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The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a \"two-hit\" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.

Studies of priming of visual perception demonstrate that observers respond more quickly to targets in a field of distractors when relevant features are repeated versus novel or role-reversed. In a recent brain imaging study by Kristjánsson et al. (2007), participants were presented with two items of one color and a single item in a different color with the task of reporting the orientation of the uniquely colored item. Consistent with previous behavioral reports, they found that observers were faster to respond when the target and distractor colors were identical to the previous trial than when they were reversed. They found reduced BOLD activity in brain areas linked with attentional control on trials where the target and distractor colors were repeated relative to reversed, which they interpreted as reflecting response suppression (decreased BOLD signal for repeated stimuli). However, since their design only compared repeated versus reversed task demands, it is logically possible that this pattern reflects increased BOLD signal for role-reversed stimuli: activity required to inhibit previously facilitated information and select previously inhibited information. We explored this possibility with a task where we contrasted the signal generated by repeated, reversed, and novel features. Our data suggest that the majority of the change in neural signal elicited by priming of pop-out reflects increased activation when selection criteria are reversed.

Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2–PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2–PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro . Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro . Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration ( FGFR2 fusions, IDH1/2 , ARAF , KRAS , BRAF and FGF19 ) that is amenable for therapeutic targeting. Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al . show a novel FGFR2–PPHLN1 fusion and ARAF mutations that may represent future potential therapeutic targets.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research. Measurement(s) stroke lesion Technology Type(s) manual segmentation in ITK-SNAP Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment brain

Sensorimotor performance after stroke is strongly related to focal injury measures such as corticospinal tract lesion load. However, the role of global brain health is less clear. Here, we examined the impact of brain age, a measure of neurobiological aging derived from whole brain structural neuroimaging, on sensorimotor outcomes. We hypothesized that stroke lesion damage would result in older brain age, which would in turn be associated with poorer sensorimotor outcomes. We also expected that brain age would mediate the impact of lesion damage on sensorimotor outcomes and that these relationships would be driven by post-stroke secondary atrophy (e.g., strongest in the ipsilesional hemisphere in chronic stroke). We further hypothesized that structural brain resilience, which we define in the context of stroke as the brain’s ability to maintain its global integrity despite focal lesion damage, would differentiate people with better versus worse outcomes. We analyzed cross-sectional high-resolution brain MRI and outcomes data from 963 people with stroke from 38 cohorts worldwide using robust linear mixed-effects regressions to examine the relationship between sensorimotor behavior, lesion damage, and brain age. We used a mediation analysis to examine whether brain age mediates the impact of lesion damage on stroke outcomes and if associations are driven by ipsilesional measures in chronic (≥180 days) stroke. We assessed the impact of brain resilience on sensorimotor outcome using logistic regression with propensity score matching on lesion damage. Stroke lesion damage was associated with older brain age, which in turn was associated with poorer sensorimotor outcomes. Brain age mediated the impact of corticospinal tract lesion load on sensorimotor outcomes most strongly in the ipsilesional hemisphere in chronic stroke. Greater brain resilience, as indexed by younger brain age, explained why people have better versus worse sensorimotor outcomes when lesion damage was fixed. We present novel evidence that global brain health is associated with superior post-stroke sensorimotor outcomes and modifies the impact of focal damage. This relationship appears to be due to post-stroke secondary degeneration. Brain resilience provides insight into why some people have better outcomes after stroke, despite similar amounts of focal injury. Inclusion of imaging-based assessments of global brain health may improve prediction of post-stroke sensorimotor outcomes compared to focal injury measures alone. This investigation is important because it introduces the potential to apply novel therapeutic interventions to prevent or slow brain aging from other fields (e.g., Alzheimer’s disease) to stroke.

ABSTRACT Background and Purpose Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Subcortical regions play critical roles in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behavior at different timepoints after stroke. Methods We pooled high-resolution T1-weighted MRI brain scans and behavioral data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behavior to non-lesioned subcortical volumes (Bonferroni-corrected, p<0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Results Worse sensorimotor behavior was associated with a smaller ipsilesional thalamic volume in both early (n=179; d=0.68) and subacute (n=274, d=0.46) stroke. In chronic stroke (n=404), worse sensorimotor behavior was associated with smaller ipsilesional putamen (d=0.52) and nucleus accumbens (d=0.39) volumes, and a larger ipsilesional lateral ventricle (d=-0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n=256) was associated with smaller ipsilesional putamen (d=0.72) and larger lateral ventricle (d=-0.41) volumes, while several measures of activity limitations (n=116) showed no significant relationships. In the full cohort across all time (n=828), sensorimotor behavior was associated with the volumes of the ipsilesional nucleus accumbens (d=0.23), putamen (d=0.33), thalamus (d=0.33), and lateral ventricle (d=-0.23). Conclusions We demonstrate significant relationships between post-stroke sensorimotor behavior and reduced volumes of subcortical gray matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings may provide additional targets for improving post-stroke sensorimotor outcomes. Competing Interest Statement N.J. and P.M.T. are MPI of a research grant from Biogen, Inc for work unrelated to the contents of this manuscript. S.C.C. has served as a consultant for Constant Therapeutics, MicroTransponder, Neurolutions, SanBio, Stemedica, Fujifilm Toyama Chemical Co., NeuExcell, Medtronic, and TRCare. M.A.P. has received Research Funding & Travel Grant (Bionic Vision Technologies Pty Ltd) unrelated to the contents of this manuscript.

