scholarly journals Optimal Chemotherapy Scheduling for Non-Genetic Drug Resistance

2021 ◽  
Author(s):  
Sasan Paryad Zanjani ◽  
Michael Saint-Antoine ◽  
Abhyudai Singh
Keyword(s):  
Growth Rate ◽  
Drug Resistance ◽  
Transient State ◽  
Continuous Therapy ◽  
Darwinian Selection ◽  
Estimated Parameters ◽  
State Switching ◽  
The Difference ◽  
Emergence Of Resistance ◽  
Resistant Cells

One of the most difficult challenges in cancer therapy is the emergence of drug resistance within tumors. Sometimes drug resistance can emerge as the result of mutations and Darwinian selection. However, recently another phenomenon has been discovered, in which tumor cells switch back and forth between drug-sensitive and pre-resistant states. Upon exposure to the drug, sensitive cells die off, and pre-resistant cells become locked in to a state of permanent drug resistance. In this paper, we explore the implications of this transient state switching for therapy scheduling. We propose a model to describe the phenomenon and estimate parameters from experimental melanoma data. We then compare the performance of continuous and alternating drug schedules, and use sensitivity analysis to explore how different conditions affect the efficacy of each schedule. We find that for our estimated parameters, a continuous therapy schedule is optimal. However we also find that an alternating schedule can be optimal for other, hypothetical parameter sets, depending on the difference in growth rate between pre- drug and post-drug cells, the delay between exposure to the drug and emergence of resistance, and the rate at which pre-resistant cells become resistant relative to the rate at which they switch back to the sensitive state.

scholarly journals A microfluidic device enabling drug resistance analysis of leukemia cells via coupled dielectrophoretic detection and impedimetric counting

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yağmur Demircan Yalçın ◽  
Taylan Berkin Töral ◽  
Sertan Sukas ◽  
Ender Yıldırım ◽  
Özge Zorlu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Drug Resistant ◽  
Wild Type ◽  
Gene Expressions ◽  
Before And After ◽  
The Difference ◽  
Selection Of ◽  
Resistant Cells

AbstractWe report the development of a lab-on-a-chip system, that facilitates coupled dielectrophoretic detection (DEP-D) and impedimetric counting (IM-C), for investigating drug resistance in K562 and CCRF-CEM leukemia cells without (immuno) labeling. Two IM-C units were placed upstream and downstream of the DEP-D unit for enumeration, respectively, before and after the cells were treated in DEP-D unit, where the difference in cell count gave the total number of trapped cells based on their DEP characteristics. Conductivity of the running buffer was matched the conductivity of cytoplasm of wild type K562 and CCRF-CEM cells. Results showed that DEP responses of drug resistant and wild type K562 cells were statistically discriminative (at p = 0.05 level) at 200 mS/m buffer conductivity and at 8.6 MHz working frequency of DEP-D unit. For CCRF-CEM cells, conductivity and frequency values were 160 mS/m and 6.2 MHz, respectively. Our approach enabled discrimination of resistant cells in a group by setting up a threshold provided by the conductivity of running buffer. Subsequent selection of drug resistant cells can be applied to investigate variations in gene expressions and occurrence of mutations related to drug resistance.

scholarly journals Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment

2010 ◽  
Vol 55 (3) ◽  
pp. 1114-1119 ◽  
Author(s):  
Jia Liu ◽  
Michael D. Miller ◽  
Robert M. Danovich ◽  
Nathan Vandergrift ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Low Frequency ◽  
Hiv Treatment ◽  
Viral Population ◽  
Virologic Suppression ◽  
Resistance Mutations ◽  
The Difference ◽  
Allele Specific Sequencing ◽  
Hiv 1

ABSTRACTRaltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients,n= 36) and those who experienced virologic rebound (failure patients,n= 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

scholarly journals Effect of Allium senescens Extract on Sorafenib Resistance in Hepatocarcinoma Cells

2021 ◽  
Vol 11 (8) ◽  
pp. 3696
Author(s):  
Sohyeon Park ◽  
Yoonjin Park ◽  
Heejong Shin ◽  
Boyong Kim ◽  
Seunggwan Lee
Keyword(s):  
Drug Resistance ◽  
Hepg2 Cells ◽  
High Performance ◽  
Quantitative Polymerase Chain Reaction ◽  
Mitochondrial Apoptosis ◽  
Coumaric Acid ◽  
Allium Species ◽  
Hepatocarcinoma Cells ◽  
Polymerase Chain ◽  
Resistant Cells

