Are glucose profiles well-controlled within the targets recommended by the International Diabetes Federation in type 2 diabetes? A meta-analysis of results from continuous glucose monitoring based studies

AIMS: To assess continuous glucose monitoring (CGM) derived intra-day glucose profiles using global guideline for type 2 diabetes recommended by the International Diabetes Federation (IDF). METHODS: The Cochrane Library, MEDLINE, PubMed, CINAHL and Science Direct were searched to identify observational studies reporting intra-day glucose profiles using CGM in people with type 2 diabetes on any anti-diabetes agents. Overall and subgroup analyses were conducted to summarise mean differences between reported glucose profiles (fasting glucose, pre-meal glucose, postprandial glucose and post-meal glucose spike/excursion) and the IDF targets. RESULTS: Twelve observational studies totalling 731 people were included. Pooled fasting glucose (0.81 mmol/L, 95% CI, 0.53-1.09 mmol/L), postprandial glucose after breakfast (1.63 mmol/L, 95% CI, 0.79-2.48 mmol/L) and post-breakfast glucose spike (1.05 mmol/L, 95% CI, 0.13-1.96 mmol/L) were significantly higher than the IDF targets. Pre-lunch glucose, pre-dinner glucose and postprandial glucose after lunch and dinner were above the IDF targets but not significantly. Subgroup analysis showed significantly higher fasting glucose and postprandial glucose after breakfast in all groups: HbA1c <7% and ≥7% (53 mmol/mol) and duration of diabetes <10 years and ≥10 years. CONCLUSIONS: Independent of HbA1c, fasting glucose and postprandial glucose after breakfast are not well-controlled in type 2 diabetes

Dose-response between frequency of breaks in sedentary time and glucose control in type 2 diabetes: a proof of concept study

Objectives This study aimed to investigate dose-response between frequency of breaks in sedentary time and glucose control.DesignRandomised three-treatment, two-period balanced incomplete block trial.MethodsTwelve adults with type 2 diabetes (age, 60 ± 11 years; body mass index, 30.2 ± 4.7 kg/m2) participated in two of the following treatment conditions: sitting for 7 h interrupted by 3 min light-intensity walking breaks every (1) 60 min (Condition 1), (2) 30 min (Condition 2), and (3) 15 min (Condition 3). Postprandial glucose incremental area under the curves (iAUCs) and 21-h glucose total area under the curve (AUC) were measured using continuous glucose monitoring. Standardised meals were provided. Results Compared with Condition 1 (6.7 ± 0.8 mmol L−1 × 3.5 h−1), post-breakfast glucose iAUC was reduced for Condition 3 (3.5 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.04). Post-lunch glucose iAUC was lower in Condition 3 (1.3 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.03) and Condition 2 (2.1 ± 0.7 mmol L−1 × 3.5 h−1, p ˂ 0.05) relative to Condition 1 (4.6 ± 0.8 mmol L−1 × 3.5 h−1). Condition 3 (1.0 ± 0.7 mmol L−1 × 3.5 h−1, p = 0.02) and Condition 2 (1.6 ± 0.6 mmol L−1 × 3.5 h−1, p ˂ 0.04) attenuated post-dinner glucose iAUC compared with Condition 1 (4.0 ± 0.7 mmol L−1 × 3.5 h−1). Cumulative 10.5-h postprandial glucose iAUC was lower in Condition 3 than Condition 1 (p = 0.02). Condition 3 reduced 21-h glucose AUC compared with Condition 1 (p < 0.001) and Condition 2 (p = 0.002). However, post-breakfast glucose iAUC, cumulative 10.5-h postprandial glucose iAUC and 21-h glucose AUC were not different between Condition 2 and Condition 1 (p ˃ 0.05).Conclusions There could be dose-response between frequency of breaks in sedentary time and glucose. Interrupting sedentary time every 15 min could produce better glucose control

Gap analysis and economic assessment for protected cropping vegetables in tropical Australia

