Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies.

Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies.

Castration promotes the browning of the prostate tumor microenvironment.

BACKGROUND: Adipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an essential player in prostate cancer progression. Since obesity is directly related to human tumor progression, and adipose tissue depots are one of the significant components of the tumor microenvironment, the molecular mediators of the communication between adipocytes and epithelial cells are in the spotlight. Although periprostatic white adipose tissue contributes to prostate cancer progression, brown adipose tissue (BAT), which has beneficial effects in metabolic pathologies, has been scarcely investigated concerning cancer progression. Given that adipose tissue is a target of androgen signaling, the actual role of androgen removal on the periprostatic adipose tissue was the aim of this work. METHODS: Surgical castration of the transgenic adenocarcinoma of the mouse prostate (TRAMP) was employed. By histology examination and software analysis, WAT and BAT tissue was quantified. 3T3-like adipocytes were used to study the role of Casodex® in modifying adipocyte differentiation and to investigate the function of the secretome of adipocytes on the proliferation of androgen-dependent and independent prostate cancer cells. Finally, the role of cell communication was assayed by TRAMP-C1 xenograft implanted in the presence of 3T3-like adipocytes. RESULTS: Androgen removal increases brown/beige adipose tissue in the fat immediately surrounding the prostate glands of TRAMP mice, concomitant with an adjustment of the metabolism. Castration increases body temperature, respiratory exchange rate, and energy expenditure. Also, in vitro, it is described that blocking androgen signaling by Casodex® increases the uncoupling protein 1 (UCP1) marker in 3T3-like adipocytes. Finally, the effect of brown/beige adipocyte secretome was studied on the proliferation of prostate cancer cells in vivo and in vitro. The secretome of brown/beige adipocytes reduces the proliferation of prostate cancer cells mediated partly by the secretion of extracellular vesicles. CONCLUSIONS: Consequently, we concluded that hampering androgen signaling plays a crucial role in the browning of the periprostatic adipose tissue. Also, the presence of brown adipocytes exhibits the opposite effect to that of white adipocytes in vitro regulating processes that govern the mechanisms of cell proliferation of prostate cancer cells. And finally, promoting the browning of adipose tissue in the periprostatic adipose tissue might be a way to handle prostate cancer cell progression. Video Abstract.

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/cationic amino acid transporter 1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via the activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a posttranslational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors, by the inhibition of deoxyhypusine synthase, abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A, and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This affected pathway is critical for eIF5A-regulated erythropoiesis, as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins (RPs) were especially sensitive to the loss of hypusine, and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in chromosome 5q deletions in myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis, and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPCs, synchronizing mitochondrial metabolism with erythroid differentiation.

Reflections on the Biology of Cell Culture Models: Living on the Edge of Oxidative Metabolism in Cancer Cells.

Nowadays, the study of cell metabolism is a hot topic in cancer research. Many studies have used 2D conventional cell cultures for their simplicity and the facility to infer mechanisms. However, the limitations of bidimensional cell cultures to recreate architecture, mechanics, and cell communication between tumor cells and their environment, have forced the development of other more realistic in vitro methodologies. Therefore, the explosion of 3D culture techniques and the necessity to reduce animal experimentation to a minimum has attracted the attention of researchers in the field of cancer metabolism. Here, we revise the limitations of actual culture models and discuss the utility of several 3D culture techniques to resolve those limitations.

Vitamin C deficiency reveals developmental differences between neonatal and adult hematopoiesis.

