Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite ...D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1(R132H) inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.
Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until ...viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.
Background and purpose
The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and ...clinical/molecular data.
Methods
Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1‐weighted and short‐tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema.
Results
The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro‐caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2.
Conclusion
This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD‐related disease spectrum.
•The FSHD European Trial Network (FSHD ETN) will have an open membership.•There will be four working groups (WG) on clinical and genetic diagnosis (WG 1), clinical outcome measures (WG2), biomarkers ...(WG 3), and imaging outcome measures (WG4).•Network members will be appointed to reach out to countries not yet connected and to collaborate with the other organizations mentioned above, including the FSHD Clinical Trial Research Network (CTRN).•Network members will contribute to the patient expectations survey FSHD Europe is currently performing.•The network members will promote the use of agreed FSHD Core dataset across all stakeholder groups and registries, with support of TREAT-NMD.
•An overview of current knowledge on anaesthesia and neuromuscular disorders was presented.•A multidisciplinary approach is essential for optimal peri-operative care for patients with neuromuscular ...disorders.•New developments in the field of malignant hyperthermia were discussed.•Experts in the field of anaesthesia, genetics and neuromuscular disorders committed to work on ENMC consensus statements concerning the anaesthetic management of patients with neuromuscular disorders and genetic counselling in RYR1-related disorders.•International registries can be of great importance for future research in the field of anaesthesia and neuromuscular disorders.
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