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Identifying changes in DNA copy number can pinpoint genes that may be involved in tumor development. Here we have defined the smallest overlapping regions of imbalance (SORI) in testicular germ cell tumors other than the 12p region, which has been previously investigated. Definition of the regions was achieved through comparative genomic hybridization (CGH) analysis of a 4559 cDNA clone microarray. A total of 14 SORI were identified, which involved at least five of the 11 samples analysed. Many of these refined regions were previously reported using chromosomal or allelic imbalance studies. The SORI included gain of material from the regions 4q12, 17q21.3, 22q11.23 and Xq22, and loss from 5q33, 11q12.1, 16q22.3 and 22q11. Comparison with parallel chromosomal CGH data supported involvement of most regions. The various SORI span between one and 20 genes and highlight potential oncogenes/tumor suppressor genes to be investigated further (Supplementary material is available at http://www.crukdmf.icr.ac.uk/array/array.html ).

We assessed the hepatic antioxidant status of spontaneously (SHR) and desoxicorticosterone acetate (DOCA)-induced hypertensive rats and that of respective normotensive Wistar Kyoto (WKY) and Sprague-Dawley (SPRD) rats. For this we evaluated, ex vivo in liver cytosols, reduced glutathione (GSH) content, glutathione-related enzyme (peroxidase, reductase and transferase) activities as well as the rate of lipid peroxidation in 9-11 week-old rats. The antioxidant status and the cytotoxicity of acetaminophen, a radical- and hydrogen peroxide-mediated hepatotoxic compound, were also assessed in vitro in cultured hepatocytes isolated from hypertensive (SHR, DOCA) and normotensive control (WKY, SPRD) rats. Our results suggest that a difference exists in the hepatic antioxidant status between rat strains, with GSH levels being lower (-15%) and lipid peroxidation rate higher (+30%) in WKY compared to SPRD rats. In hepatocyte cultures from WKY rats, both GSH content and catalase activity were lower (-30 and -70% respectively) compared to hepatocyte cultures from SPRD rats. This was associated with a 35% higher cytotoxicity of acetaminophen in cultured hepatocytes from WKY rats compared to that in hepatocytes from SPRD rats. Hypertension in DOCA rats (mmHg: 221+/-9 vs. 138+/-5 in control SPRD rats) was associated with decreases (about 30%) in both glutathione peroxidase (GSH-Px) and catalase activities, ex vivo in livers and in vitro in hepatocyte cultures. Hypertension in SHR (mmHg: 189+/-7 vs. 130+/-5 in control WKY rats) was also associated with decreases (about 50%) in GSH-Px activity, ex vivo in livers and in vitro in hepatocyte cultures but catalase activity was not modified. The IC50 of acetaminophen was also lower in hepatocytes from hypertensive rats compared to respective controls, which could be related to the weakened antioxidant status in hepatocytes from hypertensive rats. Our data thus suggest that hepatocyte cultures are appropriated tools in which to assess hepatotoxicity and hepatoprotection in hypertension.

The effects of DOCA-salt hypertensive treatment on hepatic glutathione-dependent defense system, antioxidant enzymes, lipid peroxidation, mixed function oxidase and UDP-glucuronyl transferase activities were investigated in male Sprague Dawley rats. Compared with controls, DOCA-salt hypertensive rats had lower body weights (linked to liver hypertrophy). Mixed function oxidase and p-nitrophenol-UGT activities were not affected by the treatment but a significant lower rate of the glucuronoconjugation rate of bilirubin (p < 0.001) was observed in DOCA-salt hypertensive rats. While cytosolic glutathione contents and glutathione reductase activity were not affected, glutathione peroxidase (p < 0.001), glutathione transferase (p < 0.001) and catalase (p < 0.01) activities were decreased and associated with higher malondialdehyde contents (p < 0.001) in treated rats. The imbalance in liver antioxidant status (increasing generation of cellular radical species), associated with increases in lipid peroxidation, suggests that oxidative stress might be directly related to arterial hypertension in DOCA-salt treated male Sprague Dawley rats.

