Evaluation of melanin-targeted radiotherapy in combination with radiosensitizing drugs for the treatment of melanoma

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. An [131I]-labeled benzamide - [131I]MIP-1145 - selectively targets melanin, reduces melanoma tumor burden and increases survival in preclinical models. Our purpose was to determine the potential of radiosensitizers to enhance the anti-tumor efficacy of [131I]MIP-1145. Melanotic (A2058) and amelanotic (A375 and SK-N-BE(2c)) cells were treated with [131I]MIP-1145 as a single agent or in combination with drugs with radiosenitizing potential. Cellular uptake of [131I]MIP-1145 and toxicity were assessed in monolayer culture. The interaction between radiosensitizers and [131I]MIP-1145 was evaluated by combination index analysis in monolayer cultures and by delayed growth of multicellular tumor spheroids. [131I]MIP-1145 was taken up by and was toxic to melanotic cells but not amelanotic cells. Combination treatments comprising [131I]MIP-1145 with the topoisomerase inhibitor topotecan or the PARP-1 inhibitor AG014699 resulted in synergistic clonogenic cell kill and enhanced delay of the growth of spheroids derived from melanotic melanoma cells. The proteasome inhibitor bortezomib had no synergistic cytotoxic effect with [131I]MIP-1145 and failed to enhance the delay of spheroid growth. Following combination treatment of amelanotic cells, neither synergistic clonogenic cell kill nor enhanced growth delay of spheroids was observed

Mixing and crystal scavenging in the Main Ethiopian Rift revealed by trace element systematics in feldspars and glasses

For many magmatic systems, crystal compositions preserve a complex and protracted history which may be largely decoupled from their carrier melts. The crystal cargo may hold clues to the physical distribution of melt and crystals in a magma reservoir and how magmas are assembled prior to eruptions. Here we present a geochemical study of a suite of samples from three peralkaline volcanoes in the Main Ethiopian Rift. Whilst whole-rock data shows strong fractional crystallisation signatures, the trace element systematics of feldspars, and their relationship to their host glasses, reveals complexity. Alkali feldspars, particularly those erupted during caldera forming episodes, have variable Ba concentrations, extending to high values that are not in equilibrium with the carrier liquids. Some of the feldspars are antecrysts, which we suggest are scavenged from a crystal-rich mush. The antecrysts crystallised from a Ba-enriched (more primitive) melt, before later entrainment into a Ba-depleted residual liquid. Crystal-melt segregation can occur on fast timescales in these magma reservoirs, owing to the low viscosity nature of peralkaline liquids. The separation of enough residual melt to feed a crystal-poor post caldera rhyolitic eruption may take as little as months to tens of years (much shorter than typical repose periods of 300-400 years). Our observations are consistent with these magmatic systems spending significant portions of their life cycle dominated by crystalline mushes containing ephemeral, small (< 1 km3) segregations of melt. This interpretation helps to reconcile observations of high crustal electrical resistivity beneath Aluto, despite seismicity and ground deformation consistent with a magma body.This project is funded by the Natural Environment Research Council grant NE/L013932/1 (RiftVolc)

Ultra-strong coupling of molecular materials: spectroscopy and dynamics

We report here a study of light–matter strong coupling involving three molecules with very different photo-physical properties. In particular we analyze their emission properties and show that the excitation spectra are very different from the static absorption of the coupled systems. Furthermore we report the emission quantum yields and excited state lifetimes, which are self-consistent. The above results raise a number of fundamental questions that are discussed and these demonstrate the need for further experiments and theoretical studie

Personalities, Preferences and Practicalities: Educating Nurses in Wound Sepsis in the British Hospital, 1870 – 1920

The history of nursing education has often been portrayed as the subordination of nursing to medicine. Yet, as scholars are increasingly acknowledging, the professional boundaries between medicine and nursing were fluid in the nineteenth and early twentieth centuries, when both scientific knowledge and systems of nurse training were in flux. Through its focus on the role of medical practitioners in educating nurses in wound sepsis at four British hospitals between 1870 and 1920, this article attempts to further unite histories of medicine and nursing. It demonstrates that, in this period of uncertainty, the ideas and practices relating to antisepsis, asepsis and bacteriology disseminated to nursing probationers depended on the individual instructor. In demonstrating the localised nature of nursing education, this article argues that further analyses of clinical problems like wound sepsis may enable historians to more clearly identify the importance of professional collaboration within the hospital

Delayed Achilles tendon rupture presentation: Non-operative management may be the SMART choice

