Miracle-dz/UniFAR-FTUs huggingface dataset:
A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate “on-target” toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and “on-target off-tumor” toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.
Early cellular changes of human mesenchymal stem cells and their interaction with other cells

Cell‐to–cell interactions between human mesenchymal stem cells and potential adjacent cells such as endothelial cells, dermal fibroblasts, and epidermal keratinocytes was investigated. A modified dual Boyden chamber assay using 8‐µm pores revealed a more powerful chemotactic cell migration of human mesenchymal stem cells toward human epidermal keratinocytes than other cells, such as umbilical artery endothelial cells and dermal fibroblasts, during 16 hours of incubation (336.2 ± 52.33, 36.0 ± 11.20, and 62.7 ± 18.16, cells/field, respectively, p < 0.01; comparison between endothelial cells and keratinocytes, and fibroblasts and keratinocytes). Scanning electron microscopy showed human mesenchymal stem cell migration through the pores, with endothelial cells, fibroblasts, or keratinocytes in the lower chambers. Mesenchymal stem cell ultrastructural changes occurred, including a larger euchromatin nucleus, when the cells were placed in medium containing 10 percent fetal bovine serum, whereas basic fibroblast growth factor maintained the immature cell morphology for 4 days. Monolayer coculture also showed human mesenchymal stem cell changes in ultrastructural morphology in the vicinity of the epidermal keratinocytes. These data suggest that human mesenchymal stem cells may interact with human epidermal keratinocytes to accelerate wound healing and coverage.
Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.

PURPOSE Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families. METHODS Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families. RESULTS Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02. CONCLUSIONS Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.
Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat brain

1 The ability of γ‐aminobutyric acid (GABA) to affect the release of [3H]‐dopamine in rat brain synaptosomes prepared from corpus striatum, frontal cortex and hypothalamus and prelabelled with the radioactive catecholamine in the presence of desipramine was examined. 2 GABA (10–300 μm) increased in a concentration‐dependent way the basal release of [3H]‐dopamine from striatum and cortical synaptosomes; however, its effect was much less pronounced in hypothalamic nerve terminals. 2,4‐Diaminobutyric acid (DABA) mimicked GABA although less potently. 3 Neutral amino acids such as leucine, valine or α‐aminoisobutyric acid (100–300 μm) did not affect or increased minimally the release of [3H]‐dopamine. 4 The GABA‐induced [3H]‐dopamine release was not prevented by the GABAA‐receptor antagonists, bicuculline or picrotoxin. The GABAA‐receptor agonist, muscimol (10–300 μm), displayed only a very weak, not significant, enhancing effect on [3H]‐dopamine release. The GABAB‐receptor agonist (—)‐ baclofen (100 or 300 μm) had no effect. 5 Three novel and selective inhibitors of GABA uptake, N‐(4,4‐diphenyl‐3‐butenyl)‐nipecotic acid (SK&F 89976A), N‐(4,4‐diphenyl‐3‐butenyl)‐guvacine (SK&F 100330A) and N‐(4,4‐diphenyl‐3‐butenyl)‐homo‐β‐proline (SK&F 100561) potently counteracted the enhancing effect of GABA on [3H]‐dopamine release. Nipecotic acid also reduced the effect of GABA. 6 It is concluded that carriers for the uptake of dopamine and GABA may coexist on the same nerve terminal in the rat brain.
Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein.

BACKGROUND Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed--by analogy to the process by which mutated growth factor receptors can be oncogenic--that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking an antigen-binding domain, these abnormal B-cell antigen receptors might engage in ligand-independent signalling. Normal pre-B-cell development requires the presence of the pre-B-cell receptor, formed by the association of mu heavy chains with two polypeptides--so-called surrogate light chains, Vpre-B and lambda 5--that are homologous to the variable and constant portions of immunoglobulin light chains, respectively. To assess whether amino-terminal truncation of membrane-associated heavy chains results in their constitutive activation, we have examined the ability of a HCD-associated mu protein to promote pre-B-cell development in transgenic mice. RESULTS When the mu HCD transgene is introduced into SCID mice, CD43- pre-B cells develop normally. To determine whether this pre-B-cell development requires surrogate light chains, we backcrossed mice expressing full-length or truncated mu transgenes with lambda 5-deficient mice. Our results show that the truncated heavy chain, but not the normal chain, is able to promote pre-B-cell development in the absence of lambda 5. We also show that truncated mu chains spontaneously aggregate at the surface of bone marrow cells. CONCLUSIONS Expression of the truncated mu heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated mu chain disease protein. The self-aggregation of mu chain disease proteins might account for this constitutive activation. We conclude that amino-terminal truncation of heavy chains could play a role in the genesis of HCD neoplasia if it occurs at an appropriate stage of B-cell differentiation, namely in a mature B cell.
On the PDF of the square of constrained minimal singular value for robust signal recovery analysis

