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Aberrant activation of intracellular signalling pathways confers malignant properties on cancer cells. Targeting intracellular signalling pathways has been a productive strategy for drug development, with several drugs acting on signalling pathways already in use and more continually being developed. The JAK/STAT signalling pathway provides an example of this paradigm in haematological malignancies, with the identification of JAK2 mutations in myeloproliferative neoplasms leading to the development of specific clinically effective JAK2 inhibitors, such as ruxolitinib. It is now clear that many solid tumours also show activation of JAK/STAT signalling. In this review, we focus on the role of JAK/STAT signalling in solid tumours, examining the molecular mechanisms that cause inappropriate pathway activation and their cellular consequences. We also discuss the degree to which activated JAK/STAT signalling contributes to oncogenesis. Studies showing the effect of activation of JAK/STAT signalling upon prognosis in several tumour types are summarised. Finally, we discuss the prospects for treating solid tumours using strategies targeting JAK/STAT signalling, including what can be learned from haematological malignancies and the extent to which results in solid tumours might be expected to differ.

Signalling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human malignancies. The Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway represents one such signalling cascade whose evolutionarily conserved roles include cell proliferation and haematopoiesis. Here we describe a systematic genome-wide survey for genes required for JAK/STAT pathway activity. Analysis of 20,026 RNA interference (RNAi)-induced phenotypes in cultured Drosophila melanogaster haemocyte-like cells identified interacting genes encoding 4 known and 86 previously uncharacterized proteins. Subsequently, cell-based epistasis experiments were used to classify these proteins on the basis of their interaction with known components of the signalling cascade. In addition to multiple human disease gene homologues, we have found the tyrosine phosphatase Ptp61F and the Drosophila homologue of BRWD3, a bromo-domain-containing protein disrupted in leukaemia. Moreover, in vivo analysis demonstrates that disrupted dBRWD3 and overexpressed Ptp61F function as suppressors of leukaemia-like blood cell tumours. This screen represents a comprehensive identification of novel loci required for JAK/STAT signalling and provides molecular insights into an important pathway relevant for human cancer. Human homologues of identified pathway modifiers may constitute targets for therapeutic interventions.

Conditional or temperature-sensitive (TS) alleles represent useful tools with which to investigate gene function. Indeed, much of our understanding of yeast has relied on temperature-sensitive mutations which, when available, also provide important insights into other model systems. However, the rarity of temperature-sensitive alleles and difficulty in identifying them has limited their use. Here we describe a system to generate temperature-sensitive alleles based on conditionally active inteins. We have identified temperature-sensitive splicing variants of the yeast Saccharomyces cerevisiae vacuolar ATPase subunit (VMA) intein inserted within Gal4 and transferred these into Gal80. We show that Gal80-intein TS is able to efficiently provide temporal regulation of the Gal4/upstream activation sequence (UAS) system in a temperature-dependent manner in Drosophila melanogaster . Given the minimal host requirements necessary for temperature-sensitive intein splicing, this technique has the potential to allow the generation and use of conditionally active inteins in multiple host proteins and model systems, thereby widening the use of temperature-sensitive alleles for functional protein analysis.

