Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity.

PURPOSE: Recent studies point to adipose-derived stem cells (ASCs) as a link between obesity and cancer. We aimed to determine whether survivin, which is highly secreted by ASCs from subjects with obesity, might drive a pro-tumoral phenotype in macrophages. METHODS: The effect of ASC conditioned medium on the macrophage phenotype was assessed by expression studies. Survivin intracellular localization and internalization were examined by subcellular fractionation and immunofluorescence, respectively. Loss- and gain-of-function studies were performed using adenoviral vectors, and gene expression patterns, migration and invasion capacities of cancer cells were examined. Heterotypic cultures of ASCs, macrophages and cancer cells were established to mimic the tumor microenvironment. Survivin-blocking experiments were used to determine the impact of survivin on both macrophages and cancer cells. Immunohistochemical analysis of survivin was performed in macrophages from ascitic fluids of cancer patients and healthy controls. RESULTS: We found that obese-derived ASCs induced a phenotypic switch in macrophages characterized by the expression of both pro- and anti-inflammatory markers. Macrophages were found to internalize extracellular survivin, generating hybrid macrophages with a tumor-associated phenotype that included secretion of survivin. Exogenous expression of survivin in macrophages generated a similar phenotype and enhanced the malignant characteristics of cancer cells by a mechanism dependent on survivin phosphorylation at threonine 34. Survivin secreted by both ASCs from subjects with obesity and tumor-associated macrophages synergistically boosted the malignancy of cancer cells. Importantly, survivin was mainly detected in ascites-associated macrophages from patients with a malignant diagnosis. CONCLUSION: Our data indicate that survivin may serve as a molecular link between obesity and cancer and as a novel marker for tumor-associated macrophages.

An antisense oligonucleotide targeting TGF-ß2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages.

BACKGROUND: The transforming growth factor (TGF)-ß pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-ß pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-ß isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-ß2. MATERIALS AND METHODS: We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis. RESULTS: We observed that ISTH0047 is able to significantly reduce TGF-ß2 mRNA and protein levels without altering the levels of TGF-ß1 and TGF-ß3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-ß2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86. CONCLUSION: Overall, our data point to TGF-ß2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.

Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner.

Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs have specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP-ribose) polymerase hyperactivation and cell death and reduced cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. Moreover, this study also shows that restoration of hCNT1 expression is able to reduce tumor growth in a mouse model of pancreatic adenocarcinoma. These data predict a novel role for a NT protein, hCNT1, which appears to be independent of its role as mediator of nucleoside uptake by cells. Thereby, hCNT1 fits the profile of a transceptor in a substrate translocation-independent manner and is likely to be relevant to tumor biology.

Transport of nucleoside analogs across the plasma membrane: a clue to understanding drug-induced cytotoxicity.

Nucleoside analogs are widely used in the treatment of cancer and viral-induced diseases. Efficacy of treatments relies upon a variety of events, including transport across tissue and target barriers, which determine drug pharmacokinetics and target cell bioavailability. To exert their action, nucleosides have to be chemically modified, thus compromising cellular uptake by those routes which are responsible for the uptake of natural nucleosides and nucleobases. In this review we will focus on established knowledge and recent advances in the understanding of nucleoside- and nucleobase-derived drug uptake mechanisms. Basically, these drug uptake processes involve the gene families SLC22, SLC28 and SLC29. These gene families encode Organic Anion Transporter (OAT)/Organic Cation Transporter (OCT), Concentrative Nucleoside Transporter (CNT) and Equilibrative Nucleoside Transporter (ENT) proteins, respectively. The pharmacological profiles of these plasma membrane carriers as well as their basic physiological and regulatory properties, including their tissue and subcellular distribution will be reviewed. This knowledge is crucial for the understanding of nucleoside- and nucleobase-derived drug bioavailability and therapeutic action. Moreover, changes in both transporter expression and/or transporter function (for instance as a consequence of gene variability) might also modulate response to treatment, thereby anticipating a putative diagnostic and predictive added value to the analysis of transporter expression and their corresponding genetic variants.

The concentrative nucleoside transporter family (SLC28): new roles beyond salvage?

