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Philip Hieter - One of the best experts on this subject based on the ideXlab platform.
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Synthetic Lethality and cancer
Nature Reviews Genetics, 2017Co-Authors: Nigel J. O'neil, Melanie L. Bailey, Philip HieterAbstract:Synthetic lethal genetic interactions with tumour-specific mutations may be exploited to develop anticancer therapeutics. Synthetic dosage Lethality and conditional synthetic Lethality can expand the scope of conventional synthetic lethal studies. Genetic interaction networks in model organisms provide a framework for screening cancer-relevant candidate synthetic lethal interactions in human cells. Large-scale screening for cancer gene-specific synthetic lethal candidates in human cells has progressed through advances in RNA interference and the CRISPR–Cas9 system. The CRISPR–Cas9 technology is a versatile platform for exploring genetic networks and synthetic lethal interaction phenotypes. The search for synthetic Lethality-based therapeutic strategies could be enhanced by integrating synthetic lethal interactions from three distinct sources: model organism genetic networks, human high-throughput screening and synthetic lethal predictions from statistical genetics. A synthetic lethal interaction occurs between two genes when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in the loss of viability. Key to exploiting synthetic Lethality in cancer treatment are the identification and the mechanistic characterization of robust synthetic lethal genetic interactions. Advances in next-generation sequencing technologies are enabling the identification of hundreds of tumour-specific mutations and alterations in gene expression that could be targeted by a synthetic Lethality approach. The translation of synthetic Lethality to therapy will be assisted by the synthesis of genetic interaction data from model organisms, tumour genomes and human cell lines. The authors review the concept of synthetic Lethality — when the perturbation of one of two genes alone is viable, but the perturbation of both genes simultaneously results in the loss of viability — from model organisms to human cancers, and discuss how genetic interactions can be exploited for the identification of new drug targets in cancer.
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Synthetic Lethality and cancer.
Nature Reviews Genetics, 2017Co-Authors: Nigel J. O'neil, Melanie L. Bailey, Philip HieterAbstract:A synthetic lethal interaction occurs between two genes when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in the loss of viability. Key to exploiting synthetic Lethality in cancer treatment are the identification and the mechanistic characterization of robust synthetic lethal genetic interactions. Advances in next-generation sequencing technologies are enabling the identification of hundreds of tumour-specific mutations and alterations in gene expression that could be targeted by a synthetic Lethality approach. The translation of synthetic Lethality to therapy will be assisted by the synthesis of genetic interaction data from model organisms, tumour genomes and human cell lines.
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Synthetic dosage Lethality.
Methods in enzymology, 2002Co-Authors: Vivien Measday, Philip HieterAbstract:Publisher Summary Identification of proteins that interact to perform a common function is crucial to understanding the mechanisms of cellular processes. Both genetic and biochemical methods are used to uncover an interaction between two proteins. In yeast, many genetic screens have been developed, which begin with the mutation of a gene of interest and look for a phenotype (such as cell Lethality) in combination with mutation or overexpression of another gene. This chapter discusses a screen called synthetic dosage Lethality (SDL), which is based on features of both dosage suppression and synthetic lethal screening to identify interacting proteins. An SDL interaction occurs when overexpression of a cloned wild-type (reference) gene is lethal in a target mutant strain but is viable in a wild-type strain. The chapter describes the SDL method and an example of its use to study budding yeast kinetochore function. SDL is a generally applicable technique for studying multiple cellular processes in both budding yeast and other organisms.
Wataru Marubashi - One of the best experts on this subject based on the ideXlab platform.