Abstract Introduction Manually scoring polysomnograms is both time-consuming and labor-intensive. It also increases variability in care. Generating features for use as components within larger models is an important part of building highly accurate auto-scoring systems. In this study, we examined the use of time-frequency data representations in combination with a convolutional neural networks (CNN). Methods We used just six (6) pre-scored polysomnograms from the MrOS dataset in this analysis. Only one electroencephalography (EEG) and one electrooculography (EOG) channel were extracted from each polysomnogram and split into 30 second epochs. Visual representations of each epoch in the time-frequency domain were generated using Morlet wavelets, then divided into training and validation sets in a 4:5 distribution. We then re-trained a ResNet-50 CNN using transfer learning to classify sleep stage based on the time-frequency representations. Results A total of 4971 epochs were generated. Of those, 1242 epochs formed the validation set. Performance was high for identifying Stage W with an accuracy of 94.2% (295/313 epochs). However, performance for other stages was considerably lower. Stage N3 was predicted correctly in 68.0% of cases (138/203 epochs), although in 60/75 cases of misclassification the predicted class was Stage N2. Similarly, Stage N2 was predicted correctly in 62.0% of cases (183/295 epochs), and in 63/112 cases of misclassification the predicted class was Stage N3. Accuracy for Stage REM was 64.9%. Stage N1 prediction was poor (22.0% accuracy), likely due to insufficient representation in the sample (< 10% of epochs). Conclusion This exploratory analysis of the use of time-frequency representations in conjunction with a CNN demonstrates some promise, especially with respect to prediction of Stage W using this technique. Inclusion of additional data channels and larger sample size would likely improve accuracy. Support RS - ASPIRE Fellowship (sponsored by the American Thoracic Association).

Summary Background Epidemiological surveillance of Creutzfeldt-Jakob disease (CJD) was reinstituted in the UK in 1990 to identify any changes in the occurrence of this disease after the epidemic of bovine spongiform encephalopathy (BSE) in cattle. Methods Case ascertainment of CJD was mostly by direct referral from neurologists and neuropathologists. Death certificates on which CJD was mentioned were also obtained. Clinical details were obtained for all referred cases, and information on potential risk factors for CJD was obtained by a standard questionnaire administered to patients' relatives. Neuropathological examination was carried out on approximately 70% of suspect cases. Epidemiological studies of CJD using similar methodology to the UK study have been carried out in France, Germany, Italy, and the Netherlands between 1993 and 1995. Findings Ten cases of CJD have been identified in the UK in recent months with a new neuropathological profile. Other consistent features that are unusual include the young age of the cases, clinical findings, and the absence of the electroencephalogram features typical for CJD. Similar cases have not been identified in other countries in the European surveillance system. Interpretation These cases appear to represent a new variant of CJD, which may be unique to the UK. This raises the possibility that they are causally linked to BSE. Although this may be the most plausible explanation for this cluster of cases, a link with BSE cannot be confirmed on the basis of this evidence alone. It is essential to obtain further information on the current and past clinical and neuropathological profiles of CJD in the UK and elsewhere.

IntroductionEstablishing an early clinical diagnosis in variant Creutzfeldt–Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD.MethodsRetrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system.ResultsThere is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset.ConclusionsEarly clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

Abstract Introduction: The association between atrial fibrillation (AF) and obstructive sleep apnea (OSA) is well established. We present a case of recurrent nighttime AF responsive to CPAP therapy in a patient previously treated with catheter ablation. Report of Case: A 67 year old man, with a prior history of catheter ablation of AF, presented with complaints of episodic, nighttime palpitations and excessive daytime sleepiness. Initial catheter ablation four years prior resulted in resolution of his palpitations. Approximately a year after the ablation his palpitations returned. These events would only occur at night and awaken him from sleep. Holter monitoring showed baseline sinus rhythm with multiple episodes of nocturnal AF with rates of 75 to 169 beats/min correlating with his nocturnal palpitations. The patient’s wife reported that he snored loudly and had occasional apneic episodes. He was referred for a monitored sleep study. The apnea hypopnea index (AHI) was 36/hr overall with nadir desaturation to 72%. There were occasional short runs of atrial fibrillation on the night of the polysomnography correlating with decreased air flow. CPAP at 10 cm H20 treated the sleep disordered breathing and normalized the oxygen saturation. Initially the patient was non-compliant with CPAP but upon further education and encouragement he improved compliance. The patient reported resolution of the nocturnal palpitations after adherence with CPAP. A follow-up holter monitor did not reveal further AF. Conclusion: Patients with OSA have a four-fold risk of developing AF compared to patients without sleep disordered breathing and may develop AF that recurs after catheter ablation. Patients with AF, especially if recurring after ablation should be screened for OSA. Treatment of OSA may help reduce the risk of developing incident AF.

Abstract Introduction: Hypersomnia is a common presenting symptom among patients in sleep disorders centers. The most commonly used clinical tools to assess hypersomnia are patient-completed questionnaires and laboratory multiple-sleep latency tests (MSLT). This study assessed the construct validity of wrist actigraphy for the quantification of hypersomnia severity. We hypothesized that actigraphically assessed daytime sleep parameters (i.e., total daytime minutes and % time asleep) would predict mean sleep onset latency (SOL) on the MSLT. Methods: 17 adult patients referred to the UCLA sleep disorder center who required an overnight sleep study were enrolled. Those with significant neurologic or psychiatric disorders, suspicion of parasomnias or taking sedatives or stimulants were excluded. Subjects completed the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) and wore an actigraph and completed a sleep diary for one week prior to the MSLT. Correlation coefficients relating actigraphically-derived (daytime and nighttime minutes and % time asleep) to mean sleep onset latency on the MSLT were computed. Results: Mean age 44 ± 19 years, 59% male, mean ESS 11.5 ± 5.7, mean MSLT SOL 10.1 ± 4.7 minutes. Wrist actigraphy showed total night time sleep 440 ± 63 minutes, diary night time sleep was 437 ± 81 minutes and PSQI night time sleep was 451 ± 124 minutes. Both actigraphically and diary measured night time sleep were significantly correlated with MSLT SOL (p’s <.0.03, r’s >0.53) but PSQI night sleep was not (r=0.26, p=.31). Actigraphy daytime sleep was 154 ± 113 minutes; and diary reported day time sleep was 30 ± 31 minutes. Neither of these were correlated with mean MSLT-SOL (p’s≥.27, r’s ≤ .28). Conclusion: Actigraphy total sleep time may be useful in describing insufficient sleep prior to MSLT; however, actigraphy assessed daytime sleep may not be a substitute for MSLT in patients presenting to sleep disorders clinics. Additional work is needed to determine the utility of wrist actigraphy in the assessment of hypersomnia and whether it is an optimal way to capture habitual sleep prior to an MSLT. Support (If Any): American Sleep Medicine Foundation Strategic Research Award 107-SR-13.

In April, 1996, ten cases of Creutzfeldt-Jakob disease (CJD) with an apparently new clinicopathological phenotype were published and it was suggested that these new variant cases (nvCJD) might be causally linked to bovine spongiform encephalopathy (BSE). There have now been 21 cases of nvCJD in the UK and one case in France. We report clinical features and diagnostic test results of the first 14 cases of nvCJD in the UK. Case ascertainment of CJD was mainly by direct referral from neurologists and neuropathologists. Clinical and investigative details were obtained by interview with patients' relatives and by examination of case notes. Ten cases in this report were examined while alive. Prion protein (PrP) gene analysis was carried out with informed consent from the patient or from a relative. The diagnosis of nvCJD was established histologically. Eight cases were women. Mean age at onset of symptoms was 29 (16–48) years and the median duration of illness was 14 (9–35) months. All patients had early psychiatric symptoms, most often depression, and 13 were seen by a psychiatrist early in the clinical course. Eight patients developed early sensory symptoms which were persistent and often painful. Neurological signs, including ataxia and involuntary movements, developed in all cases and towards the end of the illness, most had akinetic mutism. The electroencephalogram was abnormal in most patients but typical periodic complexes of CJD were not seen in any case. Cerebral imaging was usually normal or showed non-specific abnormalities; in two cases magnetic-resonance imaging scans showed high signal in the thalamus. Clinical features in these cases are similar and relatively distinct from other forms of CJD, suggesting that this is a new clinical phenotype consistent with a single strain of infectious agent. There is, however, some overlap with atypical cases of sporadic CJD, and the diagnosis of nvCJD remains dependent on neuropathological confirmation.