Biology subjects

Sawakuchi, G. O.

Publications and source records attributed to Sawakuchi, G. O..

4 recordsLinked to original sources

bioRxiv2024

Coordinated regulation by lncRNAs results in tight lncRNA-target couplings

The determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research [1-7]. Our efforts to improve the accuracy of lncRNA-target inference identified lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. Namely, these lncRNAs may regulate the transcription of their target and chaperone the resulting message until its translation, leading to tightly coupled lncRNA and target abundance. Our analysis suggested that hundreds of cancer genes are coordinately and tightly regulated by lncRNAs and that this unexplored regulatory paradigm may propagate the effects of non-coding alterations to effectively dysregulate gene expression programs. As a proof-of-principle we studied the regulation of DICER1 [8, 9]--a cancer gene that controls microRNA biogenesis--by the lncRNA ZFAS1, showing that ZFAS1 activates DICER1 transcription and blocks its post-transcriptional repression to phenomimic and regulate DICER1 and its target microRNAs.

bioinformatics↗

bioRxiv2020

Cell lines of the same anatomic site and histologic type show large variability in intrinsic radiosensitivity and relative biological effectiveness to protons and carbon ions

PurposeTo show that radiation response across cancer cell lines of the same anatomic site and histologic type varies remarkably for protons and carbon (C) ions. Materials and MethodsWe measured and obtained from the literature clonogenic survival of human cancer cell lines of the lung (n=18), brain (n=10) and pancreas (n=10) exposed to photons, protons, and C-ions to assess their variability in response. We also treated cancer cell lines with DNA repair inhibitors prior to irradiation to assess how DNA repair capacity affects their variability in response. We quantified the variability in response by calculating the relative range (range/mean) and the coefficient of variation (COV) of the dose at 10% survival fraction (D10%) and relative biological effectiveness (RBE10%). ResultsThe relative range of D10% for lung cancer cell lines varied from 55-92% for photons, protons, and C-ions, with the relative range in RBE varying from 16-45% for protons and C-ions. For brain and pancreatic cancer cell lines, the relative range of D10% varied from 95-112%, and 39-75%, respectively, with the relative range in RBE varying from 27-33% and 25-50%, respectively. However, the COVs in D10% were approximately equal across radiation qualities, varying from 0.24{+/-}0.07-0.35{+/-}0.10, 0.35{+/-}0.09-0.69{+/-}0.62 and 0.13{+/-}0.03- 0.21{+/-}0.04 for lung, brain and pancreatic cancer cell lines, respectively. Greater relative ranges in D10% were observed in the cell lines with inhibited DNA repair, varying from 108%-157% for photons, protons, and C-ions, with relative ranges in RBE varying from 29-67%. The COVs in the D10% were also greater for the cell lines treated with inhibitors of DNA repair, varying from 0.34{+/-}0.09-0.41{+/-}0.06. ConclusionCell lines of the same anatomic site and histologic type have a remarkable variability in response, not only to photons but also to protons and C-ions. We attributed this variability to differences in DNA repair capacity. CategoryBiological Physics and Response Prediction

biophysics↗

bioRxiv2020

An empirical model to predict survival curve and relative biological effectiveness after helium and carbon ion irradiation based solely on the cell survival after photon irradiation

PurposeTo develop an empirical model to predict radiosensitivity and relative biological effectiveness (RBE) after helium (He) and carbon (C) ion irradiation with or without DNA repair inhibitors. MethodsWe characterized survival in eight human cancer cell lines exposed to 6 MV photons and to He- and C-ions with linear energy transfer (LET) values of 2.2-60.5 keV/m to verify that the radiosensitivity parameters (D5%, D10%, D20%, D37%, D50% and SF2Gy) correlate linearly between photon and ion radiation with or without DNA-PKcs or ATR inhibitors. Then, we parameterized the LET response of the parameters governing these linear correlations up to LET values of 225 keV/m using the data in the Particle Irradiation Data Ensemble (PIDE) v3.2 database, creating a model that predicts a cells ion radiosensitivity, RBE and ion survival curve for a given LET on the basis of the cells photon radiosensitivity. We then trained this model using the PIDE database as a training dataset, and validated it by predicting the radiosensitivity of the cell lines we exposed to He- and C- ions with LET ranging from 2.2-60.5 keV/m. ResultsRadiosensitivity to ions depended linearly with radiosensitivity of photons in the range of investigated LET values and the slopes and intercepts of these linear relationships within the PIDE database vary exponentially and linearly, respectively. Our model predicted ion radiosensitivity (e.g., D10%) within 5.1-21.3%, RBED10% within 5.0-17.1%, and ion mean inactivation dose within 6.7-25.1% for He- and C-ion LET ranging from 2.2-60.5 keV/m. ConclusionsRadiosensitivity to He- and C-ions depend linearly with radiosensitivity to photons and can be used to predict ion radiosensitivity, RBE and cell survival curves for clinically relevant LET values from 2.2-60.5 keV/m, with or without drug treatment. SUMMARYWe present a new empirical model capable of predicting clonogenic cell survival of cell lines exposed to helium and carbon ion beams. Our model is based on an observed linear correlation between radiosensitivity to ions and photons across a wide range of LET values. This linear correlation can be used to predict ion RBE, radiosensitivity, and the cell survival curve for a given LET all based on a cells photon survival curve.

biophysics↗

bioRxiv2017

EGLN Inhibition Reduces Gastrointestinal Radiation Toxicity and Improves Survival in a Murine Model of Locally Advanced Pancreatic Cancer

Locally advanced pancreatic cancer (LAPC) almost always fatal since it is unresectable and chemotherapy is only modestly effective. The efficacy of radiation therapy (RT) for LAPC is limited by the potentially fatal toxicity to nearby intestines. There are no FDA-approved medications that can prevent this radiotoxicity, but we find that FG-4592, a small molecule inhibitor of EGLN proteins, significantly reduces radiation damage to the intestines without radioprotecting tumors. KPC (KrasLSL/+; Trp53FL/+; Ptf1aCre/+) animals received dose-escalated radiation treatments with and without FG-4592 for radioprotection. High-dose RT reduced death from local progression, improved survival, and shifted the patterns of failure to a late metastatic death compared to controls. The addition of FG-4592 to RT further improved survival compared to vehicle controls by eliminating radiation-induced gastrointestinal toxicity. Thus, selective protection of the intestinal tract by EGLN inhibition may enable higher, and potentially definitive doses of cytotoxic therapy to be delivered to LAPC.\n\nOne Sentence SummaryThe EGLN inhibitor FG-4592 allows higher, and potentially definitive, doses of radiation to be delivered to pancreatic cancer by reducing normal tissue toxicity without protecting tumors.

cancer biology↗