Although Allium species are involved in bioactivity, to the best of our knowledge, there is no research on the effects of Allium senescens on drug resistance in hepatocarcinoma. Ultra-high performance liquid chromatography was used to determine the concentration of several bioactive compounds in A. senescens extract; flow cytometry, reverse transcription–quantitative polymerase chain reaction, and siRNA-mediated knockdown to estimate the levels of different markers in HepG2 cells. The quantity of p-coumaric acid in the extract was 4.7291 ± 0.06 μg/mL, and the protein of relevant evolutionary and lymphoid interest (PRELI) in the resistant cells decreased 2.1 times in the presence of p-coumaric acid. The resistant cells strongly downregulated the efflux transporters (ABCB1, ABCC2, and ABCG2) when exposed to the extract or p-coumaric acid and when PRELI was knocked down, in contrast to the influx proteins (OCT-1). Additionally, the extract induced mitochondrial apoptosis and suppressed autophagy. Consequently, the extract and p-coumaric acid attenuated drug resistance of HepG2 cells through the downregulation of PRELI, a key protein associated with the modulation of drug transporter expression, the activation of autophagy, and mitochondrial apoptosis. Our results indicate that A. senescens extract is beneficial in protecting cancer cells against drug resistance and sustaining the efficacy of sorafenib against liver cancer.

A Model of Wheat Grain Growth and Its Applications to Different Temperature and Carbon Dioxide Levels

1995 ◽  
Vol 22 (5) ◽  
pp. 843 ◽  
Author(s):  
YP Wang ◽  
RM Gifford
Keyword(s):  
Growth Rate ◽  
Grain Growth ◽  
Temperature Response ◽  
Rate Sensitivity ◽  
Temperature Sensitive ◽  
Potential Growth ◽  
Carbon Supply ◽  
The Difference ◽  
Carbon Dioxide Levels ◽  
Kernel Growth

Kernel growth after anthesis is simulated as a function of the potential kernel growth rate, current photosynthate production and mobilisation of stored reserves. The potential growth rate of the kernel is simulated as two temperature-sensitive processes, cell production and cell growth. The difference between the potential and actual growth rates of the kernel depends on the carbon supply to the free space of the kernel endosperm, while the carbon supply is itself affected by the actual kernel growth rate. Sensitivity analysis showed that the growth rate of the grain per plant is most sensitive to the potential growth rate of the kernel and number of kernels per plant. This model is able to simulate the observed rates of grain growth and leaf senescence from anthesis to physiological maturity for wheat plants grown in two CO2 concentrations. The simulated temperature response of grain growth agrees well with the experimenal observations.

scholarly journals Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2284
Author(s):  
Serena Stamatakos ◽  
Giovanni Luca Beretta ◽  
Elisabetta Vergani ◽  
Matteo Dugo ◽  
Cristina Corno ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Metastatic Melanoma ◽  
Mutant Cell ◽  
Braf Inhibitor ◽  
Cancer Cell Line ◽  
Melanoma Cells ◽  
Melanoma Progression ◽  
Increased Sensitivity ◽  
Resistant Cells

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

Effect of prolonged exposition to growth factors differently on proliferation of CRC cell cultures encapsulated in alginate.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15610-e15610
Author(s):  
Svetlana Yu. Filippova ◽  
Anastasia O. Sitkovskaya ◽  
Irina V. Mezhevova ◽  
Sofia V. Timofeeva ◽  
Tatiana V. Shamova ◽  
...  
Keyword(s):  
Growth Factors ◽  
Culture Media ◽  
Alginate Beads ◽  
Encapsulated Cells ◽  
Test Systems ◽  
The Difference ◽  
High Doses ◽  
Culturing Conditions ◽  
Ht 29 ◽  
Resistant Cells

e15610 Background: Cancer stem cells (CSCs) are promising targets in modern oncology. A lot of CSCs enrichment and cultivation techniques are being currently developed. Most of the approaches deploy high doses of growth factors in culture media, - EGF and FGF2 above all, - without prior testing. Since prolonged exposition to growth factors may cause paradoxical growth inhibition it is worth developing test systems to evaluate culturing conditions before establishing the main experiment. Encapsulation in alginate may serve as a promising approach to develop such test-systems due to alginate reduced ability to adsorb proteins and maintain proper attachment to the ECM of non-stem cell even in the presence of serum. It is important to notice that serum addition may be crucial during initial stages of primary CSCs culture establishment. The aim of the study was to test EGF and FGF2 effects on anoikis resistant cells growth in permanent colorectal cancer cell lines. Methods: The cells of Caco-2, HT-29, and HCT 116 cultures were encapsulated in 1% alginate beads at a concentration of 100 000 cells/ml. Subsequently encapsulated cells were kept in 2 variants of culture media: DMEM/F12 + 10%FBS with and without addition of growth factors (EGF 20 ng/ml, FGF2 10 ng/ml). The cultivation was carried out for 10 days, after that the colonies area (A) was measured. Data are given as: Mean ± 95% confidence interval. Results: The average area of Caco-2 culture colonies increased significantly with the addition of growth factors (FBS only A = 1755.16±195.87 μm2, with additional growth factors Af = 3270.57±274.91 μm2), the difference was significant (t = 8.83, n = 300, p < 0,05). The area of HCT116 colonies after growth factors addition increased only slightly (A = 2844.89±461.57 μm2, Af = 3530.31±503.85 μm2), the difference nevertheless did not reach significant values (t = 1.94, n = 300, p > 0.05). At the same time, the area of HT-29 colonies significantly decreased in the culture medium containing additional growth factors (A = 4605.10±324.02 μm2, Af = 3167.85±249.07 μm2), the difference was significant (t = 6.92, n = 300, p < 0.05). Conclusions: Combining alginate encapsulation and colonies size measurement enabled us to evaluate culturing conditions of anoikis resistant cells in permanent CRC cultures and proved growth factors addition to be an ambiguous practice in CSCs research. This tactics can be applied in a broad spectrum of tasks concerning more effective CSCs medium formulations development.

scholarly journals The Ribosomal Protein L28 Gene Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Yi Shi ◽  
Xiaojiang Wang ◽  
Qiong Zhu ◽  
Gang Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Hepg2 Cells ◽  
Cell Model ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Resistant Gene ◽  
Key Genes ◽  
Resistant Cells

Abstract Background: Sorafenib is the first molecular-targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its treatment efficiency decreases after a short period of time because of the development of drug resistance. This study investigates the role of key genes in regulating sorafenib-resistance in hepatocellular carcinoma and elucidates the mechanism of drug resistance. Methods: The HCC HepG2 cells were used to generate a sorafenib-resistant cell model by culturing the cells in gradually increasing concentration of sorafenib. RNA microarray was applied to profile gene expression and screen key genes associated with sorafenib resistance. Specific targets were knockdown in sorafenib-resistant HepG2 cells for functional studies. The HCC model was established in ACI rats using Morris hepatoma3924A cells to validate selected genes associated with sorafenib resistance in vivo. Results: The HepG2 sorafenib-resistant cell model was successfully established. The IC50 of sorafenib was 9.988mM in HepG2 sorafenib-resistant cells. A total of 35 up-regulated genes were detected by expression profile chip. High-content screening technology was used and a potential drug-resistant gene RPL28 was filtered out. After knocking down of RPL28 in HepG2 sorafenib-resistant cells, the results of cell proliferation and apoptosis illustrated that RPL28 is the key drug-resistant gene in the cells. Furthermore, it was found that both RNA and protein expression of RPL28 increased in HepG2 sorafenib-resistant specimens of Morris Hepatoma rats. In addition, the expression of functional proteins Ki-67 increased in sorafenib-resistant cells. Conclusion: Our study suggested that RPL28 was a key gene for sorafenib resistance in HCC both in vitro and in vivo.

scholarly journals LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Enshuang Xu ◽  
Mengxin Hu ◽  
Reidong Ge ◽  
Danning Tong ◽  
Yuying Fan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mammary Gland ◽  
Tumor Cells ◽  
Luciferase Reporter ◽  
Drug Resistant ◽  
Mammary Gland Tumor ◽  
Luciferase Reporter Gene ◽  
Gland Tumor ◽  
Canine Mammary Gland ◽  
Resistant Cells

Tamoxifen is the drug of choice for endocrine therapy of breast cancer. Its clinical use is limited by the development of drug resistance. There is increasing evidence that long non-coding RNAs (lncRNAs) are associated with tumor drug resistance. Therefore, we established two TAM-resistant cell lines, CHMpTAM and CHMmTAM. The different expression levels of lncRNA and miRNA in CHMmTAM and CHMm were screened by RNA sequencing, and the lncRNA-miRNA interactions were analyzed. LncRNA ENSCAFG42060 (lnc-42060) was found to be significantly upregulated in drug-resistant cells and tumor tissues. Further functional validation revealed that the knockdown of lnc-42060 inhibited proliferation, migration, clone formation, restoration of TAM sensitivity, and reduction of stem cell formation in drug-resistant cells, whereas overexpression of lnc-4206 showed opposite results. Bioinformatics and dual-luciferase reporter gene assays confirmed that lnc-42060 could act as a sponge for miR-204-5p, further regulating SOX4 expression activity and thus influencing tumor cell progression. In conclusion, we screened lncRNAs and miRNAs associated with TAM resistance in canine mammary gland tumor cells for the first time. lnc-42060 served as a novel marker that may be used as an important biomarker for future diagnosis and treatment.