Hematopoiesis, a process that results in the differentiation of all blood lineages, is essential throughout life. The production of 1x1012 blood cells per day, including 200x109 erythrocytes, is highly dependent on nutrient consumption. Notably though, the relative requirements for micronutrients during the perinatal period, a critical developmental window for immune cell and erythrocyte differentiation, have not been extensively studied. More specifically, the impact of the vitamin C/ascorbate micronutrient on perinatal as compared to adult hematopoiesis has been difficult to assess in animal models. Even though humans cannot synthesize ascorbate, due to a pseudogenization of the L-gulono-γ-lactone oxidase (GULO) gene, its generation from glucose is an ancestral mammalian trait. Taking advantage of a Gulo-/- mouse model, we show that ascorbic acid deficiency profoundly impacts perinatal hematopoiesis, resulting in a hypocellular bone marrow (BM) with a significant reduction in hematopoietic stem cells, multipotent progenitors, and hematopoietic progenitors. Furthermore, myeloid progenitors exhibited differential sensitivity to vitamin C levels; common myeloid progenitors and megakaryocyte-erythrocyte progenitors were markedly reduced in Gulo-/- pups following vitamin C depletion in the dams, whereas granulocyte-myeloid progenitors were spared, and their frequency was even augmented. Notably, hematopoietic cell subsets were rescued by vitamin C repletion. Consistent with these data, peripheral myeloid cells were maintained in ascorbate-deficient Gulo-/- pups while other lineage-committed hematopoietic cells were decreased. A reduction in B cell numbers was associated with a significantly reduced humoral immune response in ascorbate-depleted Gulo-/- pups but not adult mice. Erythropoiesis was particularly sensitive to vitamin C deprivation during both the perinatal and adult periods, with ascorbate-deficient Gulo-/- pups as well as adult mice exhibiting compensatory splenic differentiation. Furthermore, in the pathological context of hemolytic anemia, vitamin C-deficient adult Gulo-/- mice were not able to sufficiently increase their erythropoietic activity, resulting in a sustained anemia. Thus, vitamin C plays a pivotal role in the maintenance and differentiation of hematopoietic progenitors during the neonatal period and is required throughout life to sustain erythroid differentiation under stress conditions.

Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase.

Prostate cancer is the second leading cause of cancer in men across the globe. The prostate gland accounts for some unique glycolytic metabolic characteristics, which causes the metabolic features of prostate tumor initiation and progression to remain poorly characterized. The mitochondrial superoxide dismutase (SOD2) is one of the major redox metabolism regulators. This study points out SOD2 as one major regulator for both redox and glycolytic metabolism in prostate cancer. SOD2 overexpression increases glucose transporter GLUT-1 and glucose uptake. This is not an insulin-mediated effect and seems to be sex-dependent, being present in male mice only. This event concurs with a series of substantial metabolic rearrangements at cytoplasmic and mitochondrial level. A concomitant decrease in glycolytic and pentose phosphate activity, and an increase in electron transfer in the mitochondrial electronic chain, were observed. The Krebs Cycle is altered to produce amino-acid intermediates by decreasing succinate dehydrogenase. This in turn generates a 13-fold increase in the oncometabolite succinate. The protein energy sensor AMPK is decreased at basal and phosphorylated levels in response to glucose deprivation. Finally, preliminary results in prostate cancer patients indicate that glandular areas presenting high levels of SOD2 show a very strong correlation with GLUT-1 protein levels (R2 = 0.287 p-value < 0.0001), indicating that in patients there may exist an analogous phenomenon to those observed in cell culture and mice.

Human erythroid differentiation requires VDAC1-mediated mitochondrial clearance.

Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation. Thereafter, erythroblasts are blocked at the orthochromatic stage, exhibiting a significant decreased level of enucleation, concomitant with an increased cell death. We demonstrate that mitochondria clearance starts at the transition from basophilic to polychromatic erythroblast, and that VDAC1 downregulation induces the mitochondrial retention. In damaged mitochondria from non-erythroid cells, VDAC1 was identified as a target for Parkin-mediated ubiquitination to recruit the phagophore. Here, we showed that VDAC1 is involved in phagophore's membrane recruitment regulating selective mitophagy of still functional mitochondria from human erythroblasts. These findings demonstrate for the first time a crucial role for VDAC1 in human erythroblast terminal differentiation, regulating mitochondria clearance.

