Lung cancer referral patterns in the former Yorkshire region of the UK

The purpose of this study was to find out what proportion of patients are referred as lung cancer guidelines assume, whether different referral pathways result in different management and what proportion of patients are seen within recommended time intervals between referral and treatment. A randomly selected sample of 400 lung cancer cases registered with the former Yorkshire Cancer Registry database in 1993 was selected for casenote analysis. Mode of presentation, speciality of initial referral, treatment by specialist, time intervals for key points in the referral pathways were analyzed. A total of 362 (90.5%) of case-notes were available. Less than half of lung cancer patients (173, 47.8%) presented to hospital with a chest X-ray diagnosis of lung cancer. Forty-one (11.3%) presented as self-referrals to Accident and Emergency and the remainder were referred without a diagnosis of lung cancer by other routes, mainly via GPs. Patients who did not present initially with a lung cancer diagnosis were less likely to receive specialist care (62% : 96%), or have their diagnosis histologically confirmed (57.1% : 80.3%) or receive surgery or radical radiotherapy (6.9% : 13.9%). Nine per cent of all 362 patients did not receive a specialist opinion. Eighty per cent of patients referred by a GP with CXR suspected lung cancer were seen at hospital within 2 weeks. Only 32.4% of those receiving active treatment were treated within 8 weeks of clinical diagnosis or first hospital visit. Lung cancer patients presenting to hospital without a suspicious CXR are less likely to have specialist care, histological confirmation of their cancer and have lower rates of active treatment (surgery, any radiotherapy or chemotherapy)

Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization?

The c-AMP-responsive element binding protein (CREB) and its phosphorylated product (P-CREB) are nuclear proteins expressed after stimulation of pain-producing areas of the spinal cord. There is evidence indicating that central sensitization within dorsal horn neurons is dependent on P-CREB transcriptional regulation. The objectives of the study were to investigate the expression of P-CREB in cells in rat trigeminal nucleus caudalis after noxious stimulation and to determine whether pre-treatment with specific anti-migraine agents modulate this expression. CREB and P-CREB labelling was investigated within the trigeminal caudalis by immunohistochemistry after capsaicin stimulation. Subsequently, the effect of i.v. pre-treatment with either sumatriptan (n = 5), or naratriptan (n = 7) on P-CREB expression was studied. Five animals pre-treated with i.v. normal saline were served as controls. CREB and P-CREB labelling was robust in all animal groups within Sp5C. Both naratriptan and sumatriptan decreased P-CREB expression (p = 0.0003 and 0.0013) within the Sp5C. Triptans attenuate activation of CREB within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization. P-CREB may serve as a new marker for post-synaptic neuronal activation within Sp5C in animal models relevant to migraine

Genomic Analysis of Parent-of-Origin Allelic Expression in Arabidopsis thaliana Seeds

Differential expression of maternally and paternally inherited alleles of a gene is referred to as gene imprinting, a form of epigenetic gene regulation common to flowering plants and mammals. In plants, imprinting primarily occurs in the endosperm, a seed tissue that supports the embryo during its growth and development. Previously, we demonstrated that widespread DNA demethylation at remnants of transposable elements accompanies endosperm development and that a subset of these methylation changes are associated with gene imprinting. Here we assay imprinted gene expression genome-wide by performing high-throughput sequencing of RNA derived from seeds of reciprocal intraspecific crosses. We identify more than 200 loci that exhibit parent-of-origin effects on gene expression in the endosperm, including a large number of transcription factors, hormone biosynthesis and response genes, and genes that encode regulators of epigenetic information, such as methylcytosine binding proteins, histone methyltransferases, and chromatin remodelers. The majority of these genes are partially, rather than completely, imprinted, suggesting that gene dosage regulation is an important aspect of imprinted gene expression

Transcription Factor NF-κB Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons

Mikenberg I, Widera D, Kaus A, Kaltschmidt B, Kaltschmidt C. Transcription Factor NF-kappa B Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons. PLOS ONE. 2007;2(7):e589.Background. Long-term changes in synaptic plasticity require gene transcription, indicating that signals generated at the synapse must be transported to the nucleus. Synaptic activation of hippocampal neurons is known to trigger retrograde transport of transcription factor NF-kappa B. Transcription factors of the NF-kappa B family are widely expressed in the nervous system and regulate expression of several genes involved in neuroplasticity, cell survival, learning and memory. Principal Findings. In this study, we examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-kappa B to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-kappa B p65 and reduces NF-kappa B-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-kappa B p65 is essential for this binding. Conclusion. This study shows the molecular mechanism for the retrograde transport of activated NF-kappa B from distant synaptic sites towards the nucleus

“Positive” Results Increase Down the Hierarchy of the Sciences

The hypothesis of a Hierarchy of the Sciences with physical sciences at the top, social sciences at the bottom, and biological sciences in-between is nearly 200 years old. This order is intuitive and reflected in many features of academic life, but whether it reflects the “hardness” of scientific research—i.e., the extent to which research questions and results are determined by data and theories as opposed to non-cognitive factors—is controversial. This study analysed 2434 papers published in all disciplines and that declared to have tested a hypothesis. It was determined how many papers reported a “positive” (full or partial) or “negative” support for the tested hypothesis. If the hierarchy hypothesis is correct, then researchers in “softer” sciences should have fewer constraints to their conscious and unconscious biases, and therefore report more positive outcomes. Results confirmed the predictions at all levels considered: discipline, domain and methodology broadly defined. Controlling for observed differences between pure and applied disciplines, and between papers testing one or several hypotheses, the odds of reporting a positive result were around 5 times higher among papers in the disciplines of Psychology and Psychiatry and Economics and Business compared to Space Science, 2.3 times higher in the domain of social sciences compared to the physical sciences, and 3.4 times higher in studies applying behavioural and social methodologies on people compared to physical and chemical studies on non-biological material. In all comparisons, biological studies had intermediate values. These results suggest that the nature of hypotheses tested and the logical and methodological rigour employed to test them vary systematically across disciplines and fields, depending on the complexity of the subject matter and possibly other factors (e.g., a field's level of historical and/or intellectual development). On the other hand, these results support the scientific status of the social sciences against claims that they are completely subjective, by showing that, when they adopt a scientific approach to discovery, they differ from the natural sciences only by a matter of degree

Automated Detection of Antenna Malfunctions in Large-N Interferometers: A case study With the Hydrogen Epoch of Reionization Array

We present a framework for identifying and flagging malfunctioning antennas in large radio interferometers. We outline two distinct categories of metrics designed to detect outliers along known failure modes of large arrays: cross-correlation metrics, based on all antenna pairs, and auto-correlation metrics, based solely on individual antennas. We define and motivate the statistical framework for all metrics used, and present tailored visualizations that aid us in clearly identifying new and existing systematics. We implement these techniques using data from 105 antennas in the Hydrogen Epoch of Reionization Array (HERA) as a case study. Finally, we provide a detailed algorithm for implementing these metrics as flagging tools on real data sets

Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients

Systems microscopy approaches to understand cancer cell migration and metastasis

Cell migration is essential in a number of processes, including wound healing, angiogenesis and cancer metastasis. Especially, invasion of cancer cells in the surrounding tissue is a crucial step that requires increased cell motility. Cell migration is a well-orchestrated process that involves the continuous formation and disassembly of matrix adhesions. Those structural anchor points interact with the extra-cellular matrix and also participate in adhesion-dependent signalling. Although these processes are essential for cancer metastasis, little is known about the molecular mechanisms that regulate adhesion dynamics during tumour cell migration. In this review, we provide an overview of recent advanced imaging strategies together with quantitative image analysis that can be implemented to understand the dynamics of matrix adhesions and its molecular components in relation to tumour cell migration. This dynamic cell imaging together with multiparametric image analysis will help in understanding the molecular mechanisms that define cancer cell migration