Identification of microRNA Biomarkers in HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 30% of breast cancer patients with poor prognosis. In addition, microRNAs are small non-coding RNA that have been linked to many cancers. Here we investigate which miRNAs are differentially regulated by HER2 overexpression. Using quantitative reverse-transcription prolymerase chain reaction (QRT-PCR) and matching it with the clinical data acquired from Dvinge, we find five candidate miRNAs. When comparing the miRNAs’ effect on patient survival, only three miRNAs stand as good predictors of patient survival outcome. These miRNAs are miR-146a-5p, miR-181d, and miR-195-5p. When miR-146a-5p is up-regulated, which is the case in HER2 positive patients, survival of patients drop significantly. In addition, miR-181d and miR-195-5p are down-regulated in HER2. With these two miRNA having low levels, the patient survival drops. Therefore, this data indicates that miR-146a-5p, miR-181d, and miR-195-5p are potential markers for patient survival and that their expression levels are highly associated with HER2 overexpression

Association of vitamin D (1,25OHD, 25OHD and vitamin D binding protein) and alkaline phosphatase with orthodontic tooth movement and osteoblast function

INTRODUCTION: In this study, we identified the association of Vitamin D with orthodontic tooth movement and the impact of Vitamin D 1,25OHD and 25OHD forms on osteoblast function. MATERIALS AND METHODS: This study is comprised of two parts; a clinical and a laboratory part. In part I, saliva samples were collected from orthodontic patients each month for the first six months of orthodontic treatment along with casts at the beginning and the end of the study period. The samples were measured for Vitamin D binding protein (VitDBP) and alkaline phosphatase (ALP) and correlated with clinical tooth movement using absolute change in irregularity index (II). In part II, osteoblasts were collected from the calvaria of 3-5 day old healthy wild-type mice and cultured with differing concentrations of 1,25OHD (1, 10 and 100nmol) and 25OHD (100, 200, 400 nmol). ALP, OPG, and RANKL were measured as outcomes of Vitamin D treatment of osteoblasts. Intracellular signaling in response to Vitamin D was assessed by identifying the phosphorylation of ERK 1/2, p38 and NLK in primary osteoblasts. RESULTS: Measurement of salivary Vitamin D binding protein (VitDBP) showed that both low (6.48 ng/ml) logVitDBP were associated with reduced tooth movement. There was no significant correlation between ALP levels and orthodontic treatment. Significant seasonal changes in VitDBP using a two-season year model were found with lower levels noticed in the summer (Mar-Sept) than in the winter (Oct-Feb) at p<0.05. A decrease in OPG production with higher concentrations of 1,25OHD and 25OHD with a corresponding increase in RANKL levels in primary osteoblast cultures was found. Similar to the clinical findings, ALP levels were not significantly affected by increasing concentrations of both 1,25OHD and 25OHD. The ERK 1/2 showed upregulation in response to treatment with 1,25OHD and downregulation in response to treatment with 25OHD concentrations. Meanwhile, p38 and NLK were affected by 1,25OHD and not by 25OHD. CONCLUSIONS: Clinical outcomes of orthodontic treatment are associated with a range of optimal Vitamin D binding protein (VitDBP) as detected in saliva. Different forms of Vitamin D affect osteoblast response and signaling differently

Cycloaddition Reactions of (Di)tetrelenes

This thesis examines a variety of cycloaddition reactions of multiply-bonded heavy analogues of carbon. With the aid of a mechanistic probe, the mechanism of the addition of alkynes to a germene and a digermyne was examined. In both cases, the addition does not involve the itermediacy of an vinyl radicals or cations. The addition of a variety of nitro compounds to tetramesityldisilene and tetramesityldigermene was examined. The facile formation of the novel 1,3,2,4,5-dioxazadisil- and digermolidine ring systems, respectively, was observed. In general, 1,3,2,4,5-dioxazadisilolidines and -digermolidines isomerize under thermal conditions to the 1,4,2,3,5-dioxazadisilolidines and -digermolidines ring system. The 1,3,2,4,5-dioxazadisilolidine and digermolidine systems were found also to undergo ring opening to the isomeric oximes. The addition of nitro compounds to ditetrelenes is a general reaction; the variability of products obtained from the reaction can be understood based on the nature of the substituents on the nitrogen in the nitro compound. For most part, the chemistry of ditetrelenes and the Si and Ge(100)- 2 × 1 surfaces were quite comparable although the apparent relative stabilities of the adducts varied. The addition of sulfonyl chloride compounds to tetramesityldisilene (or tetramesityldigermene) lead to the facile formation of a 1,2 addition product, a ß-disilyl (or digermyl) halosulfinate. The formation of the sulfinate compounds revealed an interesting, 2-electron reduction of the sulfur centre using a ditetrelene. The addition reactions of sulfonyl compounds with ditetrelenes illustrates the potential of ditetrelenes to serve as effective reducing agents which react rapidly, at room temperature and under mild conditions. The addition of isocyanide to tetramesityldisilene differs greatly from the addition of isocyanide to tetramesityldigermene. A C-N bond activation product was obtained from the addition of benzyl isocyanide to tetramesityldigermene. In the presence of the bulkier 2,6-dimethylphenyl- or t-butyl isocyanide, the conversion of the digermene to the cyclotrigermane is accelerated. While one equivalent of 2,6-dimethylphenyl- or t-butyl isocyanide add to tetramesityldisilene forming [2+1] cycloaddition products, the addition of two equivalent of t-butyl isocyanide yields a novel double enamine cycloadduct. The reaction was examined computationally to provide an understanding on the reaction pathway and the intermediates involved

