Synthesis and <em>In Vitro</em> Evaluation of a HER2-Specific ImmunoSCIFI Probe

Secondary Cerenkov-induced fluorescence imaging (SCIFI) is an emerging biomedical optical imaging modality that leverages Cerenkov luminescence, primarily generated by β-emitting radioisotopes, to excite fluorophores that offer near-infrared emissions with optimal tissue penetrance. Dual-functionalized immunoconjugates composed of an antibody, a near-infrared fluorophore, and a β-emitting radioisotope have potential utility as novel SCIFI constructs with high specificity for molecular biomarkers of disease. Here, we report the synthesis and characterization of [89Zr]Zr-DFO-trastuzumab-BOD665, a self-excitatory HER2-specific “immunoSCIFI” probe capable of yielding near-infrared fluorescence in situ without external excitation. The penetration depth of the SCIFI signal was measured in hemoglobin-infused optical tissue phantoms that indicated a 2.05-fold increase compared to 89Zr-generated Cerenkov luminescence. Additionally, the binding specificity of the immunoSCIFI probe for HER2 was evaluated in a cellular assay that showed significantly higher binding to SKBR3 (high HER2 expression) relative to MDA-MB-468 (low HER2) breast cancer cells based on measurements of total flux in the near-infrared region with external excitation blocked. Taken together, the results of this study indicate the potential utility of immunoSCIFI constructs for interrogation of molecular biomarkers of disease

Low-level laser therapy for carpal tunnel syndrome

BACKGROUND: The role of low-level laser therapy (LLLT) in the management of carpal tunnel syndrome (CTS) is controversial. While some trials have shown distinct advantages of LLLT over placebo and some other non-surgical treatments, other trials have not. OBJECTIVES: To assess the benefits and harms of LLLT versus placebo and versus other non-surgical interventions in the management of CTS. SEARCH METHODS: On 9 December 2016 we searched CENTRAL, MEDLINE, Embase, and Science Citation Index Expanded for randomised controlled trials (RCTs). We also searched clinical trial registries for ongoing studies. We checked the references of primary studies and review articles, and contacted trial authors for additional studies. SELECTION CRITERIA: We considered for inclusion RCTs (irrespective of blinding, publication status or language) comparing LLLT versus placebo or non-surgical treatment for the management of CTS. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials for inclusion and extracted the data. For continuous outcomes, we calculated the mean difference (MD) or standardised mean difference (SMD) with a 95% confidence interval (CI) using the random-effects model, calculated using Review Manager. For dichotomous data, we reported risk ratio (RR) and 95% CI. MAIN RESULTS: We identified 22 trials randomising 1153 participants that were eligible for inclusion; nine trials (525 participants, 256 randomised to LLLT) compared LLLT with placebo, two (150 participants, 75 randomised to LLLT) compared LLLT with ultrasound, one compared LLLT with placebo and LLLT with ultrasound, two compared LLLT with steroid injection, and one trial each compared LLLT with other non-surgical interventions: fascial manipulation, application of a pulsed magnetic field, transcutaneous electrical nerve stimulation (TENS), steroid injection, tendon gliding exercises, and applying a wrist splint combined with non-steroidal anti-inflammatory drugs. Three studies compared LLLT as part of multiple interventions. Risk of bias varied across the studies, but was high or unclear in most assessed domains in most studies. Most studies were small, with few events, and effect estimates were generally imprecise and inconsistent; the combination of these factors led us to categorise the quality of evidence for most outcomes as very low or, for a small number, low. At short-term follow-up (less than three months), there was very low-quality evidence for any effect over placebo of LLLT on CTS for the primary outcome of Symptom Severity Score (scale 1 to 5, higher score represents worsening; MD -0.36, 95% CI -0.78 to 0.06) or Functional Status Scale (scale 1 to 5, higher score represents worsened disability; MD -0.56, 95% CI -1.03 to -0.09). At short-term (less than three months) follow-up, we are uncertain whether LLLT results in a greater improvement than placebo in visual analogue score (VAS) pain (scale 0 to 10, higher score represents worsening; MD -1.47, 95% CI -2.36 to -0.58) and several aspects of nerve conduction studies (motor nerve latency: higher score represents worsening; MD -0.09 ms, 95% CI -0.16 to -0.03; range 3.1 ms to 4.99 ms; sensory nerve latency: MD -0.10 ms, 95% CI -0.15 to -0.06; range 1.8 ms to 3.9 ms), as the quality of the evidence was very low. When compared with placebo at short-term follow-up, LLLT may slightly improve grip strength (MD 2.58 kg, 95% CI 1.22 to 3.95; range 14.2 kg to 25.23 kg) and finger-pinch strength (MD 0.94 kg, 95% CI 0.43 to 1.44; range 4.35 kg to 5.7 kg); however, the quality of evidence was low. Only VAS pain and finger-pinch strength results reached the minimal clinically important difference (MCID) as previously published. We are uncertain about the effect of LLLT in comparison to ultrasound at short-term follow-up for improvement in VAS pain (MD 2.81, 95% CI 1.21 to 4.40) and motor nerve latency (MD 0.61 ms, 95% CI 0.27 to 0.95), as the quality of evidence was very low. When compared with ultrasound at short-term follow-up, LLLT may result in slightly less improvement in finger-pinch strength (MD -0.71 kg, 95% CI -0.94 to -0.49) and motor nerve amplitude (MD -1.90 mV, 95% CI -3.63 to -0.18; range 7.10 mV to 9.70 mV); however, the quality of evidence was low. There was insufficient evidence to assess the long-term benefits of LLLT versus placebo or ultrasound. There was insufficient evidence to show whether LLLT is better or worse in the management of CTS than other non-surgical interventions. For all outcomes reported within these other comparisons, the quality of evidence was very low. There was insufficient evidence to assess adverse events, as only one study reported this outcome. AUTHORS' CONCLUSIONS: The evidence is of very low quality and we found no data to support any clinical effect of LLLT in treating CTS. Only VAS pain and finger-pinch strength met previously published MCIDs but these are likely to be overestimates of effect given the small studies and significant risk of bias. There is low or very low-quality evidence to suggest that LLLT is less effective than ultrasound in the management of CTS based on short-term, clinically significant improvements in pain and finger-pinch strength. There is insufficient evidence to support LLLT being better or worse than any other type of non-surgical treatment in the management of CTS. Any further research of LLLT should be definitive, blinded, and of high quality

