scholarly journals Further genetic diversification in multiple tumors and an evolutionary perspective on therapeutics

2015 ◽  
Author(s):  
Yong Tao ◽  
Zheng Hu ◽  
Shaoping Ling ◽  
Shiou-Hwie Yeh ◽  
Weiwei Zhai ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Low Frequency ◽  
Frequency Range ◽  
Resistance Mutations ◽  
Primary Tumors ◽  
Very Low Frequency ◽  
Evolutionary Forces ◽  
Single Tumor ◽  
Multiple Hepatocellular Carcinoma

The genetic diversity within a single tumor can be extremely large, possibly with mutations at all coding sites (Ling et al. 2015). In this study, we analyzed 12 cases of multiple hepatocellular carcinoma (HCC) tumors by sequencing and genotyping several samples from each case. In 10 cases, tumors are clonally related by a process of cell migration and colonization. They permit a detailed analysis of the evolutionary forces (mutation, migration, drift and natural selection) that influence the genetic diversity both within and between tumors. In 23 inter-tumor comparisons, the descendant tumor usually shows a higher growth rate than the parent tumor. In contrast, neutral diversity dominates within-tumor observations such that adaptively growing clones are rarely found. The apparent adaptive evolution between tumors can be explained by the inherent bias for detecting larger tumors that have a growth advantage. Beyond these tumors are a far larger number of clones which, growing at a neutral rate and too small to see, can nevertheless be verified by molecular means. Given that the estimated genetic diversity is often very large, therapeutic strategies need to take into account the pre-existence of many drug-resistance mutations. Importantly, these mutations are expected to be in the very low frequency range in the primary tumors (and become frequent in the relapses, as is indeed reported (1-3). In conclusion, tumors may often harbor a very large number of mutations in the very low frequency range. This duality provides both a challenge and an opportunity for designing strategies against drug resistance (4-8).

Genetic Diversity and Drug Resistance of HIV-1 CRF55_01B in Guangdong, China

2020 ◽  
Vol 18 (3) ◽  
pp. 210-218
Author(s):  
Guolong Yu ◽  
Yan Li ◽  
Xuhe Huang ◽  
Pingping Zhou ◽  
Jin Yan ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Phylogenetic Analyses ◽  
Resistance Mutations ◽  
Protease Inhibition ◽  
Subtype B ◽  
Primary Drug Resistance ◽  
Hiv 1 ◽  
Primary Drug

Background: HIV-1 CRF55_01B was first reported in 2013. At present, no report is available regarding this new clade’s polymorphisms in its functionally critical regions protease and reverse transcriptase. Objective: To identify the diversity difference in protease and reverse transcriptase between CRF55_01B and its parental clades CRF01_AE and subtype B; and to investigate CRF55_01B’s drug resistance mutations associated with the protease inhibition and reverse transcriptase inhibition. Methods: HIV-1 RNA was extracted from plasma derived from a MSM population. The reverse transcription and nested PCR amplification were performed following our in-house PCR procedure. Genotyping and drug resistant-associated mutations and polymorphisms were identified based on polygenetic analyses and the usage of the HIV Drug Resistance Database, respectively. Results: A total of 9.24 % of the identified CRF55_01B sequences bear the primary drug resistance. CRF55_01B contains polymorphisms I13I/V, G16E and E35D that differ from those in CRF01_AE. Among the 11 polymorphisms in the RT region, seven were statistically different from CRF01_AE’s. Another three polymorphisms, R211K (98.3%), F214L (98.3%), and V245A/E (98.3 %.), were identified in the RT region and they all were statistically different with that of the subtype B. The V179E/D mutation, responsible for 100% potential low-level drug resistance, was found in all CRF55_01B sequences. Lastly, the phylogenetic analyses demonstrated 18 distinct clusters that account for 35% of the samples. Conclusions: CRF55_01B’s pol has different genetic diversity comparing to its counterpart in CRF55_01B’s parental clades. CRF55_01B has a high primary drug resistance presence and the V179E/D mutation may confer more vulnerability 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 HIV-1 genetic diversity and drug resistance mutations in the northern Brazilian region

2021 ◽  
pp. 101596
Author(s):  
Myuki Esashika Crispim ◽  
Monica Nogueira da Guarda Reis ◽  
Mariane Martins de Araujo Stefani
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv 1

scholarly journals Behavior of three colicine factors and an R (drug-resistance) factor in Hfr crosses inSalmonella typhimurium

