Biological role of fructose in the male reproductive system: Potential implications for prostate cancer.

BACKGROUND: Over the last 20 years, fructose has gradually emerged as a potential metabolic substrate capable of promoting the growth and progression of various cancers, including prostate cancer (PCa). The biological and molecular mechanisms that underlie the effects of fructose on cancer are beginning to be elucidated. METHODS: This review summarizes the biological function of fructose as a potential carbon source for PCa cells and its role in the functionality of the male reproductive tract under normal conditions. RESULTS: The most recent biological advances related to fructose transport and metabolism as well as their implications in PCa growth and progression suggest that fructose represent a potential carbon source for PCa cells. Consequently, fructose derivatives may represent efficient radiotracers for obtaining PCa images via positron emission tomography and fructose transporters/fructose-metabolizing enzymes could be utilized as potential diagnostic and/or predictive biomarkers for PCa. CONCLUSION: The existing data suggest that restriction of fructose from the diet could be a useful therapeutic strategy for patients with PCa.

Agreement analysis of stroke volume and cardiac output measurement between a oscillometric device and transthoracic echocardiogram in normotensive individuals: a preliminary report.

INTRODUCTION: The evaluation of stroke volume (SV) is useful in research and patient care. To accomplish this, an ideal device should be noninvasive, continuous, reliable, and reproducible. The Mobil-O-Graph (MOG) is a noninvasive oscillometric matrix validated for measuring aortic and peripheral blood pressure, which through conversion algorithms can estimate hemodynamic parameters. OBJECTIVES: To compare the MOG measurement of stroke volume, cardiac output, and cardiac index with the transthoracic echocardiogram (TTE). METHODS: Healthy volunteers aged 18 years or older were included. Two-dimensional TTEs were performed by a single operator. Subsequently, the measurement of noninvasive hemodynamics with MOG was performed with the operator blind to the results of the echocardiogram. Correlation analyses between stroke volume, cardiac output, and cardiac index parameters were performed. The degree of agreement between the methods was verified using the Bland-Altman method. RESULTS: A total of 38 volunteers were enrolled with a mean age of 27.6.ß...ß3.8 years; 21 (55%) were male The SV by TTE was 76.8.ß...ß19.5.ßmL and 75.7.ß...ß19.3.ßmL by MOG, Rho.ß=.ß0.726, p.ß<.ß0.0001. The CO by TTE was 5.04.ß...ß0.8 mL.min-1 and 5.1.ß...ß0.8.ßmL.min-1 by MOG Rho.ß=.ß0.510, p.ß=.ß0.001. Bland-Altman plots showed a good concordance between the two techniques. CONCLUSIONS: Our study shows that the measurement of SV and CO by noninvasive hemodynamics with the MOG device offers a good concordance with the TTE with very few values beyond the confidence limits.

Agreement analysis of stroke volume and cardiac output measurement between a oscillometric device and transthoracic echocardiogram in normotensive individuals: a preliminary report

Abstract Introduction The evaluation of stroke volume (SV) is useful in research and patient care. To accomplish this, an ideal device should be noninvasive, continuous, reliable, and reproducible. The Mobil-O-Graph (MOG) is a noninvasive oscillometric matrix validated for measuring aortic and peripheral blood pressure, which through conversion algorithms can estimate hemodynamic parameters. Objectives To compare the MOG measurement of stroke volume, cardiac output, and cardiac index with the transthoracic echocardiogram (TTE). Methods Healthy volunteers aged 18 years or older were included. Two-dimensional TTEs were performed by a single operator. Subsequently, the measurement of noninvasive hemodynamics with MOG was performed with the operator blind to the results of the echocardiogram. Correlation analyses between stroke volume, cardiac output, and cardiac index parameters were performed. The degree of agreement between the methods was verified using the Bland-Altman method. Results A total of 38 volunteers were enrolled with a mean age of 27.6 ± 3.8 years; 21 (55%) were male The SV by TTE was 76.8 ± 19.5 mL and 75.7 ± 19.3 mL by MOG, Rho = 0.726, p< 0.0001. The CO by TTE was 5.04 ± 0.8 mL.min-1 and 5.1 ± 0.8 mL.min-1 by MOG Rho = 0.510, p= 0.001. Bland-Altman plots showed a good concordance between the two techniques. Conclusions Our study shows that the measurement of SV and CO by noninvasive hemodynamics with the MOG device offers a good concordance with the TTE with very few values beyond the confidence limits.

