insights, but crucially, in a much faster processing time than traditional meta-analysis, using a relevant, real-world example. Methods The development of our RMA approach was motivated by a currently relevant clinical question: is ocular toxicity and vision compromise a side effect of hydroxychloroquine therapy? At the time of designing this study, hydroxychloroquine was a leading candidate in the treatment of coronavirus disease (COVID-19). We then leveraged AI to pull and screen articles, automatically extract their results, review the studies, and analyze the data with standard statistical methods. Results By combining AI with human analysis in our RMA, we generated a meaningful, clinical result in less than 30 minutes. The RMA identified 11 studies considering ocular toxicity as a side effect of hydroxychloroquine and estimated the incidence to be 3.4% (95% CI 1.11%-9.96%). The heterogeneity across individual study findings was high, which should be taken into account in interpretation of the result. Conclusions We demonstrate that a novel approach to meta-analysis using AI can generate meaningful clinical insights in a much shorter time period than traditional meta-analysis.
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Gulati, Nicholas, Arda Celen, Paul Johannet, Amelia Sawyers, Min Jae Kim, Janice M. Mehnert, Jeffrey S. Weber, Michelle Krogsgaard, Iman Osman, and Judy Zhong. "Association of pre-existing autoimmune diseases in melanoma patients receiving immune checkpoint inhibition with improved survival and increased toxicity." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21586-e21586. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21586.
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e21586 Background: Immune checkpoint inhibition (ICI) improves progression-free (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but induces immune-related adverse events (irAEs). Pre-existing autoimmune disease (pre-AI) is considered a relative contraindication due to concerns of inciting autoimmune flare. We here tested the impact of pre-AI on both the survival and irAEs in MM patients treated with ICI. Methods: We examined MM patients treated with ICI who were enrolled in a clinicopathological database at NYULH with protocol-driven prospective follow up. We compiled a comprehensive list of 23 autoimmune diseases and examined the presence of these diseases prior to ICI treatment. We tested the associations between pre-AI and PFS, OS, and irAEs both in univariate and multivariate models. Results: 74/485 (15.3%) patients, who received 718 lines of ICI treatment as either standard of care or in clinical trials, had pre-AI, most commonly asthma (n=42), inflammatory bowel disease (n=9), psoriasis (n=9), rheumatoid arthritis (n=7), and eczema (n=6). In patients receiving ICI as standard of care (n=535), pre-AI was associated with irAEs (P=0.05) as well as with significantly improved PFS (P=0.024) and OS (P=0.007), controlling for patients’ sex, age, stage, ECOG status, and treatment line (1st line versus 2nd or 3rd line). However, no associations were observed between pre-AI and PFS (P=0.2) or irAEs (P=0.54) in the clinical trial group. Conclusions: Our data demonstrate the disparate impact of pre-AI on response and irAEs in standard of care versus the highly controlled clinical trial settings, and underscore the importance of examining the complex interaction between autoimmune disease before and after initiation of ICI. Our data also challenge the notion that clinicians should avoid use of ICI in pre-AI patients. More mechanistic research is needed to understand how to uncouple ICI response from toxicity.
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Hurej, Michal, and James D. Dutcher. "Indirect Effect of Insecticides Used in Pecan Orchards to Larvae of Chrysoperla rufilabris (Neuroptera: Chrysopidae)." Journal of Entomological Science 29, no. 4 (October 1, 1994): 450–56. http://dx.doi.org/10.18474/0749-8004-29.4.450.
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Eight insecticides at two concentrations (low and high) were tested for toxicity to first, second, and third instars of Chrysoperla rufilabris (Burmeister). Lindane (0.65 and 1.3 g actual insecticide AI/l), endosulfan (0.375 and 0.75 g AI/l), carbaryl (1.2 and 2.4 g AI/l), azinphos-methyl (1.0 and 2.0 g AI/l, malathion (0.9 and 1.8 g AI/l), methomyl (0.225 and 0.45 g AI/l), phosmet (0.375 and 0.75 g AI/l), and esfenvalerate (0.0.15 and 0.03 g AI/l) treated cowpea aphids (Aphis craccivora Koch) were fed to the lacewing larvae in the laboratory. Among tested insecticides, azinphos-methyl was the most toxic insecticide to larvae at the low and high rates and was classified as moderately harmful. Lindane and carbaryl were slightly harmful; endosulfan, malathion, methomyl, phosmet, and esfenvalerate were harmless. In most cases the first instar larvae were the most susceptible to the insecticides tested. Both rates caused similar mortality of C. rufilabris larvae after 48 h of feeding with the exception of azinphos-methyl and methomyl which caused higher mortality at the high rate.
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Reid, B. L., and G. W. Bennett. "Dietary Toxicity Trial, 1987." Insecticide and Acaricide Tests 14, no. 1 (January 1, 1989): 382. http://dx.doi.org/10.1093/iat/14.1.382a.
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Abstract Laboratory tests evaluated the toxicity of the dihaloalkyl arylsulfone biocide, A-9248 (diiodomethyl para-tolyl sulfone), when fed continuously to German cockroach nymphs from the second and fifth (last) nymphal stage until adulthood. The toxicants were formulated into diets prepared by finely grinding Wayne Rodent Blox into 5-g portions and reconstituting each with 6 ml of water and 3 ml of an acetone solution of technical A-9248. This was mixed thoroughly, pressed into plexiglass molds, and allowed to dry for 48 h within an evacuation hood, yielding pelletized diets (75-100 mg) of the desired concentration (% AI). Seven diet concentrations (10-0.156%; 0.5 times serial dilutions) were evaluated to achieve a clear representation of A-9248 activity. Groups of 10 unsexed, newly eclosed (<24 h) second- or fifth-stage nymphs were placed into 100- by 25-mm vented plastic Petri dishes supplied with test diet, water vial, and cardboard harborage. Each diet concentration was replicated 6 times, for a total of 60 nymphs/dilution rate.
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Sembodo, Dad Resiworo Jekti, and Nana Ratna Wati. "Uji Efektivitas Campuran Herbisida Berbahan Aktif Atrazin dan Topramezon terhadap Beberapa Jenis Gulma." JURNAL AGROTROPIKA 20, no. 2 (October 3, 2021): 93. http://dx.doi.org/10.23960/ja.v20i2.5164.