The concentrative nucleoside transporter (CNT) family (SLC28) has three members: SLC28A1 (CNT1), SLC28A2 (CNT2) and SLC28A3 (CNT3). The CNT1 and CNT2 transporters are co-expressed in liver parenchymal cells and macrophages, two suitable models in which to study cell cycle progression. Despite initial observations suggesting that these transporter proteins might contribute to nucleoside salvage during proliferation, their subcellular localization and regulatory properties suggest alternative roles in cell physiology. In particular, CNT2 is a suitable candidate for modulation of purinergic responses, since it is under the control of the adenosine 1 receptor. Increasing evidence also suggests a role for CNT2 in energy metabolism, since its activation relies on the opening of ATP-sensitive K(+) channels. Animal and cell models genetically modified to alter nucleoside transporter expression levels may help to elucidate the particular roles of CNT proteins in cell physiology.

Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells.

Fludarabine is considered the treatment of choice for most patients with chronic lymphocytic leukemia (CLL). We have analyzed the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in CLL cells. Among the known plasma membrane transporters, we have previously observed a significant correlation between fludarabine uptake via ENT carriers and ex vivo sensitivity of CLL cells to fludarabine, although mRNA amounts of the equilibrative nucleoside transporters hENT1 and hENT2 do not show any predictive response to treatment. In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine. These results suggest that the equilibrative nucleoside transporter hENT2 plays a role in fludarabine responsiveness in CLL patients.

[Cross reactivity among proton pump inhibitors: does it exits?]. / 'Existe reactividad cruzada entre inhibidores de la bomba de protones?

BACKGROUND: There has been little research into adverse reactions to proton pump inhibitors (omeprazole and its analogs) of suspected allergic etiology. We found nine studies in the medical literature and only two of these describe cross reactivity between proton pump inhibitors detected by skin prick tests. CASE REPORT: We present a 24-year-old woman who twice developed total body pruritus and urticaria with facial angioedema 1-2 hours after ingesting an omeprazole capsule. In the second episode the patient also reported the sensation of having a lump in her throat. METHODS: Skin prick and intradermal tests were performed with omeprazole, pantoprazole, and lansoprazole, which were positive for the three proton pump inhibitors. For ethical reasons, oral challenge testing was not performed. CONCLUSION: The clinical picture and the positive skin test results suggest an IgE-mediated mechanism. Skin prick tests may be useful for the diagnosis of cases of suspected allergy to omeprazole and its analogs. We found cross reactivity between three proton pump inhibitors detected by skin tests.

¿Existe reactividad cruzada entre inhibidores de la bomba de protones? / Cross reactivity among proton pump inhibitors: does it exits?

Antecedentes: Los casos descritos sobre reacciones adversas a los inhibidores de la bomba de protones (omeprazol y análogos) con sospecha de etiología alérgica son escasos, encontrando un total de nueve trabajos en la literatura médica. Únicamente en dos de ellos se ha descrito la existencia de reactividad cruzada entre varios miembros del grupo mediante pruebas cutáneas. Caso clínico: Se trata de una mujer de 24 años que presentó en dos ocasiones prurito y urticaria generalizados, con angioedema facial en un intervalo de 1-2 horas tras la toma de omeprazol por vía oral; en el segundo episodio refiere además sensación de cuerpo extraño en garganta. Métodos: Se realizan pruebas cutáneas por prick e intradermorreacción con omeprazol, lansoprazol y pantoprazol, con resultado positivo para los tres fármacos. No se realiza provocación oral por razones éticas. Conclusión: El desarrollo del cuadro clínico y la positividad de los tests cutáneos sugieren un mecanismo mediado por Ig E. Destaca la validez de las pruebas cutáneas en el diagnóstico de los casos de sospecha de alergia a omeprazol y análogos. Hemos encontrado la existencia de reactividad cruzada entre los inhibidores de la bomba de protones, mediante la positividad de pruebas cutáneas (AU)

