Local Treatment Options for Unresectable Liver Metastases in Colorectal Cancer

Despite the increase in effectiveness of systemic therapy, cure for colorectal cancer with liver metastases (CRLM) is rarely achieved without surgical resection, with less than 20% of patients initially suitable for surgery. Liver-directed therapies are continually being investigated in the hope of improving cure rates in patients with unresectable liver metastases. These modalities include selective internal radiation therapy (SIRT), radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and hepatic artery infusion (HAI) chemotherapy. While there is evidence of activity for all these treatments, they are somewhat lacking in high level randomized, controlled trial evidence (RCT) with appropriate control arms relevant to current standard of care. This review examines the efficacy and safety of these treatments in unresectable CRLM

Flexible alarm calling in meerkats: the role of the social environment and predation urgency

Flexible vocal production has been demonstrated in several vertebrate species, with much work focusing on the role of the social "audience” in explaining variation in call production. It is, however, likely that the decision to call is an emergent property of both external and internal factors, and the extent to which these factors are integrated has been little investigated. We addressed this question by examining the production of alarm calls in wild male meerkats (Suricata suricatta) in different social environments and different predator-encounter contexts. Males searching for reproductive opportunities (rovers) were followed 1) in their home group and when prospecting either 2) solitarily or 3) in a coalition with other males. Results showed that conspecific presence influenced the production of flee-alarm and recruitment calls. Solitary rovers were less likely to produce flee-alarm calls compared with when they are with conspecifics, whether coalitionary rovers or the rover's home group. Experimentally elicited recruitment calls were also produced less when males were solitary than when in their home group. Bark vocalizations, emitted when meerkats were safe, were always produced irrespective of conspecific presence, indicating that these calls function to address predators. The probability of producing flee alarms also increased with the urgency of the predation event. Our results indicate that variation in alarm call production depends on whom the call is addressed to and also on the motivational state of the caller. We argue that neglecting to integrate internal and external factors when elucidating mechanisms underlying vocal production can potentially lead to misguided, parsimonious conclusions regarding vocal flexibility in animal

Shale weathering rates across a continental-scale climosequence

A transect of sites has been established in North America and England as part of the Critical Zone Exploration Network (CZEN) to investigate the rates of soil formation across a climate gradient. Sites reported here are all underlain by an organic-poor, iron-rich Silurian-age shale, providing a constant parent material lithology from which soil is forming. This climosequence includes relatively cold and wet sites in Wales, New York and Pennsylvania, with temperature increasing to the south in Virginia, Tennessee and Alabama. Puerto Rico provides a warm/wet end member for the transect, although this site does not lie on the same shale formation as the Appalachian Mountain sites. Geochemical, mineralogical, and cosmogenic isotope analyses are being completed similarly at all sites to allow direct comparisons and eventual modelling of the weathering processes. Preliminary results from Wales, Pennsylvania and Virginia show soils become more sodium-depleted and the depth to bedrock is significantly deeper at the wet/warm site in Virginia. The fraction of Na lost relative to parent material composition at each site varies linearly as a function of mean annual temperature. Overall, results from the transect will promote a better understanding of how climate changes and human activities impact soil formation rates

Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery?

Objectives - To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery. Methods - Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS. The eluted temocillin was purified by fast protein liquid chromatography and the MICs for a number of antibiotic-resistant Escherichia coli were determined. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. Results - LC-MS data showed temocillin eluted to clinically significant concentrations within 1 h in this laboratory system and the eluted temocillin retained antimicrobial activity against all organisms tested. Impact strength analysis showed no significant difference between cement samples with or without temocillin. Conclusions - Temocillin can be added to bone cement and retains its antimicrobial activity after elution. The addition of up to 10% temocillin did not affect the impact strength of the cement. The results show that temocillin is a promising candidate for use in antibiotic-loaded bone cement.</p