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The purpose of this study was to determine the effectiveness of mixing herbicides with the active ingredients atrazine and topramezone in controlling weeds and to determine the nature of the mixture of the two active ingredients. This research was conducted in a plastic house in Natar District, South Lampung Regency from October 2020 - January 2021. The study was arranged in a Completely Randomized Design (CRD). The treatments consisted of three types of herbicides with six dosage levels of the active ingredients, namely the single herbicide Atrazine 300 g/l (0, 37.5, 75, 150, 300, and 600 g ai ha-1), Topramezon 10 g/l (0. 1.25 , 2.5, 5, 10, and 20 g ai ha-1), and the herbicide mixture of Atrazine 300 g/l + Topramezone 10 g/l (0. 38.75, 77.50, 155, 310, and 620 g ai ha-1) , and repeated 6 times. The target weeds included broadleaf weeds (Ageratum conyzoides and Synedrella nodiflora), grass groups (Digitaria ciliaris, Echinochloa colonum, and Eleusine indica), and the puzzle group (Cyperus iria). The herbicides atrazine and topramezone have different ways of working so that the analytical method used is the Multiplicative Survival Model (MSM) method. The results showed that mixing the herbicide Atrazine 300 g/l + Topramezon 10 g/l had an expected LD50 value of 46.28 g ai ha-1 and a treatment LD50 of 27.22 g ai ha-1 with a co-toxicity value of 1.7 (Co-toxicity > 1) so that it is synergistic.Key words: Atrazin, Topramezon, mixing herbicide, Multiplicative Survival Model, weed, LD50
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Samadi Kalkhoran, Elham, Mohammad Taghi Alebrahim, Hamid Reza Mohammaddoust Chamn Abad, Jens Carl Streibig, Akbar Ghavidel, and Te-Ming Paul Tseng. "The Survival Response of Earthworm (Eisenia fetida L.) to Individual and Binary Mixtures of Herbicides." Toxics 10, no. 6 (June 12, 2022): 320. http://dx.doi.org/10.3390/toxics10060320.
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Frequent use of herbicides may impose a risk on non-target species. The objective was to test the combined toxic effect of binary herbicide mixtures—metribuzin:halosulfuron and metribuzin:flumioxazin—on non-target earthworms in two test systems: filter paper and a soil toxicity test system. The joint action experiments were independently run twice to substantiate the findings. The most potent individual herbicide was metribuzin, with a 50% lethal concentration (LC50) of 17.17 µg ai. cm−2 at 48 h in the filter paper test. The toxicity of the individual herbicides on the filter paper test was ranked as metribuzin>halosulfuron>flumioxazin. In the soil test, metribuzin and halosulfuron had high toxicity with an LC50 of 8.48 and 10.08 mg ai. kg−1, respectively, on day 14. Thus, the individual herbicide ranking did not change between the filter paper and artificial soil tests. The herbicide’s mixed effect in both test systems showed a consistent antagonistic effect relative to a Concentration Addition reference model. It indicates that the mixtures retracted the herbicide’s action in the earthworms.
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RICHARD, ANN M. "Application of artificial intelligence and computer-based methods to predicting chemical toxicity." Knowledge Engineering Review 14, no. 4 (December 1999): 307–17. http://dx.doi.org/10.1017/s0269888999004038.
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The toxicity prediction problem lies squarely at the interface of biology, chemistry and computational domains and will require the integrated application of knowledge and approaches from each domain for its solution. It is not a single modeling problem, but rather multiple levels of modeling compartments derived from the goals of toxicity risk assessment. These compartments include different categories and characteristics of toxicity (e.g., cancer vs. non-cancer, acute vs. delayed) and, therein, different levels of biofunctional organization and multiple mechanisms of toxicity extending to the level of individual chemical structures. A toxicity prediction model should strive to resolve the global toxicity prediction problem to local modeling compartments that reflect coherent biofunctional mechanisms and common modes of action while retaining some level of useful generalizations. This paper attempts to use these general concepts to frame the challenges and opportunities for application of Artificial Intelligence (AI) and computer-based methods to the goal of chemical toxicity prediction.
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Mahmoud, Farag. "Efficacy of eco-smart insecticides against certain biological stages of jasmine moth, Palpita unionalis Hb. (Lepidoptera: Pyralidae)." Pesticidi i fitomedicina 29, no. 1 (2014): 55–65. http://dx.doi.org/10.2298/pif1401055m.
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The efficacy of six eco-smart insecticides, Dipel 2x 6.4% WP (Bacillus thuringensis AI), Biofly 100% WP (Beauvaria bessiana AI), Radiant 12% SC (Saccharopolyspora spinosa AI), Mectin 1.8% EC (Streptomyces avermitilis AI), Nimbecidine 0.03% EC (Azadirachtin AI) and Bio-Power 50% EC (Beauvaria bessiana AI), were tested against eggs, larvae and pupae of the jasmine moth, Palpita unionalis Hb. and its parasitoid Apanteles syleptae under laboratory conditions. Data indicated that all tested insecticides had ovicidal activity against P. unionalis. Mectin was the most toxic among the tested insecticides against the egg stage, followed by Radiant or Dipel 2x, and their respective values of LC50 were 0.005 cm/l, 0.006 cm/l and 0.055 g/l. Dipel 2x was the most toxic insecticide to the 1st instar larvae of P. unionalis, whereas Mectin was the most toxic to both the 3rd and 5th instar larvae. Also, the results revealed that Mectin was the most effective against the pupal stage, followed descendingly by Radiant and Dipel 2x. The toxicity index values showed a superior efficiency of Mectin at LC50 (100%) against eggs, 3rd and 5th instar larvae, and pupal stage, whereas Dipel 2x showed such superior efficiency at LC50 (100%) only against 1st instar larvae. The results showed that the percents of pupation and emergence of moths were significantly different in all treatments compared to control, while deformed pupae and malformed adults were insignificantly different when fifth instar larvae were treated with the tested insecticides. Moreover, the rate of P. unionalis adult emergence from treated pupae was concentration-dependent and significant differences were found between insecticide treatments and control. Generally, Mectin, Radiant and Dipel 2x caused the highest impacts on adult emergence and malformed adults percentages. Regarding the toxicity of insecticides to the endoparasitoid A. syleptae, the treated cocoons developed to adult stages with no significant differences compared to control. Meanwhile, the longevity of the emerged parasitoid adults did not differ among the insecticides treatments and control.
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Song, X., G. Nicholas, S. Dent, and S. Verma. "Adjuvant hormonal therapy (AHT) in women with early stage breast cancer (BC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 11053. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.11053.
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11053 Background: The ASCO technology assessment on adjuvant use of AI states that optimal AHT for a postmenopausal woman with HR-positive BC should now include an AI. We assessed uptake and patterns of AHT use in early stage HR-positive BC at a regional cancer center. Methods: A retrospective review of patients diagnosed with HR-positive early stage BC from January 2004 to December 2005 treated at our center was performed. Data included patient demographics, dates of diagnosis, treatment, last follow-up, AHT choices considered, patient compliance, and treatment toxicity. Patient risks for disease recurrence and mortality were estimated using adjuvantonline. Factors predicting a preference for AI use were identified using univariable and multivariable analysis. Results: 900 patients were identified for the stated period of time with HR-positive early stage BC. 340 patients have been evaluated. Median age was 59 years. Menopausal status was post-/ pre- in 267/73 patients. Stage was I/IIA/IIB in 202/95/43 patients. 267 patients were lymph node (LN) negative. ER, PR and Her2/neu status were positive/negative/unknown in 332/7/1, 292/46/2 and 11/69/260 patients. Initial AHT choice was tamoxifen/anastrozole/letrozole/exemastane/none in 196/79/9/2/54 patients. Of those started upfront on tamoxifen, plan to switch to an AI was stated in 41%. Statistically significant factors associated with any adjuvant AI use included disease stage, menopausal status as well as individual physician preferences. In further analysis, patients’ compliance and toxicity will be reported. Correlation of recurrence risk, as determined through adjuvantonline, with upfront selection of an AI has also been performed. Conclusion: Guidelines have stated the use of an AI (upfront, sequential or extended) should be considered in HR-positive early stage BC. Results from this study provide further insights on the uptake of such therapy as well as factors (disease related, patient and physician preferences) influencing adjuvant treatment decision-making. A prospective trial assessing treatment decision regarding AHT is also in progress. (This study is sponsored by the Canadian Breast Cancer Foundation) No significant financial relationships to disclose.
