Haplobanking induced pluripotent stem cells for clinical use

The development of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and colleagues in 2006 has led to a potential new paradigm in cellular therapeutics, including the possibility of producing patient-specific, disease-specific and immune matched allogeneic cell therapies. One can envisage two routes to immunologically compatible iPSC therapies: using genetic modification to generate a ‘universal donor’ with reduced expression of Human Leukocyte Antigens (HLA) and other immunological targets or developing a haplobank containing iPSC lines specifically selected to provide HLA matched products to large portions of the population. HLA matched lines can be stored in a designated physical or virtual global bank termed a ‘haplobank’. The process of ‘iPSC haplobanking’ refers to the banking of iPSC cell lines, selected to be homozygous for different HLA haplotypes, from which therapeutic products can be derived and matched immunologically to patient populations. By matching iPSC and derived products to a patient’s HLA class I and II molecules, one would hope to significantly reduce the risk of immune rejection and the use of immunosuppressive medication. Immunosuppressive drugs are used in several conditions (including autoimmune disease and in transplantation procedures) to reduce rejection of infused cells, or transplanted tissue and organs, due to major and minor histocompatibility differences between donor and recipient. Such regimens can lead to immune compromise and pathological consequences such as opportunistic infections or malignancies due to decreased cancer immune surveillance. In this article, we will discuss what is practically involved if one is developing and executing an iPSC haplobanking strategy

Design requirements for a digital aid to support adults with mild learning disabilities during clinical consultations: a qualitative study with experts

Background: Adults with mild learning disabilities (MLDs) face a plethora of obstacles when accessing effective health care. Central to many of these barriers is communication, with medical practitioners often remaining untrained on how to interact with patients who have learning disabilities (LDs). To date, research on how to promote this communication has largely centered on the development of low-tech aids. Objective: The objective of this study was to assess the feasibility of utilizing tablet technologies to promote communication between general practitioners and patients with MLDs. We achieved this by identifying a set of design requirements from experts in LDs. Methods: A set of design guidelines was formed during a 2-phase process. Phase 1 involved conducting a series of requirements-gathering interviews with 10 experts in LDs-the protocol of which emerged from the results of a separate scoping review. The interviews were subjected to a framework analysis to discern the key requirements discussed by the experts, and these were embedded within a technology probe. In phase 2, this probe was presented to a subset (n=4) of the experts during a round of usability studies, and the feedback received was used to update the requirements identified in phase 1. Results: An initial set of design requirements has been produced that may assist in the development of clinical Alternative and Augmentative Communication technologies for adults with MLDs. Factors that must be considered range from the health, physical and cognitive needs of stakeholders, to the more individual needs of users. Conclusions: The experts involved in the study were optimistic about the proposed app. They believe that such technologies can help to alleviate time constraints and promote communication by presenting information in a form understood by both practitioners and patients

Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA

α7-Nicotinic Acetylcholine Receptor: Role in Early Odor Learning Preference in Mice

Recently, we have shown that mice with decreased expression of α7-nicotinic acetylcholine receptors (α7) in the olfactory bulb were associated with a deficit in odor discrimination compared to wild-type mice. However, it is unknown if mice with decreased α7-receptor expression also show a deficit in early odor learning preference (ELP), an enhanced behavioral response to odors with attractive value observed in rats. In this study, we modified ELP methods performed in rats and implemented similar conditions in mice. From post-natal days 5–18, wild-type mice were stroked simultaneously with an odor presentation (conditioned odor) for 90 s daily. Control mice were only stroked, exposed to odor, or neither. On the day of testing (P21), mice that were stroked in concert with a conditioned odor significantly investigated the conditioned odor compared to a novel odor, as observed similarly in rats. However, mice with a decrease in α7-receptor expression that were stroked during a conditioned odor did not show a behavioral response to that odorant. These results suggest that decreased α7-receptor expression has a role in associative learning, olfactory preference, and/or sensory processing deficits

R-parity violating resonant stop production at the Large Hadron Collider

We have investigated the resonant production of a stop at the Large Hadron Collider, driven by baryon number violating interactions in supersymmetry. We work in the framework of minimal supergravity models with the lightest neutralino being the lightest supersymmetric particle which decays within the detector. We look at various dilepton and trilepton final states, with or without b-tags. A detailed background simulation is performed, and all possible decay modes of the lighter stop are taken into account. We find that higher stop masses are sometimes easier to probe, through the decay of the stop into the third or fourth neutralino and their subsequent cascades. We also comment on the detectability of such signals during the 7 TeV run, where, as expected, only relatively light stops can be probed. Our conclusion is that the resonant process may be probed, at both 10 and 14 TeV, with the R-parity violating coupling {\lambda}"_{312} as low as 0.05, for a stop mass of about 1 TeV. The possibility of distinguishing between resonant stop production and pair-production is also discussed.Comment: 20 pages, 4 figures, 6 tables; Version accepted by JHE

Enhancement of electroporation facilitated immunogene therapy via T-reg depletion

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival

Cost of care for cancer patients in England: evidence from population-based patient-level data

background: Health systems are facing the challenge of providing care to an increasing population of patients with cancer. However, evidence on costs is limited due to the lack of large longitudinal databases. methods: We matched cost of care data to population-based, patient-level data on cancer patients in England. We conducted a retrospective cohort study including all patients age 18 and over with a diagnosis of colorectal (275 985 patients), breast (359 771), prostate (286 426) and lung cancer (283 940) in England between 2001 and 2010. Incidence costs, prevalence costs, and phase of care costs were estimated separately for patients age 18–64 and greater than or equal to65. Costs of care were compared by patients staging, before and after diagnosis, and with a comparison population without cancer. results: Incidence costs in the first year of diagnosis are noticeably higher in patients age 18–64 than age greater than or equal to65 across all examined cancers. A lower stage diagnosis is associated with larger cost savings for colorectal and breast cancer in both age groups. The additional costs of care because of the main four cancers amounts to £1.5 billion in 2010, namely 3.0% of the total cost of hospital care. conclusions: Population-based, patient-level data can be used to provide new evidence on the cost of cancer in England. Early diagnosis and cancer prevention have scope for achieving large cost savings for the health system

A Spatial and Temporal Risk Assessment of the Impacts of El Niño on the Tropical Forest Carbon Cycle: Theoretical Framework, Scenarios, and Implications

Strong El Niño events alter tropical climates and may lead to a negative carbon balance in tropical forests and consequently a disruption to the global carbon cycle. The complexity of tropical forests and the lack of data from these regions hamper the assessment of the spatial distribution of El Niño impacts on these ecosystems. Typically, maps of climate anomaly are used to detect areas of greater risk, ignoring baseline climate conditions and forest cover. Here, we integrated climate anomalies from the 1982–1983, 1997–1998, and 2015–2016 El Niño events with baseline climate and forest edge extent, using a risk assessment approach to hypothetically assess the spatial and temporal distributions of El Niño risk over tropical forests under several risk scenarios. The drivers of risk varied temporally and spatially. Overall, the relative risk of El Niño has been increasing driven mainly by intensified forest fragmentation that has led to a greater chance of fire ignition and increased mean annual air temperatures. We identified areas of repeated high risk, where conservation efforts and fire control measures should be focused to avoid future forest degradation and negative impacts on the carbon cycle

Multiple Parton Interactions in Z+jets production at the LHC. A comparison of factorized and non--factorized double parton distribution functions

We examine the contribution of Multiple Parton Interactions to Z+n-jets production at the LHC, n=2,3,4, where the Z boson is assumed to decay leptonically. We compare the results obtained with the correlated GS09 double parton distribution function with those obtained with two instances of fully factorized single parton distribution functions: MSTW2008LO and CTEQ6LO. It appears quite feasible to measure the MPI contribution to Z+2/3/4 jets already in the first phase of the LHC with a total luminosity of one inverse femtobarn at 7 TeV. If as expected the trigger threshold for single photons is around 80 GeV, Z+2-jets production may well turn out to be more easily observable than the gamma+3-jets channel. The MPI cross section is dominated by relatively soft events with two jets balancing in transverse momentum.Comment: 15 pages, 3 plot