Summit on cell therapy for cancer: The importance of the interaction of multiple disciplines to advance clinical therapy

The field of cellular therapy of cancer is moving quickly and the issues involved with its advancement are complex and wide ranging. The growing clinical applications and success of adoptive cellular therapy of cancer has been due to the rapid evolution of immunology, cancer biology, gene therapy and stem cell biology and the translation of advances in these fields from the research laboratory to the clinic. The continued development of this field is dependent on the exchange of ideas across these diverse disciplines, the testing of new ideas in the research laboratory and in animal models, the development of new cellular therapies and GMP methods to produce these therapies, and the testing of new adoptive cell therapies in clinical trials. The Summit on Cell Therapy for Cancer to held on November 1 and 2, 2011 at the National Institutes of Health (NIH) campus will include a mix of perspectives, concepts and ideas related to adoptive cellular therapy that are not normally presented together at any single meeting. This novel assembly will generate new ideas and new collaborations and possibly increase the rate of advancement of this field

Artificial intelligence for automated detection of diabetic foot ulcers: A real-world proof-of-concept clinical evaluation

Objective: Conduct a multicenter proof-of-concept clinical evaluation to assess the accuracy of an artificial intelligence system on a smartphone for automated detection of diabetic foot ulcers. Methods: The evaluation was undertaken with patients with diabetes (n = 81) from September 2020 to January 2021. A total of 203 foot photographs were collected using a smartphone, analysed using the artificial intelligence system, and compared against expert clinician judgement, with 162 images showing at least one ulcer, and 41 showing no ulcer. Sensitivity and specificity of the system against clinician decisions was determined and inter- and intra-rater reliability analysed. Results: Predictions/decisions made by the system showed excellent sensitivity (0.9157) and high specificity (0.8857). Merging of intersecting predictions improved specificity to 0.9243. High levels of inter- and intra-rater reliability for clinician agreement on the ability of the artificial intelligence system to detect diabetic foot ulcers was also demonstrated (Kα > 0.8000 for all studies, between and within raters). Conclusions: We demonstrate highly accurate automated diabetic foot ulcer detection using an artificial intelligence system with a low-end smartphone. This is the first key stage in the creation of a fully automated diabetic foot ulcer detection and monitoring system, with these findings underpinning medical device development

Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>It is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.</p> <p>Methods</p> <p>Study infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.</p> <p>Results</p> <p>Survival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.</p> <p>Conclusion</p> <p>The probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990's in this regionally based sample of ELGANs.</p

Near-field emission profiling of tropical forest and Cerrado fires in Brazil during SAMBBA 2012

This is the final version. Available from European Geosciences Union (EGU) / Copernicus Publications via the DOI in this record. Data availability: All raw time series data used to derive the emission ratios and factors from the FAAM research aircraft are publicly available from the Centre for Environmental Data Analysis website (http://www.ceda.ac.uk/, last access: 12 March 2018). Direct links to the flight data records are given in the reference list (Facility for Airborne Atmospheric Measurements, Natural Environment Research Council, and Met Office, 2014a, b).We profile trace gas and particulate emissions from near-field airborne measurements of discrete smoke plumes in Brazil during the 2012 biomass burning season. The South American Biomass Burning Analysis (SAMBBA) Project conducted during September and October 2012 sampled across two distinct fire regimes prevalent in the Amazon Basin. Combined measurements from a Compact Time-of-Flight Aerosol Mass Spectrometer (C-ToF-AMS) and a Single Particle Soot Photometer (SP2) are reported for the first time in a tropical biomass burning environment. Emissions from a mostly smouldering tropical forest wildfire in Rondônia state and numerous smaller flaming Cerrado fires in Tocantins state are presented. While the Cerrado fires appear to be representative of typical fire conditions in the existing literature, the tropical forest wildfire likely represents a more extreme example of biomass burning with a bias towards mostly smouldering emissions. We determined fire-integrated modified combustion efficiencies, emission ratios and emission factors for trace gas and particulate components for these two fire types, alongside aerosol microphysical properties. Seven times more black carbon was emitted from the Cerrado fires per unit of fuel combustion (EFBC of 0.13±0.04ĝ€†gĝ€†kg-1) compared to the tropical forest fire (EFBC of 0.019±0.006gĝ€†kg-1), and more than 6 times the amount of organic aerosol was emitted from the tropical forest fire per unit of fuel combustion (EFOM of 8.00±2.53gĝ€†kg-1, EFOC of 5.00±1.58gĝ€†kg-1) compared to the Cerrado fires (EFOM of 1.31±0.42gĝ€†kg-1, EFOC of 0.82±0.26gĝ€†kg-1). Particulate-phase species emitted from the fires sampled are generally lower than those reported in previous studies and in emission inventories, which is likely a combination of differences in fire combustion efficiency and fuel mixture, along with different measurement techniques. Previous modelling studies focussed on the biomass burning season in tropical South America have required significant scaling up of emissions to reproduce in situ and satellite aerosol concentrations over the region. Our results do not indicate that emission factors used in inventories are biased low, which could be one potential cause of the reported underestimates in modelling studies. This study supplements and updates trace gas and particulate emission factors for fire-type-specific biomass burning in Brazil for use in weather and climate models. The study illustrates that initial fire conditions can result in substantial differences in terms of their emitted chemical components, which can potentially perturb the Earth system.NERCMet Offic

