GLI1-induced mammary gland tumours are transplantable and maintain major molecular features

Increased expression of GLI1, the main Hedgehog signalling pathway effector, is related to unfavourable prognosis and progressive disease of certain breast cancer subtypes. We used conditional transgenic mice induced to overexpress GLI1 in the mammary epithelium either alone or in combination with deletion of one Trp53 allele to address the role of elevated GLI1 expression in breast tumour initiation and progression. Induced GLI1 expression facilitates mammary gland tumour formation and this was further increased upon heterozygous deletion of Trp53. The GLI1-induced primary tumours were of different murine molecular subtypes, including Normal-like^Ex, Class8^Ex, Claudin-Low^Ex and Erbb2-like^Ex. The gene expression profiles of some of the tumours correlated well with the PAM50 subtypes for human breast cancer. Whole-exome sequencing revealed somatic mutation profiles with only little overlap between the primary tumours. Orthotopically serially transplanted GLI1-induced tumours maintained the main morphological characteristics of the primary tumours for ≥10 generations. Independent of Trp53 status and molecular subtype, the serially transplanted GLI1-induced tumours were able to grow both in the absence of transgenic GLI1 expression and in the presence of the GLI1 inhibitor GANT61. These data suggest that elevated GLI1 expression has a determinant role in tumour initiation; however, additional genetic events are required for tumour progression.     

Multimodal fusion of structural and functional brain imaging in depression using linked independent component analysis

Previous structural and functional neuroimaging studies have implicated distributed brain regions and networks in depression. However, there are no robust imaging biomarkers that are specific to depression, which may be due to clinical heterogeneity and neurobiological complexity. A dimensional approach and fusion of imaging modalities may yield a more coherent view of the neuronal correlates of depression. We used linked independent component analysis to fuse cortical macrostructure (thickness, area, gray matter density), white matter diffusion properties and resting‐state functional magnetic resonance imaging default mode network amplitude in patients with a history of depression (n = 170) and controls (n = 71). We used univariate and machine learning approaches to assess the relationship between age, sex, case–control status, and symptom loads for depression and anxiety with the resulting brain components. Univariate analyses revealed strong associations between age and sex with mainly global but also regional specific brain components, with varying degrees of multimodal involvement. In contrast, there were no significant associations with case–control status, nor symptom loads for depression and anxiety with the brain components, nor any interaction effects with age and sex. Machine learning revealed low model performance for classifying patients from controls and predicting symptom loads for depression and anxiety, but high age prediction accuracy. Multimodal fusion of brain imaging data alone may not be sufficient for dissecting the clinical and neurobiological heterogeneity of depression. Precise clinical stratification and methods for brain phenotyping at the individual level based on large training samples may be needed to parse the neuroanatomy of depression.     

The challenges of outcome research

Cognitive pharmacy trials seek to identify interventions that benefit patients. The potential benefits of an intervention are primarily evaluated by outcome measures. The question then is: What is the optimal outcome measure? Unfortunately, the question remains unsolved. Several factors must be taken into consideration when conducting outcome research—particularly within cognitive pharmacy trials. The interventions are often complex and non-specific, and seek to improve symptom control, optimise the use of medications and reduce medication-related risks. “Hard” endpoints, such as mortality and hospital admissions, may not be the optimal outcome measures, since cognitive pharmacy interventions are unlikely to result in changes in these measures. Instead, adverse drug events or “soft” endpoints, such as quality of life, drug-related problems and patient satisfaction may be appropriate choices of outcome measures. Finally, it is not only outcome measures that may pose a challenge when conducting outcome research; other essential components include study design, type of intervention, the patient population, etc.     

Maxillary and mandibular displacement in hemifacial microsomia: a longitudinal Roentgen stereometric study of 21 patients with the aid of metallic implants.

OBJECTIVE: To record maxillary and mandibular displacement with articular growth and in response to bimaxillary surgical repositioning in patients with hemifacial microsomia (HFM) and to observe ipsilateral corpus/ramus growth in severely affected children. DESIGN: Prospective roentgen stereometric analysis (mean age 7 years 10 months to 18 years 0 months) and retrospective profile and panoramic roentgenograms. Mean total observation period was 9 years 1 month. SETTING: Department of Plastic and Reconstructive Surgery, Malm? University Hospital (Malm?, Sweden). PATIENTS: Twenty-one patients consecutively diagnosed from 1976 through 1988 with HMF, five of whom had bimaxillary surgery. INTERVENTIONS: Surgery was performed at the Department of Plastic and Reconstructive Surgery. Implants were inserted at the initial reconstructive surgical procedure under general anesthesia. Roentgen examinations were performed in connection with continued clinical evaluations and treatment. MAIN OUTCOME MEASURES: Stereo roentgenograms were digitized at the Department of Orthopedic Surgery, Malm? University Hospital (Malm?, Sweden). RESULTS: Displacement of the jaws with articular growth and in response to bimaxillary surgical repositioning varied interindividually with no apparent common pattern. Relapse displacement occurred several years after bimaxillary surgery. Mandibular growth changes were found in the corpus/ramus area and alveolar process on the affected side. CONCLUSIONS: A marked interindividual variability of maxillary and mandibular displacement indicates that the relevance of statistical analysis of HFM growth data may be questioned. We would suggest that precise and accurate longitudinal recordings of growth and response to surgery in individual HFM patients be more appropriate.     

Clinical assessment techniques for detecting ligament and membrane injuries in the upper cervical spine region--a comparison with MRI results

In this study we examined whether results from a clinical test of passive mobility of soft tissue structures in the upper cervical spine, corresponded with signs of physical injuries, as judged by magnetic resonance imaging (MRI). Results were based on examinations of 122 study participants, 92 with and 30 without a diagnosis of whiplash-associated disorder, type 2. The structures considered were the alar and the transverse ligaments, and the tectorial and the posterior atlanto-occipital membranes. Ordinary and weighted kappa coefficients were used as a measure of agreement, whereas McNemar's test was used for evaluating differences in rating. The clinical classification and the MRI examination both comprised four response categories (grades 0-3), with 0 representing a normal structure, and 3 indicating a structure with pronounced abnormality. In our sample, an abnormal clinical test reflected a hyper- rather than hypo-mobility. Considering all four-response categories, the kappa coefficient indicated moderate agreement (range 0.45-0.60) between the clinical and the MRI classification. The results for the membranes appeared somewhat better than for the ligaments. When there was disagreement, the classifications obtained by the clinical test were significantly lower than the MRI grading, but mainly within one grade difference. When combining grade 0-1 (normal) and 2-3 (abnormal), the agreement improved considerably (range 0.70-0.90). Although results from the clinical test seem to be slightly more conservative than the MRI assessment, we believe that a clinical test can serve as valuable clinical tool in the assessment of WAD patients. However, further validity- and reliability studies are needed.     

Migraine genetics: An update

A growing interest in genetic research in migraine has resulted in the identification of several chromosomal regions that are involved in migraine. However, the identification of mutations in the genes for familial hemiplegic migraine (FHM) forms the only true molecular genetic knowledge of migraine thus far. The increased number of mutations in the FHM1 (CACNA1A) and the FHM2 (ATP1A2) genes allow studying the relationship between genetic findings in both genes and the clinical features in patients. A wide spectrum of symptoms is seen in patients. Additional cerebellar ataxia and (childhood) epilepsy can occur in FHM1 and FHM2. Functional studies show a dysfunction in ion transport as the key factor in the pathophysiology of (familial hemiplegic) migraine that predict an increased susceptibility to cortical spreading depression—the underlying mechanism of migraine aura.