Background: There has been little research into adverse reactions to proton pump inhibitors (omeprazole and its analogs) of suspected allergic etiology. We found nine studies in the medical literature and only two of these describe cross reactivity between proton pump inhibitors detected by skin prick tests. Case report: We present a 24-year-old woman who twice developed total body pruritus and urticaria with facial angioedema 1-2 hours after ingesting an omeprazole capsule. In the second episode the patient also reported the sensation of having a lump in her throat. Methods: Skin prick and intradermal tests were performed with omeprazole, pantoprazole, and lansoprazole, which were positive for the three proton pump inhibitors. For ethical reasons, oral challenge testing was not performed. Conclusion: The clinical picture and the positive skin test results suggest an IgE-mediated mechanism. Skin prick tests may be useful for the diagnosis of cases of suspected allergy to omeprazole and its analogs. We found cross reactivity between three proton pump inhibitors detected by skin tests (AU)

Hacia la definición de un conjunto mínimo básico de datos de atención primaria / Towards the definition of a set of basic minimun data in primary care

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[Eating and life style habits in primary school student population from Mataro (Barcelona) associated with consumption of sugar and TV watching]. / Hábitos de vida en una población escolar de Mataró (Barcelona) asociados al número de veces diarias que se ve televisión y al consumo de azúcares.

BACKGROUND: Most important trends of knowledge and behaviour are built on childhood and adolescence. Thus, to act on non healthy habits at early ages should have more impact in the development of later diseases. METHODS: 2,898 primary school students answered a written self administered questionnaire containing items about Dietary habits life-style habits, and familiar socioeconomic level. Cluster analysis was used to obtain the profile of student groups with higher probabilities to develop the risk habits studied. RESULTS: High consumption of television is associated with older ages, refreshments intake, and moderate consumption of sugar. On the other hand, high consumption of sugar is associated with older ages, usual intake of candies, type of school, low intake of raw vegetables, and low consumption of fruits. CONCLUSIONS: Other non healthy dietary and lifestyle habits show clustering in high consumers of television and/or sugar. The influence of socioeconomic level on getting risk habits is well stated; however, the role played by this variable in the results of our study remains uncertain, probably due to the utilization of indirect data. The resultants profiles suggest that the presence of some non healthy lifestyle habits, such as high television and sugar consumption, tends to cluster other risk habits in the same person.

Sex as a prognostic factor in gastric cancer.

The aim of this study was to assess whether survival of gastric cancer patients differed between males and females. Although it is well known that the incidence of gastric cancer is higher for men than for women, the existence of a sex-specific prognosis has seldom been addressed. Studies based on population registries have not assessed the role of stage and histology. Cases of histologically confirmed gastric carcinoma were obtained from three Spanish hospitals in Soria (n = 405), Barcelona (n = 249) and Mataró (n = 197). Differences in possible confounders were tested between men and women and survival analyses were performed separately by hospital. Cox's proportional hazards models were used to account for age, tumour stage, histology and tumour sub-location. Only in Mataró was a significant difference in the stage distribution observed between women and men, with a lower proportion of local stage tumours among women (P = 0.047). No statistically significant differences of histological type between men and women were observed in any of the centres. After adjusting for tumour stage and age, women were observed to have significantly better survival in Barcelona (female to male hazard ratio (HR) = 0.578, P < 0.001); this effect was marginal in Soria (HR = 0.788, P = 0.092) and non-significant in Matar-o (HR = 0.895, P = 0.54). Age-adjusted hazard ratios were calculated within each tumour stage. For Barcelona, the effect of better prognosis among women was most marked at local stage (HR = 0.320, P = 0.013), and in Soria at the regional stage (HR = 0.426, P = 0.002). Although in Mataró all HRs were below unity, none were statistically significant. Little effect was observed at the disseminated stage. The other covariables exerted no influence. Women appear to have a better prognosis than men, and the difference could be tumour stage dependent. Confirmation of these findings would give a valuable insight into gastric cancer growth and ultimately be of use in planning treatment.

[Humoral immunity in nasal allergy]. / Inmunidad humoral en alergia nasal.

In this work, several immunological parameters were studied in a group of 40 patients diagnosed as having allergic rhinitis. As a control group we assembled 20 patients with cholinergic rhinitis. A significative increase in the level of serum IgM was detected in the patients with cholinergic rhinitis. The differences observed between other parameters (lymphocyte count, blastic transformation with PHA and Con-A), were not significative. We discuss the results.