BackgroundDepression following traumatic brain injury (TBI) is a major contributor to disability, however, published estimates vary widely and no comprehensive meta-analysis of prevalence has yet been conducted. Consequently, we synthesised prevalence rates of depression in TBI patients including all international studies and also tested for potential moderators via sub-group analyses and meta- regressions.MethodsThe review was pre-registered on PROSPERO (CRD42024499164) and followed recommendations from PRISMA 2020 guidelines. We searched CINHAL, PsycINFO (Ovid) and MEDLINE (Ovid) from 1960 onwards including studies that sampled at least 100 adult participants and met criteria for a diagnosis of TBI. All severities were included ranging from mild to severe. We excluded studies where TBI exposure could not be distinguished from non-TBI conditions within one group. We extracted data from 165 studies to examine the prevalence of depression in adult TBI patients of all severities. We used a random-effects model using the DerSimonian-Laird estimator to estimate prevalence with 95% confidence intervals (CI) and the meta-analysis was conducted in R using the meta and dmetar packages. Subgroup and meta-regression analyses examined the effects of TBI severity, setting, population, study design, measure, sample age, gender balance, year of publication and risk of bias. Publication bias tests and sensitivity analyses ensured robustness. A detailed quality assessment was carried out using Kmet et al (2004) quality scale. All coding information is available online.ResultsOur pooled sample size of 2,648,289 generated a prevalence estimate of 27% (95% CI: 25-29%) with high, significant heterogeneity (I2 = 100%, τ2 = 0.0182, p = 0). Subgroup analysis found that self-report measures and studies conducted in the USA were associated with increased prevalence of depression. Meta-regressions found age to be a small but significant moderator with increasing age leading to decreased prevalence (-0.0027, 95% CI: -0.0039 to -0.0015, p = <0.001). Evidence for moderation by TBI severity was mixed with no clear severity – prevalence relationship. No evidence of publication bias was found. Outlier and influence analyses found prevalence to be largely unaffected when influential studies were removed (26.46%). Our quality assessment found the majority of studies (n = 93) to be of moderate quality.ConclusionPost-TBI depression is prevalent but varies globally and is influenced by assessment method. Further investigations into reasons for lack of moderation by severity should be conducted.

Background Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration ISRCTN 46099296

Objective The objective of this study was to assess the feasibility and acceptability of institutionalizing Health Technology Assessment (HTA) in Malawi. Methods This study employed a document review and qualitative research methods, to understand the status of HTA in Malawi. This was complemented by a review of the status and nature of HTA institutionalization in selected countries.Qualitative research employed a Focus Group Discussion (FGD ) with 7 participants, and Key Informant Interviews (KIIs) with12 informants selected based on their knowledge and expertise in policy processes related to HTA in Malawi.Data extracted from the literature was organized in Microsoft Excel, categorized according to thematic areas and analyzed using a literature review framework. Qualitative data from KIIs and the FGD was analyzed using a thematic content analysis approach. Results Some HTA processes exist and are executed through three structures namely: Ministry of Health Senior Management Team, Technical Working Groups, and Pharmacy and Medicines Regulatory Authority (PMRA) with varyingdegrees of effectiveness.The main limitations of current HTA mechanisms include limited evidence use, lack of a standardized framework for technology adoption, donor pressure, lack of resources for the HTA process and technology acquisition, laws and practices that undermine cost-effectiveness considerations. KII and FGD results showed overwhelming demand for strengthening HTA in Malawi, with a stronger preference for strengthening coordination and capacity of existing entities and structures. Conclusion The study has shown that HTA institutionalization is acceptable and feasible in Malawi. However, the current committee based processes are suboptimal to improve efficiency due to lack of a structured framework. A structured HTA framework has the potential to improve processes in pharmaceuticals and medical technologies decision-making.In the short to medium term, HTA capacity building should focus on generating demand and increasing capacity in cost-effectiveness assessments. Country-specific assessments should precede HTA institutionalization as well as recommendations for new technology adoptions.