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International audience; Image plates (IPs) are a popular detector in the field of laser driven ion acceleration, owing to their high dynamic range and reusability. An absolute calibration of these detectors to laser-driven protons in the routinely produced tens of MeV energy range is, therefore, essential. In this paper, the response of Fujifilm BAS-TR IPs to 1–40 MeV protons is calibrated by employing the detectors in high resolution Thomson parabola spectrometers in conjunction with a CR-39 nuclear track detector to determine absolute proton numbers. While CR-39 was placed in front of the image plate for lower energy protons, it was placed behind the image plate for energies above 10 MeV using suitable metal filters sandwiched between the image plate and CR-39 to select specific energies. The measured response agrees well with previously reported calibrations as well as standard models of IP response, providing, for the first time, an absolute calibration over a large range of proton energies of relevance to current experiments.

MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

The response of the BAS-TR image plate (IP) was absolutely calibrated using CR-39 track detector for high linear energy transfer (LET) Au ions up to $\sim$1.6 GeV (8.2 MeV/nucleon), accelerated by high-power lasers. The calibration was carried out by employing a high-resolution Thomson parabola spectrometer, which allowed resolving Au ions with closely spaced ionization states up to 58$^+$. A response function was obtained by fitting the photo-stimulated luminescence (PSL) per Au ion for different ion energies, which is broadly in agreement with that expected from ion stopping in the active layer of the IP. This calibration would allow quantifying the ion energy spectra for high energy Au ions, which is important for further investigation of the laser-based acceleration of heavy ion beams., Comment: 6 pages; 4 figures. Submitted to journal for review

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, representing 60% of childhood intracranial embryonal tumors. Despite multimodal advances in therapies over the last 20 years that have yielded a 5-year survival rate of 75%, high-risk patients (younger than 3 years, subtotal resection, metastatic lesions at diagnosis) still experience a 5-year overall survival of less than 70%. In this introductory chapter on pediatric MB, we describe the initial discrimination of MB based on histopathological examination and the more recent progress made in global gene expression profiling methods that have allowed scientists to more accurately subclassify and prognosticate on MB based on molecular characteristics. The identification of subtype-specific molecular drivers and pathways presents novel therapeutic targets that could lead to MB subtype-specific treatment modalities. Additionally, we detail how the cancer stem cell (CSC) hypothesis provides an explanation for tumor recurrence, and the potential for CSC-targeted therapies to address treatment-refractory MB. These personalized therapies can potentially increase MB survivorship and negate some of the long-term neurotoxicity associated with the current standard of care for MB patients.

The purpose of this study was to determine whether there have been changes in the complexity of femoral fragility fractures presenting to our Dunedin Orthopaedic Department, New Zealand, over a period of ten years.Patients over the age of 60 presenting with femoral fragility fractures to Dunedin Hospital in 2009 −10 (335 fractures) were compared with respect to demographic data, incidence rates, fracture classification and treatment details to the period 2018-19 (311 fractures). Pathological and high velocity fractures were excluded.The gender proportion and average age (83.1 vs 83.0 years) was unchanged. The overall incidence of femoral fractures in people over 60 years in our region fell by 27% (pWhile there has been little difference in the numbers there has been a decrease in the incidence of femoral fragility fractures likely due to the increasing use of bisphosphonates. However, the incidence of unstable trochanteric fractures is increasing. This has led to the increased use of IM nails which are increasingly used for stable fractures as well.The increasing complexity of femoral fragility fractures is likely to have an impact on implant use, theatre time and cost.

Description, Gene expression profiling of medulloblastoma cells undergoing therapy identifies BPIFB4 as a novel target for recurrent disease., Medulloblastoma (MB) remains a leading cause of cancer-related mortality among children. The paucity of MB samples collected at relapse has hindered the functional understanding of molecular mechanisms driving therapy failure. New models capable of accurately recapitulating tumor progression in response to conventional therapeutic interventions are urgently needed. In this study, we developed a therapy-adapted PDX MB model that has a distinct advantage of generating human MB recurrence. The comparative gene expression analysis of MB cells collected throughout therapy led to identification of genes specifically up-regulated after therapy, including one previously undescribed in the setting of brain tumors, bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4). Subsequent functional validation resulted in a markedly diminished in vitro proliferation, self-renewal, and longevity of MB cells, translating into extended survival and reduced tumor burden in vivo. Targeting endothelial nitric oxide synthase, a downstream substrate of BPIFB4, impeded growth of several patient-derived MB lines at low nanomolar concentrations.

