Long chain branching in ethylene polymerization using constrained geometry metallocene catalyst

We report an experimental investigation on long chain branching (LCB) in ethylene polymerization with the Dow Chemical's constrained geometry catalyst system, CGC-Ti/TPFPB/MMAO, using a continuous stirred-tank reactor (CSTR) at 140°C, 3.45 × 10³ kPa, and a mean residence time (τ) of 4 min. The effects of the catalyst (CGC-Ti) and co-catalyst (TPFPB and MMAO) concentrations on the catalyst activity, polymer molecular weight, and shear thinning were systematically examined. The boron cocatalyst had a great influence on the CGC activity. Increasing the ratio TPFPB/CGC-Ti from 0.66 to 5 gave ethylene propagation rates from 1.65 × 10³ to 1.36 × 10⁴ L · mol⁻¹ · s⁻¹. The addition of MMAO appeared to be essential, most likely acting as an impurity scavenger. The LCB polyethylenes showed enhanced shear thinning properties. The melt flow index ratios I₁₀/I₂ were in the range of 6.96 to 23.4, with the I₂ of 0.172 to 0.681 g/10 min. The weight-average molecular weight M _w was correlated to I₂ using a power equation within narrow I₁₀/I₂ ranges. The exponential factors were in the range of 4.24 to 6.31. The experimental and calculated M _w's were in a good agreement.     

Methods for improving the yield and quality of metaphase preparations for FISH probing of human lymphocyte chromosomes

Procedures are described for the in vitro culture of human lymphocytes, which have been concentrated by density gradient centrifugation, and for a modified slide-making technique for the fixed cells. The method yields improved percentages of mitotic cells which are largely synchronized at harvest. Controlled placement of fixed cells on slides produces well-spread metaphase preparations with little background material to interfere with fluorescence in situ hybridization (FISH) probe procedures. The FISH reagents and microscope scanning time required are minimized by concentrating cells in a defined area of the slide. Environ. Mol. Mutagen. 29:98–104, 1997 © 1997 Wiley-Liss, Inc.     

Influence of Poor Oral Health on Physical Frailty: A Population‐Based Cohort Study of Older British Men

Objectives

To investigate the associations between objective and subjective measures of oral health and incident physical frailty.

Design

Cross‐sectional and longitudinal study with 3 years of follow‐up using data from the British Regional Heart Study.

Setting

General practices in 24 British towns.

Participants

Community‐dwelling men aged 71 to 92 (N = 1,622).

Measurements

Objective assessments of oral health included tooth count and periodontal disease. Self‐reported oral health measures included overall self‐rated oral health; dry mouth symptoms; sensitivity to hot, cold, and sweet; and perceived difficulty eating. Frailty was defined using the Fried phenotype as having 3 or more of weight loss, grip strength, exhaustion, slow walking speed, and low physical activity. Incident frailty was assessed after 3 years of follow‐up in 2014.

Results

Three hundred three (19%) men were frail at baseline (aged 71–92). Having fewer than 21 teeth, complete tooth loss, fair to poor self‐rated oral health, difficulty eating, dry mouth, and more oral health problems were associated with greater likelihood of being frail. Of 1,284 men followed for 3 years, 107 (10%) became frail. The risk of incident frailty was higher in participants who were edentulous (odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.03–3.52); had 3 or more dry mouth symptoms (OR = 2.03, 95% CI = 1.18–3.48); and had 1 (OR = 2.34, 95% CI = 1.18–4.64), 2 (OR = 2.30, 95% CI = 1.09–4.84), or 3 or more (OR = 2.72, 95% CI = 1.11–6.64) oral health problems after adjustment for age, smoking, social class, history of cardiovascular disease or diabetes mellitus, and medications related to dry mouth.

Conclusion

The presence of oral health problems was associated with greater risks of being frail and developing frailty in older age. The identification and management of poor oral health in older people could be important in preventing frailty.     

Perceived stigma, strain, and mental health among caregivers of veterans with traumatic brain injury

Background

Family caregivers of individuals with stigmatized conditions can experience stigma-by-association and discrimination. Moderate-to-severe traumatic brain injury (TBI) may elicit a stigma response if there are visible physical or neurobehavioral effects of the injury. Stigma is a considerable source of stress and may contribute to caregiver strain and stress-related mental health outcomes. We measured the frequency of perceived stigma and discrimination among caregivers of veterans with TBI and examined whether perceived stigma and discrimination are associated with caregiver strain, social isolation, depression, and anxiety.

Methods

Seventy caregivers of veterans with TBI completed a mailed survey that assessed perceptions of discrimination toward themselves or their care recipient, stigma associated with caregiving, and whether they felt the need to cover up or provide an explanation for their care recipient’s injury. Caregiver strain, social isolation, depression, and anxiety were also assessed via the questionnaire. Multivariate linear regression was used to test the associations between stigma and discrimination measures and outcomes, controlling for potential confounders and other caregiver or care recipient characteristics.

