The biological context of HIV-1 host interactions reveals subtle insights into a system hijack

<p>Abstract</p> <p>Background</p> <p>In order to replicate, HIV, like all viruses, needs to invade a host cell and hijack it for its own use, a process that involves multiple protein interactions between virus and host. The HIV-1, Human Protein Interaction Database available at NCBI's website captures this information from the primary literature, containing over 2,500 unique interactions. We investigate the general properties and biological context of these interactions and, thus, explore the molecular specificity of the HIV-host perturbation. In particular, we investigate (i) whether HIV preferentially interacts with highly connected and 'central' proteins, (ii) known phenotypic properties of host proteins inferred from essentiality and disease-association data, and (iii) biological context (molecular function, processes and location) of the host proteins to identify attributes most strongly associated with specific HIV interactions.</p> <p>Results</p> <p>After correcting for ascertainment bias in the literature, we demonstrate a significantly greater propensity for HIV to interact with highly connected and central host proteins. Unexpectedly, we find there are no associations between HIV interaction and inferred essentiality. Similarly, we find a tendency for HIV not to interact with proteins encoded by genes associated with disease. Crucially, we find that functional categories over-represented in HIV-host interactions are innately enriched for highly connected and central proteins in the host system.</p> <p>Conclusions</p> <p>Our results imply that HIV's propensity to interact with highly connected and central proteins is a consequence of interactions with particular cellular functions, rather than being a direct effect of network topological properties. The lack of a propensity for interactions with phenotypically essential proteins suggests a selective pressure to minimise virulence in retroviral evolution. Thus, the specificity of HIV-host interactions is complex, and only superficially explained by network properties.</p

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data

Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy.

OBJECTIVE: This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis. METHODS: Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004). CONCLUSIONS: Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making. ADVANCES IN KNOWLEDGE: We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes

Lung volume reproducibility under ABC control and self-sustained breath-holding.

An Active Breathing Coordinator (ABC) can be employed to induce breath-holds during CT imaging and radiotherapy of lung, breast and liver cancer, and recently during lung cancer MRI. The apparatus measures and controls respiratory volume, hence subject lung volume reproducibility is its principal measure of effectiveness. To assess ABC control quality, the intra-session reproducibility of ABC-induced lung volumes was evaluated and compared with that reached by applying the clinical standard of operator-guided self-sustained breath-holds on healthy volunteers during MRI. Inter-session reproducibility was investigated by repeating ABC-controlled breath-holds on a second visit. Additionally, lung volume agreement with ABC devices used with different imaging modalities in the same institution (MR, CT), or for a breast trial treatment, was assessed. Lung volumes were derived from three-dimensional (3D) T1-weighted MRI datasets by three observers employing semiautomatic lung delineation on a radiotherapy treatment planning system. Inter-observer variability was less than 6% of the delineated lung volumes. Lung volume agreement between the different conditions over all subjects was investigated using descriptive statistics. The ABC equipment dedicated for MR application exhibited good intra-session and inter-session lung volume reproducibility (1.8% and 3% lung volume variability on average, respectively). MR-assessed lung volumes were similar using different ABC equipment dedicated to MR, CT, or breast radiotherapy. Overall, lung volumes controlled by the same or different ABC devices agreed better than with self-controlled breath-holds, as suggested by the average ABC variation of 1.8% of the measured lung volumes (99 mL), compared to the 4.1% (226 mL) variability observed on average with self-sustained breath-holding

Low-dose cyclophosphamide induces anti-tumor T-cell responses which associate with survival in metastatic colorectal cancer

