Miracle-dz/UniFAR-FTUs huggingface dataset:
Two Doses of Bovine Viral Diarrhea Virus DNA Vaccine Delivered by Electroporation Induce Long-Term Protective Immune Responses

ABSTRACT Bovine viral diarrhea virus (BVDV) is a pathogen of major importance in cattle, so there is a need for new effective vaccines. DNA vaccines induce balanced immune responses and are relatively inexpensive and thus promising for both human and veterinary applications. In this study, newborn calves with maternal antibodies were vaccinated intramuscularly (i.m.) with a BVDV E2 DNA vaccine with the TriGrid Delivery System for i.m. delivery (TDS-IM). Two doses of this vaccine spaced 6 or 12 weeks apart were sufficient to induce significant virus-neutralizing antibody titers, numbers of activated T cells, and reduction in viral shedding and clinical presentations after BVDV-2 challenge. In contrast to the placebo-treated animals, the vaccinated calves did not lose any weight, which is an excellent indicator of the well-being of an animal and has a significant economic impact. Furthermore, the interval between the two vaccinations did not influence the magnitude of the immune responses or degree of clinical protection, and a third immunization was not necessary or beneficial. Since electroporation may enhance not only the magnitude but also the duration of immunity after DNA immunization, the interval between vaccination and challenge was extended in a second trial, which showed that two doses of this E2 DNA vaccine again significantly reduced clinical disease against BVDV for several months. These results are promising and support this technology for use against infectious diseases in cattle and large species, including humans, in general.
Pêche de la langouste rouge Palinurus elephas en france. Eléments pour fixer une taille marchande

De la fin du XIXeme siecle aux annees 1950 la peche de la langouste rouge a ete une activite economiquement importante pour la flottille des caseyeurs francais, notamment ceux de Bretagne, avec des debarquements annuels atteignant les 2000 tonnes. La surexploitation des fonds traditionnels et l'extension des eaux territoriales des etats voisins a conduit les bateaux a se reconvertir progressivement du metier de « homardier-langoustier » a celui de « crabier » (peche du tourteau et de l'araignee). Dans les annees 1980 le developpement de la peche au filet a donne un nouvel essor, tres provisoire, a la peche de la langouste mais il n'a fait qu'accroitre la surexploitation de cette ressource. La peche de l'espece n'est actuellement encadree que nationalement, par une taille minimale au debarquement et la Commission europeenne a emis le souhait qu'une taille minimale soit erigee a l'echelle europeenne. Dans cette optique le document presente les principales caracteristiques de la pecherie francaise, compile les donnees biometriques disponibles pour les pecheries europeennes et apporte des donnees sur la reproduction et la taille moyenne de maturite de l'espece. Une taille minimale au debarquement est proposee.
Design and In vitro Evaluation of Branched Peptide Conjugates: Turning Nonspecific Cytotoxic Drugs into Tumor‐Selective Agents

The use of peptide receptors as targets for tumor‐selective therapies was envisaged years ago with the findings that receptors for different endogenous regulatory peptides are overexpressed in several primary and metastatic human tumors, and can be used as tumor antigens. Branched peptides can retain or even increase, through multivalent binding, the biological activity of a peptide and are very resistant to proteolysis, thus having a markedly higher in vivo activity compared with the corresponding monomeric peptides. Oligo‐branched peptides, containing the human regulatory peptide neurotensin (NT) sequence, have been used as tumor‐specific targeting agents. These peptides are able to selectively and specifically deliver effector units, for cell imaging or killing, to tumor cells that overexpress NT receptors. Results obtained with branched NT conjugated to different functional units for tumor imaging and therapy indicate that branched peptides are promising novel multifunctional targeting molecules. This study is focused on the role of the releasing pattern of drug‐conjugated branched NT peptides. We present results obtained with oligo‐branched neurotensin peptides conjugated to 6‐mercaptopurin (6‐MP), combretastain A‐4 (CA4) and monastrol (MON). Drugs were conjugated to oligo‐branched neurotensin through different linkers, and the mode‐of‐release, together with cytotoxicity, was studied in different human cancer cell lines. The results show that branched peptides are very promising pharmacodelivery options. Among our drug‐armed branched peptides, NT4–CA4 was identified as a candidate for further development and evaluation in preclinical pharmacokinetic and pharmacodynamic studies. This peptide–drug exhibits significant activity against pancreas and prostate human cancer cells. Consequently, this derivative is of considerable interest due to the high mortality rates of pancreas neuroendocrine tumors and the high incidence of prostate cancer.
Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.

PURPOSE The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study. PATIENTS AND METHODS Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume. RESULTS Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027). CONCLUSION With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.
Assembly of the K40 Antigen in Escherichia coli: Identification of a Novel Enzyme Responsible for Addition ofl-Serine Residues to the Glycan Backbone and Its Requirement for K40 Polymerization

ABSTRACT Escherichia coli O8:K40 coexpresses two distinct lipopolysaccharide (LPS) structures on its surface. The O8 polysaccharide is a mannose homopolymer with a trisaccharide repeat unit and is synthesized by an ABC-2 transport-dependent pathway. The K40LPS backbone structure is composed of a trisaccharide repeating unit of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) and has an uncommon substitution, anl-serine moiety attached to glucuronic acid. The gene cluster responsible for synthesis of the K40 polysaccharide has previously been cloned and sequenced and was found to contain six open reading frames (ORFs) (P. A. Amor and C. Whitfield, Mol. Microbiol. 26:145–161, 1997). Here, we demonstrate that insertional inactivation of orf1 results in the accumulation of a semirough (SR)-K40LPS form which retains reactivity with specific polyclonal serum in Western immunoblots. Structural and compositional analysis of the SR-K40LPS reveals that it comprises a single K40 repeat unit attached to lipid A core. The lack of polymerization of the K40 polysaccharide indicates thatorf1 encodes the K40 polymerase (Wzy) and that assembly of the K40 polysaccharide occurs via a Wzy-dependent pathway (in contrast to that of the O8 polysaccharide). Inactivation of orf3also results in the accumulation of an SR-LPS form which fails to react with specific polyclonal K40 serum in Western immunoblots. Methylation linkage analysis and fast atom bombardment-mass spectrometry of this SR-LPS reveals that the biological repeat unit of the K40 polysaccharide is GlcNAc-GlcA-GlcNAc. Additionally, this structure lacks the l-serine substitution of GlcA. These results show that (i) orf3 encodes the enzyme responsible for the addition of the l-serine residue to the K40 backbone and (ii) substitution of individual K40 repeats withl-serine is essential for their recognition and polymerization into the K40 polysaccharide by Wzy.
Performance Evaluation of the Precision™ PCx™ Point-of-Care Blood Glucose Analyzer Using Discriminant Ratio Methodology

Abstract Point-of-care glucose testing needs to be integrated into a laboratory information system to provide continuous care. Selecting a particular glucose monitoring system is based on both analytical performance and on user's preference. We evaluated accuracy, performance and regulatory compliance of the Precision™ PCx™ glucose analyzer (Abbott), with automatic download into a central station, for remote quality control (QC) management and automatic upgrading. We used the discriminant ratio (DR) methodology, which determines the DR of a test (e.g. the ratio between the underlying SD and the within-subject SD), and compares it to that of another test allegedly measuring the same parameter. Accuracy was evaluated by Clarke's error grid method. Seven hundred and ninety four blood samples were taken from 22 diabetic patients, combined with two capillary blood samples: one for analysis by reference method and the second for PCx™ analysis. Linear regression analysis revealed, over a 2.1 to 26.9 mmol/l glucose concentration range, a correlation coefficient of 0.963, an intercept of 0.7 mmol/l and a slope of 0.851. Mean difference between meter-generated results and the reference method was −7.1±10.8%. Between-run imprecision for PCx™ using Abbott's controls at low and mid-low concentrations was 5.4 and 3.8%, respectively. Clarke's error grid did not show any clinical impact related to difference between methods. DRs were of similar magnitude using both methods. Nursing staff found PCx™ easy for everyday use. Our data show that PCx™ results agree with those obtained with the reference method, as shown by lack of significant difference in DRs, and by excellent correlation.
Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3′ kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.
A safety assessment of crizotinib in the treatment of ALK-positive NSCLC patients

Introduction: In the past decade, the treatment of NSCLC has been revolutionized by the discovery of key oncogenic driver mutations and the therapies that specifically target these mutations. Crizotinib has been shown to be an inhibitor of MET, anaplastic lymphoma kinase (ALK) and ROS1 receptor tyrosine kinases, and is FDA approved for ALK inhibition. Crizotinib is effective in NSCLC that harbors ALK translocations resulting in overexpression of oncogenic ALK fusion proteins. Areas covered: This paper will review crizotinib as a treatment for ALK-positive NSCLC. It will discuss the drug’s adverse events, drug–drug interactions and other important clinical and safety information related to crizotinib. Expert opinion: Compared to standard chemotherapy, crizotinib shows improved progression-free survival in ALK-positive NSCLC, with patient’s reporting improved quality of life. However, certain adverse events are more frequent with crizotinib versus standard chemotherapy and must be monitored for closely. The most common adverse events include ocular and gastrointestinal disturbances, cardiac and endocrine abnormalities, and peripheral edema. Many, though not all, of these side effects are likely due to the multiple tyrosine kinases inhibited by crizotinib, and will likely improve with second- and third-generation inhibitors that inhibit ALK more specifically.
Metabolomics by Gas Chromatography–Mass Spectrometry: Combined Targeted and Untargeted Profiling

Gas chromatography–mass spectrometry (GC‐MS)–based metabolomics is ideal for identifying and quantitating small‐molecule metabolites (<650 Da), including small acids, alcohols, hydroxyl acids, amino acids, sugars, fatty acids, sterols, catecholamines, drugs, and toxins, often using chemical derivatization to make these compounds sufficiently volatile for gas chromatography. This unit shows how GC‐MS‐based metabolomics allows integration of targeted assays for absolute quantification of specific metabolites with untargeted metabolomics to discover novel compounds. Complemented by database annotations using large spectral libraries and validated standard operating procedures, GC‐MS can identify and semiquantify over 200 compounds from human body fluids (e.g., plasma, urine, or stool) per study. Deconvolution software enables detection of more than 300 additional unidentified signals that can be annotated through accurate mass instruments with appropriate data processing workflows, similar to untargeted profiling using liquid chromatography–mass spectrometry. GC‐MS is a mature technology that uses not only classic detectors (quadrupole) but also target mass spectrometers (triple quadrupole) and accurate mass instruments (quadrupole–time of flight). This unit covers sample preparation from mammalian samples, data acquisition, quality control, and data processing. © 2016 by John Wiley & Sons, Inc.
Human FEZ1 has characteristics of a natively unfolded protein and dimerizes in solution

The fasciculation and elongation protein Zeta 1 (FEZ1) is the mammalian orthologue of the Caenorhabditis elegans protein UNC‐76, which is necessary for axon growth. Human FEZ1 interacts with Protein Kinase C (PKC) and several regulatory proteins involved in functions ranging from microtubule associated transport to transcriptional regulation. Theoretical prediction, circular dichroism, fluorescence spectroscopy, and limited proteolysis of recombinant FEZ1 suggest that it contains disordered regions, especially in its N‐terminal region, and that it may belong to the group of natively unfolded proteins. Small angle X‐ray scattering experiments indicated a mainly disordered conformation, proved that FEZ1 is a dimer of elongated shape and provided overall dimensional parameters for the protein. In vitro pull down experiments confirmed these results and demonstrated that dimerization involves the N‐terminus. Ab‐initio 3D low resolution models of the full‐length conformation of the dimeric constructs 6xHis‐FEZ1(1‐392) and 6xHis‐FEZ1(1‐227) were obtained. Furthermore, we performed in vitro phosphorylation assays of FEZ1 with PKC. The phosphorylation occurred mainly in its C‐terminal region, and does not cause any significant conformational changes, but nonetheless inhibited its interaction with the FEZ1 interacting domain of the protein CLASP2 in vitro. The C terminus of FEZ1 has been reported to bind to several interacting proteins. This suggests that FEZ1 binding and transport function of interacting proteins may be subject to regulation by phosphorylation. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Measurement of breathlessness during exercise in asthmatics. Predictor variables, reliability, and responsiveness.

The purpose of this study was to determine the predictor variables for breathlessness and to investigate the criteria of reliability and responsiveness for measuring breathlessness during progressive, incremental exercise on the cycle ergometer. We studied a heterogeneous group of patients with stable asthma (mean +/- SEM age, 46 +/- 4 yr) for four visits at weekly intervals. Predictor variables were determined at the first visit. Nine independent physiologic variables were obtained at each minute during exercise; the Borg rating of breathlessness (range 0 to 10) was used as the dependent variable. The regression model relating the physiologic parameters to the Borg rating of breathlessness was highly significant (model F = 43.4; p = 0.0001). Backward elimination selected the strongest predictors of the Borg rating: peak inspiratory flow (VI); tidal volume (VT)/FVC; frequency of respiration (f); and peak inspiratory mouth pressures (Pm). These four variables explained 63% of the variance in the rating of dyspnea. Each of the four variables exhibited a linear relationship with the Borg rating. Test-retest reliability was assessed by comparing results at the first and second visits. Individual slopes (except for VT/FVC) and intercepts for the four predictor variables versus Borg ratings were highly reliable. The slope for work intensity (watts) and Borg ratings, but not the intercept, was highly reliable. Responsiveness was evaluated by randomly administering inhaled methacholine or inhaled metaproterenol, alternately, at the third and fourth visits to induce acute changes in lung function before exercise. (ABSTRACT TRUNCATED AT 250 WORDS)
Connexin43, the major gap junction protein of astrocytes, is down‐regulated in inflamed white matter in an animal model of multiple sclerosis

Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter, leading to demyelination and axonal damage. Changes in astrocytic morphology and function are also prominent features of MS and EAE. Resting astrocytes form a network that is interconnected through gap junctions, composed mainly of connexin43 (Cx43) protein. Although astrocytic gap junctional connectivity is known to be altered in many CNS pathologies, little is known about Cx43 expression in inflammatory demyelinating disease. Therefore, we evaluated the expression of Cx43 in spinal cords of EAE mice compared with healthy controls. Lumbar ventral white matter areas were heavily infiltrated with CD11β‐immunoreactive monocytes, and within these infiltrated regions loss of Cx43 immunoreactivity was evident. These regions also showed axonal dystrophy, demonstrated by the abnormally dephosphorylated heavy‐chain neurofilament proteins. Astrocytes in these Cx43‐depleted lesions were strongly glial fibrillary acidic protein reactive. Significant loss (38%) of Cx43 protein in EAE mouse at the lumbar portion of spinal cords was confirmed by Western blot analysis. Decreased Cx43 transcript level was also observed on cDNA microarray analysis. In addition to changes in Cx43 expression, numerous other genes were altered, including those encoding adhesion and extracellular matrix proteins. Our data support the notion that, in addition to damage of myelinating glia, altered astrocyte connectivity is a prominent feature of inflammatory demyelination. © 2005 Wiley‐Liss, Inc.
Acetaminophen Availability Increases in Canada with No Increase in the Incidence of Reports of Inpatient Hospitalizations with Acetaminophen Overdose and Acute Liver Toxicity

In September 1999, several Canadian provinces had place-of-sale restrictions lifted that had limited the sale of acetaminophen >325 mg and packages >24 tablets (any strength) to pharmacies only. This allowed the sale of all strengths of immediate-release acetaminophen in all package sizes in nonpharmacy locations. This study’s purpose was to explore the effect that lifting restrictions on acetaminophen place of sale may have had on reported hospitalizations in Canada related to acetaminophen overdose toxicity. Using hospital discharge data, provinces with no preexisting restrictions on place of sale were compared with those in which restrictions were lifted in September 1999. Cases of reported APAP overdose included ICD-9/9-CM code 965.4, ICD-9 code E850.2, or ICD-9-CM code E850.4. Cases with reported acute liver toxicity included ICD-9/9-CM codes 570, 572.2, 572.4, V42.7, or procedure code 50.5. There were no significant differences between the 1.5-year periods pre– and post–September 1999 in annual incidence rates per 100,000 persons ages ≥12 years of hospitalizations reported with acetaminophen overdose, either overall or limited to those with death as an outcome, or in hospitalization reports with both acetaminophen overdose and acute liver toxicity, either overall (provinces with no restrictions: pre = 0.70, post = 0.80, P = 0.6328; provinces with restrictions lifted in September 1999: pre = 0.49, post = 0.47, P = 0.8649) or limited to those with death as an outcome (provinces with no restrictions: pre = 0.22, post = 0.12, P = 0.3030; provinces with restrictions lifted in September 1999: pre = 0.13, post = 0.09, P = 0.3589). In conclusion, the decision to lift Canadian place-of-sale restrictions increased acetaminophen availability and did not increase the rate of reported hospitalizations related to acetaminophen overdose toxicity.