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Desnoyers, Alexandra, Michelle Nadler, Vikaash Kumar, Ramy Saleh, and Eitan Amir. "Comparison of treatment-related adverse events (TRAE) of different CDK4/6 inhibitors (CDK4/6i) in metastatic breast cancer (MBC): A network meta-analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13052-e13052. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13052.
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e13052 Background: CDK4/6i in combination with endocrine therapy (ET) are a standard of care in hormone receptor positive, HER2 negative MBC. Palbociclib, ribociclib and abemaciclib have all been approved and while efficacy appears similar, differences in safety and tolerability are apparent. Here we quantify TRAEs comparing the 3 CDK4/6i in a network meta-analysis. Methods: We searched PubMed and ASCO and ESMO proceedings to identify randomized trials (RCT) of CDK4/6i. Data on common and serious TRAE were extracted for each approved CDK4/6i. The odd ratio (OR) for each TRAE and the hazard ratio (HR) for progression-free survival (PFS) were calculated relative to ET alone. A network meta-analysis was then performed for each ET backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib. Results: 7 RCT were included in the analysis and comprised 2715 patients receiving CDK4/6i (palbociclib: 789 patients; ribociclib: 1153 patients; abemaciclib: 773 patients). In 4 RCT (1440 patients) ET backbone was an AI and in 3 RCT (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed lower grade 3-4 hematological toxicity, but higher GI toxicity (see table). Treatment discontinuation was higher with abemaciclib than other CDK4/6i. Efficacy of the 3 CDK4/6i was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 1.00 and for abemaciclib 1.04. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively. Conclusions: The three approved CDK4/6i show comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to gastro-intestinal toxicity. [Table: see text]
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Nord, J. C., and G. L. DeBarr. "PERSISTENCE OF INSECTICIDES IN A LOBLOLLY PINE SEED ORCHARD FOR CONTROL OF THE LEAFFOOTED PINE SEED BUG, LEPTOGLOSSUS CORCULUS (SAY) (HEMIPTERA: COREIDAE)." Canadian Entomologist 124, no. 4 (August 1992): 617–29. http://dx.doi.org/10.4039/ent124617-4.
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AbstractHigh volume sprays of azinphosmethyl, chlorpyrifos, fenvalerate, permethrin, and phosmet in various concentrations and formulations were simulated on loblolly pine (Pinus taeda L.) foliage in a pine seed orchard in northern Georgia. Persistence of these insecticides under field conditions was determined by weekly bioassays with adult leaffooted pine seed bugs [Leptoglossus corculus (Say)] and gas–liquid chromatography. Fenvalerate was the most persistent insecticide tested. In the first experiment, 0.2% AI fenvalerate caused virtually 100% seed bug mortality in bioassays through the 4th week after treatment, whereas mortality from azinphosmethyl dropped to ca. 14%. By the 6th week, mortality in the fenvalerate treatment was still 91%, even after 10.5 cm of rain. The permethrin treatments persisted for 2 weeks, then mortality declined below 40% at 3 weeks. In the second experiment, fenvalerate at 0.15% AI and 0.075% AI caused 95 and 90% mortality, respectively, after 3 weeks and 16 cm of rain, and the toxicity of the 0.038% and the 0.019% AI fenvalerate treatments lasted only 2 weeks with 12 cm rain. Permethrin in Ambush® EC at 0.2% AI had initial residues of about 150 ppm and caused ca. 84% mortality for 2 weeks with 12 cm rain. Azinphosmethyl WP at 0.2% AI had initial residues of ca. 104 ppm and persisted for 1 week. Seed bug mortality from phosmet at 0.4% AI diminished quickly after 1 week in the field.
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Davis, Elizabeth J., Rashmi Chugh, Lili Zhao, J. Sybil Biermann, Sandra L. Wong, Mary Uan-Sian Feng, David Robert Lucas, et al. "Neo/adjuvant doxorubicin (A) and ifosfamide (I) versus gemcitabine (G) and docetaxel (T) in patients (PTS) with localized, high risk soft tissue sarcoma (STS): A randomized phase II comparative effectiveness trial." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10524. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10524.
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10524 Background: Approximately 50% of pts with localized, >5 cm, high grade STS develop metastatic disease. Although controversial, adjuvant chemotherapy has demonstrated improved disease-free (DFS) and overall survival (OS). AI can cause significant toxicities that often lead to hospitalization. GT is active in metastatic STS pts and as compared to AI has a favorable schedule and toxicity profile. Methods: In a single-institution phase II study, pts with localized, resectable, high grade STS >5 cm were randomized to receive AI or GT. Pts were stratified by neo- or adjuvant treatment and extremity or non-extremity tumor. Pts received A (75 mg/m2 over 48 hrs) and I (2.5 g/m2/d on D1-3) or G (900 mg/m2 over 90 min on D1,8) and T (100 mg/m2 on D8), both arms with GCSF, for 4 cycles unless progression. Radiation was given after chemotherapy. The primary endpoint of the trial was hospitalization rate during chemotherapy and was compared using a chi square test and multiple logistic regression adjusting for other variables. The trial was powered to detect a reduction in hospitalization rate from 35% to 10% using GT. Survival functions were estimated using Kaplan-Meier method. Results: 84 pts were enrolled from 11/04-8/12 with 80 pts evaluable. The median age is 56 yrs (19-76) and tumor size is 7.8 cm (3.2-25). 55 pts received neoadjuvant therapy and 48 had extremity STS. In the AI arm, 13/37 (35%) pts were hospitalized vs. 11/43 (26%) in the GT arm (p=0.25). The most frequent reason for hospitalization in AI arm was febrile neutropenia (7 events) and in GT arm was hypersensitivity reaction (4 events). The median DFS of pts treated with AI vs GT is 24 months vs not reached, respectively; median follow up is 30 (1-87) months. The 2-year DFS rate is 53% (SD 9%) in the AI arm vs. 71% (SD 7%) in the GT arm and remains marginally significant after adjusting for age, gender, neoadjuvant therapy, tumor site and size (p=0.054). OS rates are not significantly different between arms. Conclusions: Hospitalization rate was not significantly lower with GT compared to AI, although toxicity profile was different. DFS but not OS is marginally improved with GT. Clinical trial information: NCT00189137.
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Petit, Thierry, Patrick Dufour, and Ian Tannock. "A critical evaluation of the role of aromatase inhibitors as adjuvant therapy for postmenopausal women with breast cancer." Endocrine-Related Cancer 18, no. 3 (April 18, 2011): R79—R89. http://dx.doi.org/10.1530/erc-10-0162.