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genes in s and t subgenomes are responsible for hybrid Lethality in interspecific hybrids between nicotiana tabacum and nicotiana occidentalis
PLOS ONE, 2012Co-Authors: Takahiro Tezuka, Wataru MarubashiAbstract:Background Many species of Nicotiana section Suaveolentes produce inviable F1 hybrids after crossing with Nicotiana tabacum (genome constitution SSTT), a phenomenon that is often called hybrid Lethality. Through crosses with monosomic lines of N. tabacum lacking a Q chromosome, we previously determined that hybrid Lethality is caused by interaction between gene(s) on the Q chromosome belonging to the S subgenome of N. tabacum and gene(s) in Suaveolentes species. Here, we examined if hybrid seedlings from the cross N. occidentalis (section Suaveolentes)×N. tabacum are inviable despite a lack of the Q chromosome. Methodology/Principal Findings Hybrid Lethality in the cross of N. occidentalis×N. tabacum was characterized by shoots with fading color. This symptom differed from what has been previously observed in lethal crosses between many species in section Suaveolentes and N. tabacum. In crosses of monosomic N. tabacum plants lacking the Q chromosome with N. occidentalis, hybrid Lethality was observed in hybrid seedlings either lacking or possessing the Q chromosome. N. occidentalis was then crossed with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT), to reveal which subgenome of N. tabacum contains gene(s) responsible for hybrid Lethality. Hybrid seedlings from the crosses N. occidentalis×N. tomentosiformis and N. occidentalis×N. sylvestris were inviable. Conclusions/Significance Although the specific symptoms of hybrid Lethality in the cross N. occidentalis×N. tabacum were similar to those appearing in hybrids from the cross N. occidentalis×N. tomentosiformis, genes in both the S and T subgenomes of N. tabacum appear responsible for hybrid Lethality in crosses with N. occidentalis.
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Overproduced ethylene causes programmed cell death leading to temperature-sensitive Lethality in hybrid seedlings from the cross Nicotiana suaveolens × N. tabacum
Planta, 2003Co-Authors: Tetsuya Yamada, Wataru MarubashiAbstract:Reproductive isolation mechanisms (RIMs) often become obstacles in crossbreeding. Hybrid Lethality is a subtype of RIM but its physiological mechanism remains poorly elucidated. Interspecific hybrids of Nicotiana suaveolens Lehm. × N. tabacum L. cv. Hicks-2 expressed temperature-sensitive Lethality. This Lethality was induced by programmed cell death (PCD) that was accompanied by the characteristic changes of animal apoptosis in hybrid seedlings at 28 °C but not at 36 °C. When hybrid seedlings were cultured at 28 °C, DNA fragmentation started in the cotyledon, and nuclear fragmentation subsequently progressed with lethal symptoms spreading throughout the seedlings. At 28 °C, ethylene production in hybrid seedlings was detectable at a high level compared with the level in parental seedlings. In contrast, the ethylene production rate in hybrid seedlings cultured at 36 °C was equal to that in parental seedlings. Treatment with ethylene biosynthetic inhibitors, amino-oxyacetic acid and amino-ethoxyvinyl glycine, suppressed lethal symptoms and apoptotic changes, and also prolonged survival of hybrid seedlings. Thus, the increase in the ethylene production rate correlated closely with expression of lethal symptoms and apoptotic changes in hybrid seedlings. From these observations, we conclude that overproduced ethylene acts as an essential factor mediating PCD and subsequent Lethality in hybrid seedlings. Furthermore, the present study has provided the first evidence that ethylene is involved in the phenomenon of hybrid Lethality.
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possible involvement of auxin induced ethylene in an apoptotic cell death during temperature sensitive Lethality expressed by hybrid between nicotiana glutinosa and n repanda
Plant and Cell Physiology, 2001Co-Authors: Tetsuya Yamada, Teruko Nakamura, Wataru Marubashi, Masaru NiwaAbstract:: Interspecific hybrids of Nicotiana glutinosa L. x N. repanda Willd. express temperature-sensitive Lethality induced by apoptotic cell death. Hybrid seedlings cultured at 28 degrees C began to exhibit lethal symptoms during early growth stages, and then they showed a high level of endogenous auxin compared with those of parental seedlings. Meanwhile, the level of auxin in hybrid seedlings cultured at 32 degrees C, which is a condition suppressing the Lethality of this cross combination, was equal to or lower than those of parental seedlings. Administration of 2,3,5-triiodobenzoic acid (TIBA) as an auxin transport inhibitor into the hybrid seedlings suppressed lethal symptoms and had a life-extending effect. Additionally, TIBA has an effect to suppress DNA fragmentation, which is one of characteristics of apoptosis and has been detected in the hybrid seedlings expressing the Lethality. Administration of aminooxyacetic acid (AOA) as an ethylene synthesis inhibitor, which could inhibit ethylene production, also showed the same effects as TIBA for the Lethality. From these results, we suggested that auxin and ethylene were involved in an apoptotic cell death during the Lethality, and the abnormal increase of endogenous auxin may lead to the ethylene production in hybrid seedlings during early growth stages.
