Most breast cancers at diagnosis are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors (AI) has therefore become a first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, AI resistance remains a major clinical challenge. The receptor tyrosine kinase RET and its co-receptor GFRα1 are upregulated in a subset of ER-positive breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to AI treatment. In breast cancer cells in 2D and 3D culture, GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promoted the survival of AI-resistant cells and elicited resistance in AI-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor NVP-BBT594. Gene expression profiling in ER-positive cancers defined a proliferation-independent GDNF-response signature that prognosed poor patient outcome and, more importantly, predicted poor response to AI treatment with the development of resistance. We validated these findings by demonstrating increased RET protein expression levels in an independent cohort of AI-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of AI resistance in breast cancer.
aromatase inhibitor; breast cancer; GDNF; resistance; RET
Loss of consciousness in pilots during rapid ascent after bombing missions was a major problem in World War II, and experiments were undertaken to study the cause of this phenomenon. Postulating impaired cerebral blood flow as a likely mechanism, the investigators developed a neck device, the KRA Cuff, which when inflated could shut off blood supply to the brain. With cessation of blood flow for up to 100 seconds, the investigators observed a sequence of responses, including unconsciousness, followed by dilated pupils, tonic/clonic movements, loss of bladder and eventually bowel control, and appearance of pathological reflexes. This study, carried out in prisoners and patients with schizophrenia in 1941–42, largely disappeared from public discourse for a number of years. It has received occasional attention subsequently and been considered controversial. Recently discovered records, including extensive written and photographic data from the studies, shed new light on the methods and motives of the research team. We describe here this new information and its implications for the scientific and ethical assessment of the study.
CCR5 antagonists are a powerful new class of antiretroviral drugs that require a companion assay to evaluate the presence of CXCR4-tropic (non-R5) viruses prior to use in human immunodeficiency virus (HIV)-infected individuals. In this study, we have developed, characterized, verified, and prevalidated a novel phenotypic test to determine HIV-1 coreceptor tropism (VERITROP) based on a sensitive cell-to-cell fusion assay. A proprietary vector was constructed containing a near-full-length HIV-1 genome with the yeast uracil biosynthesis (URA3) gene replacing the HIV-1 env coding sequence. Patient-derived HIV-1 PCR products were introduced by homologous recombination using an innovative yeast-based cloning strategy. The env-expressing vectors were then used in a cell-to-cell fusion assay to determine the presence of R5 and/or non-R5 HIV-1 variants within the viral population. Results were compared with (i) the original version of Trofile (Monogram Biosciences, San Francisco, CA), (ii) population sequencing, and (iii) 454 pyrosequencing, with the genotypic data analyzed using several bioinformatics tools, i.e., the 11/24/25 rule, Geno2Pheno (2% to 5.75%, 3.5%, or 10% false-positive rate [FPR]), and webPSSM. VERITROP consistently detected minority non-R5 variants from clinical specimens, with an analytical sensitivity of 0.3%, with viral loads of ≥1,000 copies/ml, and from B and non-B subtypes. In a pilot study, a 73.7% (56/76) concordance was observed with the original Trofile assay, with 19 of the 20 discordant results corresponding to non-R5 variants detected using VERITROP and not by the original Trofile assay. The degree of concordance of VERITROP and Trofile with population and deep sequencing results depended on the algorithm used to determine HIV-1 coreceptor tropism. Overall, VERITROP showed better concordance with deep sequencing/Geno2Pheno at a 0.3% detection threshold (67%), whereas Trofile matched better with population sequencing (79%). However, 454 sequencing using Geno2Pheno at a 10% FPR and 0.3% threshold and VERITROP more accurately predicted the success of a maraviroc-based regimen. In conclusion, VERITROP may promote the development of new HIV coreceptor antagonists and aid in the treatment and management of HIV-infected individuals prior to and/or during treatment with this class of drugs.
Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI). NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients.
Methods and Results
Patients with POTS (n=27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP), HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121±17 beats per minute versus 105±15 beats per minute; P=0.001) in POTS patients, with a trend toward higher standing systolic BP (P=0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus −3.5 au; P=0.028) from baseline to 2 hours after study drug administration.
Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS.
Clinical Trials Registration
URL: http://clinicaltrials.gov. Unique identifier: NCT00262470.
atomoxetine; autonomic nervous system; drugs; orthostatic intolerance; sympathetic nervous system; tachycardia
Postural Tachycardia Syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have low blood volume. Increasing blood volume is a promising approach to this problem.
We tested the hypothesis that desmopressin (DDAVP) will attenuate the tachycardia and improve symptom burden in patients with POTS.
In this protocol, patients with POTS (n=30) underwent acute drug trials with DDAVP 0.2 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR and symptoms were assessed while seated and after standing for up to 10 minutes prior to and hourly for 4 hours following study drug.
Standing HR was significantly lower following DDAVP compared to placebo (101.9 ± 14.5 vs. 109.2 ± 17.4 bpm (P<0.001)). Standing blood pressure was not affected (P=0.28). The symptom burden improved with DDAVP (from a score of 18 ± 18 to 13 ± 15 arbitrary units [au] at 2 hours) compared with placebo (from 18 ± 17 to 19 ± 16 au; P=0.010).
Oral desmopressin significantly attenuated tachycardia and improved symptoms in POTS. The safety profile of this approach would need to be examined before it can be recommended for routine treatment of these patients.
tachycardia; desmopressin; autonomic nervous system; blood volume; drugs; orthostatic intolerance
To report on response to therapy in a patient with Autoimmune Autonomic Ganglionopathy, with a high titer of an autoantibody directed against the alpha-3 subunit of the nicotinic ganglionic acetylcholine receptor (nAChR).
University based referral center for Autonomic Dysfunction.
Patient with prior indolent B cell lymphoma who presented with symptomatic orthostatic hypotension and autonomic failure and was found to have a high titer of nAChR antibody.
Plasma exchange and rituximab (both initial 4 week cycle and maintenance therapy).
Autonomic ganglionic antibody titer; Autonomic assessments including orthostatic hypotension, plasma norepinephrine, and quantitative sweat testing.
Rituximab followed by plasma exchange significantly decreased the nAChR antibody titer for a short time, and then the titers increased. The titers suppressed to almost undetectable levels once regular maintenance therapy with rituximab was initiated. Reduction of nAChR antibody titer resulted in less orthostatic hypotension, increased upright plasma norepinephrine, improvement in some sweat function and improvement in symptoms.
Long-term rituximab therapy suppressed autoantibody production to undetectable levels over the course of two years, and resulted in sustained clinical improvement in this patient with debilitating Autoimmune Autonomic Ganglionopathy. Further data is needed before rituximab can be recommended as routine therapy for this disorder.
Autoimmune autonomic ganglionopathy; Pure autonomic failure; Rituximab; Plasma exchange
Biology-focused databases and software define bioinformatics and their use is central to computational biology. In such a complex and dynamic field, it is of interest to understand what resources are available, which are used, how much they are used, and for what they are used. While scholarly literature surveys can provide some insights, large-scale computer-based approaches to identify mentions of bioinformatics databases and software from primary literature would automate systematic cataloguing, facilitate the monitoring of usage, and provide the foundations for the recovery of computational methods for analysing biological data, with the long-term aim of identifying best/common practice in different areas of biology.
We have developed bioNerDS, a named entity recogniser for the recovery of bioinformatics databases and software from primary literature. We identify such entities with an F-measure ranging from 63% to 91% at the mention level and 63-78% at the document level, depending on corpus. Not attaining a higher F-measure is mostly due to high ambiguity in resource naming, which is compounded by the on-going introduction of new resources. To demonstrate the software, we applied bioNerDS to full-text articles from BMC Bioinformatics and Genome Biology. General mention patterns reflect the remit of these journals, highlighting BMC Bioinformatics’s emphasis on new tools and Genome Biology’s greater emphasis on data analysis. The data also illustrates some shifts in resource usage: for example, the past decade has seen R and the Gene Ontology join BLAST and GenBank as the main components in bioinformatics processing.
Conclusions We demonstrate the feasibility of automatically identifying resource names on a large-scale from the scientific literature and show that the generated data can be used for exploration of bioinformatics database and software usage. For example, our results help to investigate the rate of change in resource usage and corroborate the suspicion that a vast majority of resources are created, but rarely (if ever) used thereafter. bioNerDS is available at http://bionerds.sourceforge.net/.
The vast collection of biomedical literature and its continued expansion has presented a number of challenges to researchers who require structured findings to stay abreast of and analyze molecular mechanisms relevant to their domain of interest. By structuring literature content into topic-specific machine-readable databases, the aggregate data from multiple articles can be used to infer trends that can be compared and contrasted with similar findings from topic-independent resources. Our study presents a generalized procedure for semi-automatically creating a custom topic-specific molecular interaction database through the use of text mining to assist manual curation. We apply the procedure to capture molecular events that underlie ‘pain’, a complex phenomenon with a large societal burden and unmet medical need. We describe how existing text mining solutions are used to build a pain-specific corpus, extract molecular events from it, add context to the extracted events and assess their relevance. The pain-specific corpus contains 765 692 documents from Medline and PubMed Central, from which we extracted 356 499 unique normalized molecular events, with 261 438 single protein events and 93 271 molecular interactions supplied by BioContext. Event chains are annotated with negation, speculation, anatomy, Gene Ontology terms, mutations, pain and disease relevance, which collectively provide detailed insight into how that event chain is associated with pain. The extracted relations are visualized in a wiki platform (wiki-pain.org) that enables efficient manual curation and exploration of the molecular mechanisms that underlie pain. Curation of 1500 grouped event chains ranked by pain relevance revealed 613 accurately extracted unique molecular interactions that in the future can be used to study the underlying mechanisms involved in pain. Our approach demonstrates that combining existing text mining tools with domain-specific terms and wiki-based visualization can facilitate rapid curation of molecular interactions to create a custom database.
Database URL: •••
Patients with autonomic failure have disabling orthostatic hypotension due to impaired sympathetic activity. Norepinephrine transporter (NET) blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of NET blockade with atomoxetine, and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg, atomoxetine 18 mg and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for up to 10 minutes before and 1 hour post-drug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure (SBP) or orthostatic tolerance compared to placebo. The combination, however, significantly increased seated SBP and orthostatic tolerance (P<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated SBP seen with the combination was 31±33 mmHg at 60 minutes post-drug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by NET blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.
autonomic failure; orthostatic hypotension; dysautonomia; atomoxetine; yohimbine; orthostatic tolerance
Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that POTS patients had increases in plasma angiotensin II (Ang II) twice as high as normal subjects despite normal blood pressures. In this study we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.
Methods and Results
Following a 3 day sodium controlled diet, we infused Ang II (3 ng/kg/min) for 1 hour in POTS patients (n=15) and healthy controls (n=13) in the supine position. All study subjects were females with normal blood pressure (BP). Ages were similar for POTS and control subjects (30±2 [mean±SEM] vs. 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure (MAP), renal plasma flow (RPF), plasma renin activity (PRA), aldosterone, urine sodium and baroreflex sensitivity in both groups.
In response to Ang II infusion, POTS patients had a blunted increase compared with control subjects in MAP (10±1 mmHg vs. 14±1 mmHg; P=0.01), and diastolic BP (9±1 mmHg vs. 13±1 mmHg; P=0.01), but not systolic BP (13±2 mmHg vs. 15±2 mmHg; P=0.40). Renal plasma flow (RPF) decreased similarly with Ang II infusion in POTS patients and controls (−166±20 vs. −181±17 mL/min/1.73 kg/m2; P=0.58). Post-infusion, the decrease in PRA (−0.9±0.2 vs. −0.6±0.2 ng/mL/h; P=0.43) and the increase in aldosterone (17±1 vs. 15±2 pg/ml; P=0.34) were similar in POTS and controls. The decrease in urine sodium excretion was similar in both POTS and controls (−49±12 vs. −60±16 mEq/g Cr; P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in POTS compared to healthy controls (10.1±1.2 vs. 16.8±1.5 ms/mmHg, P=0.003) and it was further reduced with Ang II infusion.
Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture, and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder.
tachycardia; autonomic nervous system; angiotensin II; aldosterone; renal plasma flow
Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 104–106 RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (107–108 RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts.
We simultaneously assessed, for the first time in a natural host, the epidemiology, diversity and natural history of SIVagmVer infection in wild vervet populations from South Africa. We report that African green monkeys (AGMs) have likely been infected with SIVagm for a long period, ranging from the time of their speciation to Plio-Pleistocene migrations, refuting previous molecular clock calculations suggesting SIVagm to be of recent occurrence. As a result of virus-host coadaptation, SIVagmVer infection is characterized by a lack of disease progression in spite of robust viral replication. We show that very active SIVagm transmission in adult AGMs contrasts with a very limited transmission to their offspring, in spite of massive exposure to SIVagm both in utero and through breastfeeding. The observation that some AGMs remain uninfected in spite of life-long exposure to SIVagm identifies wild vervets as an acceptable animal model for the exposed uninfected individuals, which can be used to identify correlates of resistance to HIV/SIV infection.
Patients with Postural Tachycardia Syndrome (POTS) have excessive orthostatic tachycardia (>30 bpm) when standing from a supine position. Heart rate (HR) and blood pressure (BP) are known to exhibit diurnal variability, but the role of diurnal variability in orthostatic changes of HR & BP is not known. In this study, we tested the hypothesis that there is diurnal variation of orthostatic HR & BP in patients with POTS and healthy controls. Patients with POTS (n=54) and healthy volunteers (n=26) were admitted to the Clinical Research Center. Supine and standing (5 min) HR & BP were obtained on the evening on the day of admission and in the following morning. Overall, standing HR was significantly higher in the morning than the evening (102±3 bpm [AM] vs. 93±2 bpm [PM]; P<0.001). Standing HR was higher in the morning in both POTS patients (108±4 bpm [AM] vs. 100±3 bpm [PM]; P=0.012) and controls (89±3 bpm [AM] vs. 80±2 bpm [PM]; P=0.005), when analyzed separately. There was no diurnal variability in orthostatic BP in POTS. More subjects met the POTS HR criterion in the morning compared with the evening (P=0.008). There was significant diurnal variability in orthostatic tachycardia, with a great orthostatic tachycardia in the morning compared to the evening in both patients with POTS and healthy subjects. Given the importance of orthostatic tachycardia in diagnosing POTS, this diurnal variability should be considered in the clinic as it may affect the diagnosis of POTS.
orthostatic intolerance; diurnal variability; circadian; heart rate; blood pressure; tachycardia
Severe autonomic failure occurs in about 1 in 1000 people. Such patients are remarkable for the striking and sometimes paradoxical responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less well-understood findings also occur. These include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea and other neurological disturbances are also frequently encountered.
In this article we will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative settings. Strategies used by clinicians to diagnose and treat these patients, and the impact of these interventions on the pre-operative, intra-operative, and post-operative care that these patients undergo is a crucial element in the optimized management of care in these patients.
The correlation of genetic distances between pairs of protein sequence alignments has been used to infer protein-protein interactions. It has been suggested that these correlations are based on the signal of co-evolution between interacting proteins. However, although mutations in different proteins associated with maintaining an interaction clearly occur (particularly in binding interfaces and neighbourhoods), many other factors contribute to correlated rates of sequence evolution. Proteins in the same genome are usually linked by shared evolutionary history and so it would be expected that there would be topological similarities in their phylogenetic trees, whether they are interacting or not. For this reason the underlying species tree is often corrected for. Moreover processes such as expression level, are known to effect evolutionary rates. However, it has been argued that the correlated rates of evolution used to predict protein interaction explicitly includes shared evolutionary history; here we test this hypothesis.