Active Surveillance in Prostate Cancer: Current and Potentially Emerging Biomarkers for Patient Selection Criteria.

BACKGROUND: Prostate cancer (PCa) represents one of the most frequent malignancies and the fifth leading cause of cancer death in adult men worldwide. PCa mortality rates have been declining in several Western countries; one of the possible reasons may be related to the application of prostate-specific antigen early detection policies. These early detection protocols increase PCa-specific patient survival; however, a high percentage of these cases corresponds to low-risk PCa that grows very slowly and is unlikely to metastasize to threaten survival. Many low-risk PCa patients receive aggressive therapies, such as radical prostatectomy and radiotherapy, that are costly for patients and/or health systems and generate side effects that affect the quality of life. An alternative to surgery and radiotherapy treatments for low-risk PCa is active surveillance (AS), a strategy based on close disease monitoring and intervention only if the disease progresses. However, proper identification of low-risk PCa patients at the time of diagnosis is essential for the effectiveness AS. The selection of AS candidates remains challenging; thus, effective prognostic biomarkers are needed. SUMMARY: This review article addresses the characteristics of the current and emerging PCa prognostic biomarkers, including tests available for tissue, blood, and urine analyses, for the appropriate selection of PCa patients for AS. In addition, and based on published literature, we performed a selection of potential new biomarkers that can distinguish low-risk PCa. KEY MESSAGES: The literature search yielded four tissue-based tests, two blood-based tests, and six urine-based tests that can be used to determine PCa risk classification. However, most available tests are expensive; thus, cost-effective analyses are needed in order to obtain the approval of government agencies and to be financed by the health systems. Available prognostic urine tests have shown great progress over the last years, and they have the advantage of being minimally invasive; therefore, they may become a routine disease progression test for patients under AS. In addition, new research conducted in the last decade has shown promising biomarkers, including mRNA, miRNA, long noncoding RNA, and metabolites, that could improve existing tests or allow the development of new tools for AS patient selection.

The Differential Paracrine Role of the Endothelium in Prostate Cancer Cells.

The survival of patients with solid tumors, such as prostate cancer (PCa), has been limited and fleeting with anti-angiogenic therapies. It was previously thought that the mechanism by which the vasculature regulates tumor growth was driven by a passive movement of oxygen and nutrients to the tumor tissue. However, previous evidence suggests that endothelial cells have an alternative role in changing the behavior of tumor cells and contributing to cancer progression. Determining the impact of molecular signals/growth factors released by endothelial cells (ECs) on established PCa cell lines in vitro and in vivo could help to explain the mechanism by which ECs regulate tumor growth. Using cell-conditioned media collected from HUVEC (HUVEC-CM), our data show the stimulated proliferation of all the PCa cell lines tested. However, in more aggressive PCa cell lines, HUVEC-CM selectively promoted migration and invasion in vitro and in vivo. Using a PCa-cell-line-derived xenograft model co-injected with HUVEC or preincubated with HUVEC-CM, our results are consistent with the in vitro data, showing enhanced tumor growth, increased tumor microvasculature and promoted metastasis. Gene set enrichment analyses from RNA-Seq gene expression profiles showed that HUVEC-CM induced a differential effect on gene expression when comparing low versus highly aggressive PCa cell lines, demonstrating epigenetic and migratory pathway enrichments in highly aggressive PCa cells. In summary, paracrine stimulation by HUVEC increased PCa cell proliferation and tumor growth and selectively promoted migration and metastatic potential in more aggressive PCa cell lines.

Aberrant upregulation of CDK1 contributes to medroxyprogesterone acetate (MPA) resistance in cancer-associated fibroblasts of the endometrium.