scholarly journals Features of body weight growth in meat breeds heifers

2016 ◽  
Vol 18 (2) ◽  
Author(s):  
R. S. Oseredchuk ◽  
N. P. Babik ◽  
V. V. Fedorovych ◽  
E. I. Fedorovych ◽  
V. R. Dutka
Keyword(s):  
Growth Rate ◽  
Body Weight ◽  
Weight Changes ◽  
Body Weight Changes ◽  
Relative Growth ◽  
Weight Growth ◽  
Rate Of Increase ◽  
The Difference ◽  
Tension Increase ◽  
Better Than

The data on the dynamics of body weight changes, absolute and average daily gains, frequency rate of increase in body weight, relative growth rate and intensity of body weight growth of Limousine and Volyn Meat breeds heifers. Both studied breeds characterized by different body weight at different age periods. Newborn Limousine breed heifers are weighed 2,7 kg more (P < 0.05) than Volyn Meat breed heifers; at 3 months age the difference was 8.5 kg (P < 0.05) at 6 months – 14.6 kg, at 9 month – 20.8 kg (P < 0.05), at 12 months – 25,6 kg (P < 0.05), at 15–months – 31.9 (P<0,05), and at 18 months – 23.5 kg. Total and average daily gains in animals of both breeds were the highest for a period of 3 to 6 months of age. In the period from birth to 15 months of age preference for average daily gains were in Limousine, however, the difference was statistically significant only for the period of 0 – 3 months and amounted to 63,9 g (P < 0,05). From 15 to 18 months of age Limousine slightly conceded to Volyn Meat breeds on this parameter. In animals of both breeds magnification of body weight increased with age, but over the entire period (from birth to 18 months) this parameter in Volyn Meat heifers was 0.6 times better than Limousine heifers. The coefficients of relative intensity and tension increase of body weight in animals of both breeds were highest in the period from birth to 3 months of age. With age, these indicators declined. Mainly, the advantage was in Volyn meat breed heifers, but the difference was not statistically significant.

scholarly journals Pemberian Enzim Lignosellulosa Dalam Pakan Buatan Terhadap Pertumbuhan Dan Tingkat Kelulushidupan Benih Ikan Gurami (Osphronemus gouramy Lac.) [The Granting Of An Enzyme Lignosellulosa In Feed Artificial On The Growth And The Survival Rate Seed Gourami (Osphronemus gouramy Lac.) ]

2019 ◽  
Vol 5 (2) ◽  
pp. 163
Author(s):  
Muhammad Yusuf Akbar, Agustono, Rahayu Kusdarwat
Keyword(s):  
Water Quality ◽  
Growth Rate ◽  
Survival Rate ◽  
Conversion Ratio ◽  
Feed Conversion Ratio ◽  
Quality Data ◽  
Feed Conversion ◽  
Water Quality Data ◽  
The Difference ◽  
Range Test

Abstract Gurami having economic values of. Have abundance, namely able in waters with its oxygen relatively low. Belong to the species of carnivorous herbs herbivora. Unprofitableness is eat feed derived from herbs with content nutrition relatively low compared to animals, so it impact on its growth slow, easly diseases, easly stress, hard eat and SR low. The purpose of this research isto know the addition of enzyme lignosellulase in artificialfeedincreased growth and increased survival rate seed gourami. Method research used is experimental with delightful random complete (RAL) with five treatment and four deuterenomy. The treatment used were : control (A), enzyme 550ml (B), enzyme 600ml (C), enzyme 650ml (D), and enzyme 750ml(E). The main parameters measured were growth rate, and survival rate. The supporting parameters observedwas water quality. Data analysis used analysis of variance (ANOVA) to know the effect of the treatments.To know the difference among treatments used Duncan’s Multiple Range Test (DMRT). The result showed that the provision of enzymes give a real power (p<0.01) against growth rate daily and growth long absolute gourami (Osphronemus gouramy) To survival rate and feed conversion ratio gourami give impact which is not dissimilar real. Growth best on treatment E (0.0214), then successive followed by treatment D (0.0174), C (0.015), B (0.0142) and A (0.0128). Conversion ratio feed on all treatment e 10,415, that is, e then successive followed by treatment d (12,915), c (14,3975), b (15,6375) and a (17,5325). Survival rate obtained 100%. Water quality media maintenance gourami is temperature 26ºC - 29ºC, pH 7 – 8, oxygen dissolved 3.5 – 5 mg/l and ammonia 0.004 – 0.005 mg/l.

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