Potential protein activity modifications of amino acid variants in the human transcriptome

Background: The occurrence of widespread RNA and DNA sequence differences in the human transcriptome was reported in 2011. Similar findings were described in a second independent publication on personal omics profiling investigating the occurrence of dynamic molecular and related medical phenotypes. The suggestion that the RNA sequence variation was likely to affect disease susceptibility prompted us to investigate with a range of algorithms the amino acid variants reported to be present in the identified peptides to determine if they might be disease-causing. Results: The predictive qualities of the different algorithms were first evaluated by using nonsynonymous single-base nucleotide polymorphism (nsSNP) datasets, using independently established data on amino acid variants in several proteins as well as data obtained by mutational mapping and modelling of binding sites in the human serotonin transporter protein (hSERT). Validation of the used predictive algorithms was at a 75% level. Using the same algorithms, we found that widespread RNA and DNA sequence differences were predicted to impair the function of the peptides in over 57% of cases. Conclusions: Our findings suggest that a proportion of edited RNAs which serve as templates for protein synthesis is likely to modify protein function, possibly as an adaptive survival mechanism in response to environmental modifications

Seeking for Genetic Signature of Radiosensitivity- Methods for Data Analysis

Abstract. The aim of the study was to develop a data analysis strategy capable of discovering the genetic background of radiosensitivity. Radiosensitivity is the relative predisposition of cells, tissues, organs or organisms to the harmful effect of radiation. Effects of radiation include the mutation of DNA . Identification of polymorphisms and genes responsible for an organism's radiosensitivity increases the knowledge about the cell cycle and the mechanism of radiosensitivity, possibly providing the researchers with a better understanding of the process of carcinogenesis. To obtain this information, mathematical modelling and data mining methods were used

Radiation leukaemogenesis at low doses DE-FG02-05 ER 63947 Final Technical Report 15 May 2005 ÃÂÃÂÃÂÃÂÃÂÃÂÃÂâÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂà14 May 2010

This report provides a complete summary of the work undertaken and results obtained under US Department of Energy grant DF-FG02-05 ER 63947, Radiation leukaemogenesis at low doses. There is ample epidemiological evidence indicating that ionizing radiation is carcinogenic in the higher dose range. This evidence, however, weakens and carries increasing uncertainties at doses below 100-200 mSv. At these low dose levels the form of the dose-response curve for radiation-induced cancer cannot be determined reliably or directly from studies of human populations. Therefore animal, cellular and other experimental systems must be employed to provide supporting evidence on which to base judgements of risk at low doses. Currently in radiological protection a linear non-threshold (LNT) extrapolation of risk estimates derived from human epidemiological studies is used to estimate risks in the dose range of interest for protection purposes. Myeloid leukaemias feature prominently among the cancers associated with human exposures to ionising radiation (eg UNSCEAR 2006; IARC 2000). Good animal models of radiation-induced acute myeloid leukaemia (AML) are available including strains such as CBA, RFM and SJL (eg Major and Mole 1978; Ullrich et al 1976; Resnitzky et al 1985). Early mechanistic studies using cytogenetic methods in these mouse models established that the majority of radiation-induced AMLs carried substantial interstitial deletions in one copy of chromosome (chr) 2 (eg Hayata et al 1983; Trakhtenbrot et al 1988; Breckon et al 1991; Rithidech et al 1993; Bouffler et al 1996). Chr2 aberrations are known to occur in bone marrow cells as early as 24 hours after in vivo irradiation (Bouffler et al 1997). Subsequent molecular mapping studies defined a distinct region of chr2 that is commonly lost in AMLs (Clark et al 1996; Silver et al 1999). Further, more detailed, analysis identified point mutations at a specific region of the Sfpi1/PU.1 haemopoietic transcription factor gene which lies in the commonly deleted region of chr2 (Cook et al 2004; Suraweera et al 2005). These lines of evidence strongly implicate the Sfpi1/PU.1 gene as a tumour suppressor gene, dysregulation of which leads to myeloid leukaemia. The main focus of this project was to utilize the CBA mouse model of radiation leukaemogenesis to explore mechanisms of low dose and low dose-rate leukaemogenesis. A series of mechanistic investigations were undertaken, the central aim of which was to identify the events that convert normal cells into myeloid leukaemia cells and explore the dose-response relationships for these. Much of the work centred on the Sfpi1/PU.1 gene and its role in leukaemogenesis. Specific studies considered the dose-response and time-course relationships for loss of the gene, the functional consequences of Sfpi1/PU.1 loss and mutation on transcriptional programmes and developing an in vivo reporter gene system for radiation-induced alterations to PU.1 expression. Additional work sought further genetic changes associated with radiation-induced AMLs and a better characterization of the cell of origin or 'target cell' for radiation-induced AML. All the information gathered is of potential use in developing biologically realistic mathematical models for low dose cancer risk projection

