Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium

One of the main outcomes of aerobic endurance exercise training is the improved maximal oxygen uptake, and this is pivotal to the improved work capacity that follows the exercise training. Improved maximal oxygen uptake in turn is at least partly achieved because exercise training increases the ability of the myocardium to produce a greater cardiac output. In healthy subjects, this has been demonstrated repeatedly over many decades. It has recently emerged that this scenario may also be true under conditions of an initial myocardial dysfunction. For instance, myocardial improvements may still be observed after exercise training in post-myocardial infarction heart failure. In both health and disease, it is the changes that occur in the individual cardiomyocytes with respect to their ability to contract that by and large drive the exercise training-induced adaptation to the heart. Here, we review the evidence and the mechanisms by which exercise training induces beneficial changes in the mammalian myocardium, as obtained by means of experimental and clinical studies, and argue that these changes ultimately alter the function of the whole heart and contribute to the changes in whole-body function.     

Tertiary lymphoid structures and gastric cancer prognosis

Tertiary lymphoid structures (TLSs) are part of immune response against cancer. Their high density and high diameter have been shown to be associated with prognosis in different cancer types. The aim of this study was to examine the prognostic significance of TLS density and diameter in gastric cancer and reproducibility of their assessments. TLS densities and maximal TLS diameter were assessed from hematoxylin–eosin (HE) stained slides of 721 surgically treated gastric cancer patients from two hospitals in Finland. Mortality hazard ratios (HRs) for TLS densities and maximal TLS diameter were analyzed. TLS densities and maximal TLS diameter were assessed with moderate interobserver agreement (Cohen's kappa 0.50–0.62). Maximal TLS density was not associated with survival (adjusted HR 0.85, 95% CI 0.70–1.02) and neither was hotspot TLS density (adjusted HR 0.85, 95% CI 0.70–1.02). High maximal TLS diameter was associated with longer survival in overall study population (adjusted HR 0.74, 95% CI 0.61–0.89) and in diffuse type subgroup (adjusted HR 0.65, 95% CI 0.50–0.85). In conclusion, high maximal TLS diameter is associated with improved survival in gastric cancer and can be assessed from HE-stained slides. Its prognostic value might be limited to diffuse histological type.     

Ocular anti-allergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo

BACKGROUND: Conjunctival mast cells (MCs) are important effector cells in seasonal allergic conjunctivitis, via histamine and cytokine secretion. Several new anti-allergic eye drops stabilize MCs and block histamine receptors, but their anti-inflammatory effects are unclear. OBJECTIVE: Anti-allergic drugs were compared for their anti-inflammatory effects in an in vitro model of human MC activation and in an experimental murine model of allergic conjunctivitis. METHODS: Human cord blood stem cell-derived (CBMC) and conjunctival biopsy-derived MCs were stimulated via FcepsilonRI, degranulation and histamine release were assayed at 1 h and cytokine secretion at 24 h using multiplex arrays. Mice sensitized to short ragweed pollen were given anti-allergics topically before allergen challenge, and conjunctival immuno-staining was performed at 24 h. RESULTS: After a 1 h stimulation, 80% of the CBMC had degranulated and secreted histamine (27.9+/-4.7 ng/10(6) cells; P<0.05). Pre-treatment by all drugs significantly reduced histamine and TNF-alpha, whereas IL-5, IL-8, IL-10 and TNF-beta profiles were differentially decreased. For conjunctival biopsy-derived cultures (n=11), FcepsilonR1 stimulation increased histamine, TNF-alpha, TNF-beta, IL-5 and IL-8 levels and the production of IL-5, IL-6 (P<0.05), histamine and IL-8 (P<0.01) was inhibited by epinastine. In vivo, epinastine and olopatadine pre-treatment significantly reduced the clinical scores and eosinophil numbers (n=6; P<0.05) while epinastine also reduced neutrophils (P<0.02). CONCLUSION: Differential effects on MC cytokine inhibition were observed, with epinastine inhibiting MC secretion of IL-5, IL-8, IL-10 and conjunctival neutrophil infiltration. The anti-allergic drugs have anti-histamine and mast-cell stabilizing properties but might differ in clinical improvement depending on the individual and the cytokines involved.     

Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression.     

Treatment of Burkitt lymphoma in equatorial Africa using a simple three-drug combination followed by a salvage regimen for patients with persistent or recurrent disease

Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03‐06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10–20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non‐cross resistant second‐line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first‐line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first‐ and second‐line therapy, but verification will require a further clinical study.