Characterisation and traceability of extra virgin olive oil and table olive of Azapa variety marketed in Chile using Microsatellite Molecular Markers / Caracterización y trazabilidad de aceite de oliva virgen extra y aceituna de mesa de la variedad Azapa comercializados en Chile mediante marcadores moleculares microsatélites

Chile has two certified origin olive products: Extra-Virgin Olive Oil (EVOO) from Huasco valley and the Azapa variety table olive from the Azapa valley. However, efficient methodologies are needed to determine the varieties and raw materials involved in the end products. In this study, we assessed the size of alleles from ten microsatellites in 20 EVOOs and in leaves and fruits of 16 olive varieties cultivated in Chile to authenticate their origins. The identification of varieties relied on specific allele sizes derived from microsatellites markers UDO99-011 and DCA18-M found in leaves and fruit mesocarp. While most Chilean single-variety EVOOs matched the variety declared on the label, inconsistencies were observed in single-variety EVOOs containing multiple varieties. Our findings confirm that microsatellites serve as a valuable as diagnostic tools for ensuring the quality control of Geographical Indication certification for Azapa olives and EVOO with Designation of Origin from Huasco.

Chile cuenta con dos productos de oliva de origen certificado: El aceite de oliva virgen extra (AOVE) del valle del Huasco y la aceituna de mesa de la variedad Azapa del valle de Azapa. Sin embargo, se necesitan metodologías eficientes para determinar las variedades y materias primas involucradas en los productos finales. En este estudio, evaluamos el tamaño de los alelos de diez microsatélites en 20 AOVEs y en hojas y frutos de 16 variedades de aceituna cultivadas en Chile para autentificar sus orígenes. La identificación de las variedades se basó en los tamaños alélicos específicos derivados de los marcadores microsatélites UDO99-011 y DCA18-M encontrados en las hojas y el mesocarpio de los frutos. Aunque la mayoría de los AOVEs chilenos monovarietales coincidían con la variedad declarada en la etiqueta, se observaron incoherencias en los AOVEs monovarietales que contenían múltiples variedades. Nuestros hallazgos confirman que los microsatélites sirven como valiosas herramientas de diagnóstico para asegurar el control de calidad de la certificación de Indicación Geográfica para aceitunas de Azapa y AOVE con Denominación de Origen de Huasco.

Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo.

Dysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.

The Impact of Mild Frost Occurring at Different Harvesting Times on the Volatile and Phenolic Composition of Virgin Olive Oil.

The organoleptic characteristics of virgin olive oil (VOO), together with its nutritional and health properties, have led the olive tree to be cultivated beyond the Mediterranean basin, reaching latitudes with colder climates, with minimum temperatures below 0 °C and with a higher probability of early frosts. The freezing of olives generates destruction within the tissues and promotes degradation reactions. In this study, the impact of mild frost occurring at different harvesting times on the composition of volatiles and phenolic compounds in VOO were investigated. Arbequina variety olives were harvested at different stages of ripening. Half of the olives were subjected to oil extraction and the other half were frozen at -3 ± 1 °C for 12 h prior to oil extraction. A significant decrease of phenolic compounds with harvesting time was observed in both types of oils (fresh and frozen olives). Oils from frozen olives presented a slightly higher content of total phenols, except in the advanced ripening stage (September), and a slightly lower content of volatile compounds at all harvesting times. In addition, a higher content of 3,4-DHPEA-EDA was observed in oils from frozen olives, which is attributed to an early action of the endogenous ß-glucosidase enzyme on oleuropein in freeze-damaged olive fruits. Principal component analysis and Discriminant Partial Least Square Regression allowed the oils to be classified according to the type of fruit (fresh and frozen) and the month of harvest. This study would indicate that mild frost would have a low impact on the chemical composition of virgin olive oil, although, this depends on the ripening stage.

Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo.

Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC50 0.38-0.98 µM) over Stat1 or Stat5 (IC50 > 15.8 µM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo.