The effects of 8-week diethylmaleate (DEM) and clofibric acid (CFA) supplemented diet on blood pressure, body and liver weights, liver antioxidant status and nitric oxide synthase (NOS) activity were investigated in 8-week DOCA-salt treated and untreated Sprague-Dawley male rats. It appeared that DEM and particularly CFA treatments were associated with a significant decrease in blood pressure in DOCA-salt treated rats, and an accentuation of the decreases in body weights in both diet supplemented groups. This was not associated with increases in NO production in the liver. In contrast, hepatic lipid peroxidation was significantly decreased in both DOCA-salt treated and untreated groups on DEM and particularly on CFA supplemented diet. The protective effects of CFA and DEM against hepatic cellular damage could be involved in the decreases in blood pressure in DOCA-salt treated rats, where CFA was more efficient than DEM. In CFA supplemented groups, there was a strong increase in hepatic superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px), and catalase (CAT) activities and in DEM supplemented groups, increases in SOD and CAT activities and in GSH levels were observed. Our data suggest that normalization of blood pressure in DOCA-salt treated rats by CFA was due to an enhancement of the half-life of NO while DEM increased its availability.

Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.The most common genetic cause of ALS and frontal temporal dementia—hexanucleotide repeat expansion in C9orf72—is shown to provoke disease via synergy of gain of toxicity(ies) from repeat-encoded RNAs/dipeptide repeat proteins and reduction in the C9ORF72 protein.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS–FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.The mRNA encoding stathmin-2, a protein implicated in axonal growth, is shown to be widely suppressed by premature polyadenylation in both sporadic and C9orf72 ALS through a mechanism directly dependent on loss of nuclear TDP-43 in motor neurons.

Targeted inhibition of the PD-L1–PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC). CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing. Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6–7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5–43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7–25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2–not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7–4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37–0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group. Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC. F Hoffmann-La Roche and Genentech.

Background Clinically meaningful changes in the five‐repetition chair stand test are essential for monitoring mobility in integrated care for older people. Recommendations for the clinically meaningful change of the chair stand test are not well known. Our study aimed to estimate the absolute and relative clinically meaningful changes for older adults' five‐repetition chair stand test. Methods We applied distribution‐based and anchor‐based methods in addition to receiver operator characteristics analyses to a population‐based study of community‐dwelling adults (SAGE Mexico study, n = 897) to derive the clinically meaningful change in the chair stand test. We used three self‐reported clinical anchors: moving around, vigorous activities, and walking 1 km. Our primary outcome was the incidence of disability for basic activities of daily living (ADL). Secondly, we examined our estimates of clinically meaningful change in a clinical trial population of healthy volunteers (MAPT, France, study n = 1575) concerning the risk of incident ADL disability. Results The age of SAGE Mexico participants ranged from 60 to 96 years; mean (SD) = 69.0 (6.2); 54.4% were female. Their baseline chair stand time averaged 12.1 s (SD = 3 s). Forty‐eight participants (5.6%) showed incident disability over 3 years. The absolute and relative clinically meaningful change cut points found over 3 years of follow‐up were 2.6 s and 27.7%, respectively. Absolute clinically meaningful change ranged from 0.5 to 4.7 s, depending on the estimation method. Relative clinically meaningful change ranged from 9.6 to 46.2%. SAGE Mexico participants with absolute and relative clinically meaningful declines (increasing 2.6 s and 27.7% from baseline time, respectively) showed an increased risk of ADL disability [aRR = 1.93; P = 0.0381; 95% CI (1.05, 3.46) and aRR = 2.27; P = 0.0157; 95% CI (1.22, 4.10)], respectively, compared with those without a clinically meaningful decline. MAPT participants [age range = 70–94; mean (SD) = 75.3 (4.4); 64.8% female; incident ADL disability over 5 years = 145(14.8%)] with a relative clinically meaningful decline (≥27.7% from baseline over 3 years) had a 74% higher risk of incident ADL disability than their counterparts [aHR = 1.74; P = 0.016; CI95% (1.11, 2.72); mean follow‐up of 58 months]. Conclusions Community‐dwelling older adults with an increase of 3 s or 28% in chair stand test performance over 3 years (approximately 1 s or 10% per year) could be the target of interventions to enhance mobility and prevent incident disability.

Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicated significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFκB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provided a mechanism for ALS pathogenesis where membralin limited glutamatergic neurotoxicity, suggesting that modulating membralin had potentials in ALS therapy.