Serum Natrium Determines Outcome of Treatment of Advanced GIST with Imatinib: A Retrospective Study of 80 Patients from a Single Institution

Treatment with tyrosine kinase inhibitors (TKIs) has drastically improved overall survival (OS) of patients with advanced GIST. The aim of this study is to evaluate the results of treatment with different TKIs on advanced GIST and identify prognostic factors for OS. The medical records of all patients treated at the Department of Oncology, Aarhus University Hospital were retrospectively reviewed. Between 2001 and 2009, 80 patients with advanced GIST were treated with imatinib as first-line therapy. The median OS was 44 months (95% CI 31–56), and the 5-year OS was 40%. Since 2005, 32 patients were treated with sunitinib as 2nd-line therapy. The median time to progression was 9 months (95% CI: 3–13 months), and the 3-year OS was 30%. The data illustrate that data from large multicenter studies are reproducible in a single sarcoma centre. This retrospective study pointed to low serum sodium at the start of imatinib as a possible prognostic factor affecting OS

A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas

Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox

Culture of Mouse Embryonic Stem Cells with Serum but without Exogenous Growth Factors Is Sufficient to Generate Functional Hepatocyte-Like Cells

Mouse embryonic stem cells (mESC) have been used to study lineage specification in vitro, including towards a hepatocyte-like fate, and such investigations guided lineage differentiation protocols for human (h)ESC. We recently described a four-step protocol to induce hepatocyte-like cells from hESC which also induced hepatocyte-like cell differentiation of mouse induced pluripotent stem cells. As ESC also spontaneously generate hepatocyte-like cells, we here tested whether the growth factors and serum used in this protocol are required to commit mESC and hESC to hepatocyte-like cells. Culture of mESC from two different mouse strains in the absence of serum and growth factors did not induce primitive streak/definitive endoderm genes but induced default differentiation to neuroectoderm on day 6. Although Activin-A and Wnt3 induced primitive streak/definitive endoderm transcripts most robustly in mESC, simple addition of serum also induced these transcripts. Expression of hepatoblast genes occurred earlier when growth factors were used for mESC differentiation. However, further maturation towards functional hepatocyte-like cells was similar in mESC progeny from cultures with serum, irrespective of the addition of growth factors, and irrespective of the mouse strain. This is in contrast to hESC, where growth factors are required for specification towards functional hepatocyte-like cells. Culture of mESC with serum but without growth factors did not induce preferential differentiation towards primitive endoderm or neuroectoderm. Thus, although induction of primitive streak/definitive endoderm specific genes and proteins is more robust when mESC are exposed to a combination of serum and exogenous growth factors, ultimate generation of hepatocyte-like cells from mESC occurs equally well in the presence or absence of exogenous growth factors. The latter is in contrast to what we observed for hESC. These results suggest that differences exist between lineage specific differentiation potential of mESC and hESC, requiring optimization of different protocols for ESC from either species

Intestinal microbiota and the innate immune system – a crosstalk in Crohn’s disease pathogenesis

Crohn’s disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby supporting the hypothesis that chronic intestinal inflammation arises from an abnormal immune response against the microorganisms of the intestinal flora in genetically susceptible individuals. Given that CD patients display changes in their gut microbiota composition, collectively termed “dysbiosis,” the question raises whether the altered microbiota composition is a cause of disease or rather a consequence of the inflammatory state of the intestinal environment. This review will focus on the crosstalk between the gut microbiota and the innate immune system during intestinal inflammation, thereby unraveling the role of the microbiota in CD pathogenesis

Relative time in physical activity and sedentary behaviour across a 2-year pedometer-based intervention in people with prediabetes or type 2 diabetes : A secondary analysis of a randomised controlled trial

Background: People with prediabetes or type 2 diabetes (T2D) need to be physically active, including moderate-to-vigorous intensity physical activity (MVPA) and light-intensity physical activity (LIPA) and reduce time in sedentary behaviour (SB). Few studies have evaluated the effect of randomised controlled trials taking all movement behaviours into account. This study aimed to investigate the effects of a 2-year pedometer-based intervention in people with prediabetes or T2D on relative time in movement behaviours. Methods: Secondary analysis of longitudinal data on individuals with prediabetes or T2D from a three-armed randomised controlled trial, the Sophia Step Study, was conducted. The three groups were (1) a multi‑component group (self‑monitoring of steps with a pedometer plus counselling), (2) a single‑component group (self‑monitoring of steps with a pedometer, without counselling), and (3) a standard care group (control). The three behaviours MVPA, LIPA and SB during waking hours were measured with an ActiGraph GT1M accelerometer at baseline, 6, 12, 18 and 24 months. Relative time in MVPA, LIPA and SB for each participant at each time point was calculated and used as outcome measures. Linear mixed models assessed the effect of the intervention over time. Results: In total 184 participants with mean (SD) age 64.3 (7.6) years and 41% female was included. In the multi-component group, compared to the control group, a significant group-by-time interaction effect for relative time in all three behaviours was found at 6 and 18 months and for MVPA and SB at 24 months. In the single-component group, compared to the control group, an effect occurred in the MVPA and SB behaviours at 6 months and MVPA and LIPA at 24 months. The estimated marginal means ranged from 0.9 to 1.5% of more MVPA, 1.9–3.9% of less LIPA and from 0.5% of less SB to 1.7 more SB in the intervention groups compared to the control group. Conclusions: The findings show a beneficial effect on all behaviours over time in the two intervention groups compared to the control group. A more pronounced effect occurred in the multi-component intervention compared to the single-component intervention, implicating the importance of counselling in pedometer-based interventions. Trial registration ClinicalTrials.gov, NCT0237478

Physical activity patterns among individuals with prediabetes or type 2 diabetes across two years : A longitudinal latent class analysis

BACKGROUND: This study aimed to identify distinct profiles of physical activity (PA) patterns among individuals with prediabetes or type 2 diabetes participating in a two-year PA trial and to investigate predictors of the profiles. METHODS: Data (n = 168, collected 2013-2020) from the cohort of a randomized trial aimed at increasing PA in individuals with prediabetes and type 2 diabetes were used. PA and sedentary behaviours were assessed by waist-worn ActiGraph GT1M accelerometers at baseline and at 6, 12, 18 and 24 months. Fifteen PA and sedentary variables were entered into a latent class mixed model for multivariate longitudinal outcomes. Multinominal regression analysis modelled profile membership based on baseline activity level, age, gender, BMI, disease status and group randomisation. RESULTS: Two profiles of PA patterns were identified: "Increased activity" (n = 37, 22%) included participants increasing time in PA and decreasing sedentary time. "No change in activity" (n = 131, 78%) included participants with no or minor changes. "Increased activity" were younger (p = 0.003) and more active at baseline (p = 0.011), compared to "No change in activity". No other predictor was associated with profile membership. CONCLUSIONS: A majority of participants maintained PA and sedentary patterns over two years despite being part of a PA intervention. Individuals improving PA patterns were younger and more active at baseline