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The introduction of aromatase inhibitors (AI) has provided more options for adjuvant treatment of postmenopausal women; they are associated with improved disease-free survival, but less commonly with improvements in overall survival. Current evidence suggests that women at high risk of recurrence, especially those with node-positive disease, should receive an AI for 2 years as part of their treatment, but routine prescription of AIs to postmenopausal patients with low-risk disease is not appropriate. Not only the expected benefits but also the specific toxicity of the prescribed hormone therapy, and its cost, should be considered when selecting treatment.
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Cheema, Navneet, Anita Bhatnagar, and Abhay Singh Yadav. "Changes in behavioural and locomotory activities of freshwater fish, Cirrhinus mrigala (Hamilton) in response to sublethal exposure of Chlorpyrifos." Journal of Applied and Natural Science 10, no. 2 (June 1, 2018): 620–26. http://dx.doi.org/10.31018/jans.v10i2.1745.
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The aim of the present study was to analyze the impact of sub-lethal toxicity of chlorpyrifos, one of the largest market selling agrochemical on physiological parameters of teleost fish, Cirrhinus mrigala addressing the possible causative involvement in behavioural and locomotion responses. Primarily, the acute toxicity (96h LC50) test was carried out and the value calculated by probit analysis was found to be 0.44 mg L-1. Further, one-fifth, one-tenth and one-twentieth of 96 h LC50 were selected as sublethal concentrations for sub acute studies. The experiment was carried out for 21 days and the alternative behaviour was recorded in terms of Air Ingulping (AI), Operculum Beat Frequency (OBF), Surfacing Movement (SM), Vertical Hanging (VH) and Tail Beat Frequency (TBF) on duration day 2, 4, 7, 14 and 21. Significant effect of both the concentrations and duration was observed in fishes treated with selected doses of chlorpyrifos. It was found that AI, OBF, SM, VH, TBF was highest on day 7 at 0.08 mg L-1 concentration of Chlorpyrifos. The findings revealed that there is a need to control the use of chlorpyrifos because of its toxicity. All the fish avoidance tests proved to be an important predictive and sensitive biomarker in aquatic monitoring and pollution management.
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Henry, N. Lynn, Faouzi Azzouz, Zereunesay Desta, Lang Li, Anne T. Nguyen, Suzanne Lemler, Jill Hayden, et al. "Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer." Journal of Clinical Oncology 30, no. 9 (March 20, 2012): 936–42. http://dx.doi.org/10.1200/jco.2011.38.0261.
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Purpose Aromatase inhibitors (AIs) are effective for treatment of hormone receptor–positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. Patients and Methods Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. Results Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. Conclusion Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.
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Ingle, James N., Vera J. Suman, Kendrith M. Rowland, Deepu Mirchandani, Albert M. Bernath, John K. Camoriano, Paul A. S. Fishkin, Daniel A. Nikcevich, and Edith A. Perez. "Fulvestrant in Women With Advanced Breast Cancer After Progression on Prior Aromatase Inhibitor Therapy: North Central Cancer Treatment Group Trial N0032." Journal of Clinical Oncology 24, no. 7 (March 1, 2006): 1052–56. http://dx.doi.org/10.1200/jco.2005.04.1053.
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Purpose Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). Patients and Methods A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. Results Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. Conclusion Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.
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López González, Ana, Sonia Del Barco Berrón, Isabel Grau, Maria Galan, Beatriz Castelo Fernández, Alfonso Cortés, Pedro Sánchez Rovira, et al. "Challenging Endocrine Sensitivity of Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with the Combination of Eribulin and Endocrine Therapy: The REVERT Study." Cancers 14, no. 23 (November 29, 2022): 5880. http://dx.doi.org/10.3390/cancers14235880.
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Background: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. Methods: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/− AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. Results: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8–55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7–71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. Conclusion: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo–endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.
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Mizera, Mikolaj, Anna Sanecka-Duin, Maciej Jasiński, Paulina Król, Giovanni Mazzocco, Victor Murcia Pieńkowski, Alexander Myronov, et al. "827 Streamlining design of safe and effective TCR therapies with AI." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A866. http://dx.doi.org/10.1136/jitc-2021-sitc2021.827.
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BackgroundAdoptive cell therapies with T lymphocytes expressing engineered T cell receptors (TCRs) are one of the most promising approaches to cancer therapy.1 However, the experimentally driven development of novel TCR therapies is limited by the enormous biological variability of peptide:Human Leukocyte Antigen:TCR (pHLA:TCR) complexes. The in silico methods hold the promise to streamline the discovery of novel TCR therapies by reducing costs and time of laboratory research. In particular, the prediction of TCR binding to a target antigen, as well as the prediction of TCR off-target toxicity2 can provide useful insights supporting the development of safe therapies. We aimed at the development of an experimentally validated AI model of pHLA:TCR binding that will help to prioritize and reduce the number of in vitro assays necessary to discover novel TCRs for cancer therapies.MethodsThe limiting factor of successful pHLA:TCR binding modeling is data availability and completeness of TCR characterization. To address this issue, we are building an oncological pHLA:TCR database with paired alpha and beta chain TCR sequences. We are collecting and sequencing tumor and normal samples from 100 cancer patients, as part of an observational clinical trial. Those data are then screened with the Ardigen's ArdImmune Vax platform3 4 to select immunogenic epitopes. T cells that bind those epitopes are subsequently sorted and used to generate TCR sequencing data at single-cell resolution. We use data-driven and simulation-based models to extract insights about the dynamics of a pHLA:TCR system to predict the binding probability and explain the inference made by the model.ResultsWe optimized our data collection pipeline for the cost-efficient acquisition of a large oncological pHLA:TCR dataset. These data will enable us to build efficient models to streamline the development of TCR therapies against cancer.We benchmarked our modeling approach for pHLA:TCR binding against existing solutions5–7 on publicly available data. We also show how focus on model explainability facilitates the detection of model inconsistency of uncertain predictions by expert inspection. Our toxicity assessment solution2 extends the applicability of our system to the prediction of TCR safety profile.ConclusionsThe presented work shows perspectives and limitations of AI-aided TCR therapy development. We present results for our pHLA:TCR binding model, a TCR-toxicity-screening solution, and the study design of our observational clinical trial. Our growing database of pHLA:TCR interactions will enable us to develop highly predictive pHLA:TCR binding models, in particular for oncological targets.AcknowledgementsWe acknowledge funding through the project “Creating an innovative AI-based (Artificial Intelligence) IN SILICO TECHNOLOGY TCRact to launch a NEW SERVICE for designing and optimizing T-cell receptors (TCR) for use in cancer immunotherapies” cofunded by European Regional Development Fund (ERDF) as part of Smart Growth Operational Programme 2014–2020.ReferencesFarkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med 2016;14:73. PMCID: PMC4858828.Murcia Pienkowski VA, Mazzocco G, Niemiec I, Sanecka-Duin A, Krol P, Myronov O, Skoczylas P, Kaczmarczyk J, Blum A. Off-target toxicity prediction in cellular cancer immunotherapies [Internet]. Cytotherapy. 2021;S96. Available from: http://dx.doi.org/10.1016/s1465324921004229.Stepniak P, Mazzocco G, Myronov A, Niemiec I, Gruba K, Skoczylas P, Sanecka-Duin A, Drwal M, Kaczmarczyk J. AI-augmented design of effective therapeutic cancer vaccines and adoptive cell therapies. Journal For Immunotherapy Of Cancer. Bmc Campus, 4 Crinan St, London N1 9xw, England; 2019.Mazzocco G, Niemiec I, Myronov A, Skoczylas P, Kaczmarczyk J, Sanecka-Duin A, Gruba K, Król P, Drwal M, Szczepanik M, Pyrc K, Stȩpniak P. AI aided design of epitope-based vaccine for the induction of cellular immune responses against SARS-CoV-2. Front Genet. 2021;12:602196. PMCID: PMC8027494.Weber A, Born J, Rodriguez Martínez M. TITAN: T-cell receptor specificity prediction with bimodal attention networks. Bioinformatics. 2021;37(Suppl_1):i237–i244. PMCID: PMC8275323.Springer I, Besser H, Tickotsky-Moskovitz N, Dvorkin S, Louzoun Y. Prediction of specific TCR-peptide binding from large dictionaries of TCR-Peptide Pairs. Front Immunol 2020;11:1803. PMCID: PMC7477042.Jurtz VI, Jessen LE, Bentzen AK, Jespersen MC, Mahajan S, Vita R, Jensen KK, Marcatili P, Hadrup SR, Peters B, Nielsen M. NetTCR: sequence-based prediction of TCR binding to peptide-MHC complexes using convolutional neural networks [Internet]. Available from: http://dx.doi.org/10.1101/433706
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Soltani, Madjid, Farshad Moradi Kashkooli, Mohammad Souri, Samaneh Zare Harofte, Tina Harati, Atefeh Khadem, Mohammad Haeri Pour, and Kaamran Raahemifar. "Enhancing Clinical Translation of Cancer Using Nanoinformatics." Cancers 13, no. 10 (May 19, 2021): 2481. http://dx.doi.org/10.3390/cancers13102481.