Results

Both perceptions of caregiver discrimination and stigma associated with caregiving were significantly associated with caregiver strain, social isolation, depression, and anxiety. Perceived discrimination against the individual with TBI was associated with caregiver strain and social isolation.

Conclusions

Our findings suggest that perceived discrimination and stigma experienced by caregivers of individuals with TBI are stressors that may lead to poor caregiver mental health outcomes. In order to promote both caregiver and care recipient health, we suggest that mental health support services consider these important stressors.     

Prognostic significance of alterations in KRAS isoforms KRAS‐4A/4B and KRAS mutations in colorectal carcinoma

Somatic KRAS mutation is an early well‐known event in colorectal carcinogenesis but a complete understanding of RAS function and dysfunction in colorectal cancer is still to come. Our aim was to study the incidence of KRAS mutation; KRAS splice variants: KRAS4A and KRAS4B; and their relationships with various clinico‐pathological characteristics in colorectal cancer (CRC).In this study, 285 CRC cases were analysed for KRAS mutation by direct DNA sequencing followed by immunohistochemical analysis after validation with real‐time PCR assay, to study the protein expression of KRAS4A and ‐4B isoforms. KRAS gene mutations were seen in 80/285 CRCs (28.1%) and of the mutated cases, the majority of the mutations were seen in codon 12 (81.2%) as opposed to codon 13 (18.8%). CRCs with KRAS mutations were associated with a poor overall survival (p = 0 . 0009). Furthermore, KRAS mutations at codon 12 were associated with a poor overall survival of 64.4% at 5 years compared with a 5‐year overall survival of 75.8% and 78.2% with codon 13 mutation and absence of KRAS mutations, respectively (p = 0 . 0025). KRAS4A protein expression was predominantly seen in the cytoplasm, while KRAS4B protein was nuclear. KRAS4A overexpression was significantly associated with left colon, histology subtype of adenocarcinoma, p27kip1, and cleaved caspase3 expression. Interestingly, KRAS4A overexpression was associated with a better overall survival (p = 0 . 0053). On the other hand, KRAS4B overexpression (33.2%) was significantly associated with larger tumour size (p = 0 . 0234) and inversely correlated with p27kip1 protein (p = 0 . 0159). Both KRAS mutation and KRAS4A were independent prognostic markers in a multivariate analysis with age, gender, stage, differentiation, and MSI status. Our results highlight the differential role of KRAS isoforms in CRC, their utility as a prognostic biomarker, and underline the importance of KRAS alterations as a potential therapeutic target for CRC. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells

ABT-737 is a small molecule Bcl-2 homology (BH)-3 domain mimetic that binds to the Bcl-2 family proteins Bcl-2 and Bcl-xL and is currently under investigation in the clinic. In this study, we investigated potential mechanisms of resistance to ABT-737 in leukemia cell lines. Compared with parental cells, cells that have developed acquired resistance to ABT-737 showed increased expression of Mcl-1 in addition to posttranslational modifications that facilitated both Mcl-1 stabilization and its interaction with the BH3-only protein Bim. To sensitize resistant cells, Mcl-1 was targeted by two pan-Bcl-2 family inhibitors, obatoclax and gossypol. Although gossypol was effective only in resistant cells, obatoclax induced cell death in both parental and ABT-737-resistant cells. NOXA levels were increased substantially by treatment with gossypol and its expression was critical for the gossypol response. Mechanistically, the newly generated NOXA interacted with Mcl-1 and displaced Bim from the Mcl-1/Bim complex, freeing Bim to trigger the mitochondrial apoptotic pathway. Together, our findings indicate that NOXA and Mcl-1 are critical determinants for gossypol-mediated cell death in ABT-737-resistant cells. These data therefore reveal novel insight into mechanisms of acquired resistance to ABT-737.     

Modulation of Radiation-induced Chromosome Aberrations by DMSO,an OH Radical Scavenger. 1: Dose—response Studies in Human Lymphocytes Exposed to 220 kV X-rays

Summary

Human G₀ lymphocytes were exposed to 220 kV X-radiation in the presence or absence of DMSO, an efficient selective scavenger of OH radicals. Our studies demonstrate that DMSO affects a concentration-dependent modulation of induced asymmetrical aberrations in human lymphocytes exposed to ～ 3·0 Gy, with maximum protectible fractions of approximately 70 percent at DMSO concentrations of ≥ 1 m. The dose dependency for dicentrics in lymphocytes acutely exposed to X-ray doses of 0·51 to 4·98 Gy in the absence of DMSO is adequately described by the linear-quadratic dose—response function Y = αD + βD². Data from duplicate cultures exposed in the presence of 1 m DMSO produce an excellent fit to the regression function modified as follows: where the ‘dose modifying’ factor Δ = 0·501. We interpret these findings as providing evidence that OH radical-mediated lesions in DNA account for ～ 50 percent of the dose dependency for dicentrics resulting from either one-track or two-track events, following exposures of non-cycling cells to moderate-to-high doses of low LET radiation. These data may be used in additional calculations to derive an estimate of ～ 6 × 10⁸ s^?1 for the rate of reaction of OH radicals with DNA targets involved in aberration formation.