As cancer cell populations evolve, they accumulate a number of somatic mutations, resulting in heterogeneous subclones in the final tumor. Understanding the mechanisms that produce intratumor ...heterogeneity is important for selecting the best treatment. Although some studies have involved intratumor heterogeneity simulations, their model settings differed substantially. Thus, only limited conditions were explored in each. Herein, we developed a general framework for simulating intratumor heterogeneity patterns and a simulator (tumopp). Tumopp offers many setting options so that simulations can be carried out under various settings. Setting options include how the cell division rate is determined, how daughter cells are placed, and how driver mutations are treated. Furthermore, to account for the cell cycle, we introduced a gamma function for the waiting time involved in cell division. Tumopp also allows simulations in a hexagonal lattice, in addition to a regular lattice that has been used in previous simulation studies. A hexagonal lattice produces a more biologically reasonable space than a regular lattice. Using tumopp, we investigated how model settings affect the growth curve and intratumor heterogeneity pattern. It was found that, even under neutrality (with no driver mutations), tumopp produced dramatically variable patterns of intratumor heterogeneity and tumor morphology, from tumors in which cells with different genetic background are well intermixed to irregular shapes of tumors with a cluster of closely related cells. This result suggests a caveat in analyzing intratumor heterogeneity with simulations with limited settings, and tumopp will be useful to explore intratumor heterogeneity patterns in various conditions.
The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and ...evaluated their clinicopathological impact.
Using immunohistochemistry, we examined tumour-infiltrating CD68(+) pan-macrophages, HLA-DR(+)CD68(+) M1 macrophages (M1), CD163(+) or CD204(+) M2 macrophages (M2), CD66b(+) neutrophils (Neu), CD4(+) T cells (CD4(+)T), CD8(+) T cells (CD8(+)T), and FOXP3(+)CD4(+) regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan-Meier method and Cox proportional hazards model.
Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4(+)T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4(+)T, CD8(+)T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and tumour-infiltrating %M1(high)/M2(low). Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio.
Tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and %M1(high)/M2(low) are independent prognosticators useful for evaluating the immune microenvironment of PDC.
•Worldwide there is increasing reliance and concern for pollinators, primarily bees•Wild bees may be threatened by habitat loss, pathogens, and perhaps managed bees•The literature supports ...significant evidence for competition from managed bees•However, the factors affecting bee competition need be examined in context•Conserving pollinators requires action that focuses less on managed species
Worldwide, the use of managed bees for crop pollination and honey production has increased dramatically. Concerns about the pressures of these increases on native ecosystems has resulted in a recent expansion in the literature on this subject. To collate and update current knowledge, we performed a systematic review of the literature on the effects of managed and introduced bees on native ecosystems, focusing on the effects on wild bees. To enable comparison over time, we used the same search terms and focused on the same impacts as earlier reviews. This review covers: (a) interference and resource competition between introduced or managed bees and native bees; (b) effects of introduced or managed bees on pollination of native plants and weeds; and (c) transmission and infectivity of pathogens; and classifies effects into positive, negative, or neutral. Compared to a 2017 review, we found that the number of papers on this issue has increased by 47%. The highest increase was seen in papers on pathogen spill-over, but in the last five years considerable additional information about competition between managed and wild bees has also become available. Records of negative effects have increased from 53% of papers reporting negative effects in 2017 to 66% at present. The majority of these studies investigated effects on visitation and foraging behaviour. While only a few studies experimentally assessed impacts on wild bee reproductive output, 78% of these demonstrated negative effects. Plant composition and pollination was negatively affected in 7% of studies, and 79% of studies on pathogens reported potential negative effects of managed or introduced bees on wild bees. Taken together, the evidence increasingly suggests that managed and introduced bees negatively affect wild bees, and this knowledge should inform actions to prevent further harm to native ecosystems.
To contribute to evidence-based policy decision making for national cancer control, we conducted a systematic assessment to estimate the current burden of cancer attributable to known preventable ...risk factors in Japan in 2005.
We first estimated the population attributable fractions (PAFs) of each cancer attributable to known risk factors from relative risks derived primarily from Japanese pooled analyses and large-scale cohort studies and the prevalence of exposure in the period around 1990. Using nationwide vital statistics records and incidence estimates, we then estimated the attributable cancer incidence and mortality in 2005.