In order to identify the evolutionary mechanisms giving rise to the correlations between interaction proteins, we use phylogenetic methods to distinguish similarities in tree topologies from similarities in genetic distances. We use a range of datasets of interacting and non-interacting proteins from Saccharomyces cerevisiae. We find that the signal of correlated evolution between interacting proteins is predominantly a result of shared evolutionary rates, rather than similarities in tree topology, independent of evolutionary divergence.
Since interacting proteins do not have tree topologies that are more similar than the control group of non-interacting proteins, it is likely that coevolution does not contribute much to, if any, of the observed correlations.
Co-evolution; Correlated evolution; Protein evolution; Phylogenetic; Protein-protein complexes; Protein-protein interactions
Neurogenic orthostatic hypotension is a distinctive and treatable sign of cardiovascular autonomic dysfunction. It is caused by failure of noradrenergic neurotransmission that is associated with a range of primary or secondary autonomic disorders, including pure autonomic failure, Parkinson’s disease with autonomic failure, multiple system atrophy as well as diabetic and nondiabetic autonomic neuropathies. Neurogenic orthostatic hypotension is commonly accompanied by autonomic dysregulation involving other organ systems such as the bowel and the bladder. In the present review, we provide an overview of the clinical presentation, pathophysiology, epidemiology, evaluation and management of neurogenic orthostatic hypotension focusing on neurodegenerative disorders.
Orthostatic hypotension; Neurogenic orthostatic hypotension; Parkinson's disease; Multiple system atrophy; Pure autonomic failure; Autonomic dysfunction
HIV-1 coreceptor tropism assays are required to rule out the presence of CXCR4-tropic (non-R5) viruses prior treatment with CCR5 antagonists. Phenotypic (e.g., Trofile™, Monogram Biosciences) and genotypic (e.g., population sequencing linked to bioinformatic algorithms) assays are the most widely used. Although several next-generation sequencing (NGS) platforms are available, to date all published deep sequencing HIV-1 tropism studies have used the 454™ Life Sciences/Roche platform. In this study, HIV-1 co-receptor usage was predicted for twelve patients scheduled to start a maraviroc-based antiretroviral regimen. The V3 region of the HIV-1 env gene was sequenced using four NGS platforms: 454™, PacBio® RS (Pacific Biosciences), Illumina®, and Ion Torrent™ (Life Technologies). Cross-platform variation was evaluated, including number of reads, read length and error rates. HIV-1 tropism was inferred using Geno2Pheno, Web PSSM, and the 11/24/25 rule and compared with Trofile™ and virologic response to antiretroviral therapy. Error rates related to insertions/deletions (indels) and nucleotide substitutions introduced by the four NGS platforms were low compared to the actual HIV-1 sequence variation. Each platform detected all major virus variants within the HIV-1 population with similar frequencies. Identification of non-R5 viruses was comparable among the four platforms, with minor differences attributable to the algorithms used to infer HIV-1 tropism. All NGS platforms showed similar concordance with virologic response to the maraviroc-based regimen (75% to 80% range depending on the algorithm used), compared to Trofile (80%) and population sequencing (70%). In conclusion, all four NGS platforms were able to detect minority non-R5 variants at comparable levels suggesting that any NGS-based method can be used to predict HIV-1 coreceptor usage.
Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
Angiogenesis; Metastasis; Resistance; VEGF; Breast; Renal
The structural and functional architecture of the human brain is characterized by considerable variability with consequences for visual perception. However the neurophysiological events mediating this relationship between inter-individual differences in cortical surface area and visual perception have until now remained unknown. Here, we show that the retinotopically defined surface areas of central V1 and V2 were correlated with the peak frequency of visually-induced oscillations in the gamma band measured with magnetoencephalography (MEG). Gamma-band oscillations are thought to play an important role in visual processing. We propose that individual differences in macroscopic gamma frequency may be attributed to inter-individual variability in the microscopic architecture of visual cortex.
