Miracle-dz/UniFAR-FTUs huggingface dataset:
Microsphere priming facilitates induction of potent therapeutic T‐cell immune responses against autochthonous liver cancers

Immunotherapy of solid tumors is often hampered by the low frequency of tumor‐specific T cells elicited by current vaccination strategies. Here, we describe a prime‐boost vaccination protocol based on the administration of antigen conjugated to poly‐lactic‐co‐glycolic acid (PLGA) microspheres followed by booster vaccination with Listeria monocytogenes vectors, which rapidly generates potent immune responses within two weeks. Compared with conventional vaccination with antigen‐pulsed dendritic cells, the use of PLGA microspheres resulted in immune responses of significantly higher magnitude, which could be further enhanced via coinjection of TLR 3 agonists. In an immunocompetent model of subcutaneous hepatocellular carcinoma, PLGA/Listeria vaccination resulted in complete remission of established tumors and prolonged survival. To further test the efficacy of the novel vaccination for the treatment of solid tumors, we developed an orthotopic liver cancer model based on the injection of transposon‐flanked plasmids expressing oncogenes and model antigens. In this transgenic mouse model of liver cancer, PLGA/Listeria vaccination resulted in eradication of liver tumors, long‐term survival of animals and establishment of stable cancer‐specific memory CD8+ T‐cell populations. Therefore, combined PLGA/Listeria vaccination holds promise as a novel immunotherapeutic option for the treatment of solid cancers and as a means to boost the therapeutic efficacy of established cancer vaccines.
Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.

AIMS To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.
Identification of Two New Mechanisms That Regulate Fruit Growth by Cell Expansion in Tomato

Key mechanisms controlling fruit weight and shape at the levels of meristem, ovary or very young fruit have already been identified using natural tomato diversity. We reasoned that new developmental modules prominent at later stages of fruit growth could be discovered by using new genetic and phenotypic diversity generated by saturated mutagenesis. Twelve fruit weight and tissue morphology mutants likely affected in late fruit growth were selected among thousands of fruit size and shape EMS mutants available in our tomato EMS mutant collection. Their thorough characterization at organ, tissue and cellular levels revealed two major clusters controlling fruit growth and tissue morphogenesis either through (i) the growth of all fruit tissues through isotropic cell expansion or (ii) only the growth of the pericarp through anisotropic cell expansion. These likely correspond to new cell expansion modules controlling fruit growth and tissue morphogenesis in tomato. Our study therefore opens the way for the identification of new gene regulatory networks controlling tomato fruit growth and morphology.
Spectrum of computed tomographic findings in 58 canine elbows with fragmentation of the medial coronoid process.

OBJECTIVE To describe in detail the computed tomographic findings in elbows of dogs with fragmentation of the medial coronoid process of the ulna. METHODS Retrospective review of computed tomographic images of 58 elbows that had displaced medial coronoid process fragment(s), non-displaced medial coronoid process fragment or a stable fissure in the articular cartilage of the medial coronoid process at arthroscopy. RESULTS Bone fragments were observed in 85 per cent elbows with a displaced fragment at arthroscopy, in 18 per cent elbows with a non-displaced fragment and in 29 per cent elbows with a stable fissure. Fissures in the subchondral bone were observed in computed tomographic images of 43 per cent elbows that had a stable fissure at arthroscopy. Abnormal shape, sclerosis and lucency affecting the medial coronoid process, subchondral sclerosis of the ulna and humerus, irregular radial incisure of the ulna and periarticular osteophytes were observed in a similar proportion in dogs regardless of the arthroscopic findings. Kissing lesions affecting the medial aspect of the humeral condyle were mainly associated with displaced fragments. Signs of joint incongruity were observed in dorsal and sagittal reconstructed computed tomographic images in 24 per cent elbows. CLINICAL SIGNIFICANCE A wide range of abnormalities may be observed in computed tomographic images of dogs with fragmented medial coronoid process. Computed tomographic is moderately sensitive for detection of fragments.
The Effect on Long-Term Survivorship of Surgeon Preference for Posterior-Stabilized or Minimally Stabilized Total Knee Replacement: An Analysis of 63,416 Prostheses from the Australian Orthopaedic Association National Joint Replacement Registry

Background: Controversy still exists as to the optimum management of the posterior cruciate ligament (PCL) in total knee arthroplasty. Surgeons can choose to kinematically substitute the PCL with a posterior-stabilized total knee replacement or alternatively to utilize a cruciate-retaining, also known as minimally stabilized, total knee replacement. Proponents of posterior-stabilized total knee replacement propose that the reported lower survivorship in registries when directly compared with minimally stabilized total knee replacement is due to confounders such as selection bias because of the preferential usage of posterior-stabilized total knee replacement in more complex or severe cases. In this study, we aimed to eliminate these possible confounders by performing an instrumental variable analysis based on surgeon preference to choose either posterior-stabilized or minimally stabilized total knee replacement, rather than the actual prosthesis received. Methods: Cumulative percent revision, hazard ratio (HR), and revision diagnosis data were obtained from the Australian Orthopaedic Association National Joint Replacement Registry from September 1, 1999, to December 31, 2014, for 2 cohorts of patients, those treated by high-volume surgeons who preferred minimally stabilized replacements and those treated by high-volume surgeons who preferred posterior-stabilized replacements. All patients had a diagnosis of osteoarthritis and underwent fixed-bearing total knee replacement with patellar resurfacing. Results: At 13 years, the cumulative percent revision was 5.0% (95% confidence interval [CI], 4.0% to 6.2%) for the surgeons who preferred the minimally stabilized replacements compared with 6.0% (95% CI, 4.2% to 8.5%) for the surgeons who preferred the posterior-stabilized replacements. The revision risk for the surgeons who preferred posterior-stabilized replacements was significantly higher for all causes (HR = 1.45 [95% CI, 1.30 to 1.63]; p < 0.001), for loosening or lysis (HR = 1.93 [95% CI, 1.58 to 2.37]; p < 0.001), and for infection (HR = 1.51 [95% CI, 1.25 to 1.82]; p < 0.001). This finding was irrespective of patient age and was evident with cemented fixation and with both cross-linked polyethylene and non-cross-linked polyethylene. However, the higher revision risk was only evident in male patients. Conclusions: There was a 45% higher risk of revision for the patients of surgeons who preferred a posterior-stabilized total knee replacement compared with the patients of surgeons who preferred a minimally stabilized total knee replacement. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Emerging Applications of Stem Cell and Regenerative Medicine to Sports Injuries

Background: The treatment of sports-related musculoskeletal injuries with stem cells has become more publicized because of recent reports of high-profile athletes undergoing stem cell procedures. There has been increased interest in defining the parameters of safety and efficacy and the indications for potential use of stem cells in clinical practice. Purpose: To review the role of regenerative medicine in the treatment of sports-related injuries. Study Design: Review. Method: Relevant studies were identified through a PubMed search combining the terms stem cells and cartilage, ligament, tendon, muscle, and bone from January 2000 to August 2013. Studies and works cited in these studies were also reviewed. Results: Treatment of sports-related injuries with stem cells shows potential for clinical efficacy from the data available from basic science and animal studies. Conclusion: Cell-based therapies and regenerative medicine offer safe and potentially efficacious treatment for sports-related musculoskeletal injuries. Basic science and preclinical studies that support the possibility of enhanced recovery from sports injuries using cell-based therapies are accumulating; however, more clinical evidence is necessary to define the indications and parameters for their use. Accordingly, exposing patients to cell-based therapies could confer an unacceptable risk profile with minimal or no benefit. Continued clinical testing with animal models and clinical trials is necessary to determine the relative risks and benefits as well as the indications and methodology of treatment.
A musculoskeletal model of human locomotion driven by a low dimensional set of impulsive excitation primitives

Human locomotion has been described as being generated by an impulsive (burst-like) excitation of groups of musculotendon units, with timing dependent on the biomechanical goal of the task. Despite this view being supported by many experimental observations on specific locomotion tasks, it is still unknown if the same impulsive controller (i.e., a low-dimensional set of time-delayed excitastion primitives) can be used as input drive for large musculoskeletal models across different human locomotion tasks. For this purpose, we extracted, with non-negative matrix factorization, five non-negative factors from a large sample of muscle electromyograms in two healthy subjects during four motor tasks. These included walking, running, sidestepping, and crossover cutting maneuvers. The extracted non-negative factors were then averaged and parameterized to obtain task-generic Gaussian-shaped impulsive excitation curves or primitives. These were used to drive a subject-specific musculoskeletal model of the human lower extremity. Results showed that the same set of five impulsive excitation primitives could be used to predict the dynamics of 34 musculotendon units and the resulting hip, knee and ankle joint moments (i.e., NRMSE = 0.18 ± 0.08, and R2 = 0.73 ± 0.22 across all tasks and subjects) without substantial loss of accuracy with respect to using experimental electromyograms (i.e., NRMSE = 0.16 ± 0.07, and R2 = 0.78 ± 0.18 across all tasks and subjects). Results support the hypothesis that biomechanically different motor tasks might share similar neuromuscular control strategies. This might have implications in neurorehabilitation technologies such as human-machine interfaces for the torque-driven, proportional control of powered prostheses and orthoses. In this, device control commands (i.e., predicted joint torque) could be derived without direct experimental data but relying on simple parameterized Gaussian-shaped curves, thus decreasing the input drive complexity and the number of needed sensors.
Impact of MiRSNPs on Survival and Progression in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Purpose: A distinctive new group of polymorphisms is constituted by single-nucleotide polymorphism (SNP) in miRNA processing machinery in miRNA precursor molecules and in miRNA-binding sites, known as miRSNPs. The aim of this study was to ascertain the prognostic impact of six miRSNPs in patients with multiple myeloma and analyze the functional consequences. Experimental Design: One hundred and thirty-seven patients with chemosensitive multiple myeloma (73M/64F) intensified with autologous stem cell transplantation (ASCT) were studied. The median follow-up was 4 years. The genes and SNPs evaluated in genomic DNA by allelic discrimination were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667), and MIR196A2 (rs11614913) for miRNA target genes and TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. Results: Overall survival (OS) was significantly longer in patients with KRT81 rs3660 C/C variant (P = 0.037). Functional analysis showed that the presence of C variant in KRT81 3′ untranslated region (UTR) is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in multiple myeloma cell lines is related to a decreased proliferation. On the other hand, OS was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P = 0.012). There was also a significantly longer progression-free survival (PFS) for this SNP (P = 0.013). This SNP retained its prognostic impact on PFS and OS in a multivariate regression analysis (P = 0.028 and P = 0.014, respectively). Conclusion: This is the first report that relates miRSNPs with prognosis in multiple myeloma either in a keratin gene (KRT81), target of diverse miRNA multiple myeloma clusters, or in the miRNA biogenesis pathway–related protein exportin-5. Clin Cancer Res; 18(13); 3697–704. ©2012 AACR.
Constraining the Properties of the Proposed Super-Massive Black Hole System in 3C66B: Limits from Pulsar Timing

General expressions for the expected timing residuals induced by gravitational wave (G-wave) emission from a slowly evolving, eccentric, binary black hole system are derived here for the first time. These expressions are used to search for the signature of G-waves emitted by the proposed supermassive binary black hole system in 3C 66B. We use data from long-term timing observations of the radio pulsar PSR B1855+09. For the case of a circular orbit, the emitted G-waves should generate clearly detectable fluctuations in the pulse-arrival times of PSR B1855+09. Since no G-waves are detected, the waveforms are used in a Monte Carlo analysis in order to place limits on the mass and eccentricity of the proposed black hole system. The analysis presented here rules out the adopted system with 95% confidence. The reported analysis also demonstrates several interesting features of a G-wave detector based on pulsar timing.
Predicting the development of in-hospital cardiogenic shock in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: the ORBI risk score

Aims To derive and validate a readily useable risk score to identify patients at high-risk of in-hospital ST-segment elevation myocardial infarction (STEMI)-related cardiogenic shock (CS). Methods and results In all, 6838 patients without CS on admission and treated by primary percutaneous coronary intervention (pPCI), included in the Observatoire Régional Breton sur l'Infarctus (ORBI), served as a derivation cohort, and 2208 patients included in the obseRvatoire des Infarctus de Côte-d'Or (RICO) constituted the external validation cohort. Stepwise multivariable logistic regression was used to build the score. Eleven variables were independently associated with the development of in-hospital CS: age >70 years, prior stroke/transient ischaemic attack, cardiac arrest upon admission, anterior STEMI, first medical contact-to-pPCI delay >90 min, Killip class, heart rate >90/min, a combination of systolic blood pressure <125 mmHg and pulse pressure <45 mmHg, glycaemia >10 mmol/L, culprit lesion of the left main coronary artery, and post-pPCI thrombolysis in myocardial infarction flow grade <3. The score derived from these variables allowed the classification of patients into four risk categories: low (0-7), low-to-intermediate (8-10), intermediate-to-high (11-12), and high (≥13). Observed in-hospital CS rates were 1.3%, 6.6%, 11.7%, and 31.8%, across the four risk categories, respectively. Validation in the RICO cohort demonstrated in-hospital CS rates of 3.1% (score 0-7), 10.6% (score 8-10), 18.1% (score 11-12), and 34.1% (score ≥13). The score demonstrated high discrimination (c-statistic of 0.84 in the derivation cohort, 0.80 in the validation cohort) and adequate calibration in both cohorts. Conclusion The ORBI risk score provides a readily useable and efficient tool to identify patients at high-risk of developing CS during hospitalization following STEMI, which may aid in further risk-stratification and thus potentially facilitate pre-emptive clinical decision making.
Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab

Objective To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods GO–REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1α) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor α). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment.
Micronutrients, immunology and inflammation The impact of obesity on the immune response to infection

There is strong evidence indicating that excess adiposity negatively impacts immune function and host defence in obese individuals. This is a review of research findings concerning the impact of obesity on the immune response to infection, including a discussion of possible mechanisms. Obesity is characterised by a state of low-grade, chronic inflammation in addition to disturbed levels of circulating nutrients and metabolic hormones. The impact of these metabolic abnormalities on obesity-related comorbidities has undergone intense scrutiny over the past decade. However, relatively little is known of how the immune system and host defence are influenced by the pro-inflammatory and excess energy milieu of the obese. Epidemiological data suggest obese human subjects are at greater risk for nosocomial infections, especially following surgery. Additionally, the significance of altered immunity in obese human subjects is emphasised by recent studies reporting obesity to be an independent risk factor for increased morbidity and mortality following infection with the 2009 pandemic influenza A (H1N1) virus. Rodent models offer important insight into how metabolic abnormalities associated with excess body weight can impair immunity. However, more research is necessary to understand the specific aspects of immunity that are impaired and what factors are contributing to reduced immunocompetence in the obese. Additionally, special consideration of how infection in this at-risk population is managed is required, given that this population may not respond optimally to antimicrobial drugs and vaccination. Obesity impacts millions globally, and greater understanding of its associated physiological disturbances is a key public health concern.
De Novo Generation of Infectious Prions In Vitro Produces a New Disease Phenotype

Prions are the proteinaceous infectious agents responsible for Transmissible Spongiform Encephalopathies. Compelling evidence supports the hypothesis that prions are composed exclusively of a misfolded version of the prion protein (PrPSc) that replicates in the body in the absence of nucleic acids by inducing the misfolding of the cellular prion protein (PrPC). The most common form of human prion disease is sporadic, which appears to have its origin in a low frequency event of spontaneous misfolding to generate the first PrPSc particle that then propagates as in the infectious form of the disease. The main goal of this study was to mimic an early event in the etiology of sporadic disease by attempting de novo generation of infectious PrPSc in vitro. For this purpose we analyzed in detail the possibility of spontaneous generation of PrPSc by the protein misfolding cyclic amplification (PMCA) procedure. Under standard PMCA conditions, and taking precautions to avoid cross-contamination, de novo generation of PrPSc was never observed, supporting the use of the technology for diagnostic applications. However, we report that PMCA can be modified to generate PrPSc in the absence of pre-existing PrPSc in different animal species at a low and variable rate. De novo generated PrPSc was infectious when inoculated into wild type hamsters, producing a new disease phenotype with unique clinical, neuropathological and biochemical features. Our results represent additional evidence in support of the prion hypothesis and provide a simple model to study the mechanism of sporadic prion disease. The findings also suggest that prion diversity is not restricted to those currently known, and that likely new forms of infectious protein foldings may be produced, resulting in novel disease phenotypes.