In compressed sensing, the l1-constrained minimal singular value (l1-CMSV) of an encoder is used for analyzing (theoretically) the robustness of decoders against noise. In this paper, we show that for random encoders, the square of the l1-CMSV (S-CMSV) is a random variable. And, for the Gaussian encoders, the S-CMSV admits a simple, closed-form probability and a cumulative distribution functions. We illustrate the benefits of these distributions for analyzing the robustness of various decoders. In particular, we interpret the existing theoretical robustness results of the decoders such as the basis pursuit in terms of the maximum possible undersampling.
Rectal carcinoma: thin-section MR imaging for staging in 28 patients.

PURPOSE To evaluate the accuracy of thin-section magnetic resonance (MR) imaging (in-plane resolution, 0.6 x 0.6 mm) in the preoperative assessment of the depth of extramural tumor infiltration, which is a major prognostic indicator in rectal cancer. MATERIALS AND METHODS In a prospective study of 28 consecutive patients, preoperative MR imaging was performed. The tumor stage according to the TNM classification system and the measured depth of extramural tumor invasion in matched MR images and histopathologic slices were compared. RESULTS Preoperative MR imaging correctly indicated the histopathologic tumor stage in all 25 patients in whom comparisons were possible. The difference between the depth of extramural tumor measured on preoperative MR images and corresponding measurements on histopathologic slices of the resection specimen ranged from -5.0 mm to +5.5 mm (mean difference, +0.13 mm; 95% CI: -2.72, +2.98 mm), indicating good agreement. The mesorectal fascia, and the relation of the tumor to it, could be visualized in every case. In all five patients with involvement of the circumferential excision margins of resection specimens, extensive extramural invasion was identified on preoperative MR images. CONCLUSION Preoperative thin-section MR imaging accurately indicates the tumor stage of rectal cancer and depth of extramural tumor infiltration. It provides valuable information for identifying T3 tumors for preoperative adjuvant therapy in patients who are at high risk of failure of complete excision.
Obesity prevention strategies: Could food or soda taxes improve health?

Evidence shows that one of the main causes for rising obesity rates is excessive consumption of sugar, which is due in large part to the high sugar content of most soda and juice drinks and junk foods. Worryingly, UK and global populations are consuming increasing amounts of sugary drinks and junk foods (high in salt, sugar and saturated fats). However, there is raised public awareness, and parents in particular want something to be done to curb the alarming rise in childhood obesity. Population-wide policies (i.e. taxation, regulation, legislation, reformulation) consistently achieve greater public health gains than interventions and strategies targeted at individuals. Junk food and soda taxes are supported by increasing evidence from empirical and modelling studies. The strongest evidence base is for a tax on sugar sweetened beverages, but in order to effectively reduce consumption, that taxation needs to be at least 20%. Empirical data from a number of countries which have implemented a duty on sugar or sugary drinks shows rapid, substantial benefits. In the UK, increasing evidence from recent scientific reports consistently support substantial reductions in sugar consumption through comprehensive strategies which include a tax. Furthermore, there is increasing public support for such measures. A sugar sweetened beverages tax will happen in the UK so the question is not ‘If? ’ but ‘When? ’ this tax will be implemented. And, crucially, which nation will get there first? England, Ireland, Scotland or Wales?
Probabilistic Error Modeling for Approximate Adders

