Elaine Marshall

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

WNK1 and WNK4 are unusual serine/threonine kinases with atypical positioning of the catalytic active-site lysine (WNK: With-No-K[lysine]). Mutations in these WNK kinase genes can cause familial hyperkalemic hypertension (FHHt), an autosomal dominant, hypertensive, hyperkalemic disorder, implicating this novel WNK pathway in normal regulation of BP and electrolyte balance. Full-length (WNK1-L) and short (WNK1-S) kinase-deficient WNK1 isoforms previously have been identified. Importantly, WNK1-S is overwhelmingly predominant in kidney. Recent Xenopus oocyte studies implicate WNK4 in inhibition of both thiazide-sensitive co-transporter-mediated Na+ reabsorption and K+ secretion via renal outer medullary K+ channel and now suggest that WNK4 is inhibited by WNK1-L, itself inhibited by WNK1-S. This study examined WNK pathway gene expression in mouse kidney and its regulation in vivo. Expression of WNK1-S and WNK4 is strongest in distal tubule, dropping sharply in collecting duct and with WNK4 also expressed in thick ascending limb and the macula densa. These nephron segments that express WNK1-S and WNK4 mRNA have major influence on long-term NaCl reabsorption, BP, K+, and acid-base balance, processes that all are disrupted in FHHt. In vivo, this novel WNK pathway responds with significant upregulation of WNK1-S and WNK4 with high K+ intake and reduction in WNK1-S on chronic lowering of K+ or Na+ intake. A two-compartment distal nephron model explains these in vivo findings and the pathophysiology of FHHt well, with WNK and classic aldosterone pathways responding to drivers from K+ balance, extracellular volume, and aldosterone and cross-talk through distal Na+ delivery regulating electrolyte balance and BP.

Phase II trial of tamoxifen and goserelin in recurrent epithelial ovarian cancer.

Endocrine therapy is a recognised option in the treatment of chemo-resistant ovarian cancer. We conducted a nonrandomised phase II evaluation of combination endocrine therapy with tamoxifen and goserelin in patients with advanced ovarian cancer that had recurred following chemotherapy. In total, 26 patients entered the study, of which 17 had platinum-resistant disease. The median age was 63 years and enrolled patients had received a median of three chemotherapy regimens prior to trial entry. Patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. Using the definition of endocrine response that included patients with stable disease (SD) of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (CR) (3.8%), two partial responses (PR) (7.7%) and 10 patients with SD (38.5%). The median progression-free interval (PFI) was 4 months (95% CI 2.4–9.6) while the median overall survival (OS) was 13.6 months (95% CI 5.5–30.6). Four patients received treatment for more than 2 years (range 1–31) and one of them is still on treatment. In none of the four patients was there any evidence of recurrent or cumulative treatment related toxicity. Treatment-limiting toxicity was not seen in any of the study population. Endocrine data demonstrated a marked suppression of luteinising hormone (LH) and follicle-stimulating hormone (FSH) to less than 4% of baseline values. No consistent correlation could be established between LH/FSH suppression and tumour response. Likewise no relationship was observed between Inhibin A/B and pro-alpha C levels and tumour response. Inhibin is unlikely to be a useful surrogate marker for response in locally advanced or metastatic ovarian cancer. Combination endocrine therapy with tamoxifen and goserelin is an active regimen in platinum-resistant ovarian cancer patients. Hormonal therapy is advantageous in its relative lack of toxicity, ease of administration and tolerability, thus making it suitable for patients with heavily pretreated disease, compromised bone marrow function and other comorbid conditions that contraindicate cytotoxic therapy as well as in patients with indolent disease.

Non-Timber Forest Products in the Community of El Terrero, Sierra de Manantlán Biosphere Reserve, Mexico: Is Their Use Sustainable?

The importance of non-timber forest products (NTFPs) to rural income was examined in a highland community in the Sierra de Manantlán Biosphere Reserve, Jalisco-Colima, Mexico. Rapid Rural Appraisal (RRA) techniques were used to interview 70% of households in the community of El Terrero. Of the nine plant species identified as NTFP sources, the two principal species traded by the community were tila (derived from the flowers and fruits of the tree Ternstroemia lineata), and blackberry (Rubus spp.). Collecting and selling of NTFPs was almost exclusively undertaken by women, with 80% of respondents participating. NTFP sale ranked as the most important source of cash income for 30% of women interviewed, and either second- or third-most important for the remainder. The research examined harvesting impact on populations of T. lineata, an understory tree species characteristic of cloud forest, which this was assessed in the four most-frequented collecting sites. Our results suggested that current harvesting approaches appear to be sustainable, although 95% of the women interviewed reported a decline in resource availability within the last 15 years, apparently resulting from illegal cutting. Suggestions are made with respect to the sustainable development of NTFP resources to help alleviate poverty within the Reserve.ResumenSe evaluó la importancia de los productos forestales no maderables (PFNMs) en el ingreso familiar de un ejido ubicado en una zona montañosa de la reserva de la biósfera de Manantlan, Jalisco—Colitna, México. Se utilizaron técnicas participativas como entrevistas al 70% de las familias de el ejido “El Terrero.” De las nueve especies de plantas identificadas comofuentes de PFNMs, las dos más comercializadas por la communidad fueron tila (órganos frutales del arbol Ternstroemia lineata) y zarzamora (Rubus spp.) La colecta y venta de PFNMs fue casi exclusivamente llevada por mujeres, con una participation del 80%. La venta de PFNMs fue la principal fuente de dinero para el 30% de las mujeres entrevistadas, y el segundo o tercero en importancia por las demás. La investigatión examinó el impacto de la extractión en poblaciones silvestres deT. lineata (una especie de bosque nublado), la cual fue evaluada en cuatro de los sitios de colecta más frecuente. Nuestros resultados sugieren que el nivel y manera de extractión parecen ser sustentable; aunque el 95% de las mujeres entrevisada han notado que en los últimas 15 años la cantidad de recursos naturales ha bajado a causa de la extractión ilegal. Se hacen sugerencias en cuanto al desarollo sustentable de estos PFNMs, para ayudar a disminuir la pobreza dentro de la reserva.

In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis.

Context: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. Objective: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). Design: Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. Setting: The study was conducted at the University Research Institute. Patients: Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. Results: A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. Conclusions: Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis.