Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

<p>Abstract</p> <p>Background</p> <p>Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients ≤ 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.</p> <p>Methods</p> <p>We report our prospectively documented experience with all CRMO patients treated with pamidronate between 2003 and 2008 at a tertiary pediatric centre. Pamidronate was administered as intravenous cycles. The dose of pamidronate varied among subjects but was given as monthly to every 3 monthly cycles depending on the distance the patient lived from the infusion center. Maximum cumulative dose was ≤ 11.5 mg/kg/year. Pamidronate treatment was continued until resolution of MRI documented bone inflammation. Visual analog scale for pain (VAS) and bone resorption marker urine N-telopeptide/urine creatinine (uNTX/uCr) were measured at baseline, preceding each subsequent pamidronate treatment, at final follow-up, and/or at time of MRI confirmed CRMO flare. MRI of the affected site(s) was obtained at baseline, preceding every 2^ndtreatment, and with suspected CRMO recurrence.</p> <p>Results</p> <p>Nine patients (5 F: 4 M) were treated, with a median (range) age at treatment of 12.9 (4.5–16.3) years, and median (range) duration of symptoms of 18 (6–36) months. VAS decreased from 10/10 to 0–3/10 by the end of first 3–day treatment for all patients. The mean (range) time to complete MRI resolution of bone inflammation was 6.0 (2–12) months. The mean (confidence interval (CI)) baseline uNTX/uCr was 738.83 (CI 464.25, 1013.42)nmol/mmol/creatinine and the mean (CI) decrease from baseline to pamidronate discontinuation was 522.17 (CI 299.77, 744.56)nmol/mmol/creatinine. Median (range) of follow-up was 31.4 (24–54) months. Four patients had MRI confirmed CRMO recurrence, which responded to one pamidronate re-treatment. The mean (range) uNTX/uCr change as a monthly rate from the time of pamidronate discontinuation to flare was 9.41 (1.38–19.85)nmol/mmol/creatinine compared to -29.88 (-96.83–2.01)nmol/mmol/creatinine for patients who did not flare by the time of final follow-up.</p> <p>Conclusion</p> <p>Pamidronate resulted in resolution of pain and MRI documented inflammation in all patients. No patient flared while his/her uNTX/uCr remained suppressed. We propose that pamidronate is an effective second-line therapy in persistent CRMO.</p

LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity.

BACKGROUND LGR5 serves as a co-receptor for Wnt/β-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5 cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated. METHODS Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5 early adenoma RG/C2 cells. 2D growth assays were measured using an IncuCyte. LGR5 or MEK1/2 silencing studies were executed using siRNA and LGR5 expression was assessed by qRT-PCR and immunoblotting. Ki67 level and cell cycle status were analysed by flow cytometry. RESULTS Epidermal growth factor suppresses expression of LGR5 at both the transcript and protein level in colorectal adenoma and carcinoma cells. Suppression of LGR5 reduces the survival of EGF-treated adenoma cells by increasing detached cell yield but also inducing a proliferative state, as evidenced by elevated Ki67 level and enhanced cell cycle progression. Repression of LGR5 further increases the sensitivity of adenoma cells to EGFR inhibition. CONCLUSIONS LGR5 has an important role in the EGF-mediated survival and proliferation of early adenoma cells and could have clinical utility in predicting response of CRC patients to EGFR therapy

Links Abstract The iliac angle: a sonographic marker of trisomy 21 during the midtrimester: dependency of fetal lying?

The aim of this study was to evaluate the efficiency of the fetal iliac wing angle measurements in the detection of trisomy 21 during the second trimester and the impact of the fetal position on this measurement. During a 43-month period, the iliac wing angle was prospectively measured in 695 fetuses at genetic ultrasonography performed before amniocentesis. The iliac wing angle measurements were performed in a true axial section of the fetal pelvis and the relative position of the fetal spine was recorded (decubitus, lateral). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio (LR) were computed for multiple cutoff angles. The prevalence of trisomy 21 was 1.4%; 447 fetuses were in lateral position, 240 fetuses were in decubitus position, including, respectively, 2 and 8 fetuses with trisomy 21 (8 fetuses with other chromosomal anomalies were excluded). In euploid fetuses, the mean iliac wing angle was 83.7° in decubitus and 68.7° in lateral position; in fetuses with trisomy 21 the respective mean angles were 104.9° and 102.5°. A receiver operating characteristics (ROC) curve provided an absolute cutoff angle of 90°, predicting trisomy 21 with a sensitivity of 100%, a specificity of 72.4%, an NPV of 100%, a PPV value of 11.1%, and an LR of 3.6. The measurement of iliac wing angles in an axial section of the fetal pelvis is dependent on spine orientation and provides an efficient cutoff angle for the exclusion of trisomy 21 in patients at risk.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

SOFT X-RAY ABSORPTION AND EMISSION SPECTRA AND THE ELECTRONIC STRUCTURE OF THE Ba2 YCu3 O7-x SUPERCONDUCTOR

Nous présentons des spectres d'émission dans les X mous, du Ba2YCu3O7-x supraconducteur, excité par des faisceaux d'électrons, ainsi que les spectres du rendement total de photoélectrons du même materiau excité par des photons d'énergie comprise entre 20 et 600 eV. Nous confirmons, par la mesure de ce rendement, que le cuivre a une valence +2 dans ce composé. L'émission de rayons X mous fourni, par l'étude du spectre N4,5 du barium, du spectre M4,5 de l'yttrium et du spectre K de l'oxygène, une mesure de la densité d'états partielle de type p (p-PDOS) localisée sur chacun des sites atomiques respectifs. Dans chaque cas cette densité d'états est très petite à l'énergie de Fermi, et a un premier pic situé entre 3.5 et 4 eV en dessous du niveau de Fermi. L'étude du spectre K de l'oxygène confirme l'interprétation selon laquelle les structures observées dans les mesures de photoémission sont associées aux orbitales 2p de l'oxygène. Enfin nous n'avons observé aucun changement entre les spectres enregistré au dessus ou au dessous de la température critique Tc.We present e-beam excited soft x-ray emission spectra and total photoelectron yield spectra in the 20-600 eV photon energy range for the Ba2YCu3O7-x superconductor. We confirm the 2+ valency of Cu in the compound by total yield measurements. In soft x-ray emission, the N4.5 spectrum of Ba, the M4,5 spectrum of Y, and the K spectrum of O provide measures of the p-type partial density of states (p-PDOS) localized on the respective atomic sites. In each case the p-PDOS is very small at the Fermi energy with the first peak in the p-PDOS lying 3.5 to 4 eV below the Fermi energy. The K spectra of O confîrm the interpretation that the structure observed in the photoemission measurements are associated with the O 2p orbitals. Finally no changes are observed between spectra taken above and below Tc

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

BackgroundTo support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.MethodsWe generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.ResultsWe show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.ConclusionsTogether, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.Peer reviewe