Approximate adders are widely being advocated as a means to achieve performance gain in error resilient applications. In this paper, a generic methodology for analytical modeling of probability of occurrence of error and the Probability Mass Function (PMF) of error value in a selected class of approximate adders is presented, which can serve as performance metrics for the comparative analysis of various adders and their configurations. The proposed model is applicable to approximate adders that comprise of sub-adder units of uniform as well as non-uniform lengths. Using a systematic methodology, we derive closed form expressions for the probability of error for a number of state-of-the-art high-performance approximate adders. The probabilistic analysis is carried out for arbitrary input distributions. It can be used to study the dependence of error statistics in an adder’s output on its configuration and input distribution. Moreover, it is shown that by building upon the proposed error model, we can estimate the probability of error in circuits with multiple approximate adders. We also demonstrate that, using the proposed analysis, the comparative performance of different approximate adders can be correctly predicted in practical applications of image processing.
Design and analysis of circularly polarized slotted microstrip square patch antenna for remote vehicle wireless data transfer

In this Electronic era, our routine life travels with the aid of wireless technologies. Research in wireless communication has been active to design the methods for wireless data transmission between vehicles. Wireless data transmission holds a crucial importance in emergency services such as ambulance attendants, police officers and firemen. The foremost aim of this paper is to design a circularly polarized slotted Micro strip square patch antenna working at the frequency of 2.5 GHz for traffic management application. The model presented below is a square patch of dimension 30mm × 30mm arranged on the substrate made up of FR4 material whose dielectric constant value is 4.4. Its thickness is 8.9mm. ADS (Advanced Design System-2009) have been used for the mapping the layout, carrying out simulations associated with time and frequency. It is used to design a circularly polarized slotted Micro strip square patch antenna with enhanced return loss. Considering the design process, the important parameters to be considered are the length and patch width in-addition with dimensions of feed line (λ/4). Results obtained from the proposed circularly polarised slotted micro strip square patch antenna with different slots pattern are tabulated which can be perfectly used for Vehicle Remote Wireless Data Transfer since it operates well at the LTE band of 2.5 GHz.
Profiling outcomes of ambulatory care: casemix affects perceived performance.

OBJECTIVES The authors explored the role of casemix adjustment when profiling outcomes of ambulatory care. METHODS The authors reviewed the medical records of 656 patients with hypertension, diabetes, or chronic obstructive pulmonary disease (COPD) receiving care at one of three Department of Veterans Affairs medical centers. Outcomes included measures of physiological control for hypertension and diabetes, and of exacerbations for COPD. Predictors of poor outcomes, including physical examination findings, symptoms, and comorbidities, were identified and entered into regression models. Observed minus expected performance was described for each site, both before and after casemix adjustment. RESULTS Risk-adjustment models were developed that were clinically plausible and had good performance properties. Differences existed among the three sites in the severity of the patients being cared for. For example, the percentage of patients expected to have poor blood pressure control were 35% at site 1, 37% at site 2, and 44% at site 3 (P < 0.01). Casemix-adjusted measures of performance were different from unadjusted measures. Sites that were outliers (P < 0.05) with one approach had observed performance no different from expected with another approach. CONCLUSIONS Casemix adjustment models can be developed for outpatient medical conditions. Sites differ in the severity of patients they treat, and adjusting for these differences can alter judgments of site performance. Casemix adjustment is necessary when profiling outpatient medical conditions.
Research: Educational and Psychological Aspects Diabetes-Oriented Learning Family Intervention (DOLFIN): a feasibility study evaluating an intervention for carers of young persons with Type 1 diabetes

Aims To describe the development of an intervention for parents and carers of young people with Type 1 diabetes and assess the feasibility, acceptability and emerging clinical themes. Methods Participants were carers of young persons aged 10–18 years with a diagnosis of Type 1 diabetes of more than 12 months’ duration in two inner-city South London hospitals. Carers were invited to attend six sessions of a group workshop where they received emotional support, diabetes education and were taught motivational interviewing techniques to support their child. Results Out of 106 eligible participants, carers of 31 young people with Type 1 diabetes were recruited, 17 of whom ‘completed’ the intervention (attending four or more sessions). Participants discussed a variety of themes in session, including the increasing difficulty of diabetes management as children grow older, parenting techniques for managing diabetes in the home and the emotional challenges of having a child with a chronic illness. Conclusions Engaging parents in a carer intervention for Type 1 diabetes was a challenge, but parents who participated appeared to value the programme. Future interventions for carers need to take account of carers’ wishes and expectations in order to maximize user uptake. Diabet. Med. 31, 55–60 (2014)
Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships.

19-Norprogesterone (19-NOR-P) is a potent progestagen in mammals by s.c. injection, but is almost inactive when given p.o. In the rat, 19-NOR-P also shows marked salt-retaining and hypertensive effects, consistent with its high affinity for mineralocorticoid receptors (MR). We synthetized recently some p.o. active 19-NOR-P derivatives, and have examined the extent to which the structural changes made on the parent compound can modify the affinity for MR and the salt-retaining potency. Compared with aldosterone, 19-NOR-P has a 47% affinity for rat renal cytosolic MR, decreasing to 13% with alpha-hydroxylation on C-17 (17 alpha-OH-19-NOR-P). The addition of a methyl group combined with the formation of a double bond at C-6 led to nomegestrol, the relative affinity of which was 1.2%. Binding was almost abolished completely (0.23%) by acetylation of the 17 alpha-OH group (nomegestrol-acetate). A single s.c. injection of 19-NOR-P, 20 micrograms/animal, induced a marked decline of [Na+]/[K+] ratio in urine of adrenalectomized male rats. The antinatriuretic effect was still observed after a 11-day period of daily administrations of the same dosage. 17 alpha-OH-19-NOR-P decreased the [Na+]/[K+] ratio only at a high p.o. dose (2500 micrograms/animal). NOM-Ac did not affect the [Na+]/[K+] ratio after a single s.c. or p.o. administration, but increased it at the end of a 11-day p.o. treatment. Thus, the chemical modifications that lead to potent p.o. active progestins derived from 19-NOR-P induce stepwise reductions in the affinity for MR and of the mineralocorticoid effects of the parent compound.
Normalizing the development of cortisol regulation in maltreated infants through preventive interventions

Abstract Longitudinal effects of child maltreatment on cortisol regulation in infants from age 1 to 3 years were investigated in the context of a randomized preventive intervention trial. Thirteen-month-old infants from maltreating families (N = 91) and their mothers were randomly assigned to one of three intervention conditions: child–parent psychotherapy, psychoeducational parenting intervention, and a control group involving standard community services (CS). A fourth group of infants from nonmaltreating families (N = 52) and their mothers comprised a nonmaltreated comparison (NC) group. The two active interventions were combined into one maltreated intervention (MI) group for statistical analyses. Saliva samples were obtained from children at 10:00 a.m. before beginning a laboratory observation session with their mothers when the children were 13 months of age (preintervention), 19 months (midintervention), 26 months (postintervention), and 38 months (1-year postintervention follow-up). At the initial assessment, no significant differences among groups in morning cortisol were observed. Latent growth curve analyses examined trajectories of cortisol regulation over time. Beginning at midintervention, divergence was found among the groups. Whereas the MI group remained indistinguishable from the NC group across time, the CS group progressively evinced lower levels of morning cortisol, statistically differing from the MI and NC groups. Results highlight the value of psychosocial interventions for early child maltreatment in normalizing biological regulatory processes.
Erysipelas Outbreaks in Flocks of Geese in Poland—Biochemical and Genetic Analyses of the Isolates

SUMMARY Erysipelothrix rhusiopathiae causes erysipelas in many vertebrate species. Severe disease outbreaks have been noted in many poultry species—chickens, ducks, emus, pheasants, pigeons, and geese. This article describes the biochemical and genetic analyses of six E. rhusiopathiae strains isolated from geese for meat production. The isolates came from birds kept in different poultry houses on one farm, and were collected during two erysipelas outbreaks. We analyzed and compared the isolates by random amplified polymorphic DNA with the use of NK6 primer and pulsed-field gel electrophoresis, with the restriction enzyme SmaI. Biochemical examination was performed with API Coryne test. Analyses showed that the three strains isolated during the first outbreak differed, whereas the three isolates from the second outbreak were identical to one another, but distinct from the isolates from the first outbreak. The results of biochemical and genetic analyses of E. rhusiopathiae strains isolated from geese suggest different sources of infection for the erysipelas outbreaks.