The response to medroxyprogesterone acetate (MPA) decreases as endometrial disease progresses from the benign to malignancy. In a mouse model, progesterone receptor (PR) expression in normal fibroblasts is accountable for the MPA's inhibitory effects in cancer cells. However, it is still unclear, if and how, fibroblasts from human tumors respond to MPA. In this study, three benign-associated fibroblasts (BAFs) and four cancer-associated fibroblasts (CAFs) were isolated from human benign and cancerous endometrial tissues, respectively, to examine MPA activation on PR signaling. PR-B protein expression were heterogeneously expressed in both CAFs and BAFs, despite a lower mRNA expression in the former. In a luciferase reporter assay, MPA treatment stimulated some PR DNA-binding activity in BAFs but not in CAFs. Yet, activation of PR target gene was generally more pronounced in MPA-treated CAFs compared to BAFs. Cyclin-dependent kinase 1 (CDK1) was exclusively upregulated by 10 nM MPA in CAFs (5.1-fold vs. 1.1-fold in BAFs, P < 0.05), leading to a higher CDK1 protein expression. Subsequently in a dose-response study, CAFs showed an average of ∼20% higher cell viability when compared to BAFs, indicative of drug resistance to MPA. MPA resistance was also observed in EC-CAFs co-culture, when MPA-treated cells showed greater tumor spheroid formation than in EC-BAFs co-culture (2-fold, P < 0.01). The increased cell viability observed in CAFs was reversed with mifepristone (RU486), a PR antagonist which suppressed MPA-induced CDK1 expression. This indicates that MPA-induced abnormal upregulation of CDK1 may contribute to the enhanced CAFs cell proliferation, suggesting a new mechanism of MPA resistance within endometrial cancer microenvironment.

Pharmacological targets for the induction of ferroptosis: Focus on Neuroblastoma and Glioblastoma.

Neuroblastomas are the main extracranial tumors that affect children, while glioblastomas are the most lethal brain tumors, with a median survival time of less than 12 months, and the prognosis of these tumors is poor due to multidrug resistance. Thus, the development of new therapies for the treatment of these types of tumors is urgently needed. In this context, a new type of cell death with strong antitumor potential, called ferroptosis, has recently been described. Ferroptosis is molecularly, morphologically and biochemically different from the other types of cell death described to date because it continues in the absence of classical effectors of apoptosis and does not require the necroptotic machinery. In contrast, ferroptosis has been defined as an iron-dependent form of cell death that is inhibited by glutathione peroxidase 4 (GPX4) activity. Interestingly, ferroptosis can be induced pharmacologically, with potential antitumor activity in vivo and eventual application prospects in translational medicine. Here, we summarize the main pathways of pharmacological ferroptosis induction in tumor cells known to date, along with the limitations of, perspectives on and possible applications of this in the treatment of these tumors.

Perioperative protocol to reduce blood transfusions in total knee o hip replacement patients / [Implementación de protocolo perioperatorio para disminuir tasa de transfusiones en pacientes sometidos a reemplazo total de cadera o rodilla primarios]

Introduction: Patient Blood Management (PBM) programs improve patient care and reduce health costs. It includes detection of presurgical anemia, reduction of blood loss and improvement of patient-specific anemic reserve. The aim of this study is to assess the effect of a PBM program on transfusion rate, length of stay (LOS) and adverse events. Methods: We developed a retrospective observational study. We included patients who underwent total hip (THR) o knee replacement (TKR). Our PBM involved preoperative assessment, administration of 2 doses of tranexamic acid, application of restrictive transfusion criteria and use of IV iron. We compared results between the group of patients before and the one after the PBM implementation. Results: We included 179 patients (80 TKR and 99 THR) who underwent surgery before PBM implementation from January to December 2014 (Group A), and 187 patients (103 TKR and 84 THR) who underwent arthroplasty after PBM application from January to November 2016 (Group B). In Group A, hemoglobin drop was larger than in Group B, for TKR (5.1±1.2 vs. 4.2±1.2 g/dl; p<0,05) and for THR (4.7±1.3 vs. 3.8±1.3 g/dl; p<0,05). In group A, more patients were transfused (31.8% vs. 2.7%; p<0.001). LOS was longer for patients in group A, in both surgeries (for TKA, 3.98±1.4days vs. 2.99±0.95 days; p<0.0001; for THA 3.68±1.06days vs. 2.88±0.75days; p<0.0001). No significant differences were found regarding adverse events. Conclusion: Our PBM program saved transfusions after primary TKR and THR and lowered LOS, without risking patients to higher number of complications or death.

Introducción: Los protocolos de manejo de anemia perioperatoria mejoran el cuidado del paciente y disminuyen los costos en salud. El objetivo de este estudio fue identificar el efecto de dicho programa en pacientes sometidos a reemplazo total de cadera (RTC) o rodilla (RTR), en la tasa de transfusiones, tiempo de estadía hospitalaria y eventos adversos. Métodos: Se realizó un estudio observacional retrospectivo, incluyendo pacientes sometidos a RTC o RTR primarios. El programa abarcó la valoración preoperatoria, el uso de 2 dosis de ácido tranexámico, la aplicación de transfusiones restringidas, y el uso de hierro suplementario. Se compararon los resultados entre pacientes pre y post implementación del protocolo. Resultados: Se incluyeron 179 pacientes (80 RTR y 99 RTC) pre protocolo entre enero y diciembre 2014 (grupo A) y 187 casos (103 RTR y 84 RTC) post protocolo entre enero y noviembre 2016 (grupo B). En el grupo A, la caida de hemoglobina fue mayor que en el grupo B en RTR (5,1±1,2 vs. 4,2±1,2 g/dl; p<0,05) y en RTC (4,7±1.3 vs. 3,8±1.3 g/dl; p<0,05). Hubo mayor requerimiento transfusional en el grupo A (31,8% vs. 2,7%; p<0,001). El tiempo de estadía hospitalaria (TEH) fue mayor en el grupo A para ambas cirugías (en RTR 3,98±1,4días vs. 2,99±0,95 días; p<0,0001; en RTC 3,68±1,06días vs. 2,88±0,75días; p<0,0001). No se encontraron diferencias significativas respecto a eventos adversos. Conclusión: En ambas artroplastias, nuestro programa disminuyó la cantidad de transfusiones, la caída de hemoglobina y la estadía hospitalaria, sin aumentar el número de complicaciones.

Dietary Fructose Promotes Prostate Cancer Growth.

Clinical localization of primary tumors and sites of metastasis by PET is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer, however, PET-FDG imaging has shown limited clinical applicability, suggesting that prostate cancer cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that prostate cancer cells overexpress fructose transporters, but not glucose transporters, compared with benign cells. Here, we focused on validating the functional expression of fructose transporters and determining whether fructose can modulate the biology of prostate cancer cells in vitro and in vivo. Fructose transporters, Glut5 and Glut9, were significantly upregulated in clinical specimens of prostate cancer when compared with their benign counterparts. Fructose levels in the serum of patients with prostate cancer were significantly higher than healthy subjects. Functional expression of fructose transporters was confirmed in prostate cancer cell lines. A detailed kinetic characterization indicated that Glut5 represents the main functional contributor in mediating fructose transport in prostate cancer cells. Fructose stimulated proliferation and invasion of prostate cancer cells in vitro. In addition, dietary fructose increased the growth of prostate cancer cell line-derived xenograft tumors and promoted prostate cancer cell proliferation in patient-derived xenografts. Gene set enrichment analysis confirmed that fructose stimulation enriched for proliferation-related pathways in prostate cancer cells. These results demonstrate that fructose promotes prostate cancer cell growth and aggressiveness in vitro and in vivo and may represent an alternative energy source for prostate cancer cells. SIGNIFICANCE: This study identifies increased expression of fructose transporters in prostate cancer and demonstrates a role for fructose as a key metabolic substrate supporting prostate cancer cells, revealing potential therapeutic targets and biomarkers.

Evaluation of Antarctic Ozone Profiles derived from OMPS-LP by using Balloon-borne Ozonesondes.

Predicting radiative forcing due to Antarctic stratospheric ozone recovery requires detecting changes in the ozone vertical distribution. In this endeavor, the Limb Profiler of the Ozone Mapping and Profiler Suite (OMPS-LP), aboard the Suomi NPP satellite, has played a key role providing ozone profiles over Antarctica since 2011. Here, we compare ozone profiles derived from OMPS-LP data (version 2.5 algorithm) with balloon-borne ozonesondes launched from 8 Antarctic stations over the period 2012-2020. Comparisons focus on the layer from 12.5 to 27.5 km and include ozone profiles retrieved during the Sudden Stratospheric Warming (SSW) event registered in Spring 2019. We found that, over the period December-January-February-March, the root mean square error (RMSE) tends to be larger (about 20%) in the lower stratosphere (12.5-17.5 km) and smaller (about 10%) within higher layers (17.5-27.5 km). During the ozone hole season (September-October-November), RMSE values rise up to 40% within the layer from 12.5 to 22 km. Nevertheless, relative to balloon-borne measurements, the mean bias error of OMPS-derived Antarctic ozone profiles is generally lower than 0.3 ppmv, regardless of the season.

Hexose Transporters in Cancer: From Multifunctionality to Diagnosis and Therapy.

Cancer cells increase their metabolic activity by enhancing glucose uptake through overexpression of hexose transporters (Gluts). Gluts also have the capacity to transport other molecules besides glucose, including fructose, mannose, and dehydroascorbic acid (DHA), the oxidized form of vitamin C. The majority of research studies in this field have focused on the role of glucose transport and metabolism in cancer, leaving a substantial gap in our knowledge of the contribution of other hexoses and DHA in cancer biology. Here, we summarize the most recent advances in understanding the role that the multifunctional transport capacity of Gluts plays in biological and clinical aspects of cancer, and how these characteristics can be exploited in the search for novel diagnostic and therapeutic strategies.

Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17ß-Estradiol.

Estrogenic steroids and adenosine A2A receptors promote the wound healing and angiogenesis processes. However, so far, it is unclear whether estrogen may regulate the expression and pro-angiogenic activity of A2A receptors. Using in vivo analyses, we showed that female wild type (WT) mice have a more rapid wound healing process than female or male A2A-deficient mice (A2AKO) mice. We also found that pulmonary endothelial cells (mPEC) isolated from female WT mice showed higher expression of A2A receptor than mPEC from male WT mice. mPEC from female WT mice were more sensitive to A2A-mediated pro-angiogenic response, suggesting an ER and A2A crosstalk, which was confirmed using cells isolated from A2AKO. In those female cells, 17ß-estradiol potentiated A2A-mediated cell proliferation, an effect that was inhibited by selective antagonists of estrogen receptors (ER), ERα, and ERß. Therefore, estrogen regulates the expression and/or pro-angiogenic activity of A2A adenosine receptors, likely involving activation of ERα and ERß receptors. Sexual dimorphism in wound healing observed in the A2AKO mice process reinforces the functional crosstalk between ER and A2A receptors.

Deletion of the adenosine A2A receptor increases the survival rate in a mice model of polymicrobial sepsis.

We aim to investigate the role of A2A receptor in peritonitis-related sepsis by injection of a fecal solution (FS) as a model of polymicrobial infection. C57/black J6 wild-type (WT) and A2A-deficient mice (A2AKO) were exposed to sepsis induced by intraperitoneal injection of a FS (FS-induced peritonitis) or instead was injected with saline buffer (Sham). Survival rate and sepsis score were measured up to 48 h. The presence of bacteria in tissue homogenates was analyzed. Telemetry and speckle laser Doppler were used for systemic blood pressure and peripheral blood perfusion analysis, respectively. Histological analysis and identification of active caspase 3 were performed in selected organs, including the liver. The survival rate of A2AKO mice exposed to FS-induced peritonitis was significantly higher, and the sepsis score was lower than their respective WT counterpart. Injection of FS increases (50 to 150 folds) the number of colonies forming units in the liver, kidney, blood, and lung in WT mice, while these effects were significantly attenuated in A2AKO mice exposed to FS-induced peritonitis. A significant reduction in both systolic and diastolic blood pressure, as well as in the peripheral perfusion was observed in WT and A2AKO mice exposed to FS-induced peritonitis. Although, these last effects were significantly attenuated in A2AKO mice. Histological analysis showed a large perivascular infiltration of polymorphonuclear in the liver of WT and A2AKO mice exposed to FS-induced peritonitis, but again, this effect was attenuated in A2AKO mice. Finally, high expression of active caspase 3 was found only in the liver of WT mice exposed to FS-induced peritonitis. The absence of the A2A receptor increases the survival rate in mice exposed to polymicrobial sepsis. This outcome was associated with both hemodynamic compensation and enhanced anti-bacterial response.