Purpose: Anti-cancer T-cell responses can control tumors, but immune-suppressive mechanisms in vivo prevent their function. The role of regulatory T-cells (Tregs) in metastatic colorectal cancer (mCRC) is unclear. We have previously shown depletion of Tregs enhances CRC-specific effector T-cell responses. Low dose cyclophosphamide (CPM) targets Tregs in animal models and some human studies, however the effect of CPM in mCRC is unknown. Experimental Design: Fifty-five mCRC patients were enrolled onto a phase I/II trial and randomized to receive two week-long courses of low-dose (50mg twice-a-day) CPM or not. The absolute number, phenotype and anti-tumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, along with 18-month follow-up. Results: Initially CPM reduced proliferation in all lymphocyte subsets, however, a rapid mobilization of effector T-cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell and NK-cell numbers occurred. The expansion and subsequent activation of effector T-cells was focused on tumor-specific T-cells, producing both granzyme B and IFN-gamma. CPM-treated patients demonstrating the most enhanced IFN-gamma+ tumor-specific T-cell responses exhibited a significant delay in tumor progression (HR=0.29, 95% CI 0.12-0.69, P=0.0047), compared to non-responders and no-treatment controls. Conclusions: CPM-induced Treg-depletion is mirrored by a striking boost to anti-tumor immunity. This study provides the first direct evidence of the benefit of naturally primed T-cells in mCRC patients. Our results also support the concept that non-mutated self-antigens can act as useful targets for immunotherapies

Phase I/II study of DHA–paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours

DHA–paclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHA–paclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHA–paclitaxel 660 mg m-2 and carboplatin AUC 5 with DHA–paclitaxel 880 mg m-2. Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33–71). All patients had advanced cancer refractory to standard treatment, performance status 0–2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60–506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHA–paclitaxel 660 mg m-2 given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m-2, given every 28 days, are warranted in chemo-naive patients

Realizing the potential of magnetic resonance image guided radiotherapy in gynaecological and rectal cancer

CT-based radiotherapy workflow is limited by poor soft tissue definition in the pelvis and reliance on rigid registration methods. Current image-guided radiotherapy and adaptive radiotherapy models therefore have limited ability to improve clinical outcomes. The advent of MRI-guided radiotherapy solutions provides the opportunity to overcome these limitations with the potential to deliver online real-time MRI-based plan adaptation on a daily basis, a true “plan of the day.” This review describes the application of MRI guided radiotherapy in two pelvic tumour sites likely to benefit from this approach

3D ToF-SIMS imaging of polymer multilayer films using argon cluster sputter depth profiling

ToF-SIMS imaging with argon cluster sputter depth profiling has provided detailed insight into the three-dimensional (3D) chemical composition of a series of polymer multilayer structures. Depths of more than 15 μm were profiled in these samples while maintaining uniform sputter rates. The 3D chemical images provide information regarding the structure of the multilayer systems that could be used to inform future systems manufacturing and development. This also includes measuring the layer homogeneity, thickness, and interface widths. The systems analyzed were spin-cast multilayers comprising alternating polystyrene (PS) and polyvinylpyrrolidone (PVP) layers. These included samples where the PVP and PS layer thickness values were kept constant throughout and samples where the layer thickness was varied as a function of depth in the multilayer. The depth profile data obtained was observed to be superior to that obtained for the same materials using alternative ion sources such as C60 n+. The data closely reflected the “as manufactured” sample specification, exhibiting good agreement with ellipsometry measurements of layer thickness, while also maintaining secondary ion intensities throughout the profiling regime. The unprecedented quality of the data allowed a detailed analysis of the chemical structure of these systems, revealing some minor imperfections within the polymer layers and demonstrating the enhanced capabilities of the argon cluster depth profiling technique

From 2D leg kinematics to 3D full-body biomechanics-the past, present and future of scientific analysis of maximal instep kick in soccer

Biomechanics investigation on soccer kicking has a relatively long history, yet the body of knowledge is still small. This paper reviews articles published from 1960s to 2011, summarizing relevant findings, research trends and method development. It also discusses challenges faced by the field. The main aim of the paper is to promote soccer kicking studies through discussions on problem solving in the past, method development in the present, and possible research directions for the future