Clinical landscape of LAG-3-targeted therapy.

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.

Effect of the charge state on bare monoicosahedral [Au13]z+ and diphosphine-protected Au13 clusters [Au13(dmpe)5Cl2]z+: structural, electronic and vibrational DFT studies.

In this paper a GGA-PBE study of [Au13]z+ bare clusters (z = +3, +5) and diphosphine protected [Au13(dmpe)5Cl2]z+ clusters (z = 1, 3) is presented. To explore the application of the [Au13((P(CH3)2CH2)2)5Cl2]3+ cluster as a cisplatin carrier, we have evaluated the adsorption energy of one cisplatin dimer interacting with the complex (0.53 eV). By considering a 1+ charge state, we have determined one cluster featuring a slight reduced HOMO-LUMO gap, with an inner Au13 core heavily distorted (strong charge effects). It is found that the filling/distribution of the superatomic energy levels is affected by the addition of two electrons to the [Au13(dmpe)5Cl2]3+ cluster with a reduction of its symmetry (C1 point group). In addition, the calculated IR and Raman spectra of charged [Au13(dmpe)5Cl2]z+ clusters allow distinguishing them.

Estereolitografía: conceptos básicos / Stereolithography: basic concepts

La Estereolitografía es un sistema de prototipado rápido por el cual se obtienen modelos sólidos en tres dimensiones, a través del procesamiento de datos obtenidos de la tomografía computarizada o la imagen por resonancia magnética. Esta técnica posee una variedad de aplicaciones en el campo de la medicina y la odontología, específicamente en el diagnóstico y planificación de tratamiento quirúrgico de las deformidades faciales, reconstrucciones óseas, dentales y de la Articulación Temporo-mandibular, etc. Estos modelos sirven también como registros o documentos físicos de la historia clínica de los pacientes y para educar e informar al paciente sobre el desarrollo del tratamiento. Por otro lado, el equipamiento es costoso, puede haber errores en el tamaño real o presencia de pseudoforámenes en algunas estructuras óseas delgadas. Otra desventaja, es que no se pueden reconstruir tejidos blandos, por lo tanto, su uso en reconstrucciones faciales es muy limitado.

The Stereolytography is a Fast Prototyping System andfrom which are obtained solid and three -dimension models, trough data processing from Computed Tomography and Resonance Magnetic Image. This technique has a variety of applications in medicine, dentistry fields, specifically in diagnostic and surgery treatment plan of facial deformities, bone, dental, and Temporo Mandibular Joint reconstructions, etc. These models are made, too, as physic record or document of a patients clinic history and for teaching and reporting to the patient about the treatment development. By the other hand, equipment is expensive, real size mistakes or pseudoforamina of some thin bone structures can appear. Another disadvantage, soft tissue can't be reconstructed, by the way, its use in facial reconstructions is very limited.

Astaxanthin production by Phaffia rhodozyma and Haematococcus pluvialis: a comparative study.

Phaffia rhodozyma (now Xanthophyllomyces dendrorhous) and Haematococcus pluvialis are known as the major prominent microorganisms able to synthesize astaxanthin natural pigment. Important research efforts have been made to determine optimal conditions for astaxanthin synthesis. When the focus is on astaxanthin production, the maximal reported value of 9.2 mg/g cell is obtained within H. pluvialis grown on BAR medium, under continuous illumination (345 micromol photon m(-2) s(-1)) and without aeration. Whereas fermentation by mutated R1 yeast grown on coconut milk produced 1,850 microg/g yeast. However, when looking at astaxanthin productivity, the picture is slightly different. The figures obtained with P. rhodozyma are rather similar to those of H. pluvialis. Maximal reported values are 170 microg/g yeast per day with a wild yeast strain and 370 microg/g yeast per day with mutated R1 yeast. In the case of H. pluvialis, maximal values ranged from 290 to 428 microg/g cell per day depending on the media (BG-11 or BAR), light intensity (177 micromol photon m(-2) s(-1)), aeration, etc. The main aim of this work was to examine how astaxanthin synthesis, by P. rhodozyma and H. pluvialis, could be compared. The study is based on previous works by the authors where pigment productions have been reported.

Haematococcus pluvialis cultivation in split-cylinder internal-loop airlift photobioreactor under aeration conditions avoiding cell damage.

The effects of superficial gas velocity in the riser (U(Gr)) and gas entrance velocity (v) on the growth of Haematococcus pluvialis cultivated in a split-cylinder internal-loop airlift photobioreactor were investigated. Cell growth decreased when U(Gr) and v were increased above 12 mm s(-1) and 22.8 m s(-1), respectively. The maximum cell density of H. pluvialis was 110 x 10(4) vegetative cells ml(-1) and the chlorophyll-a titer was 7 mg l(-1). The cell damage in the photobioreactor was greater when v was increased by an increase in U(Gr) rather than by a decrease in sparger internal diameter. The overall volumetric mass transfer coefficient (k(L)a) of the photobioreactor was measured at the same U(Gr) (6-24 mm s(-1)) and v (12-80 m s(-1)). The k(L)a values reached in the airlift photobioreactor were between 10 h(-1) and 32 h(-1).

Astaxanthin hyperproduction by Phaffia rhodozyma (now Xanthophyllomyces dendrorhous) with raw coconut milk as sole source of energy.