Direct glia-to-neuron transdifferentiation gives rise to a pair of male-specific neurons that ensure nimble male mating

Sexually dimorphic behaviours require underlying differences in the nervous system between males and females. The extent to which nervous systems are sexually dimorphic and the cellular and molecular mechanisms that regulate these differences are only beginning to be understood. We reveal here a novel mechanism by which male-specific neurons are generated in Caenorhabditis elegans through the direct transdifferentiation of sex-shared glial cells. This glia-to-neuron cell fate switch occurs during male sexual maturation under the cell-autonomous control of the sex-determination pathway. We show that the neurons generated are cholinergic, peptidergic, and ciliated putative proprioceptors which integrate into male-specific circuits for copulation. These neurons ensure coordinated backward movement along the mate’s body during mating. One step of the mating sequence regulated by these neurons is an alternative readjustment movement performed when intromission becomes difficult to achieve. Our findings reveal programmed transdifferentiation as a developmental mechanism underlying flexibility in innate behaviour

Onset Rivalry: Brief Presentation Isolates an Early Independent Phase of Perceptual Competition

When the left and right eyes are simultaneously presented with different images, observers typically report exclusive awareness of only one image. This phenomenon is termed binocular rivalry, reflecting the fact that the dominant image alternates every few seconds in a cycle of perceptual competition that continues indefinitely. Despite the apparent continuity in perceptual switching, we now demonstrate that the initial “onset” period is fundamentally different to all subsequent rivalry epochs. Using brief intermittent presentations, rivalry dominance shows strong biases such that the same target is perceived with each successive stimulus onset. These biases remain consistent within any given location, but vary across the visual field in a distribution that is stable over multiple weeks but highly idiosyncratic across observers. If the presentation exceeds ∼1sec at any location, however, the very different and much more balanced alternations of sustained binocular rivalry become apparent. These powerful onset biases are observed with brief intermittent presentations at a single location or with continual smooth motion of the targets. Periods of adaptation to one of the rivaling targets induced local switches in dominance to the non-adapted target. However, these effects were generally limited to the spatial site of adaptation and had less influence over each subsequent cycle of the target. We conclude that onset rivalry is independent of sustained rivalry and cannot be explained by local regions of monocular dominance or memory of past perceptual history, but rather reflects low-level, spatially localized factors that are stable over periods of weeks. These findings suggest that brief presentation paradigms are inappropriate for their current use in studies of the mechanisms underlying sustained rivalry. However, brief presentations are ideal for investigating early stages of perceptual competition

Towards UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): protocol for an evaluation of the requirements for arthroplasty follow-up, and the production of consensus-based recommendations

Introduction: Hip and knee arthroplasties have revolutionised the management of degenerative joint diseases and, due to an ageing population, are becoming increasingly common. Follow-up of joint prostheses is to identify problems in symptomatic or asymptomatic patients due to infection, osteolysis, bone loss or potential peri-prosthetic fracture, enabling timely intervention to prevent catastrophic failure at a later date. Early revision is usually more straight-forward surgically and less traumatic for the patient. However, routine long-term follow-up is costly and requires considerable clinical time. Therefore, some centres in the UK have curtailed this aspect of primary hip and knee arthroplasty services, doing so without an evidence-base that such disinvestment is clinically- or cost-effective. Methods: Given the timeline from joint replacement to revision, conducting a randomised controlled trial (RCT) to determine potential consequences of disinvestment in hip and knee arthroplasty follow-up is not feasible. Furthermore the low revision rates of modern prostheses, less than 10% at 10 years, would necessitate thousands of patients to adequately power such a study. The huge variation in follow-up practice across the UK also limits the generalisability of an RCT. This study will therefore use a mixed-methods approach to examine the requirements for arthroplasty follow-up and produce evidence- and consensus-based recommendations as to how, when and on whom follow-up should be conducted. Four interconnected work packages will be completed: 1) a systematic literature review; 2a) analysis of routinely-collected NHS data from five national datasets to understand when and which patients present for revision surgery; 2b) prospective data regarding how patients currently present for revision surgery; 3) economic modelling to simulate long-term costs and quality-adjusted life years associated with different follow-up care models; 4) a Delphi-consensus process, involving all stakeholders, to develop a policy document which includes a stratification algorithm to determine appropriate follow-up care for an individual patient

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident

The Tyrphostin Agent AG490 Prevents and Reverses Type 1 Diabetes in NOD Mice

<div><h3>Background</h3><p>Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.</p> <h3>Materials and Methods</h3><p>Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.</p> <h3>Results</h3><p>AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.<em>Scid</em> mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.</p> <h3>Conclusion</h3><p>The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.</p> </div