Electroencefalograma cuantitativo en la predicción precoz de la isquemia cerebral tardía en hemorragia subaracnoidea aneurismática: reporte de un caso / Quantitative electroencephalogram for prediction of delayed ischemia in subarachnoid haemorrhage: report of one case

Subarachnoid hemorrhage (SAH) is a devastating disease, with a mortality rate of 35%. Among patients who survive the initial bleeding, the leading cause of morbidity and mortality is delayed cerebral ischemia (DCI). Electroencephalography (EEG) can detect cerebral ischemia in the early stages. We report a 66-year-old female patient who consulted for ictal headache and impaired consciousness. On admission, she was confused, dysarthric, and with meningeal signs. Brain angio-CT showed SAH FISHER IV and an aneurysm of the left posterior cerebral artery. After excluding the aneurysm (by coiling), the patient recovered the altered consciousness. Continuous EEG monitoring was initiated. On the sixth day of follow up, she had a transient headache and apathy. The brain MRI showed low cerebral blood flow in the left frontotemporal area, without ischemic lesions. On the seventh day, she presented expression aphasia and right facial-brachial paresis. Angiography confirmed severe vasospasm in M1 and M2 segments bilaterally. Pharmacological angioplasty with nimodipine was performed, with an excellent radiological response, although not clinical. A second MRI was carried out on the eighth day, which showed a left insular infarction and generalized vasospasm. A second therapeutic angiography was performed; the patient persisted with aphasia and left central facial paresis. The quantitative EEG analysis performed retrospectively showed a generalized reduction in the spectral edge frequency 95 (SEF95; meaning slowing in the EEG signal) at the fourth day of follow up, three days earlier than the clinical and imaging diagnosis of DCI was established.

The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis.

The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells with a rare Augustine-null blood type is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+ progenitors following short hairpin RNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia, and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cyclic adenosine monophosphate homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of 2 ENT1null individuals demonstrated a compensation by a loss-of-function variant in the ABCC4 cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1-/- mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.

An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.

The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process. IDH1 downregulation augments mitochondrial oxidation of αKG and inhibits reticulocyte generation. Furthermore, IDH1 knockdown results in the generation of multinucleated erythroblasts, a morphological abnormality characteristic of myelodysplastic syndrome and congenital dyserythropoietic anemia. We identify vitamin C homeostasis as a critical regulator of ineffective erythropoiesis; oxidized ascorbate increases mitochondrial superoxide and significantly exacerbates the abnormal erythroblast phenotype of IDH1-downregulated progenitors, whereas vitamin C, scavenging reactive oxygen species (ROS) and reprogramming mitochondrial metabolism, rescues erythropoiesis. Thus, an IDH1-vitamin C crosstalk controls terminal steps of human erythroid differentiation.

[Quantitative electroencephalogram for prediction of delayed ischemia in subarachnoid haemorrhage. Report of one case]. / Electroencefalograma cuantitativo en la predicción precoz de la isquemia cerebral tardía en hemorragia subaracnoidea aneurismática.Reporte de un caso.

Subarachnoid hemorrhage (SAH) is a devastating disease, with a mortality rate of 35%. Among patients who survive the initial bleeding, the leading cause of morbidity and mortality is delayed cerebral ischemia (DCI). Electroencephalography (EEG) can detect cerebral ischemia in the early stages. We report a 66-year-old female patient who consulted for ictal headache and impaired consciousness. On admission, she was confused, dysarthric, and with meningeal signs. Brain angio-CT showed SAH FISHER IV and an aneurysm of the left posterior cerebral artery. After excluding the aneurysm (by coiling), the patient recovered the altered consciousness. Continuous EEG monitoring was initiated. On the sixth day of follow up, she had a transient headache and apathy. The brain MRI showed low cerebral blood flow in the left frontotemporal area, without ischemic lesions. On the seventh day, she presented expression aphasia and right facial-brachial paresis. Angiography confirmed severe vasospasm in M1 and M2 segments bilaterally. Pharmacological angioplasty with nimodipine was performed, with an excellent radiological response, although not clinical. A second MRI was carried out on the eighth day, which showed a left insular infarction and generalized vasospasm. A second therapeutic angiography was performed; the patient persisted with aphasia and left central facial paresis. The quantitative EEG analysis performed retrospectively showed a generalized reduction in the spectral edge frequency 95 (SEF95; meaning slowing in the EEG signal) at the fourth day of follow up, three days earlier than the clinical and imaging diagnosis of DCI was established.

Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation during Human Terminal Erythropoiesis.

Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.

Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation.

Neuroindole melatonin, a hormone synthesized during the night mainly-but not exclusively-by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox.

Los conocimientos, actitudes y prácticas (CAP) de los médicos en los servicios de neonatología del Ecuador en relación al tratamiento del dolor / Knowledge, attitudes and practices of physicians in neonatal units in ecuador pertinent to treatment of pain

Contexto: Los neonatos hospitalizados en una unidad neonatal, diariamente son sometidos a intervenciones diagnósticas y terapéuticas dolorosas. El personal de salud tiene un papel importante en la valoración y control del dolor neonatal. El dolor es una percepción subjetiva, y hoy en día se sabe que los neonatos expresan el dolor con indicadores comportamentales, fisiológicos, hormonales, y debería ser adecuadamente evaluados para instaurar un manejo farmacológico y no farmacológico que evite daños nocivos a corto y a largo plazo. Propósito: Evaluar el nivel de conocimientos, actitudes y prácticas del personal médico del Ecuador sobre la valoración y manejo del dolor neonatal. Sujetos y métodos: Estudio multicéntrico, no experimental, cuantitativo, descriptivo de corte transversal. La herramienta de evaluación fue una encuesta vía online, semi estructurada y auto administrada, a todos los médicos de 16 provincias del Ecuador que trabajan directamente con neonatos y aceptaron participar en el estudio. La encuesta fue aplicada desde el 1 de noviembre hasta el 30 de noviembre del 2018. La encuesta tuvo 25 preguntas, y una duración estimada de 5 a 8 minutos. Su objetivo fue valorar los conocimientos, las actitudes y las prácticas de los médicos con relación al dolor neonatal. Resultados: Participaron 183 médicos en la encuesta; el 70% fueron mujeres; la edad promedio fue 34; el 82,5% labora en la sierra. El 56,8% tiene título de tercer nivel y 43,2% título de cuarto nivel; 10,5% trabaja en un hospital de nivel I, 29,3% en un hospital de nivel II y 60,2% en un hospital de nivel III. A nivel general del cuestionario CAP se observó un resultado significativamente deficiente en todos los grupos: 82% en los médicos de 25 a 35 años y 52,8% en aquellos 36 a 56 años. También se encontró que la calificación del CAP fue significativamente mala en todos los niveles de titulación siendo peor en los médicos con título de tercer nivel (81,8% vs. 49,4%) que en los de cuarto nivel. Conclusiones: Existe una abrumadora deficiencia en el conocimiento, las actitudes y las prácticas en manejo del dolor neonatal en médicos del Ecuador.

Context: Neonates hospitalized in a neonatal unit are subjected daily to painful diagnostic and therapeutic interventions. Health personnel have an important role in the assessment and control of neonatal pain. Pain is a subjective perception, and nowadays it is known that neonates express pain with behavioral, physiological, hormonal indicators, and it should be adequately evaluated to establish a pharmacological and non-pharmacological management that avoids harmful damages in the short and long term. Objective: Evaluate the level of knowledge, attitudes and practices of the medical staff of Ecuador on the assessment and management of neonatal pain. Subjects and Methods: Multicenter, non-experimental, quantitative, descriptive, cross-sectional study. The evaluation tool was an online survey, semi-structured and self-administered, sent to all the doctors of 16 Provinces of Ecuador who work directly with neonates, who agreed to participate in the study. The survey was applied from November 1 to November 30, 2018. The survey had 25 questions, which took an estimated time of 5 to 8 minutes. Its objective was to evaluate the knowledge, attitudes and practices of Physicians in relation to neonatal pain. Results: 183 physicians participated in the survey; 70% were women; the average age was 34.4 years; 82.5% work in the sierra region, 56.8% have a third level degree and 43.2% have a fourth level degree. 10.5% work in a level I hospital, 29.3% in a level II hospital and 60.2% in a level III. The CAP questionnaire revealed a significantly deficient result in every group: 82% of physicians between 25 and 35 years of age and 52.8% among those between 36 and 56. The CAP evaluation showed a significant deficiency in every level of education but it was worse among physicians with third level degree than among those with fourth level degree (81.8% vs. 49.4%). Conclusions: There is an overwhelming deficiency in knowledge, attitudes and practices in neonatal pain management among physicians in Ecuador.