Recapitulation of prostate tissue cell type-specific transcriptomes by an in vivo primary prostate tissue xenograft model.

Studies of the normal functions and diseases of the prostate request in vivo models that maintain the tissue architecture and the multiple-cell type compartments of human origin in order to recapitulate reliably the interactions of different cell types. Cell type-specific transcriptomes are critical to reveal the roles of each cell type in the functions and diseases of the prostate. A primary prostate tissue xenograft model was developed using fresh human prostate tissue specimens transplanted onto male mice that were castrated surgically and implanted with a device to maintain circulating testosterone levels comparable to adult human males. Endothelial cells and epithelial cells were isolated from 7 fresh human prostate tissue specimens and from primary tissue xenografts established from 9 fresh human prostate tissue specimens, using antibody-conjugated magnetic beads specific to human CD31 and human EpCAM, respectively. Transcriptomes of endothelial, epithelial and stromal cell fractions were obtained using RNA-Seq. Global and function-specific gene expression profiles were compared in inter-cell type and inter-tissue type manners. Gene expression profiles in the individual cell types isolated from xenografts were similar to those of cells isolated from fresh tissue, demonstrating the value of the primary tissue xenograft model for studies of the inter-relationships between prostatic cell types and the role of such inter-relationships in organ development, disease progression, and response to drug treatments.

Dehydroascorbic acid, the oxidized form of vitamin C, improves renal histology and function in old mice.

Oxidative stress and inflammation are crucial factors that increase with age. In the progression of multiple age-related diseases, antioxidants and bioactive compounds have been recognized as useful antiaging agents. Oxidized or reduced vitamin C exerts different actions on tissues and has different metabolism and uptake. In this study, we analyzed the antiaging effect of vitamin C, both oxidized and reduced forms, in renal aging using laser microdissection, quantitative reverse-transcription polymerase chain reaction, and immunohistochemical analyses. In the kidneys of old SAM mice (10 months of age), a model of accelerated senescence, vitamin C, especially in the oxidized form (dehydroascorbic acid [DHA]) improves renal histology and function. Serum creatinine levels and microalbuminuria also decrease after treatment with a decline in azotemia. In addition, sodium-vitamin C cotransporter isoform 1 levels, which were increased during aging, are normalized. In contrast, the pattern of glucose transporter 1 expression is not affected by aging or vitamin C treatment. We conclude that oxidized and reduced vitamin C are potent antiaging therapies and that DHA reverses the kidney damage observed in senescence-accelerated prone mouse 8 to a greater degree.

Afasia como debut de estado hiperosmolar hiperglicémico. Caso clínico / Aphasia as the presenting symptom of a hyperglycemic hyperosmolar state. Case report

Neurological manifestations such as seizures, disorders of consciousness and abnormal movements such as hemichorea and hemiballismus can be the presenting symptoms of hyperglycemic hyperosmolar states. Exceptionally, focal signs as hemiparesis or aphasia are described. We report a 66-year-old man, presenting with nonfluent aphasia and right subtle hemiparesis. The computed tomography, computed tomography angiography and brain magnetic resonance did not show acute ischemic lesions or obstruction of arterial vessels. The initial laboratory evaluation disclosed a blood glucose of 936 mg/dL, a plasma osmolality of 331 mOsm/Kg, and positive plasma ketones. After the treatment of hyperglycemia and hyperosmolality, focal symptoms subsided.