Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.     

Green microwave-assisted procedure to generate bio-based pectin materials

New eco-friendly materials have been developed via esterification of several natural fatty acids by pectin alcoholic functions. The quaternization of the obtained pectin-fatty acid conjugates was performed as subsequent synthetic step. By using microwave heating and solvent-free conditions, the conjugation procedure of fatty acid chains and quaternary ammonium groups to the natural polysaccharide was clean, fast and efficient. In other words, it can be considered a low environmental impact process.     

Ventricular remodeling in Loeffler endocarditis: implications for therapeutic decision making

BACKGROUND: Little is known about the morphological and functional evolution of ventricular abnormalities in Loeffler endocarditis. METHODS AND RESULTS: We describe 5 patients, including 3 with long-term echocardiographic follow-up, in whom apical obliteration due to fibro-thrombotic thickening of the endocardium showed favorable patterns of evolution. In one patient there was almost complete resolution of the obliterative process with consequently increased effective ventricular volume. In two patients formation of a flow-passage in the fibrocalcific apical 'floor' between the main medioventricular cavity and the apical chamber, leading to a 'double-chambered' left ventricle was observed. CONCLUSIONS: Medical therapy and appropriate anticoagulation, can induce favorable long-term ventricular remodeling in Loeffler endocarditis.     

Selective targeted delivery of TNFalpha to tumor blood vessels

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.     

HYPNOTIZABILITY AND PAIN MODULATION: A Body–Mind Perspective

The study investigated whether the cardiac activity and cognitive–emotional traits sustained by the behavioral inhibition/activation system (BIS/BAS) may contribute to hypnotizability-related pain modulation. Nociceptive stimulation (cold-pressor test) was administered to healthy participants with high (highs) and low (lows) hypnotizability in the presence and absence of suggestions for analgesia. Results showed that heart rate increased abruptly at the beginning of nociceptive stimulation in all participants. Then, only in highs heart rate decreased for the entire duration of hand immersion. During stimulation with suggestions of analgesia, pain threshold negatively correlated with heart rate. BIS/BAS activity partially accounted for the observed hypnotizability-related differences in the relation between cardiac interoception and pain experience.     

Suture pull-through insertion of graft donor in Descemet stripping automated endothelial keratoplasty: Results of 4-year follow-up

Purpose:

To report our clinical experience and 4-year follow-up results of Descemet stripping automated endothelial keratoplasty (DSAEK) with the suture pull-through insertion technique.

Methods:

This is a retrospective study of 195 eyes in which a posterior lamellar keratoplasty was performed between 2007 and 2011. The insertion of a folded donor lenticule was performed with a double-armed 10-0 suture using a straight transchamber needle and half-circle needle. Endothelial cell density was measured annually up to 4 years after the surgery, and cell loss was calculated based on the median preoperative donor endothelial cell density. Postoperative complications, primary graft failure, pupillary block, and dislocation of the donor tissue were assessed.

Results:

All patients underwent uncomplicated DSAEK. Data were available for 195 eyes (100%) at 1 year, 186 eyes (95.3%) at 2 years, 176 eyes (90.2%) at 3 years, and 160 eyes (82%) at 4 years. Median preop-erative donor endothelial cell density was 2688 cells/mm² [interquartile range (IQR) 207.5 cells/mm²], which decreased by 27% at 1 year (1956 cells/mm², IQR 264.8 cells/mm²), 31% at 2 years (1855 cells/mm², IQR 320.5 cells/mm²), 35% at 3 years (1756.5 cells/mm², IQR 306.5 cells/mm²), and 36% at 4 years (1709.5 cells/mm², IQR 288,0 cells/mm²). Nine patients (4.6%) had a dislocation of donor tissue; all were successfully reattached with a second air injection. Only three eyes (1.5%) developed graft failure. Pupillary block was present in 15 eyes (7.7%).

Conclusion:

DSAEK with suture pull-through insertion of donor graft represents a simplified and safe technique that has endothelial cell loss comparable with other techniques and low rates of intraoperative and postoperative complications.     

Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation

OBJECTIVE: Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow transplantation (A-BMT). A critical question is whether memory T cells resident in bone marrow (BM) of patients with hematological malignancies are resistant to either pretransplant chemotherapy or ex vivo pharmacological purging. PATIENTS AND METHODS: To address these issues, we evaluated the frequency of tetanus-toxoid (TT)-specific proliferating T-cell precursors (TT-PTCp) in BM and peripheral blood (PB) of eight patients with acute myeloid leukemia (AML) given A-BMT after in vitro purging of BM with mafosfamide. Patients were studied at the time of BM harvesting and five of them also after A-BMT. RESULTS: The range of TT-PTCp frequencies found after A-BMT were comparable with those observed in PB and in BM at the time of harvesting and did not differ significantly from those of eight age-matched healthy subjects who donated BM for a human leukocyte antigen-identical sibling. TT-PTCp frequencies in BM, studied before and after ex vivo purging, appeared not to be affected by incubation with mafosfamide. We also compared the T-cell receptor (TCR)-Vbeta-repertoire usage of TT-specific T-cell lines (TT-TCL) in BM of patients at the time of harvesting and in their PB 2 months after transplantation. The same TCR-clonotypes were detected in TT-TCL at time of harvesting and after A-BMT. CONCLUSION: These data indicate that BM-resident memory T cells of patients with AML are resistant to both pretransplant chemotherapy and ex vivo pharmacological purging and may contribute to immune reconstitution after A-BMT.     

Intraoperative forces and moments analysis on patient head clamp during awake brain surgery

In brain surgery procedures, such as deep brain stimulation, drug-resistant epilepsy and tumour surgery, the patient is intentionally awakened to map functional neural bases via electrophysiological assessment. This assessment can involve patient’s body movements; thus, increasing the mechanical load on the head-restraint systems used for keeping the skull still during the surgery. The loads exchanged between the head and the restraining device can potentially result into skin and bone damage. The aim of this work is to assess such loads for laying down the requirements of a surgical robotics system for dynamic head movements compensation by fast moving arms and by an active restraint able to damp such actions. A Mayfield^® head clamp was tracked and instrumented with strain gages (SGs). SG locations were chosen according to finite element analyses. During an actual brain surgery, displacements and strains were measured and clustered according to events that generated them. Loads were inferred from strain data. The greatest force components were exerted vertically (median 5.5 N, maximum 151.87 N) with frequencies up to 1.5 Hz. Maximum measured displacement and velocity were 9 mm and 60 mm/s, with frequencies up to 2.8 Hz. The analysis of loads and displacements allowed to identify the surgery steps causing maximal loads on the head-restraint device.     

Metabolic transitions at menopause: In post-menopausal women the increase in serum uric acid correlates with abdominal adiposity as assessed by DXA

Objectives

The present study aimed to investigate any associations between parameters of body fat mass distribution and levels of serum uric acid (sUA), a well-documented cardiovascular risk factor, among non-obese women ranging from pre- to post-menopausal status.

Methods

In this cross-sectional population-based study we assessed body fat distribution by dual-energy-X-ray absorptiometry (DXA), and sUA levels in 101 pre- and 134 post-menopausal non-obese apparently healthy women.

Results

Multivariate stepwise regression analysis revealed that sUA was independently associated to the indicators of overall fatness, i.e. body mass index (β = 0.339, p < 0.001) and DXA-assessed total and percentage body fat (β = 0.366, p < 0.001 and β = 0.412, p < 0.001, respectively), only among post-menopausal women. Within this sample subset, trunk (i.e. central) fat mass emerged as a strong predictor of sUA (β = 0.408, p < 0.001), after taking the potential confounders (including body mass index) into account.

Conclusion

Central fat accumulation was found to be independently associated with higher sUA levels among non-obese women in post- but not among those in pre-menopause.