Dopamine-β-hydroxylase (DβH) deficiency is a rare genetic syndrome characterized by the complete absence of norepinephrine in the peripheral and the central nervous system. DβH-deficient patients suffer from several physical symptoms, which can be treated successfully with L-threo-3,4-dihydroxyphenylserine, a synthetic precursor of norepinephrine. Informal clinical observations suggest that DβH-deficient patients do not have obvious cognitive impairments, even when they are not medicated, which is remarkable given the important role of norepinephrine in normal neurocognitive function. This study provided the first systematic investigation of neurocognitive function in human DβH deficiency. We tested 5 DβH-deficient patients and 10 matched healthy control participants on a comprehensive cognitive task battery, and examined their pupil dynamics, brain structure, and the P3 component of the electroencephalogram. All participants were tested twice; the patients were tested once ON and once OFF medication. Magnetic resonance imaging scans of the brain revealed that the patients had a smaller total brain volume than the control group, which is in line with the recent hypothesis that norepinephrine has a neurotrophic effect. In addition, the patients showed an abnormally small or absent task-evoked pupil dilation. However, we found no substantial differences in cognitive performance or P3 amplitude between the patients and the control participants, with the exception of a temporal-attention deficit in the patients OFF medication. The largely spared neurocognitive function in DβH-deficient patients suggests that other neuromodulators have taken over the function of norepinephrine in the brains of these patients.
dopamine-β-hydroxylase deficiency; norepinephrine; cognition; brain; DOPS; catecholamines; clinical pharmacology/clinical trials; cognition; biological psychiatry; dopamine-beta-hydroxylase deficiency; norepinephrine; brain; attention; EEG
This article aims to demonstrate computational synthesis of Web-based experiments in undertaking experimentation on relationships among the participants' design preference, rationale, and cognitive test performance. The exemplified experiments were computationally synthesised, including the websites as materials, experiment protocols as methods, and cognitive tests as protocol modules. This work also exemplifies the use of a website synthesiser as an essential instrument enabling the participants to explore different possible designs, which were generated on the fly, before selection of preferred designs.
The participants were given interactive tree and table generators so that they could explore some different ways of presenting causality information in tables and trees as the visualisation formats. The participants gave their preference ratings for the available designs, as well as their rationale (criteria) for their design decisions. The participants were also asked to take four cognitive tests, which focus on the aspects of visualisation and analogy-making. The relationships among preference ratings, rationale, and the results of cognitive tests were analysed by conservative non-parametric statistics including Wilcoxon test, Krustal-Wallis test, and Kendall correlation.
In the test, 41 of the total 64 participants preferred graphical (tree-form) to tabular presentation. Despite the popular preference for graphical presentation, the given tabular presentation was generally rated to be easier than graphical presentation to interpret, especially by those who were scored lower in the visualization and analogy-making tests.
This piece of evidence helps generate a hypothesis that design preferences are related to specific cognitive abilities. Without the use of computational synthesis, the experiment setup and scientific results would be impractical to obtain.
Background and Aims
There is good evidence for deciduous trees that competition for carbohydrates from shoot growth accentuates early fruit abscission and reduces yield but the effect for evergreen trees is not well defined. Here, whole-tree tip-pruning at anthesis is used to examine the effect of post-pruning shoot development on fruit abscission in the evergreen subtropical tree macadamia (Macadamia integrifolia, M. integrifolia × tetraphylla). Partial-tree tip-pruning is also used to test the localization of the effect.
In the first experiment (2005/2006), all branches on trees were tip-pruned at anthesis, some trees were allowed to re-shoot (R treatment) and shoots were removed from others (NR treatment). Fruit set and stem total non-structural carbohydrates (TNSC) over time, and yield were measured. In the second experiment (2006/2007), upper branches of trees were tip-pruned at anthesis, some trees were allowed to re-shoot (R) and shoots were removed from others (NR). Fruit set and yield were measured separately for upper (pruned) and lower (unpruned) branches.
In the first experiment, R trees set far fewer fruit and had lower yield than NR trees. TNSC fell and rose in all treatments but the decline in R trees occurred earlier than in NR trees and coincided with early shoot growth and the increase in fruit abscission relative to the other treatments. In the second experiment, fruit abscission on upper branches of R trees increased relative to the other treatments but there was little difference in fruit abscission between treatments on lower branches.
This study is the first to demonstrate an increase in fruit abscission in an evergreen tree in response to pruning. The effect appeared to be related to competition for carbohydrates between post-pruning shoot growth and fruit development and was local, with shoot growth on pruned branches having no effect on fruit abscission on unpruned branches.
Pruning; hedging; shoot growth; fruit set; abscission; canopy management; Macadamia integrifolia
Manual curation has long been used for extracting key information found within the primary literature for input into biological databases. The human immunodeficiency virus type 1 (HIV-1), human protein interaction database (HHPID), for example, contains 2589 manually extracted interactions, linked to 14 312 mentions in 3090 articles. The advancement of text-mining (TM) techniques has offered a possibility to rapidly retrieve such data from large volumes of text to a high degree of accuracy. Here, we present a recreation of the HHPID using the current state of the art in TM. To retrieve interactions, we performed gene/protein named entity recognition (NER) and applied two molecular event extraction tools on all abstracts and titles cited in the HHPID. Our best NER scores for precision, recall and F-score were 87.5%, 90.0% and 88.6%, respectively, while event extraction achieved 76.4%, 84.2% and 80.1%, respectively. We demonstrate that over 50% of the HHPID interactions can be recreated from abstracts and titles. Furthermore, from 49 available open-access full-text articles, we extracted a total of 237 unique HIV-1–human interactions, as opposed to 187 interactions recorded in the HHPID from the same articles. On average, we extracted 23 times more mentions of interactions and events from a full-text article than from an abstract and title, with a 6-fold increase in the number of unique interactions. We further demonstrated that more frequently occurring interactions extracted by TM are more likely to be true positives. Overall, the results demonstrate that TM was able to recover a large proportion of interactions, many of which were found within the HHPID, making TM a useful assistant in the manual curation process. Finally, we also retrieved other types of interactions in the context of HIV-1 that are not currently present in the HHPID, thus, expanding the scope of this data set. All data is available at http://gnode1.mib.man.ac.uk/HIV1-text-mining.
Next generation sequencing provides detailed insight into the variation present within viral populations, introducing the possibility of treatment strategies that are both reactive and predictive. Current software tools, however, need to be scaled up to accommodate for high-depth viral data sets, which are often temporally or spatially linked. In addition, due to the development of novel sequencing platforms and chemistries, each with implicit strengths and weaknesses, it will be helpful for researchers to be able to routinely compare and combine data sets from different platforms/chemistries. In particular, error associated with a specific sequencing process must be quantified so that true biological variation may be identified.
Segminator II was developed to allow for the efficient comparison of data sets derived from different sources. We demonstrate its usage by comparing large data sets from 12 influenza H1N1 samples sequenced on both the 454 Life Sciences and Illumina platforms, permitting quantification of platform error. For mismatches median error rates at 0.10 and 0.12%, respectively, suggested that both platforms performed similarly. For insertions and deletions median error rates within the 454 data (at 0.3 and 0.2%, respectively) were significantly higher than those within the Illumina data (0.004 and 0.006%, respectively). In agreement with previous observations these higher rates were strongly associated with homopolymeric stretches on the 454 platform. Outside of such regions both platforms had similar indel error profiles. Additionally, we apply our software to the identification of low frequency variants.
We have demonstrated, using Segminator II, that it is possible to distinguish platform specific error from biological variation using data derived from two different platforms. We have used this approach to quantify the amount of error present within the 454 and Illumina platforms in relation to genomic location as well as location on the read. Given that next generation data is increasingly important in the analysis of drug-resistance and vaccine trials, this software will be useful to the pathogen research community. A zip file containing the source code and jar file is freely available for download from http://www.bioinf.manchester.ac.uk/segminator/.