Radiation leukaemogenesis at low doses DE-FG02-05 ER 63947 Final Technical Report 15 May 2005; 14 May 2010

This report provides a complete summary of the work undertaken and results obtained under US Department of Energy grant DF-FG02-05 ER 63947, Radiation leukaemogenesis at low doses. There is ample epidemiological evidence indicating that ionizing radiation is carcinogenic in the higher dose range. This evidence, however, weakens and carries increasing uncertainties at doses below 100-200 mSv. At these low dose levels the form of the dose-response curve for radiation-induced cancer cannot be determined reliably or directly from studies of human populations. Therefore animal, cellular and other experimental systems must be employed to provide supporting evidence on which to base judgements of risk at low doses. Currently in radiological protection a linear non-threshold (LNT) extrapolation of risk estimates derived from human epidemiological studies is used to estimate risks in the dose range of interest for protection purposes. Myeloid leukaemias feature prominently among the cancers associated with human exposures to ionising radiation (eg UNSCEAR 2006; IARC 2000). Good animal models of radiation-induced acute myeloid leukaemia (AML) are available including strains such as CBA, RFM and SJL (eg Major and Mole 1978; Ullrich et al 1976; Resnitzky et al 1985). Early mechanistic studies using cytogenetic methods in these mouse models established that the majority of radiation-induced AMLs carried substantial interstitial deletions in one copy of chromosome (chr) 2 (eg Hayata et al 1983; Trakhtenbrot et al 1988; Breckon et al 1991; Rithidech et al 1993; Bouffler et al 1996). Chr2 aberrations are known to occur in bone marrow cells as early as 24 hours after in vivo irradiation (Bouffler et al 1997). Subsequent molecular mapping studies defined a distinct region of chr2 that is commonly lost in AMLs (Clark et al 1996; Silver et al 1999). Further, more detailed, analysis identified point mutations at a specific region of the Sfpi1/PU.1 haemopoietic transcription factor gene which lies in the commonly deleted region of chr2 (Cook et al 2004; Suraweera et al 2005). These lines of evidence strongly implicate the Sfpi1/PU.1 gene as a tumour suppressor gene, dysregulation of which leads to myeloid leukaemia. The main focus of this project was to utilize the CBA mouse model of radiation leukaemogenesis to explore mechanisms of low dose and low dose-rate leukaemogenesis. A series of mechanistic investigations were undertaken, the central aim of which was to identify the events that convert normal cells into myeloid leukaemia cells and explore the dose-response relationships for these. Much of the work centred on the Sfpi1/PU.1 gene and its role in leukaemogenesis. Specific studies considered the dose-response and time-course relationships for loss of the gene, the functional consequences of Sfpi1/PU.1 loss and mutation on transcriptional programmes and developing an in vivo reporter gene system for radiation-induced alterations to PU.1 expression. Additional work sought further genetic changes associated with radiation-induced AMLs and a better characterization of the cell of origin or 'target cell' for radiation-induced AML. All the information gathered is of potential use in developing biologically realistic mathematical models for low dose cancer risk projection

The evidence for excess risk of cancer and non-cancer disease at low doses and dose rates

The question of whether there are excess radiation-associated health risks at low dose is controversial. We present evidence of excess cancer risks in a number of (largely pediatrically or in utero exposed) groups exposed to low doses of radiation (10 mGy), or with possible beneficial effects from exposures. The presented data suggest that exposure to low-dose radiation causes excess cancer risks and quite possibly also excess risks of various non-cancer endpoints

The evidence for excess risk of cancer and non-cancer disease at low doses and dose rates

The question of whether there are excess radiation-associated health risks at low dose is controversial. We present evidence of excess cancer risks in a number of (largely pediatrically or in utero exposed) groups exposed to low doses of radiation (10 mGy), or with possible beneficial effects from exposures. The presented data suggest that exposure to low-dose radiation causes excess cancer risks and quite possibly also excess risks of various non-cancer endpoints

Potential protein activity modifications of amino acid variants in the human transcriptome

Background: The occurrence of widespread RNA and DNA sequence differences in the human transcriptome was reported in 2011. Similar findings were described in a second independent publication on personal omics profiling investigating the occurrence of dynamic molecular and related medical phenotypes. The suggestion that the RNA sequence variation was likely to affect disease susceptibility prompted us to investigate with a range of algorithms the amino acid variants reported to be present in the identified peptides to determine if they might be disease-causing. Results: The predictive qualities of the different algorithms were first evaluated by using nonsynonymous single-base nucleotide polymorphism (nsSNP) datasets, using independently established data on amino acid variants in several proteins as well as data obtained by mutational mapping and modelling of binding sites in the human serotonin transporter protein (hSERT). Validation of the used predictive algorithms was at a 75% level. Using the same algorithms, we found that widespread RNA and DNA sequence differences were predicted to impair the function of the peptides in over 57% of cases. Conclusions: Our findings suggest that a proportion of edited RNAs which serve as templates for protein synthesis is likely to modify protein function, possibly as an adaptive survival mechanism in response to environmental modifications

Is there any supportive evidence for low dose radiotherapy for COVID-19 pneumonia?

Artikkeli on jatkoa 6. toukokuuta samassa lehdessä julkaistulle commentary -artikkelille, jossa kirjoittajat kommentoivat matala-annoksisen sädehoidon käyttöä hengenvaarallisen COVID-19 keuhkokuumeen hoidossa. Kansainvälinen keskustelu aiheesta on intensiivistä ja aiempi artikkeli kohosi lyhyessä ajassa kaikkien aikojen luetuimpien julkaisujen joukkoon IJRB-lehdessä. Kokooma-artikkelissa kerrotaan 20.5 mennessä kirjoittajaryhmän tietoon tulleista kaikkiaan 12 hoitokokeilusta. Kliinisissä potilaskokeissa käytetyt annokset olivat yksi annos (0.1-1 Gy) tai kaksi annosta (muutama mGy jota seurasi 0.1-0.25 Gy, oletettu adaptiivinen vaste, tai 1-1.5 Gy kahdessa fraktiossa 2-3 päivän välein). Tälle ns. matala-annoksiselle (LDRT) sädehoidolle (huom. säteilysuojelussa vain alle 0.1 Gy annoksia pidetään matalina, mutta tässä artikkelissa noudatetaan sädehoidossa käytettävää terminologiaa) esitettiin kahdenlaisia tieteellisiä perusteluja. Ensimmäinen perustelu oli, että matala-annoksista sädehoitoa on ennen antibioottien keksimistä käytetty jyrsijöillä kokeellisesti keuhkokuumeen hoidossa, samoin on olemassa tapauskohtaisia raportteja ihmisille kohdistetuista hoidoista. Toisaalta perusteltiin matala-annoksisella säteilyllä mahdollisesti olevan anti-inflammatorisia ominaisuuksia, koska sitä on käytetty tulehduksellisten nivelsairauksien hoidossa erityisesti Saksassa. Kuitenkin näissä eläin- ja ihmistutkimuksissa on huomattavia rajoitteita, eikä voida varmasti sanoa, vaimentaako matala-annoksinen säteily tulehdusta keuhkossa vai lisääkö se COVID-19 viruksen aiheuttamaa vaurioitumista. Näin ollen johtopäätös on, että olemassa oleva tieteellinen kirjallisuus ei oikeuta kliinisiä kokeita matala-annoksisen säteilyn käytöstä COVID-19 keuhkokuumeen hoidossa, kun hyötyä ei tunneta ja toisaalta säteilyaltistukseen liittyy syövän ja sydänsairauksien riski. Huolimatta näistä huomattavista epävarmuuksista, joitakin kliinisiä kokeita on kuitenkin suunniteltu ja käynnissä. Artikkeli antaa yleiskuvan matala-annoksisen sädehoidon ja COVID-19 keuhkokuumeen tilanteesta