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BACKGROUND Poor cardiorespiratory fitness (CRF) is a cardinal feature of post-treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. METHODS In this parallel-group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age-sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)-cycle ergometry at 55% to >95% of peak oxygen consumption (VO2 peak); (ii) resistance training (RT)-lower and upper extremity exercises at 50-85% of maximal strength; (iii) combination training (CT)-AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2 peak, mL O2 ·kg-1 ·min-1 ). Secondary endpoints were body composition, muscle strength, patient-reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post-intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. RESULTS Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost-to-follow-up rate was 10%. Mean attendance was ≥75% in all groups. In intention-to-treat analysis, VO2 peak increased 1.1 mL O2 ·kg-1 ·min-1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2 ·kg-1 ·min-1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2 peak change between RT and AC (-0.1 mL O2 ·kg-1 ·min-1 , 95% CI: -1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps

AIMS: In thymic carcinomas, focal clear cell change is a frequent finding. In addition to a prominent, diffuse clear cell morphology, some of these carcinomas show an exuberant hyalinised extracellular matrix, and therefore probably represent a separate entity. However, a characteristic genomic alteration remains elusive. We hypothesised that, analogous to hyalinising clear cell carcinomas of the salivary gland, hyalinising clear cell carcinomas of the thymus might also harbour EWSR1 translocations. METHODS AND RESULTS: We identified nine archived cases of thymic carcinoma with focal clear cell features and two cases that showed remarkable hyalinised stroma and prominent, diffuse clear cell morphology. These two cases expressed p40 and were negative for Pax8, CD5, and CD117. Programmed death-ligand 1 was highly positive in one case (70%), and negative in the other one. EWSR1 translocation was identified in both cases of hyalinising clear cell carcinoma, and was absent in all nine carcinomas that showed clear cell features without substantial hyalinisation. In one of the EWSR1-translocated cases, a fusion between exon 13 and exon 6 of EWSR1 and ATF1, respectively was identified by next-generation sequencing. CONCLUSIONS: These findings suggest that the EWSR1 translocation and possibly the EWSR1-ATF1 fusion might be unifying genomic alterations for thymic clear cell carcinomas with prominent hyalinised stroma, for which we propose the term 'hyalinising clear cell carcinoma of the thymus'. Because the immunophenotype is unspecific, testing for the EWSR1 translocation might be helpful in discriminating this entity from other thymic neoplasms or metastases, in particular those with clear cell change. ispartof: HISTOPATHOLOGY vol:75 issue:3 pages:431-436 ispartof: location:England status: published

Anterior mediastinal biopsies consisting predominantly of small lymphocytes can be a diagnostic challenge, especially in small core biopsies. In these cases, immunophenotyping is often employed using flow cytometry, and/or immunohistochemistry. However, due the overlap in T-cell phenotype between thymic neoplasm/hyperplasia (THY), T lymphoblastic lymphoma (T-LBL) and reactive lymph nodes (RLN), biopsies consisting predominantly of T-cells may still be difficult to differentiate. Previous studies have shown a specific CD3/bcl-2 staining pattern in thymic T cells of humans and mice using flow cytometry. However, the utility of this finding in distinguishing T-cells of THY, T-LBL and RLN has not been carefully evaluated. Our findings show that the pattern of CD3/bcl-2 expression in thymic T-cells can be used to help diagnose anterior mediastinal biopsies, even when limited specimen is provided. This article is protected by copyright. All rights reserved.

Thymoma associated multiorgan autoimmunity is a rare paraneoplastic disorder, clinicopathologically similar to graft versus host disease, which is thought to be mediated by dysfunctional negative thymocyte selection and abnormally low levels of Tregs. We report a 50 year old Chinese women with a history of malignant thymoma and myasthenia gravis who developed graft versus host disease- like erythroderma after instituting chemotherapy and undergoing myasthenia crisis. Clinically her rash presented as erythematous scaly papules, which evolved to psoriasiform patches and plaques with foci of vitiligo. Histopathologically the biopsy showed a predominantly interface dermatitis with necrotic keratinocytes extending to the upper levels of the epidermis, and florid basket weave orthokeratosis. Clinical and laboratory work-up ruled out common inflammatory or infectious causes, eventually favoring the diagnosis of TAMA with GVHD-like erythroderma. Unfortunately, the patient underwent multi-organ compromise and death due to respiratory failure from myasthenia crisis. Patients with TAMA have a poor clinical outlook; rare successful treatments include high dose oral steroids and additional modalities including bone marrow transplant and chemotherapeutic or biologic agents. As the predominant findings are in the skin, dermatologists and dermatopathologists are in a unique position to enable the early diagnosis and treatment of this unusual disease.

In this paper, we present some new results on when extra risk strictly increases an option's value. We give a necessary and sufficient condition for a mean-preserving spread to strictly increase an option's value. We also give a necessary and sufficient condition for a risk change to strictly increase the values of options with strike prices in an open interval while preserving the values of all other options. These two results significantly improve the results given by Rasmusen (2007) (When does extra risk strictly increase an option's value? Review of Financial Studies, 20, 1647–1667).

