The association between lumbar paraspinal muscle functional cross-sectional area on MRI and regional volumetric bone mineral density measured by quantitative computed tomography.

Osteosarcopenia is a common condition among elderly and postmenopausal female patients. Site-specific bone mineral density is more predictive of bone-related complications. Few studies have investigated muscle-bone associations. Our results demonstrated that in women, significant positive associations between paraspinal muscles FCSA and vBMD exist at different lumbosacral levels. These regional differences should be considered when interpreting bone-muscle associations in the lumbar spine. INTRODUCTION: There is increasing evidence between bone and muscle volume associations. Previous studies have demonstrated comorbidity between osteoporosis and sarcopenia. Recent studies showed that sarcopenic subjects had a fourfold higher risk of concomitant osteoporosis compared to non-sarcopenic individuals. Although site-specific bone mineral density (BMD) assessments were reported to be more predictive of bone-related complications after spinal fusions than BMD assessments in general, there are few studies that have investigated level-specific bone-muscle interactions. The aim of this study is to investigate the associations between muscle functional cross-sectional area (FCSA) on magnetic resonance imaging (MRI) and site-specific quantitative computed tomography (QCT) volumetric bone mineral density (vBMD) in the lumbosacral region among spine surgery patients. METHODS: We retrospectively reviewed a prospective institutional database of posterior lumbar fusion patients. Patients with available MRI undergoing posterior lumbar fusion were included. Muscle measurements and FCSA were conducted and calculated utilizing a manual segmentation and custom-written program at the superior endplate of the L3-L5 vertebrae level. vBMD measurements were performed and calculated utilizing a QCT pro software at L1-L2 levels and bilateral sacral ala. We stratified by sex for all analyses. RESULTS: A total of 105 patients (mean age 61.5 years and 52.4% females) were included. We found that female patients had statistically significant lower muscle FCSA than male patients. After adjusting for age and body mass index (BMI), there were statistically significant positive associations between L1-L2 and S1 vBMD with L3 psoas FCSA as well as sacral ala vBMD with L3 posterior paraspinal and L5 psoas FCSA. These associations were not found in males. CONCLUSIONS: Our results demonstrated that in women, significant positive associations between the psoas and posterior paraspinal muscle FCSA and vBMD exist in different lumbosacral levels, which are independent of age and BMI. These regional differences should be considered when interpreting bone and muscle associations in the lumbar spine.

Postoperative decrease of regional volumetric bone mineral density measured by quantitative computed tomography after lumbar fusion surgery in adjacent vertebrae.

We investigated the effect of posterior lumbar fusion surgery on the regional volumetric bone mineral density (vBMD) measured by quantitative computed tomography. Surgery negatively affected the regional vBMD in adjacent levels. Interbody fusion was independently associated with vBMD decline and preoperative epidural steroid injections (ESIs) were associated with less postoperative vBMD decline. INTRODUCTION: Few studies investigate postoperative BMD changes after lumbar fusion surgery utilizing quantitative computed tomography (QCT). Additionally, it remains unclear what preoperative and operative factors contribute to postoperative BMD changes. The purpose of this study is to investigate the effect of lumbar fusion surgery on regional volumetric bone mineral density (vBMD) in adjacent vertebrae and to identify potential modifiers for postoperative BMD change. METHODS: The data of patients undergoing posterior lumbar fusion with available pre- and postoperative CTs were reviewed. The postoperative changes in vBMD in the vertebrae one or two levels above the upper instrumented vertebra (UIV+1, UIV+2) and one level below the lower instrumented vertebra (LIV+1) were analyzed. As potential contributing factors, history of ESI, and the presence of interbody fusion, as well as various demographic/surgical factors, were included. RESULTS: A total of 90 patients were included in the study analysis. Mean age (±SD) was 62.1 ± 11.7. Volumetric BMD (±SD) in UIV+1 was 115.4 ± 36.9 mg/cm3 preoperatively. The percent vBMD change in UIV+1 was - 10.5 ± 12.9% (p < 0.001). UIV+2 and LIV+1 vBMD changes showed similar trends. After adjusting with the interval between surgery and the secondary CT, non-Caucasian race, ESI, and interbody fusion were independent contributors to postoperative BMD change in UIV+1. CONCLUSIONS: Posterior lumbar fusion surgery negatively affected the regional vBMDs in adjacent levels. Interbody fusion was independently associated with vBMD decline. Preoperative ESIs were associated with less postoperative vBMD decline, which was most likely a result of a preoperative decrease in vBMD due to ESIs.

Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L- and TRAIL-induced apoptosis.

In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[a]pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by ß-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure.

TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signaling.

Soluble TNF-like weak inducer of apoptosis (TWEAK) trimers induce, in a variety of cell lines, translocation of cytosolic tumor necrosis factor (TNF) receptor-associated factor-2 (TRAF2) to a triton X-100-insoluble compartment without changes in the total cellular TRAF2 content. TWEAK-induced TRAF2 translocation is paralleled by a strong increase in nuclear factor kappaB 2 (NFkappaB2)/p100 processing to p52, indicating that TRAF2 redistribution is sufficient for activation of the alternative NFkappaB pathway. In accordance with the crucial role of TRAF2 in proinflammatory, anti-apoptotic TNF receptor-1 (TNFR1) signaling, we observed that TWEAK-primed cells have a reduced capacity to activate the classical NFkappaB pathway or JNK (cJun N-terminal kinase) in response to TNF. Furthermore, TWEAK-primed cells are sensitized for the TNFR1-mediated induction of apoptotic and necrotic cell death. Notably, the expression of the NFkappaB-regulated, TRAF2-interacting TRAF1 protein can attenuate TWEAK-induced depletion of the triton X-100-soluble TRAF2 fraction and improve TNFR1-induced NFkappaB signaling in TWEAK-primed cells. Taken together, we demonstrate that soluble TWEAK desensitizes cells for proinflammatory TNFR1 signaling and thus identify TWEAK as a modifier of TNF signaling.

Tumor necrosis factor receptor-associated factor-1 enhances proinflammatory TNF receptor-2 signaling and modifies TNFR1-TNFR2 cooperation.

It has been shown that tumor necrosis factor receptor-2 (TNFR2) stimulation leads to degradation of TNF receptor associated factor-2 (TRAF2) and inhibition of TNFR1-induced activation of NFkappaB and JNK. Here, we show that TRAF1 inhibits TNFR2-induced proteasomal degradation of TRAF2 and relieves TNFR1-induced activation of NFkappaB from the inhibitory effect of TNFR2. TRAF1 co-recruited with TRAF2 to both TNF receptors. Despite lacking an amino-terminal RING/zinc-finger domain, TRAF1 did not interfere with TNFR1-induced activation of JNK and NFkappaB. It is noted that physiological expression levels of TRAF1 enhanced NFkappaB activation and interleukin-8 (IL8) production induced by TNFR2. Thus, TRAF1 shifts the quality of integrated TNFR1-TNFR2 signaling from apoptosis induction to proinflammatory NFkappaB signaling.

Flt3-ITD mutations can generate leukaemia specific neoepitopes: potential role for immunotherapeutic approaches.

Flt3 internal tandem duplications (Flt3-ITD) can be detected in 25 - 30% of acute myeloid leukaemia (AML) and differ in length and sequence. We sequenced patient specific Flt3-ITD mutations in 2 Flt3-ITD positive AML cell lines and 13 Flt3-ITD harbouring AML patients. We addressed the question whether Flt3-ITD mutations can harbour HLA class I specific neoepitopes potentially able to induce a leukaemia and Flt3-ITD specific immune response. Here, we demonstrate that all but 1 Flt3-ITD mutations were unique. Interestingly, the peptide sequence of several Flt3-ITD fusion regions harbour 9 mer neoepitopes that potentially bind to HLA class I molecules in a HLA restricted manner (e.g. A1, A2, B27). The specific binding of Flt3-ITD derived neoepitopes to HLA-A2 is demonstrated. Peptide affinity of HLA-A2-restricted putative neoepitopes can be significantly improved by construction of mimotope candidates. We suggest that Flt3-ITD mutations can form new immunogenic and HLA class I-restricted peptide epitopes.