Health And Nutrition Status Of Hemodialysis Patients During Ramadan In Saudi Arabia.

During Ramadan R month, Muslims abstain from eating, drinking, and medication from sunrise to sunset, and this causes some changes in their lifestyle and often eating habits (quantity and quality). These changes could lead to affect their health and nutritional status. Among Hemodialysis (HD) patients, malnutrition is common, and it is associated with mortality. Some HD patients opt to fast R which could have an impact on their nutritional and health status. Thus, the primary objective of this study was to document nutritional changes before, during, and after Ramadan on biochemical and health parameters in HD patients. A prospective cohort study was included 45 KF undergoing HD patients from an out-patient HD clinic in Saudi Arabia, who were 18 years of age or older, not pregnant, and who had been on dialysis treatment for three months at least. Subjects were evaluated for routine biochemical, anthropometric including hand-grip strength (HGS), mid-arm muscle circumference (MAMC), plasma lipids, and lipoproteins on a monthly basis every four weeks before, during as well as one and two months after R. in addition, the dietary assessment was carried out using 24 h recalls. Then the changes of these markers were evaluated by dividing the subjects depend on first: their reporting energy intake (calculated from their ratio of energy intake (EI) and total energy expenditure (TEE)) to acceptable- reporters (AR: EI/TEE \u3e 0.76) and under-reporters (UR: EI/TEE \u3c 0.76). Second, depending on their malnutrition indicators according to protein-energy wasting (PEW) using the International Society of Renal Nutrition and Metabolism (ISRNM) criteria to PEW and Non-PEW group. The findings of this study revealed no changes were seen in terms of clinical and biochemical markers during R; however, there was only a temporary change in lipoprotein particle size distribution and MIS during Ramadan. Moreover, the intake of energy and nutrients was higher during Ramadan. This high intake showed a significant change in LDL particle size and malnutrition inflammation score (MIS). Finally, PEW was prevalent in our samples with no change in the food intake during the study period. The data suggests that there is transient change and most of them are not clinically significant and Ramadan does not have an impact on health and nutritional status

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations

Thermal comfort characteristics of knitted fabrics for abaya

Fabric material plays an important role in the thermal comfort of Abaya because it is the outer garment of Muslim women. Abaya is black in colour and covers the whole body except the hands, feet and face. It is mandatory to wear Abaya in the Saudi Arabia and certain parts of Middle East countries irrespective of the outside environmental temperature which could be up to 45°C. Therefore, the thermal transmission characteristics of the abaya are extremely important as human body responds to the external thermal environment through clothing. In a hot environment, it is extremely uncomfortable to wear several layers of clothing under the Abaya. Hence it is essential to enhance the thermal comfort of fabrics used for Abaya. This study investigated five selected knitted fabrics that could be used as Abaya fabrics for thermal resistance, air permeability, thermal comfort and vapour resistance. The results indicated that the fabrics with different knit structures, fibre composition and fabric weight have greater influence on thermal comfort performance