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of (R)-azetidine-2-carboxamide analogues that have sub-micromolar potencies. 5a, 5o, and 8i have STAT3-inhibitory potencies (IC50) of 0.55, 0.38, and 0.34 µM, respectively, compared to potencies greater than 18 µM against STAT1 or STAT5 activity. Further modifications derived analogues, including 7e, 7f, 7g, and 9k, that addressed cell membrane permeability and other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with KD of 880 nM (7g) and 960 nM (9k). 7g and 9k inhibited constitutive STAT3 phosphorylation and DNA-binding activity in human breast cancer, MDA-MB-231 or MDA-MB-468 cells. Furthermore, treatment of breast cancer cells with 7e, 7f, 7g, or 9k inhibited viable cells, with an EC50 of 0.9-1.9 µM, cell growth, and colony survival, and induced apoptosis while having relatively weaker effects on normal breast epithelial, MCF-10A or breast cancer, MCF-7 cells that do not harbor constitutively active STAT3.

Removal of nickel(II) from wastewater using a zeolite-packed anaerobic bioreactor: Bacterial diversity and community structure shifts.

In recent years, overexploited industrialization and urbanization activities have led to significant amounts of heavy metals released into the environment. Metal ion contamination of water, especially with toxic metals such as nickel(II) [Ni(II)], which is extensively applied in the electroplating industry, has been a serious problem. The aim of the present study was to evaluate the Ni(II) removal from real industrial wastewater using a 2 L, lab-scale, up-flow, anaerobic, zeolite-packed bioreactor inoculated with a heterotrophic consortium as the bioadsorbent. High-throughput sequencing of 16S rRNA genes revealed significant shifts in their bacterial diversity and structural composition along the bioreactor treatment location, where the bacterial genus was dominated by Kosmotogae followed by Firmicutes as Ruminococcus and Clostridium. However, Fervidobacterium and the Geobacter genus were absent at the end of the bioreactor treatment, suggesting that they play a key role in the beginning of Ni(II) removal anaerobic treatment. The physico-chemical results revealed that the Ni(II) removal rate was 99% for 250-500 ppm metal tested, with an efficient alkalinity rate and high production of biogas, which confirmed that anaerobic digestion of microorganisms was successfully performed through the process. Finally, this anaerobic bioreactor configuration offers an accessible and ecofriendly high-rate metal removal strategy from mining and electroplating effluents.

Las medusas en los balnearios de la provincia de Buenos Aires / The jellyfish species in the coastal waters of Buenos Aires province

Resumen Las medusas son organismos mayoritariamente marinos pertenecientes al grupo de los cnidarios, los cuales se caracterizan por presentar células urticantes especializadas, los cnidocitos. Si bien, todas las medusas son potencialmente venenosas y el grado de toxicidad depende de la especie, sus efectos sobre los humanos varían desde reacciones locales leves hasta reacciones atópicas-anafilácticas graves, llegando incluso a la muerte de la víctima. Mundialmente se conocen numerosas especies de medusas causantes de envenenamiento a humanos, tales como la avispa de mar (Chironex fleckeri), el sifonóforo carabela portuguesa (Physalia physalis) o el hidrocoral de fuego (Millepora spp.). En Argentina, tres especies de medusas revisten de im portancia clínica epidemiológica debido a su poder urticante: las hidromedusas Liriope tetraphylla y Olindias sambaquiensis, así como la escifomedusa Chrysaora lactea. Estas especies presentan sus mayores abundancias en el verano en las costas bonae renses, coincidiendo con la presencia de turistas durante el periodo vacacional. Sus afectaciones varían de leves a moderadas, registrándose desde parestesias y ardor con dermatitis, prurito, edemas y eritemas. Una infinidad de "remedios caseros" se conocen para remediar los efectos de las picaduras de medusas, sin embargo, la mayoría han resultado ineficaces y perjudiciales. Lo más recomendable es evitar frotar y lavar la zona afectada con agua dulce o aplicar hielo para tratar de contrarrestar el ardor y acudir lo antes posible al centro de salud más cercano.

