Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking.

The factors that determine progression of cervical intraepithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is an independent risk factor for cervical neoplasia, suggesting that polymorphism at detoxicating enzyme loci such as cytochrome P450 CYP2D6 and glutathione S-transferase GSTM1 may determine susceptibility to these cancers. We have studied the frequencies of genotypes at these loci in women suffering low-grade CIN, high-grade CIN and SCC. A non-cancer control group was provided by women with normal cervical histology suffering menorrhagia. Comparison of the frequency distributions of the CYP2D6 PM, HET and EM genotypes (G-->A transition at intron 3/exon 4 and base pair deletion in exon 5) revealed no significant differences between the menorrhagia and SCC groups. Frequency distributions in the menorrhagia group, however, were significantly different (P < 0.04) from those in the low- and high-grade CIN groups. Thus, the proportion of EM was significantly larger (P < 0.03) and of HET generally lower. We found that the frequency of GSTM1 null in the menorrhagia and case groups was not significantly different. Interactive effects of enzyme genotypes with cigarette smoking were studied by comparing the multinomial frequency distributions of CYP2D6 EM/GSTM1 null/smoking over mutually exclusive categories. These showed no significant differences between the menorrhagia group and SCC or low-grade CIN groups. The frequency distribution in high-grade CIN, however, was significantly different to that in the menorrhagia group and in both SCC and low-grade CIN groups. This study was identified, for the first time, an inherited characteristic in women with high-grade CIN who appear to be at reduced risk of SCC. Thus, women with CYP2D6 EM who smoke have increased susceptibility to high-grade CIN but are less likely to progress to SCC, possibly because they effectively detoxify an unidentified chemical involved in mediating disease progression

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender.

The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours

Stratospheric ozone chemistry feedbacks are not critical for the determination of climate sensitivity in CESM1(WACCM)

The Community Earth System Model‐Whole Atmosphere Community Climate Model (CESM1‐WACCM) is used to assess the importance of including chemistry feedbacks in determining the equilibrium climate sensitivity (ECS). Two 4×CO2 model experiments were conducted: one with interactive chemistry and one with chemical constituents other than CO2 held fixed at their preindustrial values. The ECS determined from these two experiments agrees to within 0.01 K. Similarly, the net feedback parameter agrees to within 0.01 W m−2 K−1. This agreement occurs in spite of large changes in stratospheric ozone found in the simulation with interactive chemistry: a 30% decrease in the tropical lower stratosphere and a 40% increase in the upper stratosphere, broadly consistent with other published estimates. Off‐line radiative transfer calculations show that ozone changes alone account for the difference in radiative forcing. We conclude that at least for determining global climate sensitivity metrics, the exclusion of chemistry feedbacks is not a critical source of error in CESM

In search of lost time: age and the promise of induced pluripotent stem cell models of the brain

This paper explores the promise of induced pluripotent stem cells as a model system for the study of neurodegenerative diseases of Alzheimer’s, Parkinson’s and other diseases of the aging brain. Research in these areas, as in neuroscience more broadly, has struggled with the imperfect mapping between human and animal brains. The paper argues that the contemporary promise of induced pluripotent stem cells for research is established through their potential to resolve problems of translation, bridging laboratory and clinical contexts by acting as a model of “real” patient bodies. However, the paper shows how this promise is contested and renewed through a rearticulation of the relationship between neurodegeneration, aging and the qualities of “young” and “aged” bodies. This not only results in the introduction of new qualities and attributes to the model system, but also a re-imagining of how aging features within both late and early-onset neurological diseases.The research was funded through the NIHR Cambridge Biomedical Research Centre, a partnership between the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust

Impregnation and encapsulation of lightweight aggregates for self-healing concrete

This study investigated a technique of impregnating potential self-healing agents into lightweight aggregates (LWA) and the self-healing performance of concrete mixed with the impregnated LWA. Lightweight aggregates with a diameter range of 4–8 mm were impregnated with a sodium silicate solution as a potential self-healing agent. Concrete specimens containing the impregnated LWA and control specimens were pre-cracked up to 300 μm crack width at 7 days. Flexural strength recovery and reduction in water sorptivity were examined. After 28 days healing in water, the specimens containing the impregnated LWA showed ∼80% recovery of the pre-cracking strength, which accounts more than five times of the control specimens’ recovery. The capillary water absorption was also significantly improved; the specimens healed with the impregnated LWA showed a 50% reduction in the sorptivity index compared with the control cracked specimens and a very similar response to the control uncracked specimens. The contribution of sodium silicate in producing more calcium silicate hydrate gel was confirmed by characterisation the healing products using X-ray diffraction, Fourier transform spectroscopy, and scanning electron microscopy.Yousef Jameel Foundation through Cambridge Commonwealth, European & International Trust, Engineering and Physical Sciences Research Council (Project Ref. EP/K026631/1 – ‘‘Materials for Life”