Background There is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40–1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions. Materials and methods We used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells. Results Oxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers. Conclusion We demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.

PurposeGlioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of brain tumor initiating cells (BTICs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here we identify CD70 as a potential therapeutic target for recurrent GBM BTICs.Experimental DesignIn the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We utilize CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70’s role in GBM. Next, we developed and tested an anti-CD70 CAR-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.ResultsCD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations.ConclusionCD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable poly-therapeutic avenue to co-target both GBM and its TIME.

Developing compact ion accelerators using intense lasers is a very active area of research, motivated by a strong applicative potential in science, industry and healthcare. However, proposed applications in medical therapy, as well as in nuclear and particle physics demand a strict control of ion energy, as well as of the angular and spectral distribution of ion beam, beyond the intrinsic limitations of the several acceleration mechanisms explored so far. Here we report on the production of highly collimated ($$\sim 0.2^{\circ }$$ ∼ 0 . 2 ∘ half angle divergence), high-charge (10s of pC) and quasi-monoenergetic proton beams up to $$\sim$$ ∼ 50 MeV, using a recently developed method based on helical coil targetry. In this concept, ions accelerated from a laser-irradiated foil are post-accelerated and conditioned in a helical structure positioned at the rear of the foil. The pencil beam of protons was produced by guided post-acceleration at a rate of $$\sim$$ ∼ 2 GeV/m, without sacrificing the excellent beam emittance of the laser-driven proton beams. 3D particle tracing simulations indicate the possibility of sustaining high acceleration gradients over extended helical coil lengths, thus maximising the gain from such miniature accelerating modules.

Background Breast tumor initiating cells (BTIC) are stem-like cells that initiate and sustain tumor growth, and drive disease recurrence. Identifying therapies targeting BTIC has been hindered due primarily to their scarcity in tumors. We previously reported that BTIC frequency ranges between 15% and 50% in multiple mammary tumors of 3 different transgenic mouse models of breast cancer and that this frequency is maintained in tumor cell populations cultured in serum-free, chemically defined media as non-adherent tumorspheres. The latter enabled high-throughput screening of small molecules for their capacity to affect BTIC survival. Antagonists of several serotonin receptors (5-HTRs) were among the hit compounds. The most potent compound we identified, SB-699551, selectively binds to 5-HT5A, a Gαi/o protein coupled receptor (GPCR). Methods We evaluated the activity of structurally unrelated selective 5-HT5A antagonists using multiple orthogonal assays of BTIC frequency. Thereafter we used a phosphoproteomic approach to uncover the mechanism of action of SB-699551. To validate the molecular target of the antagonists, we used the CRISPR-Cas9 gene editing technology to conditionally knockout HTR5A in a breast tumor cell line. Results We found that selective antagonists of 5-HT5A reduced the frequency of tumorsphere initiating cells residing in breast tumor cell lines and those of patient-derived xenografts (PDXs) that we established. The most potent compound among those tested, SB-699551, reduced the frequency of BTIC in ex vivo assays and acted in concert with chemotherapy to shrink human breast tumor xenografts in vivo. Our phosphoproteomic experiments established that exposure of breast tumor cells to SB-699551 elicited signaling changes in the canonical Gαi/o-coupled pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis. Moreover, conditional mutation of the HTR5A gene resulted in the loss of tumorsphere initiating cells and BTIC thus mimicking the effect of SB-699551. Conclusions Our data provide genetic, pharmacological and phosphoproteomic evidence consistent with the on-target activity of SB-699551. The use of such agents in combination with cytotoxic chemotherapy provides a novel therapeutic approach to treat breast cancer.

Breast tumors comprise an infrequent tumor cell population, termed breast tumor initiating cells (BTIC), which sustain tumor growth, seed metastases and resist cytotoxic therapies. Hence therapies are needed to target BTIC to provide more durable breast cancer remissions than are currently achieved. We previously reported that serotonergic system antagonists abrogated the activity of mouse BTIC resident in the mammary tumors of a HER2-overexpressing model of breast cancer. Here we report that antagonists of serotonin (5-hydroxytryptamine; 5-HT) biosynthesis and activity, including US Federal Food and Drug Administration (FDA)-approved antidepressants, targeted BTIC resident in numerous breast tumor cell lines regardless of their clinical or molecular subtype. Notably, inhibitors of tryptophan hydroxylase 1 (TPH1), required for 5-HT biosynthesis in select non-neuronal cells, the serotonin reuptake transporter (SERT) and several 5-HT receptors compromised BTIC activity as assessed by functional sphere-forming assays. Consistent with these findings, human breast tumor cells express TPH1, 5-HT and SERT independent of their molecular or clinical subtype. Exposure of breast tumor cells ex vivo to sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), reduced BTIC frequency as determined by transplanting drug-treated tumor cells into immune-compromised mice. Moreover, another SSRI (vilazodone; Viibryd) synergized with chemotherapy to shrink breast tumor xenografts in immune-compromised mice by inhibiting tumor cell proliferation and inducing their apoptosis. Collectively our data suggest that antidepressants in combination with cytotoxic anticancer therapies may be an appropriate treatment regimen for testing in clinical trials.

BackgroundBreast tumor growth and recurrence are driven by an infrequent population of breast tumor-initiating cells (BTIC). We and others have reported that the frequency of BTIC is orders of magnitude higher when breast tumor cells are propagated in vitro as clonal spheres, termed tumorspheres, by comparison to adherent cells. We exploited the latter to screen > 35,000 small molecules to identify agents capable of targeting BTIC. We unexpectedly discovered that selective antagonists of serotonin signaling were among the hit compounds. To better understand the relationship between serotonin and BTIC we expanded our analysis to include monoamine oxidase-A (MAO-A), an enzyme that metabolizes serotonin.MethodsWe used the Nanostring technology and Western blotting to determine whether MAO-A is expressed in human breast tumor cell lines cultured as tumorspheres by comparison to those grown as adherent cells. We then determined whether MAO-A activity is required for tumorsphere formation, a surrogate in vitro assay for BTIC, by assessing whether selective MAO-A inhibitors affect the frequency of tumorsphere-forming cells. To learn whether MAO-A expression in breast tumor cells is associated with other reported properties of BTIC such as anticancer drug resistance or breast tumor recurrence, we performed differential gene expression analyses using publicly available transcriptomic datasets.ResultsTumorspheres derived from human breast tumor cell lines representative of every breast cancer clinical subtype displayed increased expression of MAO-A transcripts and protein by comparison to adherent cells. Surprisingly, inhibition of MAO-A activity with selective inhibitors reduced the frequency of tumorsphere-forming cells. We also found that increased MAO-A expression is a common feature of human breast tumor cell lines that have acquired anticancer drug resistance and is associated with poor recurrence-free survival (RFS) in patients that experienced high-grade, ER-negative (ER−) breast tumors.ConclusionsOur data suggests that MAO-A activity is required for tumorsphere formation and that its expression in breast tumor cells is associated with BTIC-related properties. The discovery that a selective MAO-A inhibitor targets tumorsphere-forming cells with potencies in the nanomolar range provides the first evidence of this agent’s anticancer property. These data warrant further investigation of the link between MAO-A and BTIC.

Medulloblastoma (MB) is the most common pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors targeting BMI1 have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscores the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of the tumors extracted from the brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways to be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. The combined treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and is currently being evaluated in preclinical studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.

The divergent and broadband proton beams produced by the target normal sheath acceleration mechanism provide the unique opportunity to probe, in a point-projection imaging scheme, the dynamics of the transient electric and magnetic fields produced during laser-plasma interactions. Commonly such experimental setup entails two intense laser beams, where the interaction produced by one beam is probed with the protons produced by the second. We present here experimental studies of the ultra-fast charge dynamics along a wire connected to laser irradiated target carried out by employing a 'self proton probing arrangement i.e. by connecting the wire to the target generating the probe protons. The experimental data shows that an electromagnetic pulse carrying a significant amount of charge is launched along the wire, which travels as a unified pulse of 10s of ps duration with a velocity close to speed of light. The experimental capabilities and the analysis procedure of this specific type of proton probing technique are discussed. (C) 2016 Elsevier B.V. All rights reserved.

Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone’s cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone’s anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.

The characteristics of laser driven proton beams can be efficiently controlled and optimised by employing a recently developed helical coil technique, which exploits the transient self-charging of solid targets irradiated by intense laser pulses. Here we demonstrate a well collimated (

The characteristics of laser driven proton beams can be efficiently controlled and optimised by employing a recently developed helical coil technique, which exploits the transient self-charging of solid targets irradiated by intense laser pulses. Here we demonstrate a well collimated (

WOS: 000348594500007, …, Institute of Environmental Technologies - 'Research and Development for Innovations' Operational Programme [CZ.1.05/2.1.00/03.0100]; Structural Funds of the European Union; state budget of the Czech Republic; National Feasibility Programme I of the Czech Republic [LO1208]; SYNTHESYS project [FR-TAF-3686]; University of Ostrava [SGS27/PRF/2014]; Polish National Centre of Science [N N 303 469 338]; Institute of Botany of the Polish Academy of Sciences; Institute of Biology Bucharest of the Romanian Academy [RO1567-IBB03/2014]; Natural Environment Research Council; Scientific and Technological Research Council of Turkey (TUBITAK) [111T359]; Spanish Ministerio de Economia y Competitividad (MINECO); Flora Briofitica Iberica from MINECO [CGL2009-09530]; MINECO; Spanish 'Ministerio de Ciencia e Innovacion' [CGL2010-15959, CGL2009-07323]; FEDER; 'Ramon y Cajal' Subprogram (MICINN-European Social Fund); 'Ministerio de Economia y Competitividad' [CGL2012-30721]; MOVECLIM project (ANR under the Net-Biome call); RSF [14-14-00903, 14-24-00037]; RFBR [13-04-01427, 12-04-01476]; 'The Survey of new and unrecorded taxa in vascular plants (NIBR)' - Ministry of Environment of the Korean Government [2013-02-001]; Natural Environment Research Council [bas0100025], The contribution by V. Plasek is part of a research project of the Institute of Environmental Technologies, reg. no. CZ.1.05/2.1.00/03.0100, supported by the 'Research and Development for Innovations' Operational Programme, and financed by the Structural Funds of the European Union and by the state budget of the Czech Republic, Project LO1208 of the National Feasibility Programme I of the Czech Republic, and SYNTHESYS project FR-TAF-3686. The contribution by L. Cihal is a part of grant project SGS27/PRF/2014 financed by University of Ostrava. The contributions by R. Ochyra have been financially supported by the Polish National Centre of Science through grant no. N N 303 469 338 and, in part, by the statutory fund of the Institute of Botany of the Polish Academy of Sciences. He also thanks Helen J. Peat, Cambridge, for kindly allowing him to study the herbarium collections from AAS. S. Stefanut, acknowledges the support by project no. RO1567-IBB03/2014 through the Institute of Biology Bucharest of the Romanian Academy. J. Vana and K. K. Newsham acknowledge the logistics support that was provided by the British Antarctic Survey's Operations Group, officers and crew of the RRS Ernest Shackleton and staff at King Edward Point research station, and thank Helen J. Peat for the loan of AAS herbarium specimens. Funding was provided by the Natural Environment Research Council. All are gratefully acknowledged.; Peter Szucs and Andras Bidlo would like to thank Peter Erzberger for examining the specimen of Campylopus introflexus, and Gyorgy Pulger for his assistance in fieldwork. Tulay Ezer and Recep Kara are indebted to the Scientific and Technological Research Council of Turkey (TUBITAK) for financial support (Project Code: 111T359).; M. J. Gil-Lopez, F. Puche, and J. G. Segarra-Moragues thank H. Kharbouch (SahaTours), F. Pacheco, J. P. Peralta, and F. Rivera for their help in field work. M. J. Gil-Lopez benefited from a FPU PhD grant from the Spanish Ministerio de Economia y Competitividad (MINECO). F. Puche acknowledges funds from project CGL2009-09530, Flora Briofitica Iberica from MINECO. J. G. Segarra-Moragues benefited from a 'Ramon y Cajal' post-doctoral contract from MINECO. Juan Larrain and Amalia B. Biasuso thank Reinaldo Vargas and Gotz Palfner for their company in the field. Marta Alonso and David Long acknowledge the financial support of the Spanish 'Ministerio de Ciencia e Innovacion' (projects CGL2010-15959 co-financed by FEDER) and 'Ramon y Cajal' Subprogram (MICINN-European Social Fund). We also thank Maria J. Cano and Juan A. Jimenez for their contribution to this work.; D. Rios, M. T. Gallego, and J. Guerra are grateful to Len Ellis for organising the loan of specimens and assistance during the visit of the first author to the BM herbarium. This research was carried out with financial support from the Spanish 'Ministerio de Ciencia e Innovacion' and 'Ministerio de Economia y Competitividad' [Projects CGL2009-07323 and CGL2012-30721, respectively].; Terry Hedderson is grateful to Jean-Yves Meyer, Ravahere Tuputuari, Claudine Ah-Peng, and Oliver Flores for field assistance and companionship and to the MOVECLIM project (ANR under the Net-Biome call) for funding the fieldwork on Tahiti. The study by E.V. Sofronova was supported by RSF (project no. 14-14-00903), that by Y.S. Mamontov was partly supported by RFBR (project no. 13-04-01427 and 12-04-01476), and that by A. D. Potemkin was supported by RSF (project no. 14-24-00037). The research by Yoon Young-Jun, Benito C. Tan and Byung-Yun Sun was supported by grants from 'The Survey of new and unrecorded taxa in vascular plants (NIBR No. 2013-02-001)' funded by the Ministry of Environment of the Korean Government.