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Application of drugs in high doses has been required due to the limitations of no specificity, short circulation half-lives, as well as low bioavailability and solubility. Higher toxicity is the result of high dosage administration of drug molecules that increase the side effects of the drugs. Recently, nanomedicine, that is the utilization of nanotechnology in healthcare with clinical applications, has made many advancements in the areas of cancer diagnosis and therapy. To overcome the challenge of patient-specificity as well as time- and dose-dependency of drug administration, artificial intelligence (AI) can be significantly beneficial for optimization of nanomedicine and combinatorial nanotherapy. AI has become a tool for researchers to manage complicated and big data, ranging from achieving complementary results to routine statistical analyses. AI enhances the prediction precision of treatment impact in cancer patients and specify estimation outcomes. Application of AI in nanotechnology leads to a new field of study, i.e., nanoinformatics. Besides, AI can be coupled with nanorobots, as an emerging technology, to develop targeted drug delivery systems. Furthermore, by the advancements in the nanomedicine field, AI-based combination therapy can facilitate the understanding of diagnosis and therapy of the cancer patients. The main objectives of this review are to discuss the current developments, possibilities, and future visions in naoinformatics, for providing more effective treatment for cancer patients.
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Parvathaneni, Madhukiran, Abduselam K. Awol, Monika Kumari, Ke Lan, and Manisha Lingam. "Application of Artificial Intelligence and Machine Learning in Drug Discovery and Development." Journal of Drug Delivery and Therapeutics 13, no. 1 (January 15, 2023): 151–58. http://dx.doi.org/10.22270/jddt.v13i1.5867.
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Drug discovery has traditionally been a time consuming and expensive endeavor. Additionally, drugs weren’t as effectively designed as those that are being predicted and developed through AI and ML today. Machine learning is a form of artificial intelligence that develops and evolves based on experience (similarly to the human mind), and is more recently being utilized in drug discovery and design. The integration of AI and ML into the drug discovery and development process has allowed for higher target precision, lower toxicity, and better dosage formulations. AI more generally has been introduced to and has been leveraged at, each step of drug development, including target identification and validation, hit identification, as well as hit to lead optimization, and has been key in shortening the previously lengthy drug screening process. AI and ML has also been applied downstream in drug formulation where it has maximized resource utilization and is allowing for web-based 3D printing of drugs. Application of AI in the drug development process has also been extended to the modeling of novel drug-like compounds to predict their ADMET properties. This review will address the stages of drug discovery and development in which the application of AI and ML modeling has altered the traditional development of drugs.
Keywords: Drug discovery, machine learning, artificial intelligence, computational drug development.
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Al Mubarak, Mustafa Mohammed. "Fulvestrant for advanced breast cancer: A meta-analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e11613-e11613. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e11613.
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e11613 Background: Fulvestrant is an endocrine agent which degrades the estrogen receptor, thereby downregulating its signaling. While fulvestrant has been consistently tested in postmenopausal women with inoperable locally advanced or metastatic breast cancer, there has been substantial heterogeneity in study populations and drug dosing. The optimal use of fulvestrant in advanced breast cancer is therefore unclear. Methods: A systematic review of electronic databases was conducted to identify randomized trials of fulvestrant versus other endocrine therapy. The hazard ratios (HR) for time to progression (TTP) and the odds ratios (OR) for serious adverse events (SAEs), discontinuation of treatment due to toxicity and commonly reported toxicities (hot flashes, venous thrombosis, gastrointestinal disturbance, arthralgia, and asthenia) were pooled in a meta-analysis. Meta-regression explored heterogeneity in study population and fulvestrant dosing. Results: Eight studies were included in the analysis. Overall, there was no difference in TTP between fulvestrant and control groups (HR:0.94, 95% CI 0.85-1.03, p=0.18). On meta-regression, fulvestrant showed reduced hazards for TTP compared to aromatase inhibitors (AI) if used in first line (p for trend <0.001), in studies where fewer patients received adjuvant endocrine therapy (p for trend <0.001) and at higher doses (p for trend <0.001). Rates of SAEs and treatment discontinuation were similar for fulvestrant and control groups, but fulvestrant monotherapy was associated with significantly less arthralgia (OR:0.73,95% CI 0.57-0.95, p=0.02). The addition of fulvestrant to AI compared with AI alone was not associated with improved TTP (HR:0.88, 0.72-1.09,P=0.25), but led to increased hot flashes (OR: 1.68,95% CI 1.30-2.16, P<0.001) and gastrointestinal disturbances (OR:1.28, , 95% CI 1.01-1.63, p=0.04). Conclusions: In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia. Use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with AI. Fulvestrant combined with AI was not associated with improved efficacy but led to increased toxicity.
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Zhang, Shengnan, Limin Su, Xujia Zhang, Chao Li, Weichao Qin, Dongmei Zhang, Xiaoxia Liang, and Yuanhui Zhao. "Combined Toxicity of Nitro-Substituted Benzenes and Zinc to Photobacterium Phosphoreum: Evaluation and QSAR Analysis." International Journal of Environmental Research and Public Health 16, no. 6 (March 22, 2019): 1041. http://dx.doi.org/10.3390/ijerph16061041.