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Detection of Four Lethality Types in Interspecific Crosses among Nicotiana Species through the Use of Three Rescue Methods for Lethality
Breeding Science, 1999Co-Authors: Tetsuya Yamada, Wataru Marubashi, Masaru NiwaAbstract:Hybrid Lethality was surveyed in 186 cross combinations among 17 species from 9 sections of the genus Nicotiana. The hybrid seedlings of 14 cross combinations expressed Lethality characterized by one of four symptoms and the Lethality was classified into four types as follows: browning of the shoot apex and the root tip (Type I), browning of the hypocotyl and the roots (Type II), yellowing of the true leaves (Type III) and formation of multiple shoots (Type IV). Three kinds of rescue methods for the Lethality were applied to the 4 cross combinations expressing different types of the Lethality as follows: (1) culture of hybrid seedlings under high temperature conditions to suppress the Lethality, (2) culture of the cotyledonary segments of the hybrid seedlings to obtain regenerants overcoming the Lethality and (3) culture of the hybrid seedlings on a medium containing cytokinin to obtain regenerants overcoming the Lethality. The 1st and 2nd methods were effective in the cross of N. nudicaulis×N. tabacum expressing the Lethality Type I. All the methods were effective in the cross of N. paniculata × N. suaveolens expressing the Lethality Type II. Only the Ist method was effective in the cross of N. glutinosa× N. repanda expressing the Lethality Type III. None of the methods were effective in the cross of N. paniculata × N. alata expressing the Lethality Type IV. Each Lethality type exhibited a specific set of responses to the three rescue methods. These findings suggest that the Lethality observed in interspecific crosses of Nicotiana differs in the physiological processes leading to death.
Binaya Kumar Bastia - One of the best experts on this subject based on the ideXlab platform.
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Scale for Assessment of Lethality of Suicide Attempt
2014Co-Authors: Nilamadhab Kar, M. Arun, Manoj Kumar Mohanty, Binaya Kumar BastiaAbstract:Background: Lethality of suicidal attempt provides useful information regarding the behavior. There is a perceived need for a clinically useful scale that can be easily adapted to various methods and circumstances of attempt.Aims: The study intended to develop and test utility of a scale for measuring Lethality that can reflect overall clinical observation taking into account various indicators of Lethality and which can be used across clinical scenarios involving different methods.Settings and Design: Cross-sectional study in a hospital.Materials and Methods: The scale for assessment of Lethality of suicide attempt (SALSA) has two components: The first component has four items indicating seriousness of the attempt and its likely consequences and the second component is the global impression of Lethality. All the items are scored from 1 to 5, higher scores suggestive of increased Lethality. SALSA was used to evaluate Lethality of 82 consecutive suicide attempters; and it was compared with Lethality of suicide attempt rating scale (LSARS) and risk-rescue rating scale.Statistical Analysis: Chi-square, t-test, analysis of variance, Cronbach's alpha, binary logistic regression.Result: There was significant correlation of SALSA score with that of LSARS (r: 0.89) and risk score of risk-rescue rating (r: 0.93, P Conclusion: SALSA is a useful instrument for assessment of Lethality of suicidal behaviors during clinical evaluations considering the ease of administration, its ability to differentiate clinical groups with known variations of Lethality and clinical outcomes.