The project VG16024 aims to increase awareness and information about protected cropping opportunities and technology options for the vegetable industry in the tropics through the identification of gaps in information and potential economic viabilities. Protected cropping of vegetables in Australia (estimated at 1,341 ha) is by large located in temperate climate regions and in proximity to urban areas. In warm climate regions, near and north of the Tropic of Capricorn, the segment of the industry dedicated to producing vegetables using protected cropping technologies is scattered and relatively small (estimated at <80 ha). Vegetable growers in these regions would benefit from technologies that can mitigate risks linked to climate variability and that can help them address current and future market challenges and opportunities. Evidence from overseas, including in tropical regions, and demonstration plots and farmer experiences in the Australian tropics indicate that protective cropping technologies can cost-effectively mitigate the effects of extremes in air temperatures, rainfall, low and high relative humidity, wind, solar radiation, and pests and diseases, all which currently negatively affect yield, quality and consistency of supply. In this report, four regions, two within the tropics (Burdekin dry tropics and Atherton Tablelands) and two located a short distance south of the Tropic of Capricorn (Bundaberg and Carnarvon), are selected as examples of regions where the protected cropping industry is either small or emerging, and has the potential to expand. Vegetable production in these regions is predominantly undertaken outdoors. The establishment of protected cropping enterprises would contribute to an increase in regional production that could service both domestic and export markets. This would be facilitated by the regions’ proximity to road infrastructure, ports and airports but access to some of these market opportunities still need to be developed. In the tropics the availability of medium level, cost-effective protected cropping structures that are effective in removing heat from crops is paramount. In this report, four greenhouse structure designs (high tunnels, passively ventilated greenhouses, retractable roof structures, and net houses) are discussed, and advantages and drawbacks compared. Capsicum, cucumbers, melons, and eggplants are given as examples of vegetable crops suited to warm climates and which can benefit from a protected environment and specific agronomy practices. Possible marketable yields are provided for these crops as well as estimates of production value for a range of size of areas that could potentially establish protected cropping systems. A preliminary economic analysis was carried out for hypothetical production of capsicum crops in different protected cropping scenarios in the tropics. Under the protective structures, management practices, market prices and capsicum yields used in the analysis, preliminary results suggest that protected cropping could be a viable business opportunity for growers in the tropics. Future research investigating the heterogeneity of protected cropping enterprises would serve to further confirm these findings, especially in light of the practical implications of the technology used in a larger number of commercial sites

Gap analysis and economic assessment for protected cropping vegetables in tropical Australia

The project VG16024 aims to increase awareness and information about protected cropping opportunities and technology options for the vegetable industry in the tropics through the identification of gaps in information and potential economic viabilities. Protected cropping of vegetables in Australia (estimated at 1,341 ha) is by large located in temperate climate regions and in proximity to urban areas. In warm climate regions, near and north of the Tropic of Capricorn, the segment of the industry dedicated to producing vegetables using protected cropping technologies is scattered and relatively small (estimated at <80 ha). Vegetable growers in these regions would benefit from technologies that can mitigate risks linked to climate variability and that can help them address current and future market challenges and opportunities. Evidence from overseas, including in tropical regions, and demonstration plots and farmer experiences in the Australian tropics indicate that protective cropping technologies can cost-effectively mitigate the effects of extremes in air temperatures, rainfall, low and high relative humidity, wind, solar radiation, and pests and diseases, all which currently negatively affect yield, quality and consistency of supply. In this report, four regions, two within the tropics (Burdekin dry tropics and Atherton Tablelands) and two located a short distance south of the Tropic of Capricorn (Bundaberg and Carnarvon), are selected as examples of regions where the protected cropping industry is either small or emerging, and has the potential to expand. Vegetable production in these regions is predominantly undertaken outdoors. The establishment of protected cropping enterprises would contribute to an increase in regional production that could service both domestic and export markets. This would be facilitated by the regions’ proximity to road infrastructure, ports and airports but access to some of these market opportunities still need to be developed. In the tropics the availability of medium level, cost-effective protected cropping structures that are effective in removing heat from crops is paramount. In this report, four greenhouse structure designs (high tunnels, passively ventilated greenhouses, retractable roof structures, and net houses) are discussed, and advantages and drawbacks compared. Capsicum, cucumbers, melons, and eggplants are given as examples of vegetable crops suited to warm climates and which can benefit from a protected environment and specific agronomy practices. Possible marketable yields are provided for these crops as well as estimates of production value for a range of size of areas that could potentially establish protected cropping systems. A preliminary economic analysis was carried out for hypothetical production of capsicum crops in different protected cropping scenarios in the tropics. Under the protective structures, management practices, market prices and capsicum yields used in the analysis, preliminary results suggest that protected cropping could be a viable business opportunity for growers in the tropics. Future research investigating the heterogeneity of protected cropping enterprises would serve to further confirm these findings, especially in light of the practical implications of the technology used in a larger number of commercial sites

The Angular Momentum Evolution of Very Low Mass Stars

We present theoretical models of the angular momentum evolution of very low mass stars (0.1 - 0.5 M_sun) and solar analogues (0.6 - 1.1 M_sun). We investigate the effect of rotation on the effective temperature and luminosity of these stars. We find that the decrease in T_eff and L can be significant at the higher end of our mass range, but becomes negligible below 0.4 M_sun. Formulae for relating T_eff to mass and v_rot are presented. We compare our models to rotational data from young open clusters of different ages to infer the rotational history of low mass stars, and the dependence of initial conditions and rotational evolution on mass. We find that the qualitative conclusions for stars below 0.6 M_sun do not depend on the assumptions about internal angular momentum transport, which makes these low mass stars ideal candidates for the study of the angular momentum loss law and distribution of initial conditions. We find that neither models with solid body nor differential rotation can simultaneously reproduce the observed stellar spin down in the 0.6 to 1.1 M_sun mass range and for stars between 0.1 and 0.6 M_sun. The most likely explanation is that the saturation threshold drops more steeply at low masses than would be predicted with a simple Rossby scaling. In young clusters there is a systematic increase in the mean rotation rate with decreased temperature below 3500 K (0.4 M_sun). This suggests either inefficient angular momentum loss or mass-dependent initial conditions for stars near the fully convective boundary. (abridged)Comment: To appear in the May 10, 2000 Ap

Investigation of the filamin A-Dependent mechanisms of tissue factor incorporation into microvesicles

We have previously shown that phosphorylation of tissue factor (TF) at Ser253 increases the incorporation of TF into microvesicles (MVs) following protease-activated receptor 2 (PAR2) activation through a process involving filamin-A, whereas Ser258 phosphorylation suppresses this process. Here we examined the contribution of the individual phosphorylation of these serine residues to the interaction between filamin-A and TF, and further examined how filamin-A regulates the incorporation of TF into MVs. In vitro binding assays using recombinant filamin-A C-terminal repeats 22-24 with biotinylated phospho-TF cytoplasmic domain peptides as bait, showed that filamin-A had the highest binding affinities for phospho-Ser253 and double-phosphorylated TF peptides, whilst the phospho-Ser258 TF peptide had the lowest affinity. Analysis of MDA-MB-231 cells using an in situ proximity ligation assay revealed increased proximity between the C-terminus of filamin-A and TF following PAR2 activation, which was concurrent with Ser253 phosphorylation and TF-positive MV release from these cells. Knock-down of filamin-A expression suppressed PAR2-mediated increases in cell surface TF procoagulant activity without reducing cell surface TF antigen expression. Disrupting lipid rafts by pre-incubation with methyl-beta cyclodextrin (MβCD) prior to PAR2 activation reduced TF-positive MV release and cell surface TF procoagulant activity to the same extent as filamin-A knock-down. In conclusion, this study shows that the interaction between TF and filamin-A is dependent on the differential phosphorylation of Ser253 and Ser258. Furthermore the interaction of TF with filamin-A may translocate cell surface TF to cholesterol-rich lipid rafts, increasing cell surface TF activity as well as TF incorporation and release into MVs

A 3D Heterotypic Breast Cancer Model Demonstrates a Role for Mesenchymal Stem Cells in Driving a Proliferative and Invasive Phenotype

Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-&beta;) signalling, and of &beta;-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the &beta;-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-&beta; and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems

Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis

Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na+ driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo

Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts

PurposeThis 3D in vitro cancer model for propagation of patient-derived cells, using a synthetic self-assembling peptide gel, allows the formation of a fully characterised, tailorable tumour microenvironment. Unlike many existing 3D cancer models, the peptide gel is inert, apart from molecules and motifs deliberately added or produced by cells within the model.MethodsBreast cancer patient-derived xenografts (PDXs) were disaggregated and embedded in a peptide hydrogel. Growth was monitored by microscopic examination and at intervals, cells were extracted from the gels and passaged on into fresh gels. Passaged cells were assessed by qPCR and immunostaining techniques for the retention of characteristic markers.ResultsBreast cancer PDXs were shown to be capable of expansion over four or more passages in the peptide gel. Contaminating mouse cells were found to be rapidly removed by successive passages. The resulting human cells were shown to be compatible with a range of common assays useful for assessing survival, growth and maintenance of heterogeneity.ConclusionsBased on these findings, the hydrogel has the potential to provide an effective and practical breast cancer model for the passage of PDXs which will have the added benefits of being relatively cheap, fully-defined and free from the use of animals or animal products. Encapsulated cells will require further validation to confirm the maintenance of cell heterogeneity, genotypes and phenotypes across passage, but with further development, including the addition of bespoke cell and matrix components of the tumour microenvironment, there is clear potential to model other cancer types