Ongoing developments in laser-driven ion acceleration warrant appropriate modifications to the standard Thomson Parabola Spectrometer (TPS) arrangement in order to match the diagnostic requirements associated to the particular and distinctive properties of laser-accelerated beams. Here we present an overview of recent developments by our group of the TPS diagnostic aimed to enhance the capability of diagnosing multi-species high-energy ion beams. In order to facilitate discrimination between ions with same Z / A , a recursive differential filtering technique was implemented at the TPS detector in order to allow only one of the overlapping ion species to reach the detector, across the entire energy range detectable by the TPS. In order to mitigate the issue of overlapping ion traces towards the higher energy part of the spectrum, an extended, trapezoidal electric plates design was envisaged, followed by its experimental demonstration. The design allows achieving high energy-resolution at high energies without sacrificing the lower energy part of the spectrum. Finally, a novel multi-pinhole TPS design is discussed, that would allow angularly resolved, complete spectral characterization of the high-energy, multi-species ion beams.

Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.

Summary Rumen samples collected at different times of the year from buffalo in the Serengeti, were analysed with respect to proportions of plant parts present. Buffalo were almost exclusive grazers and were capable of selecting for grass leaf. At certain times of year it was the dominant food intake component but declined to only 11% of the diet by the end of the dry season. The amount of leaf in the diet was determined by the amount of rainfall which governed the growth of the food grasses. Experimental preference tests with tame animals indicated that they were capable of selecting for different grass species. The preferences were, however, for those species with a higher leaf: stem ratio. The mechanism of selection is discussed. The function of the behavioural selection appeared to be concerned with maximizing the nutrient quality of the food requirements. It appeared that ecological separation had evolved through interspecific competition.

The aim of this study was to determine the effects of prolonged exercise in hot conditions on saliva IgA (s-IgA) responses in trained cyclists. On two occasions, in random order and separated by 1 week, 12 male cyclists cycled for 2 h on a stationary ergometer at 62 (3)% VO2 max [194 (4) W; mean (SEM)], on one occasion (HOT: 30.3°C, 76% RH) and on another occasion (CONTROL: 20.4°C, 60% RH). Water was available ad-libitum. Venous blood samples and 2-min whole unstimulated saliva samples were collected at pre, post and 2 h post-exercise. The s-IgA concentration was determined using a sandwich-type ELISA. Exercising heart rate, rating of perceived exertion, rectal temperature, corrected body mass loss (P

Laser driven proton beams driven by the Target Normal Sheath Acceleration (TNSA) mechanism exhibit large divergence and a broad energy distribution with low particle number at high energy. Such undesirable characteristics of the beam can be controlled and optimised by employing a recently developed helical coil technique, which exploits the transient self-charging of solid targets irradiated by intense laser pulses. Highly chromatic focusing of the broadband proton beams was achieved by employing this technique at the TARANIS laser system, where the selected energy slice was tuned by varying the pitch of the coil. Using a longer coil of larger pitch, a quasi-collimated, narrow energy band proton beam of ~10^7 particles at 10 MeV was achieved, through a combination of focussing, energy selection and in-situ post-acceleration. This technique may provide a platform for the next generation of compact, all-optical ion accelerators.

Accelerated proton beams have become increasingly common for treating cancer. The need for cost and size reduction of particle accelerating machines has led to the pioneering investigation of optical ion acceleration techniques based on laser-plasma interactions as a possible alternative. Laser-matter interaction can produce extremely pulsed particle bursts of ultra-high dose rates (≥ 109 Gy/s), largely exceeding those currently used in conventional proton therapy. Since biological effects of ionizing radiation are strongly affected by the spatio-temporal distribution of DNA-damaging events, the unprecedented physical features of such beams may modify cellular and tissue radiosensitivity to unexplored extents. Hence, clinical applications of laser-generated particles need thorough assessment of their radiobiological effectiveness. To date, the majority of studies have either used rodent cell lines or have focussed on cancer cell killing being local tumour control the main objective of radiotherapy. Conversely, very little data exist on sub-lethal cellular effects, of relevance to normal tissue integrity and secondary cancers, such as premature cellular senescence. Here, we discuss ultra-high dose rate radiobiology and present preliminary data obtained in normal human cells following irradiation by laser-accelerated protons at the LULI PICO2000 facility at Laser Lab Europe, France.

Purpose: To report the utilization of services offered and pregnancy outcomes for a unique statewide prenatal triple marker screening program and to present a cost-benefit analysis. A state population of 32 million with consider-able ethnic and age distribution and with a wide variety of delivery systems providing prenatal care was considered. The entire pregnant population who appeared for care before 20 weeks gestation, approximately one-half million per year during the years of 1995 to 1997, was included in the study. Methods: Mandatory offering of serum testing, using alpha-fetoprotein from 1986 to 1995, and the addition of human chorionic gonadotropin and unconjugated estriol in 1995, with systematic follow-up of serum screen positives with ultrasound and amniocentesis. This study collected and analyzed the program data and reports of outcomes and collected similar information from the birth defects registry. Results: Triple marker serum screening was accepted by 67.4% of the women eligible and yielded an initial positive rate of 7.3%. More than 90% of the initially screen positive pregnancies were seen at a prenatal diagnostic center. After correction of gestational age, 71.3% had amniocentesis. The overall amniocentesis rate among women screened was 2.6%. The Program's detection rate was predicted to be 85% for neural tube defects, and, based on Monte Carlo modeling, was theoretically calculated to be 62% for Down syndrome. In practice, detection rates were 75% for neural tube defects and 41% for Down syndrome due to lower than expected amniocentesis acceptance rate. Nevertheless, at a 5% discount rate, the screening program was cost beneficial at a ratio of 2.69:1. The cost per case detected was 35,365 and per case prevented was 110,741. Conclusion: It is possible to implement a cost-effective population-based screening in compliance with quality standards in a diverse ethnic population with a variety of health-care providers. Triple marker screening in the second trimester is a cost beneficial program even if utilization of all services is less than ideal.

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it's potential to affect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis (MS). Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases, and GGF2 treatment led to delayed signs, decreased severity and resulted in statistically significant reductions in relapse rate. Further, rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased expression of myelin basic protein exon 2, a marker for remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated upon the clinical, pathologic and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a Th2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of MS (Cannella et al., 1998).