RNA sequencing and functional studies of patient-derived cells reveal that neurexin-1 and regulators of this pathway are associated with poor outcomes in Ewing sarcoma

Purpose The development of biomarkers and molecularly targeted therapies for patients with Ewing sarcoma (ES) in order to minimise morbidity and improve outcome is urgently needed. Here, we set out to isolate and characterise patient-derived ES primary cell cultures and daughter cancer stem-like cells (CSCs) to identify biomarkers of high-risk disease and candidate therapeutic targets. Methods Thirty-two patient-derived primary cultures were established from treatment-naïve tumours and primary ES-CSCs isolated from these cultures using functional methods. By RNA-sequencing we analysed the transcriptome of ES patient-derived cells (n = 24) and ES-CSCs (n = 11) to identify the most abundant and differentially expressed genes (DEGs). Expression of the top DEG(s) in ES-CSCs compared to ES cells was validated at both RNA and protein levels. The functional and prognostic potential of the most significant gene (neurexin-1) was investigated using knock-down studies and immunohistochemistry of two independent tumour cohorts. Results ES-CSCs were isolated from all primary cell cultures, consistent with the premise that ES is a CSC driven cancer. Transcriptional profiling confirmed that these cells were of mesenchymal origin, revealed novel cell surface targets for therapy that regulate cell-extracellular matrix interactions and identified candidate drivers of progression and relapse. High expression of neurexin-1 and low levels of regulators of its activity, APBA1 and NLGN4X, were associated with poor event-free and overall survival rates. Knock-down of neurexin-1 decreased viable cell numbers and spheroid formation. Conclusions Genes that regulate extracellular interactions, including neurexin-1, are candidate therapeutic targets in ES. High levels of neurexin-1 at diagnosis are associated with poor outcome and identify patients with localised disease that will relapse. These patients could benefit from more intensive or novel treatment modalities. The prognostic significance of neurexin-1 should be validated independently

A Tale of Two Current Sheets

I outline a new model of particle acceleration in the current sheet separating the closed from the open field lines in the force-free model of pulsar magnetospheres, based on reconnection at the light cylinder and "auroral" acceleration occurring in the return current channel that connects the light cylinder to the neutron star surface. I discuss recent studies of Pulsar Wind Nebulae, which find that pair outflow rates in excess of those predicted by existing theories of pair creation occur, and use those results to point out that dissipation of the magnetic field in a pulsar's wind upstream of the termination shock is restored to life as a viable model for the solution of the "$\sigma$" problem as a consequence of the lower wind 4-velocity implied by the larger mass loading.Comment: 17 pages, 6 figures, Invited Review, Proceedings of the "ICREA Workshop on The High-Energy Emission from Pulsars and their Systems", Sant Cugat, Spain, April 12-16, 201

Temporal changes in key maternal and fetal factors affecting birth outcomes: A 32-year population-based study in an industrial city

<p>Abstract</p> <p>Background</p> <p>The link between maternal factors and birth outcomes is well established. Substantial changes in society and medical care over time have influenced women's reproductive choices and health, subsequently affecting birth outcomes. The objective of this study was to describe temporal changes in key maternal and fetal factors affecting birth outcomes in Newcastle upon Tyne over three decades, 1961–1992.</p> <p>Methods</p> <p>For these descriptive analyses we used data from a population-based birth record database constructed for the historical cohort <b>Pa</b>rticulate <b>M</b>atter and <b>P</b>erinatal <b>E</b>vents <b>R</b>esearch (PAMPER) study. The PAMPER database was created using details from paper-based hospital delivery and neonatal records for all births during 1961–1992 to mothers resident in Newcastle (out of a total of 109,086 singleton births, 97,809 hospital births with relevant information). In addition to hospital records, we used other sources for data collection on births not included in the delivery and neonatal records, for death and stillbirth registrations and for validation.</p> <p>Results</p> <p>The average family size decreased mainly due to a decline in the proportion of families with 3 or more children. The distribution of mean maternal ages in all and in primiparous women was lowest in the mid 1970s, corresponding to a peak in the proportion of teenage mothers. The proportion of older mothers declined until the late 1970s (from 16.5% to 3.4%) followed by a steady increase. Mean birthweight in all and term babies gradually increased from the mid 1970s. The increase in the percentage of preterm birth paralleled a two-fold increase in the percentage of caesarean section among preterm births during the last two decades. The gap between the most affluent and the most deprived groups of the population widened over the three decades.</p> <p>Conclusion</p> <p>Key maternal and fetal factors affecting birth outcomes, such as maternal age, parity, socioeconomic status, birthweight and gestational age, changed substantially during the 32-year period, from 1961 to 1992. The availability of accurate gestational age is extremely important for correct interpretation of trends in birthweight.</p

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org