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Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response ( r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Recently, the World Health Organization recognized that efforts to interrupt schistosomiasis transmission through mass drug administration have been ineffective in some regions; one of their new recommended strategies for global schistosomiasis control emphasizes targeting the freshwater snails that transmit schistosome parasites. We sought to identify robust indicators that would enable precision targeting of these snails. At the site of the world’s largest recorded schistosomiasis epidemic—the Lower Senegal River Basin in Senegal—intensive sampling revealed positive relationships between intermediate host snails (abundance, density, and prevalence) and human urogenital schistosomiasis reinfection (prevalence and intensity in schoolchildren after drug administration). However, we also found that snail distributions were so patchy in space and time that obtaining useful data required effort that exceeds what is feasible in standard monitoring and control campaigns. Instead, we identified several environmental proxies that were more effective than snail variables for predicting human infection: the area covered by suitable snail habitat (i.e., floating, nonemergent vegetation), the percent cover by suitable snail habitat, and size of the water contact area. Unlike snail surveys, which require hundreds of person-hours per site to conduct, habitat coverage and site area can be quickly estimated with drone or satellite imagery. This, in turn, makes possible large-scale, high-resolution estimation of human urogenital schistosomiasis risk to support targeting of both mass drug administration and snail control efforts.

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

Andy Feinberg and colleagues show in a colon cancer model that most DNA methylation alterations occur in sequence regions distinct from promoters or canonical CpG islands, termed 'CpG island shores', and that this methylation is strongly related to gene expression and can discriminate tissue types regardless of species of origin. For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45–65%) of the locations of colon cancer–related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

Biodiversity runs hot and cold Although biodiversity hotspots are central to many conservation strategies, a key assumption, that areas ‘hot’ for one aspect of diversity are hot for others, is untested. A new study addresses this question on a global level and shows that this is not the case: different types of hotspot are in found in different areas. For birds, the mountains of South America and Africa are hotspots of species richness, yet the hotspots of extinction risk are on the islands of New Zealand, Madagascar and the Philippines. Conservation strategy therefore needs to be based on multiple measures of diversity. Biodiversity hotspots have a prominent role in conservation biology 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , but it remains controversial to what extent different types of hotspot are congruent 4 , 10 , 11 , 12 , 13 , 14 . Previous studies were unable to provide a general answer because they used a single biodiversity index, were geographically restricted, compared areas of unequal size or did not quantitatively compare hotspot types 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Here we use a new global database on the breeding distribution of all known extant bird species to test for congruence across three types of hotspot. We demonstrate that hotspots of species richness, threat and endemism do not show the same geographical distribution. Only 2.5% of hotspot areas are common to all three aspects of diversity, with over 80% of hotspots being idiosyncratic. More generally, there is a surprisingly low overall congruence of biodiversity indices, with any one index explaining less than 24% of variation in the other indices. These results suggest that, even within a single taxonomic class, different mechanisms are responsible for the origin and maintenance of different aspects of diversity. Consequently, the different types of hotspots also vary greatly in their utility as conservation tools.

IntroductionEthiqa XR is an extended-release formulation of the potent partial opioid buprenorphine and has been FDA-indexed for mice and other laboratory animal species to relieve pain. Unfortunately, the use of analgesia may produce confounding effects that distort physiological and pathophysiological responses during laboratory animal studies. Since various reports have indicated that Ethiqa XR can affect the inflammatory response in several in vivo models, we sought to evaluate the effects of Ethiqa XR treatment on the immune response to and disease pathogenesis associated with bacterial biothreat agents.MethodsBALB/c and C57BL/6 mouse strains were treated or not with Ethiqa XR before and 48 h after challenge with aerosolized Burkholderia pseudomallei K96243 or Yersinia pestis CO92. Control mice were similarly treated with Ethiqa XR but were not challenged. Mice were euthanized 60-72 hours post-treatment/challenge to harvest blood, serum, lung, brain and spleen for bacterial burden and immunological profiling.ResultsBoth C57BL/6 and BALB/c mouse strains showed higher bacterial dissemination to the spleen 60-72 h after B. pseudomallei challenge when treated with Ethiqa XR. Consistently, we found increased concentration of pro-inflammatory cytokines in the spleen (e.g., IFN-γ and IL-6) in Ethiqa XR-treated mice. Compared to BALB/c, C57BL/6 mice had trends of higher cytokine dysregulation not only in the spleens, but also in the lungs and brains. In contrast, we found less profound differences in either mouse strain treated with Ethiqa XR and challenged with Y. pestis . In the absence of bacterial challenge, both BALB/c and C57BL/6 mouse strains treated with Ethiqa XR had an overall higher concentration of pro-inflammatory cytokines in the lungs and spleens. However, C57BL/6 mice showed a higher dysregulation of the cytokine profile in both lungs and spleens. We also found decreased macrophage activity (iNOS concentration) in the spleens of BALB/c mice and decreased neutrophil activity (MPO concentration) in the lung of C57BL/6 mice treated with Ethiqa XR.DiscussionThese results suggest that the effect of Ethiqa XR on the immune response and disease pathogenesis increases the complexity of data interpretation. Thus, prior to providing analgesia to laboratory animals, bridging studies and cost benefit analyses must be considered to avoid misinterpretation of immunological data collected during the development, testing, and evaluation of medical countermeasures.