Lysyl oxidase like-2 anabolic role in TMJ and knee osteoarthritis

INTRODUCTION: Osteoarthritis (OA) is the most common chronic degenerative joint disease that leads to damage and disability of the joints. Several studies mentioned the association between inflammatory process and clinical changes. However, there is no drug approved yet to cure the disease and to regenerate the tissues. Lysyl Oxidase-Like-2 (LOXL2) could be a potential candidate as shown in our previous studies. We showed that LOXL2 is elevated during fracture healing and critical regulator of chondrogenesis. Recently, we showed that LOXL2 is shown to be anabolic to human OA cartilage. The goal of this study is to determine the protective effect of LOXL2 in temporomandibular (TMJ) and knee joint OA and to evaluate if LOXL2 attenuates the adverse effects induced by IL-1β in chondrocytes and osteoblasts. MATERIALS AND METHODS: To evaluate the anti-catabolic effect of LOXL2 in vitro, ATDC5 and MC3T3 cells have been transduced with Adv-RFP-LOXL2 and treated with IL-1β. The protective effect of LOXL2 in vivo was evaluated by systemic injection of adenovirus LOXL2 in a chondrodysplasia mouse model (Cho/+) and intra-articular MIA injection in LOXL2 in transgenic mice followed by an analysis of TMJ and knee joints structural and functional analysis. RESULTS: LOXL2 protects from adverse effects induced by IL-1β in ATDC5 and MC3T3 cells by inhibiting the phospho-NF-κB signaling pathway independent of LOXL2 enzymatic activity. Also, LOXL2 increased the mRNA expression of Aggrecan and SOX9 and decreased the level of ADAMTS5, MMP13 and RANKL induced by IL-1β. LOXL2 promotes the mRNA level of ACAN and SOX9 in Cho/+ in TMJ and knee joints. Moreover, IHC analysis showed that ACAN expression is increased and MMP13 decreased in TMJ and knee tissues. LOXL2 overexpressed mice injected with MIA covered more distances and spent more time on the treadmill than wild-type littermates in a treadmill test. IHC analysis showed more ACAN and less MMP13 staining in the LOXL2 overexpressed group than the control one. CONCLUSION: LOXL2 was shown to attenuate adverse effects induced by IL-1β in chondrocytes and osteoblasts. LOXL2 has a protective and anabolic role in TMJ and knee joints affected by OA. Further, LOXL2 was shown to have a protective function during OA-related disability

The effect of zirconia surface treatment on bond strength of various cement systems

OBJECTIVES: The aim of this in-vitro study is to evaluate the effect of different zirconia surface pretreatments, different cement types and the effect of accelerated aging on the adherence of bonding cements to zirconia. MATERIALS AND METHODS: 64 zirconia 3Y-TZP tapered rings were pressed from TZ-3YSB-E zirconia powder, pre-treated with different surface treatments, then cemented to titanium abutment pins using 8 different cements: Maxcem Elite chroma (Kerr), TheraCem (Bisco), RelyX Unicem2 (3M ESPE), Multilink Automix (Ivoclar Vivadent), Panavia SA Cement Plus (Kuraray), Ceramir C&B (Doxa), CemEZ Universal (Zest Dental), and Bifix SE (VOCO). The partitally sintered zirconia specimens were divided according to design of experment (DOE). Zirconia surface treatments: 1) control group with no surface treatment, 2) airborne particle abrasion of fully sintered zirconia ring (FS-APA50), 3) airborne particle abrasion of partially sintered zirconia (PS-APA50), 4) tribochemical silica coating of fully sintered zirconia (FS-CoJet30), 5) tribochemical silica coating of partial sintered zirconia (PS-CoJet30), and 6) nano-structured alumina coating of fully sintered zirconia (NanoAl). Zirconia rings were subjected to post-treatment:1) control 24h incubation after cementing proceedure, and 2) accelerated aging . The pull-out axial tensile retention load was tested using an Instron Model 5566A. Multi factorial linear regression model (JMP Pro 15) was used for data analysis (α=0.05). RESULTS: The retention force (N) of zirconia rings to titanium abutment pins was evaluated using a pull-out test. Four key factors were investigated in this study: zirconia surface pre-treatment, cement type, post-treatment and firing effect. There was a significant effect of zirconia surface pre-treatment on retention force (nano-structured alumina coating ≥ tribochemical abrasion = airborne-particle abrasion ≥ control). There was a significant effect of cement type on retention force [Multilink AM ≥ (Cem EZ = TheraCem = Panivia SA = RelyX Unicem2 = BiFix) ≥ Ceramir CB = Maxcem Elite]. There is a significant difference in retention strength to zirconia among post-treatment effect, with accelerated aging groups achieving slightly higher bond strength than 24h water storage groups. CONCLUSIONS: Significant different retention loads were found among tested groups. Nano-structured alumina coating surface pre-treatment has significantly higher bond strength than other treatments. Some cement systems with functional monomer had significant higher bond strengths