Summary Background Colorectal cancer is the third most common cancer worldwide. Previous analyses have only reported follow-up after flexible sigmoidoscopy for a maximum of 12 years. We aimed to ...examine colorectal cancer incidence and mortality after a single flexible sigmoidoscopy screening and 17 years of follow-up. Methods In this multicentre randomised trial (UK Flexible Sigmoidoscopy Screening Trial), done between Nov 14, 1994, and March 30, 1999, 170 432 eligible men and women, who had indicated on a previous questionnaire that they would probably attend screening if invited, were randomly assigned (1:2) to an intervention group (offered flexible sigmoidoscopy screening) or a control group (not contacted). Randomisation was done centrally in blocks of 12, and stratified by trial centre, general practice, and household type. The nature of the intervention did not allow the staff to be masked to arm of the trial; however, randomisation was done in batches so that the control group and participants not yet randomised were unaware of their allocation status. The primary outcomes were incidence and mortality of colorectal cancer. Hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality were estimated for intention-to-treat and per-protocol analyses. The trial is registered with ISRCTN, number 28352761. Findings Our cohort analysis included 170 034 people: 112 936 in the control group and 57 098 in the intervention group, 40 621 (71%) of whom were screened and 16 477 (29%) were not screened. During screening and a median of 17·1 years' follow-up, colorectal cancer was diagnosed in 1230 individuals in the intervention group and 3253 in the control group, and 353 individuals in the intervention group versus 996 individuals in the control group died from colorectal cancer. In intention-to-treat analyses, colorectal cancer incidence was reduced by 26% (HR 0·74 95% CI 0·70–0·80; p<0·0001) in the intervention group versus the control group and colorectal cancer mortality was reduced by 30% (0·70 0·62–0·79; p<0·0001) in the intervention group versus the control group. In per-protocol analyses, adjusted for non-compliance, colorectal cancer incidence and mortality were 35% (HR 0·65 95% CI 0·59–0·71) and 41% (0·59 0·49–0·70) lower in the screened group. Interpretation A single flexible sigmoidoscopy continues to provide substantial protection from colorectal cancer diagnosis and death, with protection lasting at least 17 years. Funding National Institute for Health Research Efficacy and Mechanism Evaluation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Background Country comparisons that consider the effect of fatal and non-fatal disease outcomes are needed for health-care planning. We calculated disability-adjusted life-years (DALYs) to ...estimate the global burden of cancer in 2008. Methods We used population-based data, mostly from cancer registries, for incidence, mortality, life expectancy, disease duration, and age at onset and death, alongside proportions of patients who were treated and living with sequelae or regarded as cured, to calculate years of life lost (YLLs) and years lived with disability (YLDs). We used YLLs and YLDs to derive DALYs for 27 sites of cancers in 184 countries in 12 world regions. Estimates were grouped into four categories based on a country's human development index (HDI). We applied zero discounting and uniform age weighting, and age-standardised rates to enable cross-country and regional comparisons. Findings Worldwide, an estimated 169·3 million years of healthy life were lost because of cancer in 2008. Colorectal, lung, breast, and prostate cancers were the main contributors to total DALYs in most world regions and caused 18–50% of the total cancer burden. We estimated an additional burden of 25% from infection-related cancers (liver, stomach, and cervical) in sub-Saharan Africa, and 27% in eastern Asia. We noted substantial global differences in the cancer profile of DALYs by country and region; however, YLLs were the most important component of DALYs in all countries and for all cancers, and contributed to more than 90% of the total burden. Nonetheless, low-resource settings had consistently higher YLLs (as a proportion of total DALYs) than did high-resource settings. Interpretation Age-adjusted DALYs lost from cancer are substantial, irrespective of world region. The consistently larger proportions of YLLs in low HDI than in high HDI countries indicate substantial inequalities in prognosis after diagnosis, related to degree of human development. Therefore, radical improvement in cancer care is needed in low-resource countries. Funding Dutch Scientific Society, Erasmus University Rotterdam, and International Agency for research on Cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Interest is growing in the use of macrocycles in pharmaceutical discovery. Macrocylization may provide a gateway to an expanded chemical space for small-molecule drug discovery, and this could be ...beneficial in prosecuting difficult targets, e.g., protein–protein interactions. Most, but not all, macrocycle drugs are derived from natural products. Studies on synthetic drug-like small-molecule macrocycles are limited, and our current understanding of macrocycle drugs is similarly limited. Following some background discussion, we review several examples of the structure-based design of synthetic macrocycles. Our opinion is that in conformationally suitable systems macrocycles are an analog class worthy of consideration. We then summarize an approach for the initial evaluation of molecules as candidates for macrocyclization.