Providing a satisfactory, functional prosthesis following lower-limb amputation is a primary goal of rehabilitation. The objectives of this study were to describe the rate of successful prosthetic fitting over a 12 mo period; describe prosthetic use after amputation; and determine factors associated with greater prosthetic fitting, function, and satisfaction. The study design was a multicenter prospective cohort study of individuals undergoing their first major lower-limb amputation because of vascular disease and/or diabetes. At 4 mo, unsuccessful prosthetic fitting was significantly associated with depression, prior arterial reconstruction, diabetes, and pain in the residual limb. At 12 mo, 92% of all subjects were fit with a prosthetic limb and individuals with transfemoral amputation were significantly less likely to have a prosthesis fit. Age older than 55 yr, diagnosis of a major depressive episode, and history of renal dialysis were associated with fewer hours of prosthetic walking. Subjects who were older, had experienced a major depressive episode, and/or were diagnosed with chronic obstructive pulmonary disease had greater functional restriction. Thus, while most individuals achieve successful prosthetic fitting by 1 yr following a first major nontraumatic lower-limb amputation, a number of medical variables and psychosocial factors are associated with prosthetic fitting, utilization, and function.

Mercury’s images obtained by the 1974 Mariner 10 flybys show extensive cratered landscapes degraded into vast knob fields, known as chaotic terrain (AKA hilly and lineated terrain). For nearly half a century, it was considered that these terrains formed due to catastrophic quakes and ejecta fallout produced by the antipodal Caloris basin impact. Here, we present the terrains’ first geologic examination based on higher spatial resolution MESSENGER (MErcury Surface Space ENvironment GEochemistry and Ranging) imagery and laser altimeter topography. Our surface age determinations indicate that their development persisted until ~1.8 Ga, or ~2 Gyrs after the Caloris basin formed. Furthermore, we identified multiple chaotic terrains with no antipodal impact basins; hence a new geological explanation is needed. Our examination of the Caloris basin’s antipodal chaotic terrain reveals multi-kilometer surface elevation losses and widespread landform retention, indicating an origin due to major, gradual collapse of a volatile-rich layer. Crater interior plains, possibly lavas, share the chaotic terrains’ age, suggesting a development associated with a geothermal disturbance above intrusive magma bodies, which best explains their regionality and the enormity of the apparent volume losses involved in their development. Furthermore, evidence of localized, surficial collapse, might reflect a complementary, and perhaps longer lasting, devolatilization history by solar heating.

Mechanical properties and microstructure characterization of a series of graded commercial rigid polyurethane foams commonly used to mimic trabecular bone in testing orthopaedic devices is reported. Compressive testing conducted according to ASTM standard F1839-08, which requires large specimens (50.8 mm × 50.8 mm × 25.4 mm blocks) gave elastic modulus and compressive strength values ranging from 115 to 794 MPa and 4.7 to 24.7 MPa, respectively, for foams having densities of 0.240–0.641 g/cm 3 . All these results were within the requirements of the specification for the corresponding grades. Compression testing using smaller specimens (7.5 mm diameter × 15 mm) typical of testing bone, gave results in good agreement with those obtained in the standard tests. Microstructural measurements showed the average pore size ranged from 125 to 234 μm for densities ranging from 0.641 to 0.159 g/cm 3 , respectively. The relative modulus as a function of relative density of the foams fit well to the model of Gibson and Ashby. Cyclic testing revealed hysteresis in the lower density foams with a loading modulus statistically equivalent to that measured in monotonic testing. Shore DO durometry (hardness) measurements show good correlations to elastic modulus and compressive strength. The results suggest additional parameters to consider for the evaluation of polyurethane foams for bone analog applications.

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.