Siameses toracópagos: Reporte de un caso / Thoracic Siamese: Case Report

Los gemelos siameses son una entidad rara, cuya incidencia varía de 1 en 50.000 a 1 en 100.000 nacidos vivos; solo el 18 % sobrevive y aproximadamente el 35 % de los nacidos vivos muere en las primeras 24 horas. Se reportó un caso de siameses toracópagos, con diagnóstico prenatal mediante ultrasonografía a las 32.1 semanas de gestación, cuyas cabezas y extremidades son individuales; poseen genitales femeninos; a nivel del tórax se observó la existencia de un corazón que envía un vaso arterial a lo que se asemeja a una masa cardiaca inerte y rudimentaria al feto contralateral; comparten los órganos abdominales. El embarazo se interrumpió a las 32.1 semanas de gestación y los pacientes sobrevivieron dos horas, luego de lo cual fallecieron por la cardiopatía compleja.

Siamese twins are rare, occurring 1 in 50 000 to 1 in 100 000 live births; only 18% survive and approximately 35% of live births die in the first 24 hours. We report a case of thoracopagu twins. The prenatal diagnosis was made by ultrasound at 32 weeks of gestation. They had separated heads and extremities; they were females; at the joint thorax there was a single heart that sent an arterial vessel to what resembles a rudimentary cardiac mass in the contralateral fetus. They shared abdominal organs. Pregnancy was interrupted at 32.1 weeks of gestation; patients survived 2 hours.

Comparación de escalas de predicción mortalidad neonatal (crib, crib ii, snap ii, snappe ii) entre recién nacidos prematuros y a término / Comparison of neonatal mortality prediction scales (crib, crib ii, snap ii, snappe ii) between preterm and full term infants

Objetivo: Este artículo compara 4 escalas de predicción de mortalidad y gravedad de la enfermedad (CRIB, CRIB II, SNAPPE, SNAPPE II) en recién nacidos prematuros y a términos, ingresados a las unidades de cuidaos intensivos neonatales (UCIN) para determinar cuál de ellas, tiene mayor discriminación pronostica. Métodos: es un estudio transversal, observacional, multicéntrico para comparar varias escalas de predicción de mortalidad y de la enfermedad. Se recolectaron datos de 227 recién nacidos ingresados a las UCIN de 4 hospitales desde julio a diciembre del 2018. Evaluamos las escalas CRIB, CRIB II, SNAPII y SNAP-PE score en recién nacidos prematuros y a término. El área bajo la curva (ROC) fue usada para evaluar y comparar los resultados de predicción de mortalidad y morbilidad. Resultados: Un total of 227 recién nacidos fueron evaluados (media CRIB: 7,81±3,52 media CRIB-II: 11,96±3,91; media SNAP-II: 34,99±16,83, SNAPPE II: 14,61±13,30). Se evidenció una mayor discriminación para las escalas CRIB II y CRIB en relación con SNAP-II y SNAPP II (AUC 0.94 y 0.93 vs 0.86 y 0,77). Además de cada puntuación, varias variables influyeron significativamente en la supervivencia en los modelos de regresión logística. Conclusiones: Todas las escalas de predicción de mortalidad y de gravedad de la enfermedad sirven para utilizarse en las UCIN estudiadas, siendo la escala CRIB II la de mejor rendimiento para aplicarse en nuestro medio.

