Our study investigated the relationship between CT signs of colon cancer and the expression of miR-146a, to evaluate their predictive value in early diagnosis and of colon cancer. A total of 216 patients with colon cancer who were admitted to the Department of Hematology and Oncology in Yingcheng Hospital, the Second Hospital of Shandong University in Zhaoyuan City from January 2013 to March 2017 were selected as the study group. At the same time, 150 patients with benign colitis were also included to serve as the control group. CT scan was performed for patients in both the study and control groups. The expression of miR-146a in serum of patients in the study and control groups was detected by RT-qPCR, and of CT signs and miR-146a expression were analyzed. The relative expression level of miR-146a in peripheral blood of study group was significantly lower than that of the control group (t=12.180, p=0.001). Sensitivity and specificity of combined detection of CT and miR-146a in the study and control groups were 91.4 and 93.6%, respectively, which were higher than those of the single test (p<0.05). Among CT signs of study group, luminal wall, cavity and diameter changes, as well as size of tumor and surrounding tissues showed no significant correlation with the expression of miR-146a (p>0.05). The expression level of miR-146a in patients with high-risk of invasion was significantly higher than that in patients with low-risk of invasion (t=4.791, p=0.001). The expression level of miR-146a in lymph node metastasis was significantly lower than that in non-lymph node metastasis (t=3.104, p=0.002). miR-146a may be involved in the development and progression of colon cancer. Combined detection of CT and miR-146a may enhance the sensitivity and specificity of the diagnosis of colon cancer, and may provide a good predictive value for invasion and metastasis of colon cancer.

Pancreatic cancer often has a very poor prognosis, even after complete resection. The recurrence of hepatic and peritoneal metastases is an important prognostic factor; therefore, the development of improved adjuvant therapy is urgently required. Mesothelin is a cell surface glycoprotein whose expression is restricted to a variety of cancer types, including pancreatic cancer. This expression pattern makes mesothelin an attractive target for cancer therapy, and several agents targeting mesothelin are currently in clinical trials. Here, we used the chimerized high-affinity anti-mesothelin monoclonal antibody amatuximab to investigate its effect on peritoneal metastasis. We used the AsPC-1 pancreatic cancer cell line engineered to express Gaussia luciferase (Gluc), (AsPC-1-Gluc) for in vivo experiments. Results showed that while amatuximab was not directly cytotoxic on an AsPC-1-Gluc tumor cells in a peritoneal metastasis model, it prevented the formation of tumor growth. In combination therapy with gemcitabine, amatuximab exhibited synergistic killing. Our results suggest that blockade of mesothelin by amatuximab may be a useful strategy for preventing the peritoneal dissemination of pancreatic cancer under an adjuvant setting.

Bromodomain and extra-terminal domain (BET) proteins regulate the transcription of many genes including c-MYC, a proto-oncogene, which is upregulated in many types of cancers. The thienodiazepine class of BET inhibitors, such as JQ1, inhibits growth of cancer cells and triggers apoptosis. However, the effects of BET inhibitors on normal cells and mesenchymal stem cells (MSCs), which are important in routine maintenance or regeneration of damaged cells and tissues, are poorly investigated. Previously, we have shown that JQ1 causes human umbilical cord MSCs to undergo cell cycle arrest and neural differentiation. In this study, we determined that JQ1 is more deleterious to neuronal derivatives (NDs) than adipogenic, chondrogenic or osteogenic derivatives of MSCs. NDs treated with JQ1 showed a significant decrease in cell proliferation, viability, and neuronal markers. JQ1 caused cell death through the intrinsic apoptotic pathway in NDs as determined by activation of Caspase 9 and increased expression of Cytochrome C. A comparative analysis showed differential action of JQ1 on MSCs and NDs. The results showed selective neuronal toxicity of JQ1 in NDs but not in the undifferentiated MSCs. These findings suggest a more careful examination of the selection and use of BET inhibitors as therapeutic agents, as they may cause unwanted damage to non-target cells and tissues.