Abstract Medusae are mainly a marine group belonged to cnidarians, which are characterized by specialized stinging cells, cnidocyts. Although all medusae are potentially poisonous, their toxicity depends on the species and the effects on humans vary- ing from mild local reactions to severe atopic-anaphylactic reactions, even the death of the victim. Numerous species of cnidar ians are known worldwide to affect humans, such as the sea wasp {Chironex fleckeri), the siphonophore portuguese man-of-war (Physaliaphysalis) or the fire-coral (Millepora spp.). In Argentina, three species of medusae are known with clinical epidemiological importance due to their stinging power: the hydromedusae Liriopetetraphylla and Olindias sambaquiensis, as well as the scypho- medusae Chrysaora lactea. These species have their highest abundances in the summer on Buenos Aires coasts, coinciding with the presence of tourists during the summer vacations. Its affectations vary from mild to moderate, registering from paresthesias and burning with dermatitis, itching, edemas, and erythema. An infinity of "home remedies" are known formedusae stings, how- ever, most of them have proven ineffective and harmful. It is best to avoid rubbing and washing the affected area with fresh water or applying ice to try to counteract the burning in the region and to go the health center as soon as possible.

Policondritis recidivante: manifestaciones clínicas y tratamiento / Recurrent polychondritis. Clinical, diagnosis and treatment

La policondritis recidivante es una enfermedad rara caracterizada por la inflamación recurrente del cartílago y otros tejidos en todo el cuerpo. La afectación del oído es la característica más común, pero puede afectar otras áreas del cuerpo, incluidos el cartílago costal, los ojos, la nariz, las vías respiratorias, el corazón, el sistema vascular, la piel, las articulaciones, los riñones y el sistema nervioso. Los signos y síntomas varían de persona a persona según las partes del cuerpo afectadas. La causa subyacente exacta de la policondritis recidivante se desconoce, aunque los científicos sospechan que se trata de una enfermedad autoinmune. Las complicaciones respiratorias (colapso de la tráquea e infecciones) son la causa más común de muerte, seguidas de la afectación cardiovascular. Los objetivos principales del tratamiento son aliviar los síntomas actuales y preservar la estructura del cartílago afectado. Gracias a las mejoras en el tratamiento, en los últimos años las tasas de supervivencia han aumentado, incluso después de 10 años(AU)

Recurrent polychondritis is a rare condition characterized by recurrent inflammation of cartilage and other tissues throughout the body. Ear involvement is the most common feature, but a variety of other areas of the body may be compromised, including costal cartilage, eyes, nose, airways, heart, vascular system, skin, joints, kidneys and nervous system. The signs and symptoms vary from person to person depending on the body parts affected. The exact underlying cause of recurrent polychondritis is unknown; however, scientists suspect it is an autoimmune condition. The main goals of treatment for people with recurrent polychondritis are to alleviate current symptoms and preserve the structure of the affected cartilage(AU)

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer.

Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

Spatial Distribution of Medusa Cunina octonaria and Frequency of Parasitic Association with Liriope tetraphylla (Cnidaria: Hydrozoa: Trachylina) in Temperate Southwestern Atlantic Waters.

This study examined the spatial distribution of the medusae phase of Cunina octonaria (Narcomedusae) in temperate Southwestern Atlantic waters using a total of 3,288 zooplankton lots collected along the Uruguayan and Argentine waters (34-56°S), which were placed in the Medusae collection of the Universidad Nacional de Mar del Plata, Argentina. In addition, we reported the peculiar parasitic association between two hydrozoan species: the polypoid phase (stolon and medusoid buds) of C. octonaria (parasite) and the free-swimming medusa of Liriope tetraphylla (Limnomedusae) (host) over a one-year sampling period (February 2014 to March 2015) in the coasts of Mar del Plata, Argentina. We examined the seasonality, prevalence, and intensity of parasitic infection. Metadata associated with the medusa collection was also used to map areas of seasonality where such association was observed. Cunina octonaria was found from southern Uruguay to the coast of Mar del Plata (34.8-38.2°S, 57.2-54.0°W), with the highest abundances and frequency of occurrence in the Río de la Plata estuary. The parasitic association was identified from the austral warm period (spring-summer season) until mid-autumn. Out of the 21,734 L. tetraphylla specimens that were examined, 316 were parasitized (prevalence = 1.5%) exclusively in the manubrium and gastric peduncle, with an infection intensity of 1 to 2 stolons per host. Furthermore, the medusoid buds per stolon ranged from 11 and 29 at different stages of development. No significant differences were observed between the umbrella diameter of parasitized and non-parasitized L. tetraphylla specimens, nor was any significant correlation identified between umbrella diameter and prevalence, and intensity of infection. According to the aggregation coefficient, C. octonaria had an overdispersed distribution in the host population. All parasitized hosts showed stomach vacuity due to the location of the stolon, which blocked the mouth of the host. We identified the parasitic association in the coasts of Mar del Plata, as well as in both coasts of the Río de la Plata Estuary (Uruguayan-Argentinean coasts). In the Southwestern Atlantic, several biological interactions between medusae and other groups have been identified; however, the specific host selectivity of C. octonaria for L. tetraphylla was not previously identified. Here we discuss the ecological importance of this association during the holoplanktonic life history of the narcomedusae. Additionally, we report the southern limit of the spatial distribution of this particular parasitic association in the Southwestern Atlantic, thus increasing the knowledge of biological associations of gelatinous zooplankton (Cnidaria and Ctenophora) on Uruguayan and Argentinean coasts.

