Polygenic architecture informs potential vulnerability to drug-induced liver injury

Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market, and this is partially due to the inability to identify patients who are at risk1. Here, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS)2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin, and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over 10 different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy might potentially inform designs of safer, more efficient, and robust clinical trials

Evaluation of stress distribution due to shearing in non-oriented electrical steel by using synchrotron radiation

The influence of the shearing process on the iron loss of non-oriented electrical steels with grain sizes of 10 μm-150 μm was investigated. The deterioration ratio of iron loss was clearly smaller in sample with small grain sizes. The droop height, reflecting the amount of plastic deformation, displayed a good relationship with the deterioration of iron loss under the effect of the material grain size. To clarify the strain distribution around the sheared edge, the elastic strain in a sheet sample with the thickness of 0.30 mm and grain size of 10 μm was evaluated by using synchrotron radiation. The width of the region of elastic strain due to shearing was two or three times of the material thickness. The results of the plastic strain distribution obtained by the measurements were then used to estimate the iron loss deterioration rate in 5 mm width sheared samples. The estimated loss deteriotation coincided with the actual measured iron loss

Predictive value of 3\u27-deoxy-3\u27-[(18)F]fluorothymidine positron emission tomography/computed tomography for outcome of carbon ion radiotherapy in patients with head and neck mucosal malignant melanoma.

Objective The purpose of this prospective study was to assess the prognostic value of 30-deoxy-30-[18F]fluorothymidine (FLT) positron emission tomography/computedtomography (PET/CT) for the outcome of carbon ion radiotherapy (CIRT) in patients with mucosal malignant melanoma (MMM) of the head and neck.Methods Thirteen patients (69 +- 13 years) with histologicallyproven MMM tumor were enrolled. CIRT was performed with a total dose of 57.6–64.0 gray equivalents per 16 fractions over a period of 4 weeks. FLT-PET/CT was performed before and again 1 month after CIRT.Tumor FLT uptake was quantitatively assessed using the maximum standardized uptake value (SUVmax). FLT-PET parameters [pre-CIRT SUVmax, post-CIRT SUVmax, andthe reduction rate (RR)] and clinical parameters [age, gender, tumor site, tumor status, gross tumor volume (GTV), and regional lymph node involvement] wereevaluated in relation to survival estimates. The follow-up period was 16.1 +- 5.9 months for 9 deceased patients, and 36.7 +- 7.9 months for 4 survivors.Results Pre-CIRT SUVmax of C4.3, age of C80 years old, sinonasal cavity tumor site, and GTV of C39 mL were found to be statistically significant prognostic factors forbetter overall survival. Pre-CIRT SUVmax of C5.0, age of C80 years old, sinonasal cavity tumor site, and the absence of regional lymph node involvement were statistically significant prognostic factors for better metastasis-free survival. RR of C35 % and GTV of 73 mL were predictive of better local control.Conclusions The present study indicated for the first time that in patients with the head and neck MMM, FLT-PET/ CT imaging was useful for predicting the therapeutic outcome of CIRT. Our results will contribute to the establishment of an effective staging system for MMM based on prognostic factors, depending on treatment choice

Predictive value of 3\u27-deoxy-3\u27-[18F]fluorothymidine positron emission tomography/computed tomography for outcome of carbon ion radiotherapy in patients with head and neck mucosal malignant melanoma

Aim: In this prospective clinical study, we assessed the predictive value of 3\u27-deoxy-3\u27-[18F]fluorothymidine (FLT) positron emission tomography/computed tomography (PET/CT) for the outcome of carbon ion radiotherapy (CIRT) in patients with mucosal malignant melanoma (MMM) of the head and neck.Materials & Methods: Thirteen patients (69 +- 13 years) with histologically-proven MMM tumor were enrolled. CIRT was performed with a total dose of 57.6&#8211;64.0 gray equivalents per 16 fractions over a period of 4 weeks. FLT-PET/CT was performed before and again 1 month after CIRT. Tumor FLT uptake was quantitatively assessed using the maximum standardized uptake value (SUVmax). FLT-PET parameters (pre-CIRT SUVmax, post-CIRT SUVmax, and the reduction rate [RR]) and clinical parameters (age, gender, tumor site, tumor status, gross tumor volume [GTV], regional lymph node involvement and primary response) were evaluated in relation to survival estimates. The follow-up period was 36.7 +- 7.9 months for 4 survivors, and 16.1 +- 5.9 months for 9 deceased patients.Results: Pre-CIRT SUVmax of &#8805; 4.3, age of &#8805; 80-years-old, sinonasal cavity tumor site, and GTV of &#8805; 39-mL were found to be statistically significant prognostic factors for better overall survival. Pre-CIRT SUVmax of &#8805; 5.0, age of &#8805; 80-years-old, sinonasal cavity tumor site, and the absence of regional lymph node involvement were significant prognostic factors for better metastasis-free survival. RR of &#8805; 35% and GTV of < 73-mL were predictive of better local control.Conclusion: Our investigation suggests that FLT-PET/CT may be useful for predicting outcome of CIRT in patients with MMM of the head and neck. These results will contribute to the establishment of an effective staging system for MMM based on prognostic factors, depending on patient selection and treatment choice.Annual Congress of the European Association of Nuclear Medicin

Spontaneous formation of suboxidic coordination around Co in ferromagnetic rutile Ti0.95Co0.05O2 film

To evaluate local atomic structures around Co in high temperature diluted ferromagnetic semiconductor Co-doped TiO2, x-ray fluorescence holography and x-ray absorption fine structure experiments were carried out on rutile paramagnetic Ti0.99Co0.01O2 and ferromagnetic Ti0.95Co0.05O2 films. The Co atoms in the Ti0.99Co0.01O2 simply substituted for Ti sites in the rutile structure, whereas a suboxidic arrangement of CoO2Ti4 formed around Co in the Ti0.95Co0.05O2 films. A theoretical investigation based on a series of first-principles calculations indicated the stability of the aggregated suboxidic clusters in the rutile TiO2, supporting our hypothesis for the formation of suboxidic coordination in the highly Co-doped sample. The suboxidic coordination may be the source of strong exchange interaction, resulting in the high Curie temperature in Co-doped TiO2