The mechanisms and efficiency of charge transport in lithium peroxide (Li sub(2)O sub(2)) are key factors in understanding the performance of non-aqueous Li-air batteries. Towards revealing these ...mechanisms, here we use first-principles calculations to predict the concentrations and mobilities of charge carriers and intrinsic defects in Li sub(2)O sub(2) as a function of cell voltage. Our calculations reveal that changes in the charge state of O sub(2) dimers controls the defect chemistry and conductivity of Li sub(2)O sub(2). Negative lithium vacancies (missing Li super(+)) and small hole polarons are identified as the dominant charge carriers. The electronic conductivity associated with polaron hopping (5 10 super(-20) S cm super(-1)) is comparable to the ionic conductivity arising from the migration of Li-ions (4 10 super(-19) S cm super(-1)), suggesting that charge transport in Li sub(2)O sub(2) occurs through a mixture of ionic and polaronic contributions. These data indicate that the bulk regions of crystalline Li sub(2)O sub(2) are insulating, with appreciable charge transport occurring only at moderately high charging potentials that drive partial delithiation. The implications of limited charge transport on discharge and recharge mechanisms are discussed, and a two-stage charging process linking charge transport, discharge product morphology, and overpotentials is described. We conclude that achieving both high discharge capacities and efficient charging will depend upon access to alternative mechanisms that bypass bulk charge transport. More generally, we describe how the presence of a species that can change charge state - e.g., O sub(2) dimers in alkaline metal-based peroxides - may impact rechargeability in metal-air batteries.
Many layered oxide and sulfide intercalation compounds used in secondary batteries undergo stacking-sequence-change phase transformations during (de)intercalation. However, the underlying reasons ...why different intercalants result in different stacking-sequence changes are not well understood. This work reports on high-throughput density functional theory calculations on the prototype systems A x CoO2 and A x TiS2 (where A = Li, Na, K, Mg, and Ca), which show that a few simple rules explain the relative stability among the O1, O3, and P3 stacking sequences. First, for large intercalants (Na, K, and Ca), P3 stacking is favorable at intermediate concentrations (x ∼ 0.5) as its intercalant site topology minimizes in-plane electrostatic repulsion. At the extreme compositions (x ∼ 0 and x ∼ 1), O1 or O3 are stable, with more ionic compounds preferring O3 and covalent ones O1. These rules explain why stacking-sequence changes are much more common in Na materials than Li ones.
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IJS, KILJ, NUK, PNG, UL, UM
On the basis of current evidence regarding human papillomavirus (HPV) and cancer, this chapter provides estimates of the global burden of HPV-related cancers, and the proportion that are actually ...“caused” by infection with HPV types, and therefore potentially preventable. We also present trends in incidence and mortality of these cancers in the past, and consider their likely future evolution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun ...to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo . Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, to extracellular matrix (ECM) and cell–cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here, we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study ...demonstrates how the same activating principles used for decades to make simple C–N (amide) bonds from carboxylic acids with loss of water can be used to make C–C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Fibroblast growth factor (FGF)21 is an endocrine hormone that is expressed in multiple tissues and functions physiologically to maintain energy homeostasis. FGF21 is being pursued as a therapeutic ...target for diabetes and obesity because of its rapid and potent effects on improving insulin sensitivity. However, whether FGF21 enhances insulin sensitivity under physiologic conditions remains unclear. Here, we show that liver-derived FGF21 enters the circulation during fasting but also remains present and functional during the early stage of refeeding. After a prolonged fast, FGF21 acts as an insulin sensitizer to overcome the peripheral insulin resistance induced by fasting, thereby maximizing glucose uptake. Likewise, FGF21 is produced from the liver during overfeeding and mitigates peripheral insulin resistance. DIO FGF21 liver-specific knockout, but not FGF21 adipose-specific knockout, mice have increased insulin resistance and decreased brown adipose tissue-mediated glucose disposal. These data are compatible with the concept that FGF21 functions physiologically as an insulin sensitizer under conditions of acute refeeding and overfeeding.
Background The decision as to whether a patient can tolerate surgery is often subjective and can misjudge a patient's true physiologic state. The concept of frailty is an important assessment tool in ...the geriatric medical population, but has only recently gained attention in surgical patients. Frailty potentially represents a measureable phenotype, which, if quantified with a standardized protocol, could reliably estimate the risk of adverse surgical outcomes. Study Design Frailty was prospectively evaluated in the clinic setting in patients consenting for major general, oncologic, and urologic procedures. Evaluation included an established assessment tool (Hopkins Frailty Score), self-administered questionnaires, clinical assessment of performance status, and biochemical measures. Primary outcome was 30-day postoperative complications. Results There were189 patients evaluated: 117 from urology, 52 from surgical oncology, and 20 from general surgery clinics. Mean age was 62 years, 59.8% were male, and 71.4% were Caucasian. Patients who scored intermediately frail or frail on the Hopkins Frailty Score were more likely to experience postoperative complications (odds ratio OR 2.07, 95% CI 1.05 to 4.08, p = 0.036). Of all other preoperative assessment tools, only higher hemoglobin (p = 0.033) had a significant association and was protective for 30-day complications. Conclusions The aggregate score of patients as “intermediately frail or frail” on the Hopkins Frailty Score was predictive of a patient experiencing a postoperative complication. This preoperative assessment tool may prove beneficial when weighing the risks and benefits of surgery, allowing objective data to guide surgical decision-making and patient counseling.
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