Extensive Dental Caries in Patients with Oral Chronic Graft-versus-Host Disease

The oral cavity is one of the sites most frequently affected by chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (alloHCT) and can be a significant source of patient morbidity due to both mucosal and salivary gland involvement. The development of dental decay is a potentially devastating oral complication that has only rarely been reported in the transplantation literature. The purpose of this study was to comprehensively characterize a cohort of patients with cGVHD who subsequently developed extensive dental caries. A retrospective case-record review was conducted for patients who had undergone alloHCT at Dana-Farber/Brigham and Women's Cancer Center between 1990 and 2010 and developed cGVHD-associated rampant dental decay. All patients underwent dental evaluation, involving soft and hard tissue examination and dental radiography, before and after alloHCT. Any dental caries diagnosed at the pre-alloHCT evaluation were treated definitively, such that all patients were considered free of caries at the time of admission for alloHCT. A total of 21 patients were identified, with a median time of cGVHD onset of 5.4 months (range, 2.2-18.5 months) after alloHCT. All patients were diagnosed with oral cGVHD, with 90% demonstrating mucosal involvement and 95% demonstrating salivary gland involvement. Post-alloHCT dental evaluation was performed at a median of 22 months (range, 4-81) after alloHCT, when 10 patients were diagnosed with gross caries and 8 patients had 4 or more affected teeth. Cervical and interproximal patterns of dental caries were frequently diagnosed. The proportions of patients with gross caries, one surface caries, and more than one surface caries (classified as 0, 1-3, and ≥4, respectively) were significantly higher after alloHCT than before alloHCT, with at least 50% of patients experiencing an increase. Patients with oral cGVHD who were free of caries at the time of transplantation developed extensive areas of cervical decay at a median of less than 2 years after alloHCT. This is the first comprehensive characterization of this severe late complication of alloHCT and oral cGVHD. Greater awareness by transplantation oncologists and dentists, as well as more aggressive preventive measures, are needed, as are further prospective studies to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of preventive interventions

Three-Dimensional Atmospheric Circulation Models of HD 189733b and HD 209458b with Consistent Magnetic Drag and Ohmic Dissipation

We present the first three-dimensional circulation models for extrasolar gas giant atmospheres with geometrically and energetically consistent treatments of magnetic drag and ohmic dissipation. Atmospheric resistivities are continuously updated and calculated directly from the flow structure, strongly coupling the magnetic effects with the circulation pattern. We model the hot Jupiters HD 189733b (Teq \approx 1200 K) and HD 209458b (Teq \approx 1500 K) and test planetary magnetic field strengths from 0 to 30 G. We find that even at B = 3 G the atmospheric structure and circulation of HD 209458b are strongly influenced by magnetic effects, while the cooler HD 189733b remains largely unaffected, even in the case of B = 30 G and super-solar metallicities. Our models of HD 209458b indicate that magnetic effects can substantially slow down atmospheric winds, change circulation and temperature patterns, and alter observable properties. These models establish that longitudinal and latitudinal hot spot offsets, day-night flux contrasts, and planetary radius inflation are interrelated diagnostics of the magnetic induction process occurring in the atmospheres of hot Jupiters and other similarly forced exoplanets. Most of the ohmic heating occurs high in the atmosphere and on the day side of the planet, while the heating at depth is strongly dependent on the internal heat flux assumed for the planet, with more heating when the deep atmosphere is hot. We compare the ohmic power at depth in our models, and estimates of the ohmic dissipation in the bulk interior (from general scaling laws), to evolutionary models that constrain the amount of heating necessary to explain the inflated radius of HD 209458b. Our results suggest that deep ohmic heating can successfully inflate the radius of HD 209458b for planetary magnetic field strengths of B \geq 3 - 10 G.Comment: 35 pages, 12 figures, minimal revisions due to referee's comments, ApJ accepte

Pigeons and People: Resource Ecology and Human Dimensions of Urban Wildlife

Urban areas and human populations are growing. Cities provide highly modified habitat for species that can adapt their feeding and other behaviours. The growth of urban landscapes and human populations may result in an increase in human-wildlife conflict. Businesses which prepare and sell food (food establishments) may be more likely to encounter conflict with urban wildlife, which may lead to negative attitudes towards urban wildlife. Negative attitudes towards wildlife could create polarised communities and possibly affect the success of environmental initiatives. This study sought to understand (1) how feral pigeons use urban environments and the resources key to their distribution and congregation; (2) whether feral pigeons are food limited in Wellington City; and (3) how the interactions of owners and managers of food establishments with feral pigeons influence their attitudes to feral pigeons. I used 8 transects through the central City which covered a representative sample of urban habitats, including the central business district, green space, and waterfront to estimate resource selection. Bird capture and banding were used to determine feral pigeon condition at a range of sites across the City and included a mix of high, medium and low anthropogenic fed sites. A written survey of owners and managers of food establishments in Wellington was conducted to evaluate attitudes to feral pigeons (n = 62). Feral pigeon resource selection is mainly influenced by people and where they choose to eat (∆AIC ≤ W = 0.999), such as sites with outdoor seating where people may directly feed feral pigeons. However, once a site has been selected, areas with tertiary vegetation and disposed food (W = 0.324 and W = 0.297) are the most likely to attract larger flocks of feral pigeons (although a number of other variables also influence flock size, such as availability of freshwater). Feral pigeons do not appear to be food limited in Wellington as condition was not significantly different between sites (n=48, body condition, (body mass/tarsus length) Kruskal-Wallis = 2.06, p = 0.36; keel condition, Kruskal-Wallis = 0.7283, p = 0.6948; feather condition Kruskal-Wallis = 2.7943, p = 0.2473). Attitudes of food establishment owners and managers towards feral pigeons are most influenced by how often they see feral pigeons (∆AICc ≤ W = 0:465). Therefore, direct experience rather than knowledge, engagement, action or socio-demographics has the most influence on attitudes of owners and managers of food establishments. These results suggest that feral pigeon populations are largely dependent on the availability of anthropogenic foods. Reducing the food provided by people may limit feral pigeon populations. Reductions in pigeon populations are also likely to change attitudes of business owners and reduce conflict because they will be less likely to encounter pigeons. Limiting feeding and access to food waste is probably the most effective way of managing pigeon populations

CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells

CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker. Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1331-4) contains supplementary material, which is available to authorized users

Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia

Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF

Keys of a Mission to Uranus or Neptune, the Closest Ice Giants

Uranus and Neptune are the archetypes of "ice giants", a class of planets that may be among the most common in the Galaxy. They are the last unexplored planets of the Solar System, yet they hold the keys to understand the atmospheric dynamics and structure of planets with hydrogen atmospheres inside and outside the solar system

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

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