Appropriate gestational weight gain (GWG) is important for fetal development and maternal health, but it is unclear what dietary factors predict GWG. The aim of this study was to investigate the ...association between dietary quality during pregnancy and GWG. In total, 1113 pregnant women were recruited when registering for antenatal care. GWG was defined according to the Institute of Medicine (IOM) guidelines. GWG was calculated as measured body weight at registration for antenatal care, to gestational week 37 ± 2. Dietary intake was assessed using a food frequency questionnaire (FFQ) administered in gestational week >31. In total, 40% gained within the IOM GWG recommendations, 25% had insufficient GWG and 35% excessive GWG. Women with a poor or fair quality diet gained approximately 2 kg more than women with a high-quality diet. Poor dietary quality was also associated with higher odds of excessive GWG, due to fat quality and intake of discretionary foods. In conclusion, poor quality dietary intake is associated with lower adherence to the guidelines on weight gain in pregnancy. A diet characterised by high-quality fat intake, low consumption of discretionary foods and high nutrient intake may promote healthy weight gain and prevent excessive GWG.
Mechanisms influencing breast cancer (BC) development and recurrence include hyperglycemia, hyperinsulinemia, high insulin-like growth factor-1, high circulating estrogen, inflammation and impaired ...cellular differentiation/apoptosis. A lifestyle program that targets all the above mechanisms may be warranted. Low glycemic index (GI) foods produce lower post-prandial glucose and insulin responses and have been associated with lower BC risk. Moderate physical activity post-diagnosis reduces BC recurrence and mortality, partly explained by reduced insulin and estrogen levels. Vitamin D increases cell differentiation/apoptosis and high serum vitamin D levels improve BC survival. Yet no trial has evaluated the combined effect of a low GI diet, moderate physical activity and vitamin D supplementation on BC recurrence in the context of a Mediterranean lifestyle setting.
Women (30-74 yr) who had undergone surgery for primary histologically confirmed BC (stages I-III) within the previous 12 months, in cancer centres in Italy, will be randomized to follow, for a maximum of 33 months, either a high intensity treatment (HIT) composed of low GI diet + exercise + vitamin D (60 ng/mL serum concentration) or a lower intensity treatment (LITE) with general advice to follow a healthy diet and exercise pattern + vitamin D to avoid insufficiency. Both interventions are on a background of a Mediterranean diet. Considering a 20% recurrence rate within 3 years for BC cases and a predicted rate of 10% in the HIT group, with power of 80% and two-sided alpha of 0.05, the subject number required will be 506 (n = 253 in each arm). Clinic visits will be scheduled every 3 months. Dietary and exercise counselling and vitamin D supplements will be given at each clinic visit when blood samples, anthropometric measures and 7-day food records will be collected.
DEDiCa study aims to reduce BC recurrence in women with BC using a lifestyle approach with additional vitamin D and to investigate possible cardio-metabolic benefits as well as epigenetic modifications according to lifestyle changes. Given the supporting evidence and safety of the components of our intervention we believe it is feasible and urgent to test it in cancer patients.
May 11, 2016; NCT02786875 .
2015-005147-14.
The use of nanoparticles for the controlled drug delivery to cells has emerged as a good alternative to traditional systemic delivery. Quantum dots (QDs) offer potentially invaluable societal ...benefits such as drug targeting and
biomedical imaging. In contrast, QDs may also pose risks to human health and the environment under certain conditions. Here, we demonstrated that a unique combination of nanocrystals core components (Ag-In-Zn-S) would eliminate the toxicity problem and increase their biomedical applications. The alloyed quaternary nanocrystals Ag-In-Zn-S (QD
, Ag
In
Zn
S
; QD
, Ag
In
Zn
S
) were used to transport new unsymmetrical bisacridine derivatives (UAs, C-2028 and C-2045) into lung H460 and colon HCT116 cancer cells for improving the cytotoxic and antitumor action of these compounds. UAs were coupled with QD through physical adsorption. The obtained results clearly indicate that the synthesized nanoconjugates exhibited higher cytotoxic activity than unbound compounds, especially toward lung H460 cancer cells. Importantly, unsymmetrical bisacridines noncovalently attached to QD strongly protect normal cells from the drug action. It is worth pointing out that QD
or QD
without UAs did not influence the growth of cancer and normal cells, which is consistent with
results. In noncellular systems, at pH 5.5 and 4.0, which relates to the conditions of endosomes and lysosomes, the UAs were released from QD-UAs nanoconjugates. An increase of total lysosomes content was observed in H460 cells treated with QDs-UAs which can affect the release of the UAs from the conjugates. Moreover, confocal laser scanning microscopy analyses revealed that QD-UAs nanoconjugates enter H460 cells more efficiently than to HCT116 and normal cells, which may be the reason for their higher cytotoxicity against lung cancer. Summarizing, the noncovalent attachment of UAs to QDs increases the therapeutic efficiency of UAs by improving cytotoxicity toward lung H460 cancer cells and having protecting effects on normal cells.