Countries across sub-Saharan Africa are scaling up Community Health Worker (CHW) programmes, yet there remains little high-quality research assessing strategies for CHW supervision and performance improvement. This randomised controlled trial aimed to determine the effect of a personalised performance dashboard used as a supervision tool on the quantity, speed, and quality of CHW care.

The era of evidence-informed decision-making has seen increased use of the scientific advisory committee (SAC) to provide decision-makers with scientific advice, despite limited evidence of the effectiveness or best strategies for designing these committees. In this study, an in-depth review of academic and gray literature is undertaken to outline the global landscape of SACs. The development of a typology is also undertaken that categorizes SACs along six dimensions: 1) sector, 2) level of operation, 3) permanence, 4) target audience, 5) autonomy, and 6) nature of advice. It is found that SACs differ profoundly in each of these dimensions and provide examples demonstrating this variation. The landscape and typology can help decision-makers understand the key elements of SAC design and reform, and the results will also inform future research on the design and effectiveness of SACs. With SACs expected to promote evidence-informed decision-making, it is imperative that the design of these committees themselves is guided by evidence.

β-Galactosidase is widely used for hydrolysis of whey lactose. However, galactose inhibition has acted as a major constraint on the catalytic process. Thus, it is sensible to improve upon this defect in β-galactosidase through protein modification. To reduce the galactose inhibition of Aspergillus candidus β-galactosidase (LACB), four amino acid positions were selected for mutation based on their molecular bindings with galactose. Four mutant libraries (Tyr96, Asn140, Glu142, and Tyr364) of the LACB were constructed using site-directed mutagenesis. Among all of the mutants, Y364F was superior to the wild-type enzyme. The Y364F mutant has a galactose inhibition constant (K i) of 282 mM, 15.7-fold greater than that of the wild-type enzyme (K i = 18 mM). When 18 mg/ml galactose was added, the activity of the wild-type enzyme fell to 57% of its initial activity, whereas Y364F activity was maintained at over 90% of its initial activity. The wild-type enzyme hydrolyzed 78% of the initial lactose (240 mg/ml) after 48 h, while the Y364F mutant had a hydrolysis rate greater than 90%. The β-galactosidase Y364F mutant with reduced galactose inhibition may have greater potential applications in whey treatment compared to wild-type LACB.

The adsorption characteristics of sodium dodecylbenzene sulfonate (SDBS) on the surface of montmorillonite can lay a foundation for obtaining the optimum concentration of the anionic surfactant. The best absorption wavelength of SDBS was determined using an ultraviolet spectrophotometer. The standard curves of concentration and absorbance of SDBS were established. The amount of SDBS adsorbed on the surface of montmorillonite at various concentrations was calculated by stirring adsorption method. Scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDS), X-ray diffraction (XRD), zeta potentiometer, and Fourier transform infrared (FTIR) spectroscopy were used to observe the changes of the structure, main ions, interlayer spacing, potential, and main functional groups on the montmorillonite surface before, and after, adsorption. The test results of SEM with EDS (SEM-EDS) showed that the surface of the montmorillonite after SDBS adsorption was rougher, and the adsorption capacity of the surface was enhanced as the SDBS concentration increased. The XRD results indicated that SDBS adsorbed on the interlayer of montmorillonite repulsed interlayer water and reduced the interlayer water content. With the increase of SDBS concentration, the interlayer spacing of the montmorillonite available for adsorbing SDBS decreased further. Additionally, interlayer adsorption and surface adsorption exist simultaneously in montmorillonite in SDBS solution. The distribution of total adsorption capacity of SDBS in the layers and on the surface of montmorillonite accords with the adsorption result simulated by a pseudo-second-order kinetic model. The increase in concentration of SDBS adsorbed by montmorillonite is the main reason for the decreased initial adsorption rate. The zeta potential test showed that the addition of H+ to the SDBS solution could reduce electrostatic repulsion and promote the adsorption of SDBS on montmorillonite. The results of this study provide an experimental basis for the study of the mechanism of SDBS adsorption on montmorillonite.