Shale weathering rates across a continental-scale climosequence

A transect of sites has been established in North America and England as part of the Critical Zone Exploration Network (CZEN) to investigate the rates of soil formation across a climate gradient. Sites reported here are all underlain by an organic-poor, iron-rich Silurian-age shale, providing a constant parent material lithology from which soil is forming. This climosequence includes relatively cold and wet sites in Wales, New York and Pennsylvania, with temperature increasing to the south in Virginia, Tennessee and Alabama. Puerto Rico provides a warm/wet end member for the transect, although this site does not lie on the same shale formation as the Appalachian Mountain sites. Geochemical, mineralogical, and cosmogenic isotope analyses are being completed similarly at all sites to allow direct comparisons and eventual modelling of the weathering processes. Preliminary results from Wales, Pennsylvania and Virginia show soils become more sodium-depleted and the depth to bedrock is significantly deeper at the wet/warm site in Virginia. The fraction of Na lost relative to parent material composition at each site varies linearly as a function of mean annual temperature. Overall, results from the transect will promote a better understanding of how climate changes and human activities impact soil formation rates

Brown Fat Paucity Due to Impaired BMP Signaling Induces Compensatory Browning of White Fat

Summary Maintenance of body temperature is essential for survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation1. Due to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans2-5, BAT holds great promise for the treatment of obesity and metabolic syndrome1. Rodent data suggest the existence of two types of brown fat cells: the constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the interscapular region of mice, and the recruitable BAT (rBAT) that resides within white adipose tissue (WAT)6 and skeletal muscle7, that has alternatively been called beige8, brite9, or inducible BAT10. Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT10-12. We here provide evidence for a systemically active regulatory mechanism that serves to control whole body BAT-activity for thermoregulation and energy homeostasis. Genetic ablation of type 1A BMP-receptor (Bmpr1A) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between the constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease

Engage: redoing how we talk about depression

Engage is a workshop tool for facilitating difficult discussions around mental health among young adults. It was born of the need to challenge stigma and misconceptions around mental health and depression, as these are a major barrier for sufferers to seek help or feel able to discuss their condition with others. Structured as a 90 minute workshop, it provides an opportunity for college students to engage in open discussion about mental health, in order to raise awareness and articulacy, and reduce the high levels of stigma that surround this topic. Initially the project focused on elderly depression, and on the stigma attached to mental health conditions. Field research in Senior Centers in New York and with several senior-focused NGOs resulted in the first design proposal, the Engage Toolkit. The toolkit contains a set of prompt activities designed to enable senior centre members to engage in open dialogue about mental health, through sharing perceptions, experiences and worries, in order to promote a culture of empathy, understanding, and free of stigma. The project was later taken to Tokyo, Japan, where the concept was tested within Keio University. Based on the insights and experiences that came out of the research and user testing in Japan, the second iteration was developed into the Engage Workshop, introducing physical prompts and fictional scenarios and personae to facilitate and structure discussions. This key difference was informed by direct experience of Japanese culture: by centring the discussion around fictional scenarios and personae, as opposed to participants’ own experiences, they feel safe and free to talk openly in an atmosphere of confidentiality, sensitivity and respect. This allows them to develop the skills to discuss sensitive but necessary topics, somewhat taboo in Japan, without feeling pressured to share personal experiences which may require a more specialised approach, or support from a mental health professional. The designers of this project are postgraduate students who have spent the past year in New York, Tokyo and London, immersively exploring cultural differences as opportunities for design innovation, in particular researching and designing to address negative attitudes and stigma surrounding mental health. They are currently working to further validate and refine the Engage concept, in collaboration with UK mental health charity Sane, including a version specifically for the British context

Synthesis of an intriguing steroidal constitutional isomer

We recently described the synthesis of an unusual tricyclic system, whereby a cis-decalin was fused to a cis-hydrindane. Herein, we wish to describe the elaboration of this system towards steroid-like frameworks. This report describes how, en route to an attempted cardiotonic steroid synthesis, we stereoselectively functionalized the leftmost cyclohexyl ring with an ester ready for steroidal A-ring formation. Ultimately however, the required transposition of the cyclohexylketone did not occur as expected and resulted in the subsequent Robinson annulation forming an unusual steroidal constitutional isomer – the saturated cyclopenta[c]phenanthrene. Remarkably, such unusual tetracyclic connectivity has been reported just once in 70 years