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The single toxicity (IC50) of zinc (Zn) and 11 nitro-substituted benzenes to Photobacterium phosphoreum were determined, respectively. On basis of single toxicity, the joint toxicity of binary mixtures of Zn and 11 nitro-substituted benzenes at different Zn concentrations of 0.2 IC50, 0.5 IC50, and 0.8 IC50 were measured. The joint toxicity was evaluated by toxic unit (TU) and additive index (AI) methods. The results indicated that the joint toxicity was not only depending on the Zn concentrations but also on the substituted groups of nitro-substituted benzenes. The quantitative structure-activity relation (QSAR) equations were developed and the results showed that the toxicity of nitro-substituted benzenes has different joint effect at the different Zn concentrations. At the Zn concentration of 0.2 IC50, the binary joint effects were mainly antagonism and the joint toxicity was negatively related to descriptors called VE2_B(p) and TIC3. At the Zn concentration of 0.5 IC50 and 0.8 IC50, the binary joint effects were mainly antagonism and simple addition, and the joint toxicity was related to the same descriptor Eig06_ AEA(dm). It indicated that the joint toxic actions were similar when combined at the medium and high concentrations of Zn.
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Li, Yu, Lan Wang, Xiao Li Li, Xiao Peng Li, and Long Jiang. "Joint Toxicity of Multiple Heavy Metal Compounds to Photobacterium phosphoreum." Advanced Materials Research 663 (February 2013): 926–29. http://dx.doi.org/10.4028/www.scientific.net/amr.663.926.
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In this article, we take photobacterium phosphoreum (T3) as indication organism, test the joint toxicity of 8 heavy metal compounds (Cu(NO3)2•3H2O, Cd(NO3)2•4H2O, Zn(NO3)2•6H2O, Pb(NO3)2, Cr(NO3)3•9H2O, Ni(NO3)2•6H2O, Co(NO3)2•6H2O, and Sr(NO3)2) with fixed ratio design method (the first two mixed systems designed using equivalent-effect concentration ratio: EC30s and EC50s, and the third one using equivalent-molar concentration ratio which the highest concentration was 0.02mmol/L lower than EC99 of each single heavy metal toxicity). The joint toxicity of the three mixed systems was assessed by Additive Index (AI). The results showed the first two mixed systems were antagonistic action and the third one was synergistic action.
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Lee, Jai Woo, Miguel A. Maria-Solano, Thi Ngoc Lan Vu, Sanghee Yoon, and Sun Choi. "Big data and artificial intelligence (AI) methodologies for computer-aided drug design (CADD)." Biochemical Society Transactions 50, no. 1 (January 25, 2022): 241–52. http://dx.doi.org/10.1042/bst20211240.
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There have been numerous advances in the development of computational and statistical methods and applications of big data and artificial intelligence (AI) techniques for computer-aided drug design (CADD). Drug design is a costly and laborious process considering the biological complexity of diseases. To effectively and efficiently design and develop a new drug, CADD can be used to apply cutting-edge techniques to various limitations in the drug design field. Data pre-processing approaches, which clean the raw data for consistent and reproducible applications of big data and AI methods are introduced. We include the current status of the applicability of big data and AI methods to drug design areas such as the identification of binding sites in target proteins, structure-based virtual screening (SBVS), and absorption, distribution, metabolism, excretion and toxicity (ADMET) property prediction. Data pre-processing and applications of big data and AI methods enable the accurate and comprehensive analysis of massive biomedical data and the development of predictive models in the field of drug design. Understanding and analyzing biological, chemical, or pharmaceutical architectures of biomedical entities related to drug design will provide beneficial information in the biomedical big data era.
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Vinuesa-Hernando, Jose Manuel, Galadriel Pellejero-Sagastizabal, Mercedes Gimeno-Gracia, Isabel Sanjoaquin-Conde, Maria Jose Crusells-Canales, Raquel Fresquet-Molina, and Raquel Gracia-Piquer. "Efficacy and Tolerability of Dolutegravir-Based Dual-Therapies in HIV Naive and Switch Patients." Journal of Biomedical Research & Environmental Sciences 3, no. 1 (January 2022): 018–19. http://dx.doi.org/10.37871/jbres1395.
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Objectives: The introduction of dual-therapy both as preferred starting therapy and in switches has been a revolution, allowing the same efficacy results to be obtained as therapies with more Active Ingredients (AI) with a lower risk of toxicity and interactions. The aim of the study is to analyze the efficacy, tolerability and reasons for switching patients to dolutegravir-based dual therapies.
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Phuagphong, Patamawan, Srisombat Nawanopparatsakul, and Nudchanart Kitcharoen. "Effect of Azadirachta indica A. Juss var indica, Nicotiana tabacum L., and Derris elliptica (Roxb.) on Growth of Duckweed." Advanced Materials Research 1060 (December 2014): 211–14. http://dx.doi.org/10.4028/www.scientific.net/amr.1060.211.
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The study was designed to evaluate the inhibitory effects of selected herbs on plant growth. Three insecticides containing plants (leaf of Azadirachta indica A. Juss var indica (AI), Nicotiana tabacum L. (NT), and root of Derris elliptica (Roxb.) (DE) were selected for various solvent extractions. Five extraction solvents: methanol, hexane, dichloromethane, butanol and aqueous were used in this study. The test method was lemna phytotoxicity assay which measured the inhibitory effect on duckweed, Lemna minor growth. This toxicity test proved to be a practical bioassay method because this method is simple, sensitive and cost effective. Butanol extracts of AI were shown to have more inhibition activity on duckweed growth than NT (% inhibition growth rate is 66.08, 27.08 respectively). Butanol extracts of AI had inhibitory effect (EC10) of 40.87 μg/ ml while dichloromethane extracts had EC10 of 131.72 μg/ ml. It could therefore be concluded that butanol extracts of AI showed the greatest inhibitory effects. The results from this study suggest that butanol extracts of AI were the most promising candidates for biological weed control and might be used as potential natural herbicides or as alternatives for the reduction of chemical herbicides. The study is worthy of further investigation since this could provide potential bioherbicide and may lead to the discovery of new effective and applicable bioherbicide.
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Marmé, Frederik, Miguel Martin, Michael Untch, Herve R. Bonnefoi, Sung-Bae Kim, Harry Douglas Bear, Nicole Mc Carthy, et al. "Palbociclib combined with endocrine treatment in breast cancer patients with high relapse risk after neoadjuvant chemotherapy: Subgroup analyses of premenopausal patients in PENELOPE-B." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 518. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.518.
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518 Background: PENELOPE-B assessed efficacy of the CDK4/6 inhibitor 1-year palbociclib versus placebo added to endocrine therapy (ET) as post-neoadjuvant treatment in a high-risk breast cancer population. Palbociclib did not improve invasive disease-free survival (iDFS) compared to placebo (3-year iDFS 81.3% vs 77.7%) (Loibl et al. J Clin Oncol 2021). Here we report results from the subpopulation of premenopausal women. Methods: Patients with hormone receptor positive, HER2-negative breast cancer without pathological complete response after taxane‐containing neoadjuvant chemotherapy and at high risk of relapse (CPS‐EG score ≥3 or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine treatment including tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRH) and aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age ( < 50 vs ≥50 years), Ki-67, region, and CPS-EG score. Results: 616/1250 patients were premenopausal at the time of enrollment, 185 of these patients (30.0%) were younger than 40 years of age. 95.2% had ypN+ after surgery; 42.8% had ypT2 and 46.8% a CPS-EG score of 3. 23.1% of the premenopausal women had a Ki67 of > 15% in residual disease. 66.1% started with TAM alone; 19.3% with TAM and ovarian function suppression (OFS); and 13.6% received an AI+OFS. There was no difference in iDFS between palbociclib and placebo in the premenopausal women HR 0.948 (0.693-1.30). The 3-year iDFS was 80.6% and 78.3%, respectively. Palbociclib vs placebo in subgroups by endocrine treatment: TAM alone HR 1.05 (0.715-1.53) p = 0.817; TAM+GnRH HR 0.52 (0.267-1.02) p = 0.057 and AI+GnRH HR 1.58 (0.548-4.56) p = 0.397; pinteraction0.124. Hematologic toxicity was significantly more common with palbociclib. Non-hematological toxicity any grade palbociclib vs placebo were: fatigue 67.4% vs 51.3%; hot flushes 52.2% vs 54.8%; bone pain 15.6% vs 16.6%; and vaginal dryness 11.0% vs 11.5%. When receiving palbociclib fewer patients in the AI+GnRH group vs the TAM +/- GnRH cohort experienced anemia (54.1% vs 80.5%) and thrombocytopenia (37.8% vs 65.1%). Fatigue (75.7% vs 66.3%) and nausea (40.5% vs 24.9%) were more common with AI+GnRH than TAM +/-GnRH when palbociclib was added. Thromboembolic events were low with overall 9 events (4 vs 5; AI+GnRH 2.4% vs 1.3% TAM+/-GnRH). Conclusions: The addition of palbociclib to endocrine therapy did not improve iDFS in premenopausal women. These are the first safety results from a phase III study for the combination tamoxifen +/-GnRH and palbociclib. The addition of palbociclib to tamoxifen +/-GnRH in premenopausal women did not increase side effects compared to AI+GnRH and seems to be an alternative to AI+GnRH. Clinical trial information: NCT01864746.
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Sartori Oliveira, Carla Elena, Simone Pinton, Juliana Trevisan da Rocha, Bibiana Mozzaquatro Gai, and Cristina Wayne Nogueira. "The hypolipidemic action of a diet supplemented withp,p’-methoxyl-diphenyl diselenide is not directly related to its antioxidant property." Canadian Journal of Physiology and Pharmacology 94, no. 6 (June 2016): 662–68. http://dx.doi.org/10.1139/cjpp-2015-0411.
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The present study investigated whether a p,p’-methoxyl-diphenyl diselenide (MeOPhSe)2-supplemented diet causes toxicity in rats. A second aim of this study was to determine whether a 10 ppm (MeOPhSe)2-supplemented diet has hypolipidemic effect on Triton WR-1339-induced hyperlipidemia in rats. To rule out the antioxidant property of (MeOPhSe)2in its hypolipidemic action, parameters of oxidative stress were carried out. Wistar rats were fed with 3, 10, or 30 ppm of (MeOPhSe)2-supplemented diet for 30 days. None of (MeOPhSe)2-supplemented diets caused alteration in general parameters of toxicity and lipid profile of rats. The hypolipidemic effect of 10 ppm of (MeOPhSe)2-supplemented diet on rats treated with Triton WR-1339 (400 mg/kg, intraperitoneal) was investigated. The (MeOPhSe)2-supplemented diet partially protected against the levels of total cholesterol (TC) and non-HDL-C and reduced the atherogenic index (AI) increased by Triton WR-1339 in rats. A positive correlation between TC and triglyceride levels (r = 0.679) and non-HDL-C levels (r = 0.929) and AI (r = 0.889) was demonstrated. Triton WR-1339 altered parameters of oxidative stress in livers of rats but (MeOPhSe)2-supplemented diet did not protect against these alterations. The results demonstrated that the hypolipidemic action of (MeOPhSe)2-supplemented diet is not directly related to its antioxidant property and devoid of systemic toxicity in rats at the parameters analyzed.
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Piperno-Neumann, S., B. Bui, J. Blay, H. Roché, F. Pichon, A. Peny, B. Duclos, M. Jimenez, D. Perol, and A. Le Cesne. "A multicentric prospective study of intensive induction chemotherapy (API-AI) in localized osteosarcoma patients: Results of a phase II trial coordinated by the French Sarcoma Group (FSG) and the FNCLCC BECT." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9521. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9521.
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9521 Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders <95% necrosis (PR) a salvage regimen of 3 cycles of etoposide 100 mg/m2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival. No significant financial relationships to disclose.
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Li, T., P. Christos, J. A. Sparano, D. L. Hershman, K. O’Brien, S. Hoschander, J. Wright, and L. T. Vahdat. "Phase II study of the farnesyl transferase inhibitor tipifarnib plus fulvestrant in postmenopausal patients with hormone receptor-positive breast cancer: New York Cancer Consortium Trial P6205." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 1037. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1037.
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1037 Background: Tipifarnib and fulvestrant both have single agent activity in hormone receptor-positive (HR+) metastatic breast cancer (MBC), and tipifarnib enhances the activity of anti-estrogens in HR+ breast cancer cell lines. Methods: Eligibility criteria: measurable HR+ MBC, postmenopausal status, ECOG PS of 0–2, and no prior chemotherapy for MBC. Treatment: fulvestrant 250 mg IM on day 1 plus oral tipifarnib 300 mg BID on days 1–21 every 28 days (defined as one cycle). Response was evaluated by RECIST criteria every 3 cycles. The study was suspended for efficacy/futility analysis after 33 of 46 patients were accrued. It was designed to detect an improvement in clinical benefit rate (CBR; defined as objective response or stable disease for at least 24 weeks) from 50% to 70% (90% power, type I error 10%), and would require at least 26 of 42 eligible/evaluable patients to have clinical benefit (CB). The expected CBR for fulvestrant alone is 30% in aromatase inhibitor (AI) resistant disease (Ingle, 2006), 45% in tamoxifen (tam)-resistant disease (Osborne, 2002), and 60% when used as first line endocrine therapy (ET) (Howell, 2004). Results: Of 33 patients enrolled, 28 are currently assessable for CBR (2 were ineligible, and 3 have stable disease for < 6 months and remain on treatment). Grade 3/4 toxicity: neutropenia (15%), pain (11%) and gastrointestinal toxicity (11%). Tipifarnib was either reduced in dose (N=10) or discontinued (N=8) due to toxicity or non-compliance. The overall CBR is shown; should accrual continue, all 14 evaluable patients must have CB in order to meet the pre-specified efficacy objective. For the ET-resistant group, 18 were resistant to AI therapy (or AI plus tam in 5) and 2 to tam. * Number eligible/evaluable for CBR. Conclusions: The tipifarnib-fulvestrant combination is not likely to produce a CBR of at least 70%. The 45% CBR in ET-resistant disease may merit further evaluation in this setting. [Table: see text] No significant financial relationships to disclose.
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Pulikkan, John Anto, Anuradha Illendula, Jolanta Grembecka, Liting Xue, Roger Rajewski, Monica L. Guzman, John H. Bushweller, and Lucio H. Castilla. "Selective Inhibition of the Leukemia Fusion Protein CBFβ-SMMHC By Small Molecule AI-10-49 in the Treatment of Inv(16) AML." Blood 124, no. 21 (December 6, 2014): 390. http://dx.doi.org/10.1182/blood.v124.21.390.390.
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Abstract The leukemia fusion protein CBFβ-SMMHC, associated with acute myeloid leukemia (AML) with chromosome inversion inv(16)(p13q22), is a driver mutation in leukemia development. Studies by our laboratory and others have established that CBFβ-SMMHC outcompetes CBFβ for binding to RUNX1, deregulates RUNX1 transcription factor activity in hematopoiesis, and induces AML. Studies in mice and patient AML cells support the concept that CBFβ-SMMHC generates pre-leukemic myeloid progenitors, which acquire cooperating mutations to progress to leukemia. Current inv(16) AML treatment using non-selective cytotoxic chemotherapy results in a good initial response, but long-term survival is approximately 60%. This suggests that additional efforts are necessary for the development of improved therapeutic response for CBF AML patients. We have identified AI-4-57 as the active compound that inhibits CBFβ-SMMHC/RUNX1 binding (IC50= 22 uM), using a screen of the NCI diversity set library. AI-4-57 specifically binds to the CBFβ portion of CBFβ-SMMHC, as determined by NMR. This compound was modified in order to improve its potency and stability, and identified the divalent derivative AI-10-49 for further characterization. AI-10-49 showed increased potency (IC50= 0.26 µM) improved in vivo pharmacokinetics (serum t1/2 = 380 min), and enhanced activity in inv(16) positive ME-1 cells (IC50 = 0.6 uM). Importantly, AI-10-49 showed negligible activity (IC50>25 μM) in normal human bone marrow, defining a robust potential therapeutic window. Co-immunoprecipitation assays of ME-1 cells demonstrated that AI-10-49 (1µM for six hours) effectively and specifically dissociated RUNX1/CBFβ-SMMHC when compared to CBFβ/RUNX1 binding (Meandiss: 90% and 15%, respectively). Expression of RUNX1 target genes RUNX3, CSF1R, and CEBPA is repressed by CBFβ-SMMHC in inv(16) AML. The occupancy of RUNX1 in their promoters was significantly increased by chromatin-immunoprecipitation (8, 2.2, and 8 fold, respectively) in 6 hour treated (1µM AI-10-49) ME-1 cells, suggesting that CBFβ-SMMHC represses RUNX1 targets by blocking RUNX1 binding to target regulatory sites. In addition, RUNX3, CSF1R, and CEBPA expression increased 2 to 8 fold when compared to DMSO treated ME-1 cells. Importantly, RUNX1 occupancy and target expression changes were not observed in inv(16)-negative U937 cells. These data establish AI-10-49 selectivity in inhibiting CBFβ-SMMHC binding to RUNX1 and validate our approach of using bivalent inhibitors to achieve this specificity. To test AI-10-49 activity in vivo, mice were transplanted with leukemic cells expressing CBFβ-SMMHC and NrasG12D (from Cbfb+/MYH11:Ras+/G12Dknock-in mice), and treated, starting at day five post transplantation, with vehicle (DMSO) or 200 mg/kg AI-10-49 for ten days. The median latency of leukemia was delayed one fold in AI-10-49 treated mice (MLAI-10-49= 61 days, MLDMSO= 33.5 days, P=2.7x10-6; Log-rank test). In addition, toxicity assays revealed no detectable cumulative toxicity in mice treated with AI-10-49 for seven days. To test the efficacy of AI-10-49 in human inv(16) AML, the survival of four inv(16) and four normal karyotype AML patient samples were tested in 48 hour dose response assays. The viability of inv(16) patient cells was clearly reduced by AI-10-49 (viability: 50%, 10 μM AI-10-49/DMSO). In contrast, the viability of normal karyotype AML samples was unaffected at concentrations below 20µM. These studies show that AI-10-49 selectively inhibits viability in inv(16) AML blasts, while having negligible effects on AML blasts with normal karyotype or on normal human hematopoietic progenitors. Dysregulated gene expression is a hallmark of cancer and is particularly important for the maintenance of cancer stem cells, such as self-renewal, leading to relapse. The targeting of proteins that drive transcriptional dysregulation, so called “transcription therapy”, represents an avenue for drug development with immense potential. This study reports the development of a small molecule with high efficacy and specific in the inhibition of CBFβ-SMMHC activity while having a minimal effect on CBFβ function. In summary, AI-10-49 is a potent first generation CBFβ-SMMHC inhibitor that induces cell death in inv(16) AML cells and establishes a proof-of-principle that transcription factor fusion oncoproteins can be directly targeted for leukemia treatment. Disclosures No relevant conflicts of interest to declare.
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Linden, Hannah M., Brenda F. Kurland, Jeanne Link, Vijayakrishna K. Gadi, Jennifer M. Specht, Julie Gralow, Erin K. Schubert, Lanell Peterson, Janet F. Eary, and David A. Mankoff. "Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic breast cancer: A phase II clinical trial with ER imaging correlates." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS3109. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps3109.
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TPS3109 Background: Endocrine refractory,Indolent, soft tissue, and bone dominant metastatic breast cancer is a clinical problem, for which alternatives to chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit. HDACi restore ER expression in ER-negative cells which are then sensitive to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors. We hypothesized that HDACi therapy could restore sensitivity to aromatase inhibitor (AI) therapy, in patients with prior progression on AI, and allow continued endocrine therapy. Recent data suggest clinical benefit of Tamoxifen and vorinostat given continuously (Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior work has shown the feasibility of monitoring regional ER expression and ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging (Linden 2011) providing a biomarker to interrogate the molecular target. Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on AI therapy are eligible. Patients must be off ER blocking therapies, and functionally postmenopausal. Baseline FES and FDG PET are performed and patients receive investigational vorinostat treatment at 400 mg po BID for 2 weeks followed by serial FES and FDG PET to assess the impact of vorinostat on ER expression and tumor metabolism. Patients are retreated on their prior AI as a single agent for 6 weeks, followed by paired FES and FDG and clinical assessment. Patients with clinical benefit may continue on treatment: 2 weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.
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Howie, Lynn J., Harpreet Singh, Erik Bloomquist, Suparna Wedam, Laleh Amiri-Kordestani, Shenghui Tang, Rajeshwari Sridhara, et al. "Outcomes of Older Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis." Journal of Clinical Oncology 37, no. 36 (December 20, 2019): 3475–83. http://dx.doi.org/10.1200/jco.18.02217.
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PURPOSE Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.