Explore the vast range of titles available.

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells. Fusion oncogenes (FO) are common in cancers, but specific targeting of these chimeric genes are challenging. Here the authors report a CRISPR/Cas9 strategy that targets two intronic regions to disrupt the FOs in cancer cells and show that this approach reduces tumour growth and prolongs survival in animal models of cancer.

Oncogene amplifications fuel some of the most lethal, therapy‑refractory cancers, yet remain clinically untargeted. We report a single‑guide CRISPR/Cas9 strategy that converts the sheer copy‑number excess of oncogene amplicons into an Achilles' heel. A solitary intronic double‑strand break is innocuous in diploid genomes but collapses oncogene amplification‑positive cells across neuroblastoma, small‑cell lung and colorectal carcinoma models, driving > 90% loss of viability, G₂/M blockade and catastrophic DNA‑damage signalling. Amplified‑locus cleavage rewires transcription toward cell death activation, necroptosis and cGAS-STING-mediated immunogenic cell death, enabling dendritic‑cell cross‑priming and T‑cell activation and proliferation. In xenografts, delivery of the intronic sgRNA shrinks tumours by 90%, prolongs survival and remodels the innate tumour microenvironment. Deep sequencing confirms negligible off‑target editing, and combination with doxorubicin achieves supra‑additive killing. These findings establish amplification density, not sequence content, as a tractable, tumour‑exclusive target and unveil a dual‑action platform that is simultaneously cytotoxic and immunostimulatory. Editing of tumor amplifications therefore offers a blueprint for translating copy‑number aberrations into precision genome‑editing therapies for treatment‑resistant cancers.

TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene ( TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 ( SOD1). TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein–protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació ‘la Caixa’.

The efficacy of thrombolysis in clinical stroke subtypes is unclear. We compared the benefit of intravenous rt-PA in 11 patients with lacunar syndrome with that in 33 patients with a non-lacunar syndrome. Patients were matched by NIHSS score and time to treatment. Although no statistically significant differences were detected in outcome, the benefit was greater in the non- lacunar syndrome group.

An 8-year-old boy with an 18 month history of left limb hemi-dystonia due to a right lenticular nucleus astrocytoma originating in the putamen is reported. Subsequent neuropathological study demonstrated that the tumour was mainly localised to the right lenticular nucleus, with cystic necrosis in the infero-lateral putamen. Solid tumour also infiltrated the right hypothalamus, the anterior commisure and the optic chiasm, and there was perivascular spread into the globus pallidus, internal capsule and roof of the right lateral ventricle. This case, and the few other published reports of symptomatic dystonia due to focal brain lesions verified pathologically, indicate that damage to the lenticular nucleus, and to the putamen in particular, can cause limb dystonia in man.

The effect of cinnarizine on motor function in Parkinson's disease was evaluated in a randomised double-blind parallel study of 20 patients. Both groups were comparable in age, duration of the disease, dose of levodopa and degree of disability. A significant worsening of mobility was observed in patients treated with cinnarizine (75 mg bd), whilst no change was recorded in patients receiving placebo. Cinnarizine should be added to the list of drugs capable of aggravating Parkinson's disease.

Two patients with a diagnosis of olivo-ponto-cerebellar atrophy developed cortical reflex myoclonus to visual (flash) and somaesthetic stimuli. Oral treatment with levodopacarbidopa (1000/100 mg) or subcutaneous administration of apomorphine (1 mg) abolished the visually-triggered myoclonus, without modifying reflex myoclonus to electrical or tactile stimulation. Intravenous administration of lisuride (0.1 mg) produced a marked reduction in both types of reflex myoclonus. These results indicate a selective inhibitory effect of dopamine agonist drugs on visual reflex myoclonus of cortical origin.

Abstract BACKGROUND: Glioblastoma is an aggressive and highly infiltrative brain cancer. Standard surgical resection is guided by enhancement on postcontrast T1-weighted (T1) magnetic resonance imaging, which is insufficient for delineating surrounding infiltrating tumor. OBJECTIVE: To develop imaging biomarkers that delineate areas of tumor infiltration and predict early recurrence in peritumoral tissue. Such markers would enable intensive, yet targeted, surgery and radiotherapy, thereby potentially delaying recurrence and prolonging survival. METHODS: Preoperative multiparametric magnetic resonance images (T1, T1-gadolinium, T2-weighted, T2-weighted fluid-attenuated inversion recovery, diffusion tensor imaging, and dynamic susceptibility contrast-enhanced magnetic resonance images) from 31 patients were combined using machine learning methods, thereby creating predictive spatial maps of infiltrated peritumoral tissue. Cross-validation was used in the retrospective cohort to achieve generalizable biomarkers. Subsequently, the imaging signatures learned from the retrospective study were used in a replication cohort of 34 new patients. Spatial maps representing the likelihood of tumor infiltration and future early recurrence were compared with regions of recurrence on postresection follow-up studies with pathology confirmation. RESULTS: This technique produced predictions of early recurrence with a mean area under the curve of 0.84, sensitivity of 91%, specificity of 93%, and odds ratio estimates of 9.29 (99% confidence interval: 8.95-9.65) for tissue predicted to be heavily infiltrated in the replication study. Regions of tumor recurrence were found to have subtle, yet fairly distinctive multiparametric imaging signatures when analyzed quantitatively by pattern analysis and machine learning. CONCLUSION: Visually imperceptible imaging patterns discovered via multiparametric pattern analysis methods were found to estimate the extent of infiltration and location of future tumor recurrence, paving the way for improved targeted treatment.