1967 ◽  
Vol 9 (3) ◽  
pp. 283-297 ◽  
Author(s):  
Eugenie Dubnau ◽  
B. A. D. Stocker
Keyword(s):  
Drug Resistance ◽  
Low Frequency ◽  
Resistance Factor ◽  
Chromosomal Locus ◽  
Very Low Frequency ◽  
R Factor ◽  
Phage P22 ◽  
Donor Chromosome ◽  
Image Position ◽  
Line Analysis

An LT2 Hfr strain,his metC gal, was crossed to a multiply marked LT2 F−line. Analysis of recombinant yields, segregation of unselected markers and interrupted matings indicated injection of the Hfr chromosome in the sequenceThe introduction into the Hfr of the colicine factorscolI, colE1andcolE2and the R factorR2had little or no effect on its fertility. All four factors were transmitted at low frequency to the F−population, and to recombinants at higher frequencies (colI5–30%,colE130–80%,colE25–30%,R20–9%). Transfer ofcolE1occurred before 20 min., that ofcolE2andcolIlater than 100 min. Segregation data did not reveal close linkage of any factor to any chromosomal locus, but recombinants with a long stretch of donor chromosome were more likely than others to have acquiredcolE2andcolI. Nearly all recombinants andF−cells which acquiredcolIorcolE2acquired both, andcolE1also. Most cells which acquiredR2acquired one or more colicine factors. These plasmid associations can be formally represented by transfer of plasmids, independently of the chromosome, in the sequencecolE1—(colI, colE2)—R2. Phage P22 grown on the Hfr carrying the four plasmids transduced thetet-rtrait ofR2at very low frequency, and thesul-r str-rcharacters, together, at low frequency. Some of each sort of drug-resistance transductant, but no transductants in respect of chromosomal characters, acquiredcolEl or colE2by co-transduction.

scholarly journals Drug Resistance Mutations and Genetic Diversity in Patients Treated for HIV Type 1 Infection in Rural Care Centers in Togo

2016 ◽  
Vol 06 (03) ◽  
pp. 111-115
Author(s):  
Anoumou Dagnra ◽  
Abla Konou ◽  
Mounerou Salou ◽  
Pascal Kodah ◽  
Damobé Kombate ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv Type 1 ◽  
Rural Care

scholarly journals Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

2016 ◽  
Vol 60 (6) ◽  
pp. 3380-3397 ◽  
Author(s):  
Fred Kyeyune ◽  
Richard M. Gibson ◽  
Immaculate Nankya ◽  
Colin Venner ◽  
Samar Metha ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Sanger Sequencing ◽  
Antiretroviral Treatment ◽  
Low Frequency ◽  
Drug Resistant ◽  
Viral Quasispecies ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv 1

Most patients failing antiretroviral treatment in Uganda continue to fail their treatment regimen even if a dominant drug-resistant HIV-1 genotype is not detected. In a recent retrospective study, we observed that approximately 30% of HIV-infected individuals in the Joint Clinical Research Centre (Kampala, Uganda) experienced virologic failure with a susceptible HIV-1 genotype based on standard Sanger sequencing. Selection of minority drug-resistant HIV-1 variants (not detectable by Sanger sequencing) under antiretroviral therapy pressure can lead to a shift in the viral quasispecies distribution, becoming dominant members of the virus population and eventually causing treatment failure. Here, we used a novel HIV-1 genotyping assay based on deep sequencing (DeepGen) to quantify low-level drug-resistant HIV-1 variants in 33 patients failing a first-line antiretroviral treatment regimen in the absence of drug-resistant mutations, as screened by standard population-based Sanger sequencing. Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified low-frequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drug-resistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

Extremely low frequency detection of electrical discharges at Minamidake crater (Sakurajima volcano, Japan)

2020 ◽  
Author(s):  
Caron E.J. Vossen ◽  
Corrado Cimarelli ◽  
Alec J. Bennett ◽  
André Geisler ◽  
Damien Gaudin ◽  
...  
Keyword(s):  
Low Frequency ◽  
Japan Meteorological Agency ◽  
Frequency Range ◽  
Electrical Discharges ◽  
Very Low Frequency ◽  
Extremely Low Frequency ◽  
Sakurajima Volcano ◽  
Frequency Detection ◽  
The World ◽  
Active Volcanoes