Spontaneous portosystemic shunts (SPSS) have been associated with hepatic encephalopathy (HE). Little is known about their prevalence among patients with cirrhosis or clinical effects. We ...investigated the prevalence and characteristics of SPSS in patients with cirrhosis and their outcomes.
We performed a retrospective study of 1729 patients with cirrhosis who underwent abdominal computed tomography or magnetic resonance imaging analysis from 2010 through 2015 at 14 centers in Canada and Europe. We collected data on demographic features, etiology of liver disease, comorbidities, complications, treatments, laboratory and clinical parameters, Model for End-Stage Liver Disease (MELD) score, and endoscopy findings. Abdominal images were reviewed by a radiologist (or a hepatologist trained by a radiologist) and searched for the presence of SPSS, defined as spontaneous communications between the portal venous system or splanchnic veins and the systemic venous system, excluding gastroesophageal varices. Patients were assigned to groups with large SPSS (L-SPSS, ≥8 mm), small SPSS (S-SPSS, <8 mm), or without SPSS (W-SPSS). The main outcomes were the incidence of complications of cirrhosis and mortality according to the presence of SPSS. Secondary measurements were the prevalence of SPSS in patients with cirrhosis and their radiologic features.
L-SPSS were identified in 488 (28%) patients, S-SPSS in 548 (32%) patients, and no shunt (W-SPSS) in 693 (40%) patients. The most common L-SPSS was splenorenal (46% of L-SPSS). The presence and size of SPSS increased with liver dysfunction: among patients with MELD scores of 6–9, 14% had L-SPSS and 28% had S-SPSS; among patients with MELD scores of 10–13, 30% had L-SPSS and 34% had S-SPSS; among patients with MELD scores of 14 or higher, 40% had L-SPSS and 32% had S-SPSS (P < .001 for multiple comparison among MELD groups). HE was reported in 48% of patients with L-SPSS, 34% of patients with S-SPSS, and 20% of patients W-SPSS (P < .001 for multiple comparison among SPSS groups). Recurrent or persistent HE was reported in 52% of patients with L-SPSS, 44% of patients with S-SPSS, and 37% of patients W-SPSS (P = .007 for multiple comparison among SPSS groups). Patients with SPSS also had a larger number of portal hypertension-related complications (bleeding or ascites) than those W-SPSS. Quality of life and transplantation-free survival were lower in patients with SPSS vs without. SPSS were an independent factor associated with death or liver transplantation (hazard ratio, 1.26; 95% confidence interval, 1.06–1.49) (P = .008) in multivariate analysis. When patients were stratified by MELD score, SPSS were associated with HE independently of liver function: among patients with MELD scores of 6–9, HE was reported in 23% with L-SPSS, 12% with S-SPSS, and 5% with W-SPSS (P < .001 for multiple comparison among SPSS groups); among those with MELD scores of 10–13, HE was reported in 48% with L-SPSS, 33% with S-SPSS, and 23% with W-SPSS (P < .001 for multiple comparison among SPSS groups); among patients with MELD scores of 14 or more, HE was reported in 59% with L-SPSS, 57% with S-SPSS, and 48% with W-SPSS (P = .043 for multiple comparison among SPSS groups). Patients with SPSS and MELD scores of 6–9 were at higher risk for ascites (40.5% vs 23%; P < .001) and bleeding (15% vs 9%; P = .038) than patients W-SPSS and had lower odds of transplant-free survival (hazard ratio 1.71; 95% confidence interval, 1.16–2.51) (P = .006).
In a retrospective analysis of almost 2000 patients, we found 60% to have SPSS; prevalence increases with deterioration of liver function. SPSS increase risk for HE and with a chronic course. In patients with preserved liver function, SPSS increase risk for complications and death. ClinicalTrials.gov ID NCT02692430.
Display omitted
ObjectivesTo examine the associations between maternal vitamin D intake and childhood growth and risk of overweight up to 8 years. We further examined the effect modification by maternal prepregnancy ...body mass index (BMI).DesignProspective population-based pregnancy cohort study.SettingThe Norwegian Mother, Father and Child Cohort Study.ParticipantsIn total, 58 724 mothers and 66 840 singleton children, with information on maternal vitamin D intake during the pregnancy and minimum one postnatal anthropometric measurement.Outcome measuresPredicted weight and height growth trajectories and velocities from 1 month to 8 years, rapid growth during infancy and toddlerhood, and risk of overweight in preschool and school age.ResultsOverall, maternal vitamin D intake was associated with lower weight trajectory, lower odds of rapid weight growth and higher odds of childhood overweight. In children of mothers with prepregnancy normal weight, maternal vitamin D intake was negatively associated with weight trajectory and lower OR of a rapid weight growth during the first year, compared with reference (<5 µg/day). Children of mothers with normal weight, with maternal vitamin D intakes of 10–15 and >15 µg/day, also had 0.86 (95% CI 0.77 to 0.97) and 0.88 (95% CI 0.79 to 0.99) lower odds for overweight at 3 years, compared with reference. In contrast, in children of mothers with prepregnancy overweight (BMI ≥25 kg/m2), vitamin D intake was positively associated with weight trajectory. Children of mothers with overweight, with maternal vitamin D intake of 5–9.9 µg/day, also had (1.09 (95% CI 1.01 to 1.18) and 1.12 (95% CI 1.02 to 1.23)) higher odds for overweight at 5 years and 8 years, compared with reference.ConclusionsMaternal vitamin D intake affects postnatal growth and is inversely associated with childhood overweight in children of mothers with normal weight. Associations between maternal vitamin D intake and child growth and risk of overweight varied by prepregnancy BMI.
Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the ...underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.
Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell-derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167.
Context:
Lactation is associated with decreased areal bone mineral density (aBMD). Replenishment occurs especially after ceased lactation. Changes in volumetric bone mineral density (vBMD), ...microstructure, and dimensional parameters are unknown and may clarify the role of lactation for skeletal health.
Objective and Main Outcomes:
The objective of the study was to test the hypothesis that lactation is associated with changes in aBMD, vBMD, microstructure, and dimensional parameters.
Design:
At baseline (0.5 mo after delivery) and 4, 12, and 18 months thereafter, bone was assessed using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography.
Participants and Setting:
Eighty-one fair-skinned postpartum women and 21 controls aged 25–40 years were recruited. The completion ratio was 73%. Postpartum women were categorized depending on duration of lactation: 0–3.9, 4–8.9, and 9 months or longer.
Results:
During the first 4 months, aBMD decreased at several sites (geometric mean ± SE; −0.73% ± 0.21% to −3.98% ± 0.76%) in women lactating at least 4 months. During the same time, cortical vBMD at the ultradistal tibia decreased in women lactating 4–8.9 months (−0.26% ± 0.08%) and 9 months or longer (−0.49% ± 0.10%). At 12 months postpartum, cortical thickness (≥9 mo, −2.48% ± 0.41%) and trabecular thickness (4–8.9 mo, −2.14% ± 0.92%; ≥ 9 mo, −2.56% ± 1.21%) also were lower than baseline. No decreases were found in women lactating less than 4 months or in controls in these parameters. At 18 months postpartum, both cortical vBMD (≥9 mo, −0.77% ± 0.17%) and trabecular thickness (4–8.9 mo, −2.25% ± 1.25%; ≥ 9 mo, −3.21% ± 1.41%) were lower in women with long lactation.
Conclusions:
Decreases in cortical vBMD, thickness, and trabecular thickness at the ultradistal tibia were found in women lactating 4 months or longer. Longer follow-up is needed to confirm whether women with extended lactation recover fully or whether the changes could potentially lead to an increased risk of fracture in later life.
Early placement of a transjugular intrahepatic portosystemic shunts (TIPS) is considered the treatment of choice for patients with acute variceal bleeding (AVB) and cirrhosis who have a high risk of ...death (Child-Pugh class B with active bleeding at endoscopy or Child-Pugh class C). It has been proposed that patients of Child-Pugh class B, even with active bleeding, should not be considered high risk. Alternative criteria have been proposed for identification of high-risk patients, such as Child-Pugh class C with plasma level of creatinine of 1 mg/dL or more (ChildC-C1) and a model for end-stage liver disease (MELD) score of 19 or more. We analyzed outcomes of a large cohort of patients with AVB who received the standard of care at different centers to validate these systems of risk stratification.
We performed an observational study of 915 patients with liver cirrhosis and AVB who received standard treatment (drugs, antibiotics, and endoscopic ligation, with TIPS as the rescue treatment), over different time periods between 2006 and 2014 in Canada and Europe. All patients were followed until day 42 (week 6) after index AVB or death. Child-Pugh and MELD scores were calculated at time of hospital admission. The primary outcome was mortality 6 weeks after index AVB among patients who met the early TIPS criteria (Child-Pugh class B with active bleeding at endoscopy or Child-Pugh class C), MELD19 criteria (patients with MELD scores of 19 or more), and ChildC-C1 criteria.
Among 915 patients with AVB, 18% died within 6 weeks. Among the 523 patients who met the early TIPS criteria, 17% died within 6 weeks. All 3 rules discriminated patients at high risk of death from those with low risk: 28.3% of the patients classified as high risk by the early TIPS criteria died whereas only 7.0% of patients classified as low risk died; 46.0% of patients classified as high risk by the MELD19 criteria died vs 8.1% of patients classified as low risk; 51.9% of patients classified as high risk by the ChildC-C1 criteria died compared with 10.9% of patients classified as low risk. Mortality was significantly lower among patients with Child-Pugh class B (11.7%) than with Child-Pugh class C (35.6%) (P ≤ .001). Mortality was similar between patients with Child-Pugh class B cirrhosis with or without active bleeding (11.7%). Patients with Child-Pugh class A cirrhosis or MELD scores of 11 or less had low mortality (2%-4%), patients with Child-Pugh class B cirrhosis or MELD scores of 12 to 18 had intermediate mortality (10%-12%), and patients with Child-Pugh class C cirrhosis or MELD scores of 19 or more had high mortality (22%-46%).
Patients with Child-Pugh class B cirrhosis and AVB who receive standard therapy, regardless of the presence of active bleeding, have 3-fold lower mortality than patients with Child-Pugh C cirrhosis and might not need TIPS. Patients with Child-Pugh class C and/or MELD scores of 19 or more should be considered at high risk of death. These findings might help refine criteria for early TIPS.
Neuro-vascular communication is essential to synchronize central nervous system development. Here, we identify angiopoietin/Tie2 as a neuro-vascular signaling axis involved in regulating dendritic ...morphogenesis of Purkinje cells (PCs). We show that in the developing cerebellum Tie2 expression is not restricted to blood vessels, but it is also present in PCs. Its ligands angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are expressed in neural cells and endothelial cells (ECs), respectively. PC-specific deletion of Tie2 results in reduced dendritic arborization, which is recapitulated in neural-specific Ang1-knockout and Ang2 full-knockout mice. Mechanistically, RNA sequencing reveals that Tie2-deficient PCs present alterations in gene expression of multiple genes involved in cytoskeleton organization, dendritic formation, growth, and branching. Functionally, mice with deletion of Tie2 in PCs present alterations in PC network functionality. Altogether, our data propose Ang/Tie2 signaling as a mediator of intercellular communication between neural cells, ECs, and PCs, required for proper PC dendritic morphogenesis and function.
Display omitted
•Ang1 and Ang2 are expressed in cerebellar neural and endothelial cells, respectively•The angiopoietin receptor Tie2 is expressed in blood vessels and Purkinje cells•Tie2 signaling regulates PC dendritic morphogenesis in a cell-autonomous manner•PCs network functionality is altered in PC specific Tie2-deficient mice
Luck et al. describe a mechanism regulating Purkinje cell dendritic morphogenesis. They show that Tie2 signaling acts in a cell-autonomous manner in Purkinje cells. The ligands, Ang1 and Ang2, are expressed in neural and endothelial cells, respectively. This pathway is required for proper dendritic morphogenesis and neuronal functionality.
PDF