Positron annihilation lifetime experiments in a series of polystyrene (PS) nano-composites of different wt% of SiO2 as a function of temperature have been performed and the glass transition temperatures are determined. Previously, in PS/CNF(carbon nanofiber), a system with strong interfacial bonding, we found single glass transition temperature (Tg), which increases with wt% of CNF. Currently, in PS/SiO2 nano-composites, a weak interfacial interaction system, we found that there are two Tgs, one at 57 oC, which is lower than the PS bulk Tg (= 91 °C). The lower Tg is interpreted from the free volume in the weak bonding interface between PS and SiO2. This result is consistent with our previous slow positron beam results of PS on Si substrate, which shows a significant lower Tg in the interface than in the bulk PS. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The prognosis of acute lymphoblastic leukemia (ALL) has improved considerably with advancements in multidisciplinary therapy [1]. However, 20% of patients relapse and over 50% of these patients die of disease. A number of clinical trials have demonstrated the prognostic importance of rapidity of cytoreduction in induction therapy for children with ALL [2-14]. Indeed, the Children’s Oncology Group (COG) recently reported minimal residual disease (MRD) at end induction as the most powerful predictor of outcome by multivariate analysis [15]. Treatment failure is complex and at least partially due to intrinsic or acquired cellular drug resistance [16]. Curative treatment of ALL requires eradication of all leukemic clones, including those with inherent drug resistance. The current COG treatment approach relies upon end of induction MRD to fully define slow early responders (SERs) before intensifying therapy. However, it is possible that modifications of therapy early in induction will improve outcome of patients with relatively resistant disease. The degree to which each drug in induction contributes to lymphoblast cell death probably varies among individuals within different clinical and cytogenetic ALL subsets. Laboratory tests to measure lymphocyte cell death after exposure to cytotoxic agents were initially developed over 90 years ago. The first report was made by Pappenheimer in 1917 when he used trypan blue to detect non-viable lymphocytes after exposure of fresh thymic lymphocytes to toxic agents [17]. Significant improvements in cell culture assays of cytotoxicity have been utilized since then, leading to the evolution of current assays [17-19]. Over the past 20 years, a number of studies from Europe and Japan measured in vitro drug resistance of diagnostic lymphoblasts and consistently demonstrated significant correlations of in vitro chemosensitivity results with outcome in pediatric ALL [20-24]. Based on these data, the German COALL (Cooperative Study Group for Childhood ALL) designed a prospective trial that incorporated in vitro drug resistance profiles into the treatment stratification of newly diagnosed childhood ALL [20, 23]. Whether in vitro drug sensitivity correlates with measures of in vivo MRD remains to be determined. Indeed, three European cooperative groups are currently studying this question in prospective clinical trials [25, 26]. Most of the studies mentioned above rely on the MTT (methyl-thiazol-tetrazolium) assay to determine chemosensitivity profiles of lymphoblasts in childhood ALL. With this technique, MTT is reduced to colored formazan crystals by living cells and leukemia cell survival is calculated from optical density [27]. However, this assay is relatively labor-intensive, requires 4 days incubation, and is unable to completely exclude from its results the chemosensitivity response of normal marrow lymphocytes from malignant lymphoblasts. Several recent reports suggest that techniques studying in vitro drug sensitivity using flow cytometry may be readily applicable to the study of childhood ALL [28-31]. We applied a high throughput, multiparameter flow cytometric chemosensitivity assay (FCCA) [31] with a rapid 48 hour turnaround time to evaluate apoptosis induction in leukemic blasts with standard induction drugs. The purpose of this study was two-fold: to assess the feasibility of this assay applied to blasts of ALL and to determine the relationship between a patient’s lymphoblast sensitivity to induction drugs in vitro and his/her rapidity of response to induction therapy. Additionally, we analyzed the in vitro drug response among clinical subsets. We report our initial results using this FCCA on leukemic blasts from 30 children with newly diagnosed ALL.

Stromelysin has been proposed to play a major role in the pathologic degradation of diseased cartilage of osteoarthritis and rheumatoid arthritis patients. A truncated, recombinant form of this enzyme, with the sequence Phe83 to Thr260 (mSL-t), has been expressed and purified from E. coli to investigate its biochemical and biophysical properties, and to develop inhibitors for arthritis treatment. LC/ESI-MS technique was utilized for the characterization of mSL-t. The mass spectra of mSL-t showed the presence of a number of different protein components in addition to the full-length mSL-t form. We have demonstrated that protein degradation arose from autolysis. Molecular weights determined by LC/ESI-MS of these autolysis products allowed for the identification of new autolytic sites in mSL-t. Furthermore, two strategies were undertaken to prepare mSL-t free of degradation products. These include preparation of a mutant form of the enzyme in which Arg163 was substituted for Leu163 and purification of mSL-t using affinity chromatography. The LC/ESI-MS data of the mutant protein confirmed the Leu to Arg mutation. The affinity-purified material showed only one LC peak in the LC/MS chromatograms, and the mass spectrum of the peak identified only the intact protein, demonstrating that the full-length protein has been successfully separated from the autodegradation products and further autolysis of the enzyme has been prevented. © Munksgaard 1997.

Background and Objective Reports in the literature indicate that low energy laser irradiation has a biostimulatory effect on wound healing; however, no mechanism of this effect has been elucidated. Study Design/Materials and Methods: We attempted to establish a model from which to study the mechanism of biostimulation. The effects of low energy helium-neon irradiation on wound healing were observed in two rat models. In the first model, 1.5 cm diameter full thickness excisional skin defects were created in the dorsal midline of rats (n = 32). All animals were anesthetized and all eschars were debrided daily. Wound area was determined by caliper measurements for 2 weeks postoperatively. Rats that received a treatment of 1 J/cm2 had two defects in the dorsal skin. One wound was treated and the second was used as its own control. These measurements were not blinded. Rats that received 2 J/cm2, 4 J/cm2, or anesthesia alone had one defect on the dorsal skin. Caliper measurements of these wounds were blinded. We were unable to demonstrate any difference in the rate of wound contracture in rats that received a daily dose of 1 J/cm2, 2 J/cm2, 4 J/cm2, or anesthesia alone (P > 0.8 by student's t-test). In the second model, a single 2 cm longitudinal full thickness skin incision was created in the dorsal midline of each rat (n = 24). No difference was found between rats that received anesthesia alone and those treated daily with 2 J/cm2 as assessed by tensile strength measurements on postoperative days 7 and 14 (P > 0.8 by student's t-test between groups at both time points). These determinations were blinded. Results Despite our intentions of studying the mechanism of low energy HeNe biostimulation, we were unable to demonstrate a beneficial effect. Conclusion In this study, helium-neon laser irradiation produced no measurable benefit on wound healing. Lasers Surg. Medicine 20:340–345, 1997. © 1997 Wiley-Liss, Inc.

Both methionine residues in phospholipase A2 (PLA2) from porcine pancreas have been replaced by leucines with retention of full enzymatic activity. The methionine-less mutant has been expressed as a Cro-LacZ fusion protein in Escherichia coli, from which a pro-PLA2 was liberated by chemical cleavage with CNBr. The general applicability of CNBr cleavage of proteins lacking methionine residue(s) was demonstrated by replacing the single Met8 in human platelet phospholipase A2 (HP-PLA2) by a leucine residue, and the introduction of a methionine at a position just preceding the HP-PLA2 sequence. This protein was expressed in E. coli as a 68-kDa Cro-LacZ fusion protein. CNBr cleavage liberated the HP-PLA2 fragment which was reoxidized in vitro. The [Met8----Leu]HP-PLA2 is monomeric in aqueous solutions, requires calcium ions in the millimolar range for enzymatic activity and has optimal activity around pH 8. p-Bromophenacyl bromide rapidly inactivates the enzyme with calcium ions having a protective effect. The highest specific activities, 2400 U/mg and 9300 U/mg, were found with pure micelles of 1,2-dioctanoyl-sn-glycero-3-phosphoglycol and with mixed micelles of taurodeoxycholate and 1,2-dioctanoyl-sn-glycero-3-phosphoglycol, respectively. In mixed micelles the activity on dioleoyl phospholipids decreases in the order phosphatidylglycerol greater than phosphatidylethanolamine much greater than phosphatidylcholine. The enzyme has low activity on monomeric 1,2-diheptanoyl-sn-glycero-3-phosphocholine as a substrate, but high activity on micelles with a distinct jump in activity at the critical micellar concentration. The binding of the HP-PLA2, porcine pancreatic PLA2 and PLA2 from Naja melanoleuca venom to lipid/water interfaces was determined with micellar solutions of the substrate analog n-hexadecylphosphocholine. The HP-PLA2 has a high apparent Kd (2 mM) compared to pancreatic (0.2 mM) and venom (0.03 mM) PLA2. In mixed micelles of taurodeoxycholate and 1,2-didodecanoyl-sn-glycero-3-phosphocholine, the competitive inhibition of HP-PLA2 by the R and S enantiomers of 2-tetradecanoylaminohexanol-1-phosphocholine, its phosphoglycol, and its phosphoethanolamine derivatives were tested. The S enantiomers are only weak inhibitors, whereas the R enantiomers are potent inhibitors. The inhibitory power depends on the nature of the polar head group and increases in the order phosphocholine much less than phosphoethanolamine less than phosphoglycol. The best inhibitor, (R)-2-tetradecanoylaminohexanol-1-phosphoglycol, binds 2200 times stronger than the substrate to the HP-PLA2 active site.

Mesure de la diffusion du rouge de methyle et de l'azobenzene dans 3 systemes polymere-solvant. PS/toluene, PS/ethylbenzene et PVA/toluene, par diffusion de Rayleigh forcee. Mesure de la diffusion de polystyrenes dans des solutions PVME/o-fluoro toluene de concentration variable en PVME