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Scale for assessment of Lethality of suicide attempt.
Indian journal of psychiatry, 2014Co-Authors: Nilamadhab Kar, M. Arun, Manoj Kumar Mohanty, Binaya Kumar BastiaAbstract:BACKGROUND: Lethality of suicidal attempt provides useful information regarding the behavior. There is a perceived need for a clinically useful scale that can be easily adapted to various methods and circumstances of attempt. AIMS: The study intended to develop and test utility of a scale for measuring Lethality that can reflect overall clinical observation taking into account various indicators of Lethality and which can be used across clinical scenarios involving different methods. SETTINGS AND DESIGN: Cross-sectional study in a hospital. MATERIALS AND METHODS: The scale for assessment of Lethality of suicide attempt (SALSA) has two components: The first component has four items indicating seriousness of the attempt and its likely consequences and the second component is the global impression of Lethality. All the items are scored from 1 to 5, higher scores suggestive of increased Lethality. SALSA was used to evaluate Lethality of 82 consecutive suicide attempters; and it was compared with Lethality of suicide attempt rating scale (LSARS) and risk-rescue rating scale. STATISTICAL ANALYSIS: Chi-square, t-test, analysis of variance, Cronbach's alpha, binary logistic regression. RESULT: There was significant correlation of SALSA score with that of LSARS (r: 0.89) and risk score of risk-rescue rating (r: 0.93, P CONCLUSION: SALSA is a useful instrument for assessment of Lethality of suicidal behaviors during clinical evaluations considering the ease of administration, its ability to differentiate clinical groups with known variations of Lethality and clinical outcomes. Language: en
Teresa J. Carrette - One of the best experts on this subject based on the ideXlab platform.
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Temperature effects on box jellyfish venom: a possible treatment for envenomed patients?
Medical Journal of Australia, 2002Co-Authors: Teresa J. Carrette, Paul Cullen, Mark Little, Peter L. Peiera, Jamie SeymourAbstract:Objective: To determine the effect of temperature on Lethality of venom from Chironex fleckeri (the potentially fatal box jellyfish). Design: Venom extracted from nematocysts of mature Chironex fleckeri specimens was exposed to temperatures between 4°C and 58°C for periods of two, five or 20 minutes, and then injected into freshwater crayfish (Cherax quadricarinatus) to assess Lethality. Main outcome measure: Venom Lethality, assessed as time to cardiac standstill in crayfish after intramuscular injection. Results: Venom Lethality was significantly affected by both temperature (F7,34 = 21915; P < 0.0001) and time of exposure (F2,34 = 9907; P < 0.0001). No significant loss of Lethality was seen after exposure to temperatures ≤ 39°C, even after 20 minutes' exposure. At temperatures ≥ 43°C, venom lost its Lethality more rapidly the longer the exposure time. Venom was non-lethal after exposure to 48°C for 20 minutes, 53°C for five minutes, and 58°C for two minutes. Conclusion: Exposure to heat dramatically reduces the Lethality of extracted C. fleckeri venom. Although heat application may be of limited use in treating C. fleckeri envenoming because of the speed of symptom onset, its use in other box-jellyfish envenomings, such as Irukandji syndrome, requires investigation.
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Temperature effects on box jellyfish venom: a possible treatment for envenomed patients?
The Medical journal of Australia, 2002Co-Authors: Teresa J. Carrette, Paul Cullen, Mark Little, Peter L. Peiera, Jamie E. SeymourAbstract:To determine the effect of temperature on Lethality of venom from Chironex fleckeri (the potentially fatal box jellyfish). Venom extracted from nematocysts of mature Chironex fleckeri specimens was exposed to temperatures between 4 degrees C and 58 degrees C for periods of two, five or 20 minutes, and then injected into freshwater crayfish (Cherax quadricarinatus) to assess Lethality. Venom Lethality, assessed as time to cardiac standstill in crayfish after intramuscular injection. Venom Lethality was significantly affected by both temperature (F(7,34) = 21915; P < 0.0001) and time of exposure (F(2,34) = 9907; P < 0.0001). No significant loss of Lethality was seen after exposure to temperatures <or= 39 degrees C, even after 20 minutes' exposure. At temperatures >or= 43 degrees C, venom lost its Lethality more rapidly the longer the exposure time. Venom was non-lethal after exposure to 48 degrees C for 20 minutes, 53 degrees C for five minutes, and 58 degrees C for two minutes. Exposure to heat dramatically reduces the Lethality of extracted C. fleckeri venom. Although heat application may be of limited use in treating C. fleckeri envenoming because of the speed of symptom onset, its use in other box-jellyfish envenomings, such as Irukandji syndrome, requires investigation.
Masaru Niwa - One of the best experts on this subject based on the ideXlab platform.
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possible involvement of auxin induced ethylene in an apoptotic cell death during temperature sensitive Lethality expressed by hybrid between nicotiana glutinosa and n repanda
Plant and Cell Physiology, 2001Co-Authors: Tetsuya Yamada, Teruko Nakamura, Wataru Marubashi, Masaru NiwaAbstract:: Interspecific hybrids of Nicotiana glutinosa L. x N. repanda Willd. express temperature-sensitive Lethality induced by apoptotic cell death. Hybrid seedlings cultured at 28 degrees C began to exhibit lethal symptoms during early growth stages, and then they showed a high level of endogenous auxin compared with those of parental seedlings. Meanwhile, the level of auxin in hybrid seedlings cultured at 32 degrees C, which is a condition suppressing the Lethality of this cross combination, was equal to or lower than those of parental seedlings. Administration of 2,3,5-triiodobenzoic acid (TIBA) as an auxin transport inhibitor into the hybrid seedlings suppressed lethal symptoms and had a life-extending effect. Additionally, TIBA has an effect to suppress DNA fragmentation, which is one of characteristics of apoptosis and has been detected in the hybrid seedlings expressing the Lethality. Administration of aminooxyacetic acid (AOA) as an ethylene synthesis inhibitor, which could inhibit ethylene production, also showed the same effects as TIBA for the Lethality. From these results, we suggested that auxin and ethylene were involved in an apoptotic cell death during the Lethality, and the abnormal increase of endogenous auxin may lead to the ethylene production in hybrid seedlings during early growth stages.
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Detection of Four Lethality Types in Interspecific Crosses among Nicotiana Species through the Use of Three Rescue Methods for Lethality
Breeding Science, 1999Co-Authors: Tetsuya Yamada, Wataru Marubashi, Masaru NiwaAbstract:Hybrid Lethality was surveyed in 186 cross combinations among 17 species from 9 sections of the genus Nicotiana. The hybrid seedlings of 14 cross combinations expressed Lethality characterized by one of four symptoms and the Lethality was classified into four types as follows: browning of the shoot apex and the root tip (Type I), browning of the hypocotyl and the roots (Type II), yellowing of the true leaves (Type III) and formation of multiple shoots (Type IV). Three kinds of rescue methods for the Lethality were applied to the 4 cross combinations expressing different types of the Lethality as follows: (1) culture of hybrid seedlings under high temperature conditions to suppress the Lethality, (2) culture of the cotyledonary segments of the hybrid seedlings to obtain regenerants overcoming the Lethality and (3) culture of the hybrid seedlings on a medium containing cytokinin to obtain regenerants overcoming the Lethality. The 1st and 2nd methods were effective in the cross of N. nudicaulis×N. tabacum expressing the Lethality Type I. All the methods were effective in the cross of N. paniculata × N. suaveolens expressing the Lethality Type II. Only the Ist method was effective in the cross of N. glutinosa× N. repanda expressing the Lethality Type III. None of the methods were effective in the cross of N. paniculata × N. alata expressing the Lethality Type IV. Each Lethality type exhibited a specific set of responses to the three rescue methods. These findings suggest that the Lethality observed in interspecific crosses of Nicotiana differs in the physiological processes leading to death.
