Citations

AbstractSarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six‐minute walk distance (6MWD) and health‐related quality of life (HRQOL) as assessed by short form 36 scores (SF‐36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF‐36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 [0.9–4.7]). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia.

Abstract Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS and cure rates remain below 20%. AML/MDS arise following the accumulation of stepwise genetic and epigenetic changes in hematopoietic stem and progenitor cells (HSPC). Utilizing a novel strategy of parallel transcriptional analysis of sorted HSPC populations in distinct subtypes of AML, we compared the gene expression in AML HSPC with identical compartments from age-matched healthy controls and identified Interleukin 1 receptor accessory protein (IL1RAP) as one of the most significantly upregulated genes in HSPC in all examined subtypes of AML. Fluorescence in situ hybridization of sorted IL1RAP+ and IL1RAP- cells from patients with monosomy 7 AML (-7) indicated that the aberrant clone was restricted to IL1RAP+ cells, demonstrating that IL1RAP overexpression is a distinguishing feature of the -7 clone. Multivariate analysis of a large cohort of patients with normal karyotype AML showed that patients with high IL1RAP levels had inferior overall survival than patients with lower IL1RAP levels, suggesting an independent prognostic value for this molecule in AML. IL1RAP expression levels in MDS were found elevated on stem cells of patients with high risk disease, proposing a role of IL1RAP in higher risk MDS and progression to AML. Downregulation of IL1RAP expression by lentivirally expressed shRNAs decreased clonogenicity in cell lines and AML/MDS primary patient samples, induced apoptosis of AML cells, and reduced proliferation of AML cells and infiltration of hematopoietic organs in vivo. IL1RAP is a transmembrane protein required for signaling through several receptors of the IL1 family. Downregulation of IL1RAP expression in AML cells led to phosphorylation changes in several kinases and their substrates suggesting participation of IL1RAP in multiple signaling pathways and highlighting its potential as therapeutic target. We investigated whether inhibition of IL1RAP with pharmacological compounds is feasible and effective. Antibody-mediated inhibition of IL1RAP led to inhibition of AML cell growth in vitro. In addition, we designed peptides to interfere with IL1RAP-receptor interactions which lead to inhibition of AML cell growth. Both types of agents are being further tested and optimized. In summary, our study reveals IL1RAP as aberrantly expressed on HSPC of AML and high-risk MDS patients. Inhibition of IL1RAP is feasible and functionally effective, and thus has the potential to lead to novel therapies specifically directed at such stem cells. Beyond IL1RAP, our study provides a map of dysregulated transcripts in HSPC from patients with AML, which may offer further opportunities for therapeutic intervention. The strategy of comparative analysis of sorted stem and progenitor cells in cancer versus healthy controls may be applicable to other type of cancers with a suspected stem cell origin, and instrumental for the identification of targets for stem cell-directed therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C225. Citation Format: Laura Barreyro, Kelly Mitchell, Britta Will, Boris Bartholdy, Li Zhou, Tihomira Todorova, Robert Stanley, Susana Ben-Neriah, Cristina Montagna, Samir Parekh, Andrea Pellagatti, Jacqueline Boultwood, Elisabeth Paietta, Rhett Ketterling, Larry Cripe, Hugo Fernandez, Peter Greenberg, Jacob Rowe, Martin Tallman, Christian Steidl, Constantine Mitsiades, Amit Verma, Ulrich Steidl. IL1RAP as functionally relevant target for stem-cell directed therapy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C225.

Background: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown. Objective: Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability. Methods: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability. Results: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm 2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT. Conclusion: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.

AbstractVitamin D deficiency is common among patients with end‐stage liver disease (ESLD). The primary aim of our study was to assess the prevalence of vitamin D deficiency, secondary hyperparathyroidism, and bone disease in patients with ESLD awaiting LT.MethodsWe retrospectively studied 190 patients at our center. Serum total 25‐hydroxyvitamin D (25‐OH D), parathyroid hormone (PTH), calcium, and bone mineral analysis (BMA) were recorded. Standard World Health Organization (WHO) criteria were used to diagnose osteopenia/osteoporosis. Only patients with normal serum creatinine were analyzed.ResultsThirty‐two of 190 patients were excluded from the final analysis (missing serum total 25‐OH D levels in three patients and elevated serum creatinine, 29 patients). 105 of 158 (66.4%) evaluable patients had 25‐OH D levels <25 ng/mL. Patients included in the analysis (n = 158) were divided according to serum total 25‐OH D levels: 0–10 ng/mL (n = 23), 11–20 ng/mL (n = 64), and >20 ng/mL (n = 71). There were no significant differences in mean serum PTH and corrected calcium levels among the three subgroups. Only three patients had elevated serum PTH. Patients with total 25‐OH D ≤ 10 ng/mL had higher model for end‐stage liver disease (MELD) scores vs. those with 25‐OH D > 20 ng/mL (13.3 ± 3, range 8–21, vs. 11.9 ± 3.4, range 6–29, p = 0.004). Irrespective of vitamin D status, bone disease was present in 64.6% of patients.ConclusionLow vitamin D levels and bone disease are common among patients with ESLD awaiting LT. Despite a high prevalence of low serum total 25‐OH D, our cohort maintained normal corrected calcium levels and did not develop secondary hyperparathyroidism. We propose that free serum 25‐OH D and vitamin D‐binding protein may be necessary to accurately establish the diagnosis of vitamin D deficiency in the setting of ESLD. Additional studies are needed to further define mechanisms of bone disease in patients with ESLD.

ABSTRACTThe chromatin remodeling complex SWI/SNF and the transcription factor C/EBPβ play critical roles in osteoblastic cells as they jointly control transcription of a number of bone‐related target genes. The largest C/EBPβ isoform, LAP*, possesses a short additional N‐terminal domain that has been proposed to mediate the interaction of this factor with SWI/SNF in myeloid cells. Here we examine the requirement of a functional N‐terminus in C/EBPβ‐LAP* for binding SWI/SNF and for recruiting this complex to the Ric‐8B gene to mediate transcriptional repression. We find that both C/EBPβ‐LAP* and SWI/SNF simultaneously bind to the Ric‐8B promoter in differentiating osteoblasts that repress Ric‐8B expression. This decreased expression of Ric‐8B is not accompanied by significant changes in histone acetylation at the Ric‐8B gene promoter sequence. A single aminoacid change at the C/EBPβ‐LAP* N‐terminus (R3L) that inhibits C/EBPβ‐LAP*‐SWI/SNF interaction, also prevents SWI/SNF recruitment to the Ric‐8B promoter as well as C/EBPβ‐LAP*‐dependent repression of the Ric‐8B gene. Inducible expression of the C/EBPβ‐LAP*R3L protein in stably transfected osteoblastic cells demonstrates that this mutant protein binds to C/EBPβ‐LAP*‐target promoters and competes with the endogenous C/EBPβ factor. Together our results indicate that a functional N‐terminus in C/EBPβ‐LAP* is required for interacting with SWI/SNF and for Ric‐8B gene repression in osteoblasts. J. Cell. Physiol. 229: 1521–1528, 2014. © 2014 Wiley Periodicals, Inc.