Healthy bone remodeling results from a balanced bone formation and bone resorption realized by bone-forming osteoblasts and bone-resorbing osteoclasts, respectively. Recently, Thy-1 (CD90) was identified as positive regulator of osteoblast differentiation and activation, thus, promoting bone formation while concurrently inhibiting adipogenesis and obesity in mice. Additionally, Thy-1 did not affect bone resorption. An obesity-related co-morbidity that is increasing in prevalence is a disturbed bone formation resulting in an increased fracture risk. The underlying mechanisms of obesity-induced bone alterations are not yet fully elucidated and therefore therapy options for efficient bone-anabolic treatments are limited. Therefore, we investigated the impact of Thy-1 on bone metabolism under obese conditions. Indeed, high fat diet (HFD) induced obese mice lacking Thy-1 (Thy-1-/-) showed increased body fat mass compared to wildtype (WT) mice while bone mass (-38%) and formation (-57%) were decreased as shown by micro-computed tomography (μCT) measurement, histological analysis, and fourier-transform infrared spectroscopy (FTIR). Interestingly, under obese conditions, lack of Thy-1 affected both osteoblast and osteoclast function. Number (-30%) and activity of osteoblasts were decreased in obese Thy-1-/- mice while osteoclast number (+39%) and activity were increased. Facilitated bone marrow fat accumulation (+56%) in obese Thy-1-/- mice compared to obese WT mice was associated with upregulated tumor necrosis factor α (Tnfα, +46%) and colony stimulating factor 1 receptor (Csf1r) expression, strong promoters of osteoclast differentiation. Moreover, lack of Thy-1 was accompanied by a reduction of osteoprotegerin (Tnfrsf11b) expression (-36%), an inhibitor of osteoclast differentiation. Altered Tnfα, Csf1r, and Tnfrsf11b expression might be responsible for elevated osteoclast activity in obese Thy-1-deficient mice. In summary, our findings show that lack of Thy-1 promotes obesity under HFD conditions while concurrently decreasing bone mass and formation. Mechanistic studies revealed that under obese conditions lack of Thy-1 impairs both bone formation and bone resorption.

An elastomer is a three-dimensional network with a cross-linked polymer chain that undergoes large deformation with a small external force and returns to its original state when the external force is removed. Because of this hyperelasticity, elastomers are regarded as one of the best candidates for the matrix material of soft robots. However, the comprehensive performance required of matrix materials is a special challenge because improvement of some matrix properties often causes the deterioration of others. For example, an improvement in toughness can be realized by adding a large amount of filler to an elastomer, but to the impairment of optical transparency. Therefore, to produce an elastomer exhibiting optimum properties suitable for the desired purpose, very elaborate, complicated materials are often devised. Here, we have succeeded in creating an optically transparent, easily fabricated elastomer with good extensibility and high toughness by using a polyrotaxane (PR) composed of cyclic molecules and a linear polymer as a cross-linking agent. In general, elastomers having conventional cross-linked structures are susceptible to breakage as a result of loss of extensibility at high cross-linking density. We found that the toughness of the transparent elastomer prepared using the PR cross-linking agent is enhanced along with its Young's modulus as cross-linking density is increased.

High-entropy alloys (HEAs) are a class of metallic materials that have revolutionized alloy design. They are known for their high compressive strengths, often greater than 1 GPa; however, the tensile strengths of most reported HEAs are limited. Here, we report a strategy for the design and fabrication of HEAs that can achieve ultrahigh tensile strengths. The proposed strategy involves the introduction of a high density of hierarchical intragranular nanoprecipitates. To establish the validity of this strategy, we designed and fabricated a bulk Fe25Co25Ni25Al10Ti15 HEA to consist of a principal face-centered cubic (fcc) phase containing hierarchical intragranular nanoprecipitates. Our results show that precipitation strengthening, as one of the main strengthening mechanisms, contributes to a tensile yield strength (σ0.2) of ~1.86 GPa and an ultimate tensile strength of ~2.52 GPa at room temperature, which heretofore represents the highest strength reported for an HEA with an appreciable failure strain of ~5.2%.

Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC.

Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo.

MiR-34 is a tumour suppressor in breast cancer. Neurokinin-1 receptor (NK1R), which is the predicted target of the miR-34 family, is overexpressed in many cancers. This study investigated the correlation and clinical significance of miR-34 and NK1R in breast cancer.

Histone lysine methylation plays an important role in the regulation of ventricular remodelling. NSD2 is involved in many types of tumours through enhancing H3K36me2 expression. However, the role of NSD2 in the regulation of histone lysine methylation during ventricular remodelling remains unclear. In this study, we established cardiac hypertrophy model in C57BL/6 mice by transverse aortic constriction and found that histone lysine methylation participated in ventricular remodelling regulation via the up-regulation of H3K27me2 and H3K36me2 expression. In addition, we constructed transgenic C57BL/6 mice with conditional knockout of NSD2 (NSD2-/- ) in the myocardium. NSD2-/- C57BL/6 mice had milder ventricular remodelling and significantly improved cardiac function compared with wild-type mice, and the expression of H3K36me2 but not H3K27me2 was down-regulated. In conclusion, NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.

Ionizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation-induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG-4592), against radiation-induced haematopoietic injuries in vitro and in vivo.

Adolescent girls and young women (AGYW) in South Africa bear a disproportionate burden of HIV. Community mobilization (CM), defined as community members taking collective action to achieve a common goal related to health, equity and rights, has been associated with increased HIV testing and condom use and has been called a 'critical enabler' for addressing the HIV epidemic. However, limited research has examined whether CM is associated with HIV incidence among AGYW.

Background and purpose - Teriparatide accelerates fracture healing in animals and probably in man. Abaloparatide is a new drug with similar although not identical effects on the teriparatide receptor. Given at 4 times the teriparatide dose in a human osteoporosis trial, abaloparatide increased bone density more than teriparatide, and both reduced fracture risk. We investigated in mice whether abaloparatide stimulates fracture healing, and if it does so with the suggested dose effect relation (4:1). Patients and methods - In a validated mouse model for metaphyseal healing (burr hole with screw pull-out), 96 mice were randomly allocated to 11 groups: control (saline), teriparatide or abaloparatide, where teriparatide and abaloparatide were given at 5 different doses each. In a femoral shaft osteotomy model, 24 mice were randomly allocated to 3 groups: control (saline), teriparatide (15 µg/kg) or abaloparatide (60 µg/kg). Each treatment was given daily via subcutaneous injections. Results were evaluated by mechanical testing and microCT. Results - In the metaphyseal model, a dose-dependent increase in screw pull-out force could be seen. In a linear regression analysis (r = 0.78) each increase in ln(dose) by 1 (regardless of drug type) was associated with an increase in pull-out force by 1.50 N (SE 0.18) (p < 0.001). Changing drug from teriparatide to abaloparatide increased the force by 1.41 N (SE 0.60; p = 0.02). In the diaphyseal model, the callus density was 23% (SD 10), 38% (SD 10), and 47% (SD 2) for control, for teriparatide and abaloparatide respectively. Both drugs were significantly different from controls (p = 0.001 and p = 0.008), but not from each other. Interpretation - Both drugs improve fracture healing, but in these mouse models, the potency per µg of abaloparatide seems only 2.5 times that of teriparatide, rather than the 4:1 relation chosen in the clinical abaloparatide-teriparatide comparison trial.

Klinefelter syndrome (KS) is a common sex chromosome-related abnormality seen among men. KS negatively affects spermatogenesis and testosterone production. It increases the risk of thrombosis but its molecular mechanism has not been well described yet. Elevated PAI-1 is a risk factor for thrombosis. The rs1799889 polymorphism located in the promoter region of the PAI-1 gene was detected in patients with deep venous thrombosis. In this study, the PAI-1 gene variant and its plasma levels in KS patients were examined. Forty-one KS patients (47, XXY) and 50 age-matched healthy controls participated. DNA was isolated from peripheral blood and a real-time PCR method was used to detect known SNPs in the PAI-1 gene. In addition, PAI-1 plasma levels were measured by using ELISA method. There was no significant difference between PAI-1 gene polymorphisms of KS patients and controls ( p > .05). The significant difference was observed in PAI-1 plasma levels between two groups (high PAI-1 plasma level in KS patients compared to controls). The patients' group mean was 55.13 and control group mean in PAI-1 level was 29.89 ng/ml ( p = .020). Clinical features related to thromboembolism especially varicose veins were detected in KS patients frequently ( p = .04). These results suggest that thromboembolism related to clinical features is seen more frequently in cases with KS, but it may not be dependent only on the PAI-1 gene polymorphism structure.

Clinical practice guidelines (CPGs) document evidence-based information and recommendations on treatment and management of conditions. CPGs usually focus on management of a single condition; however, in many cases a patient will be at the centre of multiple health conditions (multimorbidity). Multiple CPGs need to be followed in parallel, each managing a separate condition, which often results in instructions that may interact with each other, such as conflicts in medication. Furthermore, the impetus to deliver customised care based on patient-specific information, results in the need to be able to offer guidelines in an integrated manner, identifying and managing their interactions. In recent years, CPGs have been formatted as computer-interpretable guidelines (CIGs). This enables developing CIG-driven clinical decision support systems (CDSSs), which allow the development of IT applications that contribute to the systematic and reliable management of multiple guidelines. This study focuses on understanding the use of CIG-based CDSSs, in order to manage care complexities of patients with multimorbidity. The literature between 2011 and 2017 is reviewed, which covers: (a) the challenges and barriers in the care of multimorbid patients, (b) the role of CIGs in CDSS augmented delivery of care, and (c) the approaches to alleviating care complexities of multimorbid patients. Generating integrated care plans, detecting and resolving adverse interactions between treatments and medications, dealing with temporal constraints in care steps, supporting patient-caregiver shared decision making and maintaining the continuity of care are some of the approaches that are enabled using a CIG-based CDSS.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in the proliferation and survival of multiple myeloma. And inactivation of STAT3 is considered a promising strategy for the treatment of multiple myeloma. Here we show that the sinomenine derivative YL064 could selectively reduce the cell viability of multiple myeloma cell lines and primary multiple myeloma cells. Moreover, YL064 also induces cell death of myeloma cells in the presence of stromal cells. Western blot analysis showed that YL064 inhibited the constitutive activation and IL-6-induced activation of STAT3, reflected by the decreased phosphorylation of STAT3 on Tyr705. Consistent with this, YL064 inhibited the nuclear translocation of STAT3 and the expression of STAT3 target genes, such as cyclin D1 and Mcl-1. Using biotin- and FITC-labeled YL064, we found that YL064 could pull-down STAT3 from myeloma cells and colocalized with STAT3, suggesting that YL064 directly targets STAT3. Cellular thermal shift assay further demonstrated the engagement of YL064 to STAT3 in cells. Molecular docking studies indicated that YL064 may interact with STAT3 in its SH2 domain, thereby inhibiting the dimerization of STAT3. Finally, YL064 inhibited the growth of human myeloma xenograft in vivo. Taken together, this study demonstrated that YL064 may be a promising candidate compound for the treatment of multiple myeloma by directly targeting STAT3.