IntroductionThis biomechanical study aims to assess the function of patients who were treated non-operatively for delayed diagnosis Achilles tendon rupture. Patients were treated using the Swansea Morriston Achilles Rupture Treatment protocol (SMART), which is a physiotherapy led non-operative treatment program.Methods19 patients (16 M:3F) were enrolled and prospectively assessed using ARS/ATRS (PROMS), Ankle ROM and isokinetic peak torque for plantarflexion of the ankle. MRI scans of both the injured and uninjured TA were performed to compare both AP diameter and length.ResultsBoth ATRS and ARS improved between short and long-term follow-up. The mean difference in plantar torque between the injured and uninjured leg was 21.9%. There was no significant difference in ankle plantarflexion or dorsiflexion. There was no significant difference in length of the injured and uninjured TA on MRI. 3 patients failed the SMART protocol requiring surgical fixation.DiscussionThe SMART protocol can be an effective method of treatment even in younger and active patients especially if delay to treatment is less than 12 weeks. It may still be preferable for patients with a large gap size or high functional demand to elect for surgical intervention, but clinicians should consider the SMART protocol as an alternative to surgery and discuss it with some patients as a viable alternative.KeywordsTendoachillesConservativeChronicDelayedAbbreviationsTATendoachillesSMARTSwansea Morriston Achilles Rupture Treatmen

Mixing and crystal scavenging in the Main Ethiopian Rift revealed by trace element systematics in feldspars and glasses

For many magmatic systems, crystal compositions preserve a complex and protracted history which may be largely decoupled from their carrier melts. The crystal cargo may hold clues to the physical distribution of melt and crystals in a magma reservoir and how magmas are assembled prior to eruptions. Here we present a geochemical study of a suite of samples from three peralkaline volcanoes in the Main Ethiopian Rift. Whilst whole‐rock data shows strong fractional crystallisation signatures, the trace element systematics of feldspars, and their relationship to their host glasses, reveals complexity. Alkali feldspars, particularly those erupted during caldera‐forming episodes, have variable Ba concentrations, extending to high values that are not in equilibrium with the carrier liquids. Some of the feldspars are antecrysts, which we suggest are scavenged from a crystal‐rich mush. The antecrysts crystallised from a Ba‐enriched (more primitive) melt, before later entrainment into a Ba‐depleted residual liquid. Crystal‐melt segregation can occur on fast timescales in these magma reservoirs, owing to the low viscosity nature of peralkaline liquids. The separation of enough residual melt to feed a crystal‐poor post‐caldera rhyolitic eruption may take as little as months to tens of years (much shorter than typical repose periods of 300‐400 years). Our observations are consistent with these magmatic systems spending significant portions of their life cycle dominated by crystalline mushes containing ephemeral, small (< 1 km3) segregations of melt. This interpretation helps to reconcile observations of high crustal electrical resistivity beneath Aluto, despite seismicity and ground deformation consistent with a magma body

Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities

Brain Biomarkers and Pre-Injury Cognition are Associated with Long-Term Cognitive Outcome in Children with Traumatic Brain Injury

BACKGROUND: Children with traumatic brain injury (TBI) are frequently at risk of long-term impairments of attention and executive functioning but these problems are difficult to predict. Although deficits have been reported to vary with injury severity, age at injury and sex, prognostication of outcome remains imperfect at a patient-specific level. The objective of this proof of principle study was to evaluate a variety of patient variables, along with six brain-specific and inflammatory serum protein biomarkers, as predictors of long-term cognitive outcome following paediatric TBI. METHOD: Outcome was assessed in 23 patients via parent-rated questionnaires related to attention deficit hyperactivity disorder (ADHD) and executive functioning, using the Conners 3rd Edition Rating Scales (Conners-3) and Behaviour Rating Inventory of Executive Function (BRIEF) at a mean time since injury of 3.1 years. Partial least squares (PLS) analyses were performed to identify factors measured at the time of injury that were most closely associated with outcome on (1) the Conners-3 and (2) the Behavioural Regulation Index (BRI) and (3) Metacognition Index (MI) of the BRIEF. RESULTS: Higher levels of neuron specific enolase (NSE) and lower levels of soluble neuron cell adhesion molecule (sNCAM) were associated with higher scores on the inattention, hyperactivity/impulsivity and executive functioning scales of the Conners-3, as well as working memory and initiate scales of the MI from the BRIEF. Higher levels of NSE only were associated with higher scores on the inhibit scale of the BRI. CONCLUSIONS: NSE and sNCAM show promise as reliable, early predictors of long-term attention-related and executive functioning problems following paediatric TBI

The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities.

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in group-housed adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneus-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed