Additive Manufacturing of CrFeNiTi Multi-Principal Element Alloys.

High entropy alloys (HEAs) and their closely related variants, called multi-principal element alloys (MPEAs), are the topic of a rather new area of research, and so far, the gathered knowledge is incomplete. This is especially true when it comes to material libraries, as the fabrication of HEA and MPEA samples with a wide variation in chemical compositions is challenging in itself. Additive manufacturing technologies are, to date, seen as possibly the best option to quickly fabricate HEA and MPEA samples, offering both the melting metallurgical and solid-state sintering approach. Within this study, CrFeNiTi MPEA samples were fabricated via laser powder-bed fusion (PBF-LB) and solid-state sintering of mechanically alloyed powder feedstock. The main emphasis is on the PBF-LB process, while solid-state sintering serves as benchmark. Within a volumetric energy density (VED) window of 50 J/mm3 to 83 J/mm3, dense samples with large defect-free sections and an average micro-hardness of 965 HV0.1 were fabricated. Clear correlations between the local chemical alloy composition and the related micro-hardness were recorded, with the main factor being the evaporation of titanium at higher VED settings through a reduction in the C14_Laves phase fraction.

Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration.

Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytically activated immune cells often become anergic, leading to an increase in immune checkpoint proteins such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Therefore, using a nanoparticle-delivered agent to preferentially inhibit glycolysis in tumor cells, and not in immune cells, has the potential to attenuate the expression of checkpoint proteins. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) containing a prodrug of dichloroacetate (DCA), a PDK1 inhibitor. We demonstrated that the targeted NP alters the TME which results in increased immunological activation against cancer cells, causing a decrease in mean tumor volume. Here, we also show findings that when Mito-DCA, a prodrug of DCA, was combined with anti-PD-1, a checkpoint inhibitor, results from in vivo syngeneic models showed an upregulation in the number of tumor infiltrating lymphocytes. This work provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells.

Development of a neural rosette formation assay (RoFA) to identify neurodevelopmental toxicants and to characterize their transcriptome disturbances.

The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpoints. To address this issue, we developed a new version of the human stem cell-based test STOP-tox(UKN). For this purpose, the capacity of the cells to self-organize to neural rosettes was assessed as functional endpoint: pluripotent stem cells were allowed to differentiate into neuroepithelial cells for 6 days in the presence or absence of toxicants. Then, both transcriptome changes were measured (standard STOP-tox(UKN)) and cells were allowed to form rosettes. After optimization of staining methods, an imaging algorithm for rosette quantification was implemented and used for an automated rosette formation assay (RoFA). Neural tube toxicants (like valproic acid), which are known to disturb human development at stages when rosette-forming cells are present, were used as positive controls. Established toxicants led to distinctly different tissue organization and differentiation stages. RoFA outcome and transcript changes largely correlated concerning (1) the concentration-dependence, (2) the time dependence, and (3) the set of positive hits identified amongst 24 potential toxicants. Using such comparative data, a prediction model for the RoFA was developed. The comparative analysis was also used to identify gene dysregulations that are particularly predictive for disturbed rosette formation. This 'RoFA predictor gene set' may be used for a simplified and less costly setup of the STOP-tox(UKN) assay.

Congenital hydrocephalus in a Belgian draft horse associated with a nonsense mutation in B3GALNT2.

Congenital hydrocephalus has been reported for a number of horse breeds, and for Friesian horses this condition has been associated with a nonsense mutation of B3GALNT2. We report the first case of congenital hydrocephalus associated with the said mutation in a Belgian draft horse. Genetic testing and consideration of the testing results in breeding programs are warranted.

Hydrocéphalie congénitale chez un cheval de trait Belge associée à une mutation non-sens de B3GALNT2. L'hydrocéphalie congénitale a été signalée pour plusieurs races de chevaux et, pour les chevaux Frisons, cette affection a été associée à une mutation non-sens de B3GALNT2. Nous signalons le premier cas d'hydrocéphalie congénitale associée à cette mutation chez un cheval de trait Belge. Les tests génétiques et la considération des résultats des tests sont justifiés dans le cadre des programmes d'élevage.(Traduit par Isabelle Vallières).

Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity.

Cisplatin is a major chemotherapeutic that continues to have a significant impact in the treatment of more than 50% of all cancers. Since its Food and Drug Administration approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity- and nausea-related side effects, but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin- A, a prodrug of cisplatin and aspirin, using preclinical mouse- and guinea pig-based models and demonstrated its efficacy with reduced ototoxicity. In addition, in vitro studies documented that when Platin- A is used in combination with a clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bioenergetic profiles, producing multiple modes of DNA damage, and delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin- A, highlighting its superior efficacy with reduced toxicity.

Seminal plasma does not aid in the transport of phenolsulfonphthalein across the uterotubal junction in mares.

This study tested the hypothesis that the presence of prostaglandin E2 in seminal plasma would aid in the transport of phenolsulfonphthalein (PSP) across the uterotubal junction. Five mares in estrus were inseminated during estrus with PSP dissolved in phosphate-buffered saline and during the subsequent estrus with PSP added to a standard insemination dose. Serum and urine samples were obtained at hours 0, 1, 2, and 3 following treatment and examined for the presence of PSP. Phenolsulfonphthalein could not be detected in any of the urine samples collected from mares following either treatment. None of the serum samples collected following intrauterine installation of PSP in PBS contained PSP. Phenolsulfonphthalein was detected in serum samples from 1 mare following insemination with semen containing PSP. Components in seminal plasma such as PGE2 did not facilitate the transport of PSP across the uterotubal junction as had been hypothesized.

Le plasma séminal ne facilite pas le transport de la phénolsulfonphtaléine au travers de la jonction utéro-tubaire des juments. Cette étude a testé l'hypothèse voulant que la présence de la prostaglandine E2 dans le plasma séminal facilite le transport de la phénolsulfonphtaléine (PSP) au travers de la jonction utéro-tubaire. Cinq juments en oestrus ont été inséminées avec de la PSP dissoute dans une solution saline tamponnée au phosphate et, durant l'oestrus subséquent, avec de la PSP ajoutée à une dose d'insémination standard. Des prélèvements de sérum et d'urine ont été obtenus aux heures 0, 1, 2 et 3 ainsi qu'après le traitement et examinés pour déceler la présence de la PSP. La phénolsulfonphtaléine n'a pas pu être détectée dans aucun des échantillons d'urine prélevés auprès des juments après l'un ou l'autre des traitements. Aucun des échantillons de sérum prélevés après l'installation intra-utérine de la PSP dans PBS ne contenait de PSP. La phénolsulfonphtaléine a été détectée dans des échantillons de sérum provenant d'une jument après l'insémination avec du sperme contenant de la PSP. Des composants dans le plasma séminal comme le PGE2 n'ont pas facilité le transport de la PSP au travers de la jonction utéro-tubaire conformément à l'hypothèse émise.(Traduit par Isabelle Vallières).

Efficacy and clinical safety of pegbovigrastim for preventing naturally occurring clinical mastitis in periparturient primiparous and multiparous cows on US commercial dairies.

Periparturient dairy cows experience impaired immune function, exhibited as a transient decrease in neutrophil function. This decrease in immune competence is associated with an increase in susceptibility to bacterial infections, including mastitis and metritis. Bovine granulocyte colony stimulating factor (bG-CSF) is an endogenous protein that enhances neutrophil bactericidal functions and increases the production of neutrophils from bone marrow precursors. Administration of pegbovigrastim (recombinant bG-CSF covalently bound to polyethylene glycol) around the time of calving has been shown to reduce the incidence of new clinical mastitis cases in a natural disease model system. To further explore the application of pegbovigrastim under herd management systems typical of those found in the US dairy industry, we conducted a multicenter field study to evaluate the efficacy and clinical safety of pegbovigrastim administered to multiparous cows and heifers approximately 7 d before calving and within 24 h of calving. Responses of treated cows were compared with those of animals treated with sterile saline. Animals treated with pegbovigrastim exhibited 4- to 5-fold increases in circulating neutrophil numbers within 24 h of treatment initiation, and this increase persisted at least a week beyond the second dose. Pegbovigrastim-treated animals exhibited a 35% decrease in the incidence of clinical mastitis relative to the controls during the first 30 d of lactation. Animals treated with pegbovigrastim also exhibited a 52% reduction in failure to return to visual estrus within 80 d of calving. We observed no differences in somatic cell count or milk composition between treated and control animals. We also found no differences in the duration of pregnancy or proportion of viable calves in treated cows relative to control animals. These results indicate that administration of pegbovigrastim provides a well-tolerated, novel approach to overcoming periparturient immune suppression, resulting in reduced susceptibility to clinical mastitis during early lactation.

Acute brachial diplegia due to Lyme disease.

OBJECTIVE: to describe acute brachial diplegia as the initial manifestation of Lyme disease. BACKGROUND: bilateral, predominantly motor, cervical radiculoplexus neuropathy, the "dangling arm syndrome," has not been reported as a complication of acute Lyme infection. METHODS: retrospective series of 5 patients from 2 tertiary neuromuscular centers. RESULTS: there were 4 men and 1 woman with an average age of 69 years. One recalled a tick bite, and preceding constitutional symptoms included headache (2) and fever, arthralgias, and fatigue in 1 patient each. Proximal arm weakness and acute pain developed within 3 weeks from onset; pain was bilateral in 3 patients and unilateral in 2 patients, and was described as severe throbbing. Arm weakness was bilateral at onset in 3 patients, and right sided in 2 patients followed by spread to the left arm within days. All the patients had weakness in the deltoid and biceps that was 3/5 or less (Medical Research Council scale), with variable weakness of the triceps and wrist extensors; 1 patient had a flail right arm and moderate (4/5) weakness of the proximal left arm muscles. Light touch was normal in the regions of weakness, and 1 patient had mildly reduced pin sensation over the forearm. Serum IgM Lyme titers were elevated in all the patients and were detected in the cerebrospinal fluid in 4 tested patients. The cerebrospinal fluid protein ranged between 135 and 176 mg/dL with lymphocytic pleocytosis (range, 42 to 270 cells). Electrodiagnostic studies showed normal median and ulnar motor potentials with asymmetrically reduced sensory amplitudes in the median (4), ulnar (3), and radial, and lateral antebrachial cutaneous potentials in 1 patient each. Two patients had acute denervation in the cervical or proximal arm muscles. There was full recovery after antibiotic therapy in 4 patients and considerable improvement in 1 patient after 2 months. CONCLUSION: acute brachial diplegia is a rare manifestation of acute Lyme infection and responds promptly to antibiotic therapy.

Cerebral lesions incidentally detected on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography images of patients evaluated for body malignancies.

OBJECTIVES: The purpose of this work was done to evaluate the value of including the brain in the field of view of a whole-body 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography (FDG-PET) study of patients referred for the evaluation of body malignancies. METHODS: A total of 1026 consecutive patients were included in this work. The primary diagnoses were the following: lung (n = 253), colorectal (n = 148), head and neck (n = 61), lymphoma (n = 249), melanoma (n = 84), and others (n = 231). Whole-body FDG images including the brain were acquired with a dedicated PET tomograph (GE advance, General Electronic Medical Systems, Milwaukee, WI) one hour after the intravenous administration of 10 mCi of FDG. Two experienced nuclear medicine physicians interpreted the images. Positive findings in the brain or the skull were correlated with other imaging studies and clinical follow-up. RESULTS: Abnormal findings were detected in 3.9% (40/1026) of the patients. Among the 40 abnormal focal lesions, 29 patients had a known history of cerebral disease, cerebrovascular or metastatic disease in most patients. Of the 11 patients without a prior history of cerebral disease, four patients had increased focal FDG uptake suggestive of metastases. Among these, two were proven clinically, one was proven to be a skull base metastasis on MRI, and the other had negative clinical follow-up, but only of two months duration. The other seven patients had a decreased focal FDG uptake most consistent with infarct, one was proven clinically, and the other six had a negative clinical follow-up (mean of 6.3 months, range 1-10), but had multiple risk factors for cerebrovascular disease. CONCLUSIONS: We conclude that FDG-PET screening for cerebral lesions in patients with body malignancy has little clinical impact. Unsuspected cerebral or skull metastases were detected in 0.4% (4/1026) of the patients.

Psicología de las organizaciones: problemas contemporáneos / Organizational psychology: readings on human behavior in organization

Este libro se propone ser fuente de material fundamental de psicología de las organizaciones para quienes estudien, a cualquiera de los tres niveles posibles la administración de empresas. Figuran aquí trabajos de numerosos autores que han contribuido a nuestra comprensión de la conducta humana tanto en grupos como en organizaciones

Psicología de las organizaciones: experiencia / Organizational psichology: an experimental approach

Este libro trata de comunicar ciertos principios generales de psicología y pericia de posible aplicación en sociedades y empresas. La ciencia intenta aclarar una realidad concreta descubriendo las leyes y los principios generales que determinan esa realidad. La generalización da sentido al caso concreto, pero el caso sitúa la generalización en el mundo real; la hace aplicable. El experimentar situaciones sociales para después analizar tal experiencia produce el enlace eficaz de generalización y realidad concreta