Natural carbon sources, such as those present in cane sugar molasses and grape juice, promote the synthesis of astaxanthin in different Phaffia rhodozyma yeasts. One of these, coconut milk, has a very rich nutrient composition. The aim of this work was to investigate the utility of coconut milk as sole source of energy for astaxanthin pigment production by P. rhodozyma strains. Currently, coconut pulp is widely used in industrial processes in Mexico for the production of shampoos, candies, food, etc. However, coconut milk is a waste product. We show that coconut milk enhances astaxanthin production. The fermentation yielded 850 microg/g yeast with the NRRL-10921 wild-type strain and 1850 microg/g yeast with the mutated R1 strain. Production was better than reported results employing other natural carbon sources.

Influence of environmental and nutritional factors in the production of astaxanthin from Haematococcus pluvialis.

Astaxanthin extracted from green algae is desirable in the food and pharmaceutical industries due to its antioxidant properties. The green unicellular clear water microalga Haematococcus pluvialis has a high production rate of astaxanthin; indeed, it contains more than 80% astaxanthin content in its cells. This remarkable astaxanthin production is commonly obtained under stress conditions such as nutrient deficiency (N or P), high NaCl concentrations, variations of temperature, and other factors. In this vein, a great research effort has been oriented to determine optimal conditions for astaxanthin production by H. pluvialis. The objective of the present study was the analysis of environmental factors, such as light intensity, aeration and nutrients on the growth and astaxanthin production of H. pluvialis. Maximum growth of H. pluvialis obtained was 3.5x10(5) cells/ml in BBM medium at 28 degrees C under continuous illumination (177 micromol photon m(-2)s(-1)) of white fluorescent light, with continuous aeration (1.5 v.v.m.). Meanwhile, maximal astaxanthin production was 98 mg/g biomass in BAR medium with continuous illumination (345 micromol photon m(-2)s(-1)), with 1 g/l of sodium acetate and without aeration.

Diets containing a high percentage of Nori or Konbu algae are well-accepted and efficiently utilised by growing rats but induce different degrees of histological changes in the liver and bowel.

The consumption of algae has increased considerably in recent years. However, the nutritional consequences of the algae consumption have scarcely been studied and there are some indications of serious adverse effects of algae consumption in children and adolescents. This study aims to assess the effects of balanced diets containing 7% algae (Nori or Konbu) for 3 weeks on (i) dietary intake, growth, and dietary efficiency ratio (DER), (ii) absolute absorption of several minerals, and (iii) size and histology of the liver, spleen, kidney, heart and bowel of growing rats. All rats were fed a diet containing 93% casein-soybean oil-base. The remaining 7% of the diet consisted of a cellulose/wheat starch mix (35/65) in control rats, freeze-dried Nori (33.8% fibre) in that of the Nori group and freeze-dried Konbu (36.1% fibre) in rats fed Konbu. Food intake was similar in all groups. Body weight gain and DER, however, were somewhat lower in the Konbu group than the other groups but this effect was not statistically significant. The algae diets had a higher content of most of the minerals studied and with some exceptions alga fed rats also presented a higher absolute absorption of these minerals than control. There was no effect of algae consumption on organ weight except that the spleen weight, whose size appeared to be related to the dietary Na/K ratio, was significantly lower in the Konbu fed rats than in the other groups. Histological analyses did not demonstrate any remarkable changes in the kidneys, spleen or heart. However, the incidence of non-dense glycogen-like vacuole presence observed in livers of the Nori rats was significantly higher (P<0.05) than in Konbu and control rat livers. The Nori fed rats had a higher incidence of submucosal oedema than the Konbu fed rats, which may be related to the higher Na/K ratio in the Nori diet. Konbu rats had a lower score for most of the various histological parameters than Nori and control animals suggesting that Konbu is preferable to that of Nori. Further studies are needed to investigate the positive and negative effects of large-scale consumption of Nori and Konbu algae.

High-frequency FSH and LH pulses in obese menopausal women.

We studied the pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretory patterns, at early or intermediate years of menopause in seven normal women with different degrees of obesity, taking blood samples every minute for 40 min to 2 h. The hormones were assayed with an immunoradiometric assay (IRMA) system, analyzing with the cluster pulse algorithm. All women showed hormone pulses every 8-10 min. In five of them were found periods of discrete pulses with oscillations of high amplitude alternating with periods of pulses of low amplitude. In two cases, the high-frequency oscillatory pattern with low amplitude was found around low mean levels of 22.8 and 25.7 IU/L. The LH oscillatory pattern also had a high frequency, but at a lower level, giving a high FSH/LH ratio. The coincidence index of FSH with LH peaks was 76.6%. We concluded that at menopause, the frequency of FSH and LH secretion increases with a high FSH/LH ratio. Obese menopausal women may have the same high-frequency oscillatory patterns, but at low levels.

Glutathione status and sensitivity to GSH-reacting compounds of Escherichia coli strains deficient in glutathione metabolism and/or catalase activity.

The intracellular concentrations of total glutathione, GSSG and protein X S-SG, the total excreted glutathione concentration, and the susceptibility towards GSH-reacting compounds were assayed in strains of Escherichia coli deficient in biosynthesis and/or reduction of glutathione. A deficiency in glutathione reductase displaced the glutathione status towards the oxidized forms. This displacement was more clearly appreciated in strains additionally deficient in glutathione biosynthesis. A deficiency in catalase activity also produced an increase in the oxidation of glutathione. The most severe changes were observed in the concentrations of protein-glutathione mixed disulfides and in the amount of glutathione excreted to the medium. Increased sensitivities towards compounds known to interact with cellular GSH were observed in glutathione reductase deficient strains, although these effects were enhanced in strains additionally deficient in GSH biosynthesis.