Osteoartrosis. Una revisión de literatura / Osteoarthrosis A literature review

Introducción: la osteoartrosis es la más frecuente de las enfermedades articulares. Objetivo: exponer los referentes bibliográficos que actualmente se refieren a la osteoartrosis en el marco de la revisión de literatura realizada. Desarrollo: como síndrome anatomoclínico se identifica por dolor mecánico que usualmente se relaciona con rigidez y que provoca poco a poco una pérdida o mengua de la función articular. Diversos factores de riesgo se relacionan con el progreso de esta enfermedad entre los que destacan, además de la edad y el sexo femenino, la obesidad, los microtraumas repetitivos en la práctica de determinados deportes y el cumplimiento de actividades profesionales específicas. Conclusiones: el tratamiento de la osteoartrosis debería ejecutarse a nivel de medicina familiar, tanto en el componente preventivo, como en el del control y manejo conservador, instruyendo al paciente en sus cuidados y acciones diarias y operando esquemas de medicamentos, ejercicios, apoyos funcionales como rodilleras, bastones y andadores. La educación médica debe asumir este paradigma, y no solicitar acto seguido la interconsulta a la especialidad cuando el paciente no responde, sin tener en cuenta que el manejo del paciente con artrosis se encuentra distante de la prescripción farmacológica(AU)

Introduction: osteoarthrosis is the most frequent joint disease. Objective: to expose the bibliographic references that currently refer to osteoarthrosis in the framework of the literature review carried out. Development: as anatomoclinic syndrome is identified by mechanical pain that is usually related to stiffness and that gradually causes a loss or decline of joint function. Several risk factors are related to the progress of this disease, among which stand out, in addition to age and female sex, obesity, repetitive microtrauma in the practice of certain sports and compliance with specific professional activities. Conclusions: treatment of osteoarthrosis should be carried out at the level of family medicine, both in the preventive component, as well as in the control and conservative management, instructing the patient in his daily care and actions and operating medication schemes, exercises, functional supports such as knee pads, canes and walkers. The medical education must assume this paradigm, and not immediately request the interconsultation to the specialty when the patient does not respond, without taking into account that the management of the patient with osteoarthritis is distant from the pharmacological prescription(AU)

Los wixáritari con diabetes mellitus y sus vínculos con la enfermedad: desde la aparición del síntoma hasta una primera explicación / Wixáritari with diabetes mellitus and their links with the disease: From the appearance of the symptom to a first explanation

RESUMEN Se recuperó el proceso de construcción del esquema conceptual, referencial y operativo (ECRO) de los wixáritari sobre la diabetes mellitus tipo 2 en una comunidad de Jalisco, México, desde la aparición del primer síntoma hasta una posible explicación de la enfermedad. Se realizó un estudio cualitativo con el método fenomenológico a partir de entrevistas en profundidad para la recolección de información. Se contó con siete participantes. Los datos se procesaron con el método de análisis del discurso de Bajtín, a partir de la teoría del vínculo de Pichon-Rivière. Se encontró que el wixárika con diabetes construye su esquema conceptual, referencial y operativo durante un periodo de tres a cinco años, a partir de tres vínculos: los síntomas en el cuerpo, la explicación del wixárika a sus síntomas, y las explicaciones del espacio social a su enfermedad. El wixárika construye una serie de vínculos y un esquema conceptual, referencial y operativo que le permite validar una explicación de lo que experimenta en el cuerpo, en medio de un proceso confrontativo y doloroso, lleno de afirmaciones y negaciones hasta llegar a una síntesis, que le permita comprender su situación e instrumentar una conducta para el cuidado de su salud.

