Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

Caracterización petrológica y geoquímica del moteado leucocrático en rocas basálticas alcalinas.

La presencia de un moteado leucocrático en basaltos alcalinos es un aspecto bastante frecuente en este tipo de lavas. A pesar de ello los estudios sobre su origen e implicaciones son hoy en día escasos y controvertidos. Es por ello que en el presente trabajo se presenta un estudio detallado del moteado en el que se incluyen relaciones de campo así como una caracterización textural, mineralógica y geoquímica de una selección de muestras. Los resultados obtenidos permiten sugerir que el moteado leucocrático se desarrolla como consecuencia del remplazamiento postmagmático de leucita primaria intersticial, dispuesta en forma de cuerpos poiquilíticos, por analcima secundaria. El aumento de volumen que supone este remplazamiento explica el mayor grado de fracturación de los minerales esenciales (olivino, clinopiroxeno y plagioclasa) así como la formación de grietas capilares que se disponen de forma radial desde los motes y que pueden llegar a comprometer la coherencia de la roca. Las observaciones realizadas indican que el desarrollo y tipología de moteado están fuertemente condicionados por la temperatura de la roca y la presencia de agua. Palabras clave: moteado leucocrático, basaltos alcalinos, analcimitización, leucita poiquilítica intersticial. /// The presence of sunburns is a common feature in alkaline basaltic rocks. Despite their frequent occurrence, works that have studied the origin and implications of sunburn presence are still scarce and controversial. In this study we present a detailed work on sunburns including field relations and a textural, mineralogical and geochemical characterization of a set of selected samples. The obtained results evidence that leucocratic discolorations are developed as a consequence of post-magmatic replacement of primary interstitial groundmass leucite arranged in poikilitic bodies by secondary analcime. The volume increase associated to this replacement explains the major degree of fracturing of the framework minerals (olivine, clinopyroxene and plagioclase) as well as the development of radial capillary cracks that radiate outwards from the sunburns. Both characteristics can compromise the coherence of the rock. Al the observations indicate that the combination of rock temperature and water supply strongly conditions de development and type of sunburns

Interrogation of gossypol therapy in glioblastoma implementing cell line and patient-derived tumour models

Background: Glioblastoma (GBM), being a highly vascularised and locally invasive tumour, is an attractive target for anti-angiogenic and anti-invasive therapies. The GBM/endothelial cell response to gossypol/temozolomide (TMZ) treatment was investigated with a particular aim to assess treatment effects on cancer hallmarks. Methods: Cell viability, endothelial tube formation and GBM tumour cell invasion were variously assessed following combined treatment in vitro. The U87MG-luc2 subcutaneous xenograft model was used to investigate therapeutic response in vivo. Viable tumour response to treatment was interrogated using immunohistochemistry. Combined treatment protocols were also tested in primary GBM patient-derived cultures. Results: An endothelial/GBM cell viability inhibitory effect, as well as an anti-angiogenic and anti-invasive response, to combined treatment have been demonstrated in vitro. A significantly greater anti-proliferative (P=0.020, P=0.030), anti-angiogenic (P=0.040, P<0.0001) and pro-apoptotic (P=0.0083, P=0.0149) response was observed when combined treatment was compared with single gossypol/TMZ treatment response, respectively. GBM cell line and patient-specific response to gossypol/TMZ treatment was observed. Conclusions: Our results indicate that response to a combined gossypol/TMZ treatment is related to inhibition of tumour-associated angiogenesis, invasion and proliferation and warrants further investigation as a novel targeted GBM treatment strategy

Transcriptional role of cyclin D1 in development revealed by a “genetic-proteomic” screen

Author manuscript: 2010 September 22.Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers[superscript 1, 2]. The full repertoire of cyclin D1 functions in normal development and oncogenesis is unclear at present. Here we developed Flag- and haemagglutinin-tagged cyclin D1 knock-in mouse strains that allowed a high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location analyses (chromatin immunoprecipitation coupled to DNA microarray; ChIP-chip) showed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas—an organ that critically requires cyclin D1 function[superscript 3, 4]—cyclin D1 binds the upstream regulatory region of the Notch1 gene, where it serves to recruit CREB binding protein (CBP) histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch1 transcript and protein in cyclin D1-null (Ccnd1-/-) retinas. Transduction of an activated allele of Notch1 into Ccnd1-/- retinas increased proliferation of retinal progenitor cells, indicating that upregulation of Notch1 signalling alleviates the phenotype of cyclin D1-deficiency. These studies show that in addition to its well-established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development. Our approach, which we term ‘genetic–proteomic’, can be used to study the in vivo function of essentially any protein

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα and is an independent prognostic factor in node-negative breast cancer

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n = 690; P = 0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy

Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model

INTRODUCTION: The purpose of the present study was to determine whether cytotoxic chemotherapeutic agents administered prior to immunotherapy with gene vaccines could augment the efficacy of the vaccines. METHODS: Mice were injected in the mammary fat pad with an aggressive breast tumor cell line that expresses HER2/neu. The mice were treated 3 days later with a noncurative dose of either doxorubicin or paclitaxel, and the following day with a gene vaccine to HER2/neu. Two more doses of vaccine were given 14 days apart. Two types of gene vaccines were tested: a plasmid vaccine encoding a self-replicating RNA (replicon) of Sindbis virus (SINCP), in which the viral structural proteins were replaced by the gene for neu; and a viral replicon particle derived from an attenuated strain of Venezuelan equine encephalitis virus, containing a replicon RNA in which the Venezuelan equine encephalitis virus structural proteins were replaced by the gene for neu. RESULTS: Neither vaccination alone nor chemotherapy alone significantly reduced the growth of the mammary carcinoma. In contrast, chemotherapy followed by vaccination reduced tumor growth by a small, but significant amount. Antigen-specific CD8(+ )T lymphocytes were induced by the combined treatment, indicating that the control of tumor growth was most probably due to an immunological mechanism. The results demonstrated that doxorubicin and paclitaxel, commonly used chemotherapeutic agents for the treatment of breast cancer, when used at immunomodulating doses augmented the antitumor efficacy of gene vaccines directed against HER2/neu. CONCLUSIONS: The combination of chemotherapeutic agents plus vaccine immunotherapy may induce a tumor-specific immune response that could be beneficial for the adjuvant treatment of patients with minimal residual disease. The regimen warrants further evaluation in a clinical setting