Role of trabectedin in the treatment of soft tissue sarcoma.

Interest in marine natural products has allowed the discovery of new drugs and trabectedin (ET-743, Yondelis), derived from the marine tunicate Ecteinascidia turbinata, was approved for clinical use in 2007. It binds to the DNA minor groove leading to interferences with the intracellular transcription pathways and DNA-repair proteins. In vitro antitumor activity was demonstrated against various cancer cell lines and soft tissue sarcoma cell lines. In phase I studies tumor responses were observed also in osteosarcomas and different soft tissue sarcoma subtypes. The most common toxicities were myelosuppression and transient elevation of liver function tests, which could be reduced by dexamethasone premedication. The efficacy of trabectedin was established in three phase II studies where it was administered at 1.5 mg/m2 as a 24 h intravenous infusion repeated every three weeks, in previously treated patients. The objective response rate was 3.7%-8.3% and the tumor control rate (which included complete response, partial response and stable disease) was obtained in half of patients for a median overall survival reaching 12 months. In nonpretreated patients the overall response rate was 17%. Twenty-four percent of patients were without progression at six months. The median overall survival was almost 16 months with 72% surviving at one year. Predictive factors of response are being explored to identify patients who are most likely to respond to trabectedin. Combination with other agents are currently studied with promising results. In summary trabectedin is an active new chemotherapeutic agents that has demonstrated its role in the armamentarium of treatments for patients with sarcomas.

Soft tissue artifact assessment during treadmill walking in subjects with total knee arthroplasty.

Accurate measurement of knee kinematics during functional activities suffers mainly from soft tissue artifact (STA): the combination of local surface deformations and rigid movement of markers relative to the underlying bone (also called rigid STA movement: RSTAM). This study proposes to assess RSTAM on the thigh, shank, and knee joint and to observe possible features between subjects. Nineteen subjects with knee arthroplasty were asked to walk on a treadmill while a biplane fluoroscopic system (X-rays) and a stereophotogrammetric system (skin markers) recorded their knee movement. The RSTAM was defined as the rigid movement of the cluster of skin markers relative to the prosthesis. The results showed that RSTAM amplitude represents approximately 80-100% of the STA. The vertical axis of the anatomical frame of the femur was influenced the most by RSTAM. Combined with tibial error, internal/external rotation angle and distraction-compression were the knee kinematics parameters most affected by RSTAM during the gait cycle, with average rms values of 3.8° and 11.1 mm. This study highlighted higher RSTAM during the swing phase particularly in the thigh segment and suggests new features for RSTAM such as the particular shape of some RSTAM waveforms and the absence of RSTAM in certain kinematics during the gait phases. The comparison of coefficient of multiple correlations showed some similarities of RSTAM between subjects, while some correlations were found with gait speed and BMI. These new insights could potentially allow the development of new methods of compensation to avoid STA.

Direct mapping of 19F in 19FDG-6P in brain tissue at subcellular resolution using soft X-ray fluorescence

Low energy x-ray fluorescence (LEXRF) detection was optimized for imaging cerebral glucose metabolism by mapping the fluorine LEXRF signal of 19 F in 19 FDG, trapped as intracellular 19 F-deoxyglucose-6-phosphate ( 19 FDG-6P) at 1μm spatial resolution from 3μm thick brain slices. 19 FDG metabolism was evaluated in brain structures closely resembling the general cerebral cytoarchitecture following formalin fixation of brain slices and their inclusion in an epon matrix. 2-dimensional distribution maps of 19 FDG-6P were placed in a cytoarchitectural and morphological context by simultaneous LEXRF mapping of N and O, and scanning transmission x-ray (STXM) imaging. A disproportionately high uptake and metabolism of glucose was found in neuropil relative to intracellular domains of the cell body of hypothalamic neurons, showing directly that neurons, like glial cells, also metabolize glucose. As 19 F-deoxyglucose-6P is structurally identical to 18 F-deoxyglucose-6P, LEXRF of subcellular 19 F provides a link to in vivo 18 FDG PET, forming a novel basis for understanding the physiological mechanisms underlying the 18 FDG PET image, and the contribution of neurons and glia to the PET signal.

Epithelioid soft tissue tumors.

Epithelioid neoplasms are generally carcinomas. As confirmation that every rule is meant to be broken, some sarcomas demonstrate epithelioid morphology, and can even express cytokeratins. These sarcomas have unique behavior, for example, a much higher rate of lymph node metastasis than other sarcomas. This group of sarcomas also presents diagnostic and therapeutic challenges to those clinicians who help patients contend with these difficult tumors. In this review, some of the major categories of epithelioid soft tissue tumors are described, with clinical data reported as available. Some of these tumors provide excellent opportunities to examine newer protein-targeted agents in investigational settings.

Effect of nitrogen and phosphorus supply on growth, chlorophyll content and tissue composition of the macroalga Chaetomorpha linum (O.F. Mull), Kutz, in a Mediterranean Coastal Lagoon

The effect of dissolved nutrients on growth, nutrient content and uptake rates of Chaetomorpha linum in a Mediterranean coastal lagoon (Tancada, Ebro delta, NE Spain) was studied in laboratory experiments. Water was enriched with distinct forms of nitrogen, such as nitrate or ammonium and phosphorus. Enrichment with N, P or with both nutrients resulted in a significant increase in the tissue content of these nutrients. N-enrichment was followed by an increase in chlorophyll content after 4 days of treatment, although the difference was only significant when nitrate was added without P. P-enrichment had no significant effect on chlorophyll content. In all the treatments an increase in biomass was obseved after 10 days. This increase was higher in the N+P treatments. In all the treatments the uptake rate was significantly higher when nutrients were added than in control jars. The uptake rate of N, as ammonium, and P were significantly higher when they were added alone while that of N as nitrate was higher in the N+P treatment. In the P-enriched cultures, the final P-content of macroalgal tissues was ten-fold that of the initial tissue concentrations, thereby indicating luxury P-uptake. Moreover, at the end of the incubation the N:P ratio increased to 80, showing that P rather than N was the limiting factor for C. linum in the Tancada lagoon. The relatively high availability of N is related to the N inputs from rice fields that surround the lagoon and to P binding in sediments.

Severe ischemia of the hand following intra-arterial promazine injection: effects of vasodilation, anticoagulation, and local thrombolysis with tissue-type plasminogen activator.

Promazine hydrochloride was injected accidentally in the antecubital artery of a 42-year-old woman, resulting in severe ischemia of the second and third fingers of her right hand which lasted for four days before she was hospitalized. Vasodilation by combining axillary plexus block and intravenous sodium nitroprusside did not improve ischemia and local thrombolysis was performed using recombinant tissue-type plasminogen activator (50 mg over 8 hours), resulting in normalization of digital pressure in one of the two affected fingers. The outcome was favourable and amputation could be avoided.

Adverse tissue reaction to corrosion at the neck-stem junction after modular primary total hip arthroplasty.

Complications related to the neck-stem junction of modular stems used for total hip arthroplasty (THA) are generating increasing concern. A 74-year-old male had increasing pain and a cutaneous reaction around the scar 1 year after THA with a modular neck-stem. Imaging revealed osteolysis of the calcar and a pseudo-tumour adjacent to the neck-stem junction. Serum cobalt levels were elevated. Revision surgery to exchange the stem and liner and to resect the pseudo-tumour was performed. Analysis of the stem by scanning electron microscopy and by energy dispersive X-ray and white light interferometry showed fretting corrosion at the neck-stem junction contrasting with minimal changes at the head-neck junction. Thus, despite dry assembly of the neck and stem on the back table at primary THA, full neck-stem contact was not achieved, and the resulting micromotion at the interface led to fretting corrosion. This case highlights the mechanism of fretting corrosion at the neck-stem interface responsible for adverse local tissue reactions. Clinical and radiological follow-up is mandatory in patients with dual-modular stems.

An active strain electromechanical model for cardiac tissue

We propose a finite element approximation of a system of partial differential equations describing the coupling between the propagation of electrical potential and large deformations of the cardiac tissue. The underlying mathematical model is based on the active strain assumption, in which it is assumed that a multiplicative decomposition of the deformation tensor into a passive and active part holds, the latter carrying the information of the electrical potential propagation and anisotropy of the cardiac tissue into the equations of either incompressible or compressible nonlinear elasticity, governing the mechanical response of the biological material. In addition, by changing from an Eulerian to a Lagrangian configuration, the bidomain or monodomain equations modeling the evolution of the electrical propagation exhibit a nonlinear diffusion term. Piecewise quadratic finite elements are employed to approximate the displacements field, whereas for pressure, electrical potentials and ionic variables are approximated by piecewise linear elements. Various numerical tests performed with a parallel finite element code illustrate that the proposed model can capture some important features of the electromechanical coupling, and show that our numerical scheme is efficient and accurate.

HIV-1 immune activation induces Siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells.

BACKGROUND: Myeloid cells are key players in the recognition and response of the host against invading viruses. Paradoxically, upon HIV-1 infection, myeloid cells might also promote viral pathogenesis through trans-infection, a mechanism that promotes HIV-1 transmission to target cells via viral capture and storage. The receptor Siglec-1 (CD169) potently enhances HIV-1 trans-infection and is regulated by immune activating signals present throughout the course of HIV-1 infection, such as interferon α (IFNα). RESULTS: Here we show that IFNα-activated dendritic cells, monocytes and macrophages have an enhanced ability to capture and trans-infect HIV-1 via Siglec-1 recognition of viral membrane gangliosides. Monocytes from untreated HIV-1-infected individuals trans-infect HIV-1 via Siglec-1, but this capacity diminishes after effective antiretroviral treatment. Furthermore, Siglec-1 is expressed on myeloid cells residing in lymphoid tissues, where it can mediate viral trans-infection. CONCLUSIONS: Siglec-1 on myeloid cells could fuel novel CD4(+) T-cell infections and contribute to HIV-1 dissemination in vivo.

Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors.

Lentivirus-based gene delivery vectors carrying multiple gene cassettes are powerful tools in gene transfer studies and gene therapy, allowing coexpression of multiple therapeutic factors and, if desired, fluorescent reporters. Current strategies to express transgenes and microRNA (miRNA) clusters from a single vector have certain limitations that affect transgene expression levels and/or vector titers. In this study, we describe a novel vector design that facilitates combined expression of therapeutic RNA- and protein-based antiangiogenic factors as well as a fluorescent reporter from back-to-back RNApolII-driven expression cassettes. This configuration allows effective production of intron-embedded miRNAs that are released upon transduction of target cells. Exploiting such multigenic lentiviral vectors, we demonstrate robust miRNA-directed downregulation of vascular endothelial growth factor (VEGF) expression, leading to reduced angiogenesis, and parallel impairment of angiogenic pathways by codelivering the gene encoding pigment epithelium-derived factor (PEDF). Notably, subretinal injections of lentiviral vectors reveal efficient retinal pigment epithelium-specific gene expression driven by the VMD2 promoter, verifying that multigenic lentiviral vectors can be produced with high titers sufficient for in vivo applications. Altogether, our results suggest the potential applicability of combined miRNA- and protein-encoding lentiviral vectors in antiangiogenic gene therapy, including new combination therapies for amelioration of age-related macular degeneration.

Treatment of rats with a self-selected hyperlipidic diet, increases the lipid content of the main adipose tissue sites in a proportion similar to that of the lipids in the rest of organs and tissues

Adipose tissue (AT) is distributed as large differentiated masses, and smaller depots covering vessels, and organs, as well as interspersed within them. The differences between types and size of cells makes AT one of the most disperse and complex organs. Lipid storage is partly shared by other tissues such as muscle and liver. We intended to obtain an approximate estimation of the size of lipid reserves stored outside the main fat depots. Both male and female rats were made overweight by 4-weeks feeding of a cafeteria diet. Total lipid content was analyzed in brain, liver, gastrocnemius muscle, four white AT sites: subcutaneous, perigonadal, retroperitoneal and mesenteric, two brown AT sites (interscapular and perirenal) and in a pool of the rest of organs and tissues (after discarding gut contents). Organ lipid content was estimated and tabulated for each individual rat. Food intake was measured daily. There was a surprisingly high proportion of lipid not accounted for by the main macroscopic AT sites, even when brain, liver and BAT main sites were discounted. Muscle contained about 8% of body lipids, liver 1-1.4%, four white AT sites lipid 28-63% of body lipid, and the rest of the body (including muscle) 38-44%. There was a good correlation between AT lipid and body lipid, but lipid in"other organs" was highly correlated too with body lipid. Brain lipid was not. Irrespective of dietary intake, accumulation of body fat was uniform both for the main lipid storage and handling organs: large masses of AT (but also liver, muscle), as well as in the"rest" of tissues. These storage sites, in specialized (adipose) or not-specialized (liver, muscle) tissues reacted in parallel against a hyperlipidic diet challenge. We postulate that body lipid stores are handled and regulated coordinately, with a more centralized and overall mechanisms than usually assumed.

Tissue-Specific Evolution of Protein Coding Genes in Human and Mouse.

Protein-coding genes evolve at different rates, and the influence of different parameters, from gene size to expression level, has been extensively studied. While in yeast gene expression level is the major causal factor of gene evolutionary rate, the situation is more complex in animals. Here we investigate these relations further, especially taking in account gene expression in different organs as well as indirect correlations between parameters. We used RNA-seq data from two large datasets, covering 22 mouse tissues and 27 human tissues. Over all tissues, evolutionary rate only correlates weakly with levels and breadth of expression. The strongest explanatory factors of purifying selection are GC content, expression in many developmental stages, and expression in brain tissues. While the main component of evolutionary rate is purifying selection, we also find tissue-specific patterns for sites under neutral evolution and for positive selection. We observe fast evolution of genes expressed in testis, but also in other tissues, notably liver, which are explained by weak purifying selection rather than by positive selection.