ABSTRACT This article explores the process of construction of the conceptual, referential and operative schema among the wixáritari population regarding type 2 diabetes mellitus in a community of Jalisco, Mexico, from the appearance of the first symptom to a possible explanation of the disease. This is a qualitative study performed with the phenomenological method using in-depth interviews to collect information. There were seven participants. The data was processed with Bakhtin's discourse analysis, based on Pichon Rivière's theory of the link. It was found that the wixáritari population with diabetes develop their conceptual, referential and operative schema over a period of three to five years, based on three links: the symptoms in the body, the explanation the wixáritari give regarding their symptoms, and the explanations of the social space of the disease. The wixáritari develop a series of links and conceptual, referential and operative schema that allow them to validate an explanation of what they experience in their body, in a confrontational and painful process full of affirmations and denial until reaching a synthesis that allows them to achieve a full understanding of their situation and implement behaviors to care for their health.

Linker Variation and Structure-Activity Relationship Analyses of Carboxylic Acid-based Small Molecule STAT3 Inhibitors.

The molecular determinants for the activities of the reported benzoic acid (SH4-54), salicylic acid (BP-1-102), and benzohydroxamic acid (SH5-07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH2 group of the glycinamide scaffold were separately modified. The replacement of the pentafluorobenzene or cyclohexylbenzene, or replacing the benzene ring of the aromatic carboxylic or hydroxamic acid motif with heterocyclic components (containing nitrogen and oxygen elements) all decreased potency. Notably, the Ala-linker analogues, 1a and 2v, and the Pro-based derivative 5d, all with (R)-configuration at the chiral center, had improved inhibitory activity and selectivity against STAT3 DNA-binding activity in vitro, with IC50 of 3.0 ± 0.9, 1.80 ± 0.94, and 2.4 ± 0.2 µM, respectively. Compounds 1a, 2v, 5d, and other analogues inhibited constitutive STAT3 phosphorylation and activation in human breast cancer and melanoma lines, and blocked tumor cell viability, growth, colony formation, and migration in vitro. Pro-based analogue, 5h, with a relatively polar tetrahydropyranyl (THP) ring, instead of the cyclohexyl, showed improved permeability. In general, the (R)-configuration Pro-based analogs showed the overall best profile, including physicochemical properties (e.g., microsomal metabolic stability, Caco-2 permeability), and in particular, 5d showed improved tumor-cell specificity.

Effect of the composition of extra virgin olive oils on the differentiation and antioxidant capacities of twelve monovarietals.

The effect of the composition of twelve varieties of extra virgin olive oils (EVOOs) on their differentiation based in agronomic criteria and on the antioxidant capacity was studied. Principal component analysis permitted an overview of the samples and their compositions, showing evidence of grouping and correlation between antioxidant capacity, oleuropein and ligstroside derivatives (OLD) and specific extinction at 270. Oleic and linoleic acids, 3,4-DHPEA-EA and p-HPEA-EDA (OLD), unsaturated/saturated ratio and induction time (IT) allowed the correct classification of samples according to year of harvest, ripening stage and variety. The antioxidant capacity of EVOOs was satisfactory predicted through a partial least square model based on ΔK, hydroxytyrosol, pinoresinol, oleuropein derivate and IT. Validation of the model gave a correlation R>0.83 and an error of 7% for independent samples. This model could be a useful tool for the olive industry to highlight the nutritional quality of EVOOs and improve their marketing.

Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo.

STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA-binding activities, STAT3-independent gene transcription, or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast, and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates for further development as cancer therapeutics.

Comparación entre los efectos de la varicocelectomía microquirúrgica subinguinal bilateral vs la unilateral en los parámetros seminales / Comparison of the effects of unilateral vs bilateral microsurgical subinguinal varicocelectomy in seminal parameters

INTRODUCCIÓN: El varicocele es una causa frecuente de infertilidad en el hombre, encontrándose en el 40 por ciento de los hombres que consultan por infertilidad, existiendo diversas teorías que explican esta situación. Numerosos estudios apuntan a que la reparación del varicocele se asociaría a una mejoría en los parámetros seminales e incluso en las tasas de fertilidad. Entre las técnicas reparativas la varicocelectomía microquirúrgica (VM) se ha posicionado como la técnica gold standard dado sus mejores resultados en cuanto a éxito, recidiva y seguridad. OBJETIVO: evaluar el rol de la VM en los parámetros seminales de varones que consultan por infertilidad y que son sometidos a VM bilateral en comparación con aquellos en que se realiza VM unilateral. Materiales y método: se seleccionó a pacientes con varicocele clínico que consultaron por infertilidad y que tenían el espermiograma alterado, a los que se realizó VM uni o bilateral según tuvieran la enfermedad en uno o ambos lados. Se tomó el promedio de los parámetros seminales de 2 espermiogramas pre-operatorios y otras variables clínicas y demográficas y se comparó con los parámetros seminales a 6 meses post-cirugía. Además se comparó los resultados del grupo de VM bilateral con el unilateral. RESULTADOS: no hubo diferencias entre los grupos en el pre-operatorio, evidenciándose una mejoría en ambos grupos al analizar los resultados a los 6 meses post-VM. Esta mejoría fue significativamente mayor en el grupo de VM unilateral en cuanto a la concentración espermática (mediana de 6 mill/ml, comparado con 0.75 mill/ml en el grupo de pacientes sometidos a VM bilateral. p Value = 0.02)...

Introduction: Varicocele is a common cause of infertility in men, present in 40 percent of men with infertility, there are several theories that explain this situation. Numerous studies suggest that varicocele repair would be associated with an improvement in semen parameters and even fertility rates. Among the reparative techniques microsurgical varicocelectomy (VM) has positioned itself as the gold standard technique given the best results in terms of success, recurrence and security. Objective: To evaluate the role of the VM in semen parameters of men consulting for infertility and who undergo bilateral VM compared to those VM is performed unilaterally. Materials and Methods: We enrolled patients with clinical varicocele who consulted for infertility and had altered semen analysis, in which VM was performed unilateral or bilateral depending if they had the disease in one or both sides. The average of 2 pre-operative semen parameters was used and other clinical and demographic variables and they were compared with semen parameters at 6 months post-surgery. We also compared the results of the group with unilateral versus that with bilateral VM. Results: There were no differences between groups in the pre-operative, evidence-dose improvement in both groups in analyzing the results at 6 months post-VM. This improvement was significantly greater in the group of unilateral VM regarding sperm concentration (median of 6 mill / ml, compared with 0.75 million / ml in the group of patients undergoing bilateral VM. P Value = 0.02).Discussion: VM improves seminal parameters in patients with unilateral or bilateral varicocele, being unilateral VM group that benefits the most. This could be explained by a greater cumulative damage spermatogenesis in the case of bilateral varicocele. Randomized controlled prospective studies are needed, allowing to determine the real effect of unilateral vs. bilateral VM.

Identification of glutathione-derived metabolites from an IP receptor antagonist.

The metabolic fate of three aromatic carboxylic acid analogs under evaluation as prostaglandin I2-preferring receptor antagonists was studied. The initial analog with unsubstituted phenyl groups was subject to a complex set of aromatic oxidative biotransformations. By introduction of one or two fluorines, these pathways were inhibited. All three analogs were metabolized to a wide variety of carboxylic acid conjugates. Among these were several conjugates formed via secondary metabolism and oxidation of acyl glutathione intermediates. Two of the structure classes, represented by the S-methyl-N-cysteinylglycine conjugate and the N-cysteinylglycine disulfide conjugates, have been described only rarely in the literature. The related S-oxide of the S-methyl-N-cysteinylglycine conjugate and the N,S-bis-acyl derivative of cysteinylglycine are here described for the first time as conjugate metabolites of carboxylic drugs.