Objective: This article compares 4 scales of prediction of mortality and disease severity (CRIB, CRIB II, SNAPPE, SNAPPE II) in preterm and term new borns admitted to neonatal intensive care units (NICU) to determine which of them has greater forecast discrimination. Methods: it is a cross-sectional, observational, multicenter study that compares several mortality and disease prediction scales. Data were collected from 227 newborns admitted to the NICU of 4 hospitals from July to December 2018. We evaluated the CRIB, CRIB II, SNAPII and SNAP-PE score scales in preterm and full term infants. The area under the curve (ROC) was used to evaluate and compare the prediction results of mortality and morbidity. Results: A total of 227 newborns were evaluated (mean CRIB: 7.81 ± 3.52 mean CRIB-II: 11.96 ± 3.91, average SNAP-II: 34.99 ± 16.83, SNAPPE II: 14.61 ± 13.30). There was evidence of greater discrimination for the CRIB II and CRIB scales in relation to SNAP-II and SNAPP II (AUC 0.94 and 0.93 vs 0.86 and 0.77). In addition to each score, several variables significantly influenced survival in the logistic regression models. Conclusions: All the prediction scales of mortality and severity of the disease serve to be used in the studied NICUs, being the CRIB II scale the best performance to apply in our environment.

GLUT1 protects prostate cancer cells from glucose deprivation-induced oxidative stress.

Glucose, chief metabolic support for cancer cell survival and growth, is mainly imported into cells by facilitated glucose transporters (GLUTs). The increase in glucose uptake along with tumor progression is due to an increment of facilitative glucose transporters as GLUT1. GLUT1 prevents cell death of cancer cells caused by growth factors deprivation, but there is scarce information about its role on the damage caused by glucose deprivation, which usually occurs within the core of a growing tumor. In prostate cancer (PCa), GLUT1 is found in the most aggressive tumors, and it is regulated by androgens. To study the response of androgen-sensitive and insensitive PCa cells to glucose deprivation and the role of GLUT1 on survival mechanisms, androgen-sensitive LNCaP and castration-resistant LNCaP-R cells were employed. Results demonstrated that glucose deprivation induced a necrotic type of cell death which is prevented by antioxidants. Androgen-sensitive cells show a higher resistance to cell death triggered by glucose deprivation than castration-resistant cells. Glucose removal causes an increment of H2O2, an activation of androgen receptor (AR) and a stimulation of AMP-activated protein kinase activity. In addition, glucose removal increases GLUT1 production in androgen sensitive PCa cells. GLUT1 ectopic overexpression makes PCa cells more resistant to glucose deprivation and oxidative stress-induced cell death. Under glucose deprivation, GLUT1 overexpressing PCa cells sustains mitochondrial SOD2 activity, compromised after glucose removal, and significantly increases reduced glutathione (GSH). In conclusion, androgen-sensitive PCa cells are more resistant to glucose deprivation-induced cell death by a GLUT1 upregulation through an enhancement of reduced glutathione levels.

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

One of the hallmarks of cancer cells is the increased ability to acquire nutrients, particularly glucose and glutamine. Proliferating cells need precursors for cell growth and NADPH reducing equivalents for survival. The principal responsible for glucose uptake is facilitative glucose transporters (GLUTs), which usually are overexpressed in cancer cells. Besides their role in glucose uptake, GLUT transporters are able to transport other compounds such as dehydroascorbic acid or uric acid. They play a major role in tumor progression and cellular processes such as regulated cell death. The prostate gland has the particular characteristic of being more glycolytic than other non-pathological tissues given an accumulation of citrate in the seminal fluid and the inhibition of m-aconitase that affects to tricarboxylic acid cycle. In prostate cancer (PCa), androgens increase glucose uptake, upregulate GLUT transporters such as GLUT1 and GLUT3 and stimulate AMP-activated protein kinase pathway, suggesting a possible connection between glycolytic and androgenic signaling. Interestingly, diabetes is not a risk factor for PCa, as it is in other cancers, while insulin stimulates progression and insulin-like growth factor 1 pathway plays an important role in PCa progression. It was recently found that PCa cells overexpress GLUT4 and, more importantly, that it seems to be related to the castration-resistant prostate cancer (CRPC) phenotype, although little is known about its participation in tumor progression. This review will focus on the role of GLUT transporters along with PCa progression, and the involvement of GLUT4 on CRPC phenotype transition would be considered.