<p>Volcanoes are increasingly better monitored around the world. Nonetheless, the detection and monitoring of volcanic ash plumes remains difficult, especially in remote areas. Intense electrical activity and lightning in volcanic plumes suggests that electrical monitoring of active volcanoes can aid the detection of ash emissions in near real-time. Current very low frequency and wide-band thunderstorm networks have proven to be able to detect plumes of large magnitude. However, the time delay and the relatively high number of non-detected explosive episodes show that the applicability of these systems to the detection of smaller (and often more frequent) ash-rich explosive events is limited. Here we use a different type of thunderstorm detector to observe electrical discharges generated by the persistent Vulcanian activity of Minamidake crater at Sakurajima volcano in Japan. The sensors consist of two antennas that measure the induced current due to the change in electric field with time. In contrast to the current thunderstorm networks, these sensors measure within the extremely low frequency range (1-45 Hz) and can detect lightning up to 35 kilometres distance.</p><p>Two detectors were installed at a distance of 3 and 4 kilometres from Minamidake crater and recorded almost continuously since July 2018. Within this period, the ash plumes reached a maximum height of 5.5 kilometres above the crater rim. Using a volcanic lightning detection algorithm and the catalogue of volcanic explosions compiled by the Japan Meteorological Agency (JMA), the number of electrical discharges was determined for each individual explosive event. In addition, the start of electrical discharges was compared to the eruption onset estimated by the JMA.</p><p>Preliminary results show that the detector closest to the crater had the highest detection efficiency. It detected electrical discharges during 60% of the eruptions listed by the JMA. This is significantly higher than for the World Wide Lightning Location Network, which detected electrical discharges (in the very low frequency range) within 20 kilometres of Sakurajima for less than 0.005% of the eruptions. Furthermore, the results show that for 40% of the detected eruptions, electrical discharges were detected before the estimated JMA timing. Hence, electrical discharges can mark the inception of the explosion with a higher precision and are an indication of ash emission. This demonstrates the value of the cost-effective sensors used here as a monitoring tool at active volcanoes.</p>

scholarly journals Dynamic cerebral autoregulation during passive heat stress in humans

2009 ◽  
Vol 296 (5) ◽  
pp. R1598-R1605 ◽  
Author(s):  
David A. Low ◽  
Jonathan E. Wingo ◽  
David M. Keller ◽  
Scott L. Davis ◽  
Jian Cui ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heat Stress ◽  
Transfer Function ◽  
High Frequency ◽  
Cerebral Autoregulation ◽  
Low Frequency ◽  
Passive Heating ◽  
Frequency Range ◽  
Very Low Frequency ◽  
Dynamic Cerebral Autoregulation

This study tested the hypothesis that passive heating impairs cerebral autoregulation. Transfer function analyses of resting arterial blood pressure and middle cerebral artery blood velocity (MCA Vmean), as well as MCA Vmean and blood pressure responses to rapid deflation of previously inflated thigh cuffs, were examined in nine healthy subjects under normothermic and passive heat stress (increase core temperature 1.1 ± 0.2°C, P < 0.001) conditions. Passive heating reduced MCA Vmean [change (Δ) of 8 ± 8 cm/s, P = 0.01], while blood pressure was maintained (Δ −1 ± 4 mmHg, P = 0.36). Coherence was decreased in the very-low-frequency range during heat stress (0.57 ± 0.13 to 0.26 ± 0.10, P = 0.001), but was >0.5 and similar between normothermia and heat stress in the low- (0.07–0.20 Hz, P = 0.40) and high-frequency (0.20–0.35 Hz, P = 0.12) ranges. Transfer gain was reduced during heat stress in the very-low-frequency (0.88 ± 0.38 to 0.59 ± 0.19 cm·s−1·mmHg−1, P = 0.02) range, but was unaffected in the low- and high-frequency ranges. The magnitude of the decrease in blood pressure (normothermia: 20 ± 4 mmHg, heat stress: 19 ± 6 mmHg, P = 0.88) and MCA Vmean (13 ± 4 to 12 ± 6 cm/s, P = 0.59) in response to cuff deflation was not affected by the thermal condition. Similarly, the rate of regulation of cerebrovascular conductance (CBVC) after cuff release (0.44 ± 0.22 to 0.38 ± 0.13 ΔCBVC units/s, P = 0.16) and the time for MCA Vmean to recover to precuff deflation baseline (10.0 ± 7.9 to 8.7 ± 4.9 s, P = 0.77) were not affected by heat stress. Counter to the proposed hypothesis, similar rate of regulation responses suggests that heat stress does not impair the ability to control cerebral perfusion after a rapid reduction in perfusion pressure, while reduced transfer function gain and coherence in the very-low-frequency range during heat stress suggest that dynamic cerebral autoregulation is improved during spontaneous oscillations in blood pressure within this frequency range.

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