In 2005, ∼55% of cancer among men was attributable to preventable risk factors in Japan. The corresponding figure was lower among women, but preventable risk factors still accounted for nearly 30% of cancer. In men, tobacco smoking had the highest PAF (30% for incidence and 35% for mortality, respectively) followed by infectious agents (23% and 23%). In women, in contrast, infectious agents had the highest PAF (18% and 19% for incidence and mortality, respectively) followed by tobacco smoking (6% and 8%).
In Japan, tobacco smoking and infections are major causes of cancer. Further control of these factors will contribute to substantial reductions in cancer incidence and mortality in Japan.
Recently, the concept of oral frailty, defined as accumulated deficits in oral health, has been introduced in Japan. However, data about its association with nutritional status are limited. Thus, ...this cross-sectional study aimed to investigate the association between oral frailty and malnutrition among community-dwelling older adults.
Cross-sectional study.
Community.
One thousand and fifty-four individuals (428 men and 626 women, mean age: 77.0 years) from the Takashimadaira Study.
Based on a multifaceted oral health assessment, oral frailty was defined as greater than or equal to three of the following components: (1) low number of remaining teeth, (2) decreased masticatory performance, (3) reduced articulatory oral motor skill, (4) low tongue pressure, and difficulties in (5) eating and (6) swallowing. The nutritional status was evaluated using the Mini Nutritional Assessment®-Short Form (MNA®-SF) and serum albumin. An ordinal logistic regression model was used to evaluate the association between oral frailty and nutritional status.
Oral frailty was observed in 217 (20.4%) participants. After adjusting for potential confounders, the participants with oral frailty had higher odds of more severe malnutrition evaluated using MNA®-SF (adjusted odds ratio: 2.17; 95% confidence interval: 1.58-2.98) and serum albumin level (adjusted odds ratio: 1.59; 95% confidence interval: 1.10-2.31).
Oral frailty was associated with nutritional status among Japanese older adults. Maintaining comprehensive oral health and function may be effective for malnutrition prevention in community-dwelling older adults. However, further studies must be conducted to validate the generalizability of the results of the current study.
Although neuroimaging plays an important role in the diagnosis of idiopathic normal pressure hydrocephalus, its predictive value for response to shunt surgery has not been established. The purpose of ...the current study was to identify neuroimaging markers that predict the shunt response of idiopathic normal pressure hydrocephalus.
Sixty patients with idiopathic normal pressure hydrocephalus underwent presurgical brain MR imaging and clinical evaluation before and 1 year after shunt surgery. The assessed MR imaging features included the Evans index, high-convexity tightness, Sylvian fissure dilation, callosal angle, focal enlargement of the cortical sulci, bumps in the lateral ventricular roof, and deep white matter and periventricular hyperintensities. The idiopathic normal pressure hydrocephalus grading scale total score was used as a primary clinical outcome measure. We used measures for individual symptoms (ie, the idiopathic normal pressure hydrocephalus grading scale subdomain scores, such as gait, cognitive, and urinary scores), the Timed Up and Go test, and the Mini-Mental State Examination as secondary clinical outcome measures. The relationships between presurgical neuroimaging features and postoperative clinical changes were investigated by using simple linear regression analysis. To identify the set of presurgical MR imaging features that best predict surgical outcomes, we performed multiple linear regression analysis by using a bidirectional stepwise method.
Simple linear regression analyses demonstrated that presurgical high-convexity tightness, callosal angle, and Sylvian fissure dilation were significantly associated with the 1-year changes in the clinical symptoms. A multiple linear regression analysis demonstrated that presurgical high-convexity tightness alone predicted the improvement of the clinical symptoms 1 year after surgery.
High-convexity tightness is a neuroimaging feature predictive of shunt response in idiopathic normal pressure hydrocephalus.
The domestication process of plants and animals typically involves intense inbreeding and directional selection for various traits. Here, we genotyped 370 Japanese Thoroughbred horses using the ...recently developed 670k SNP array and performed various genome-wide analysis also using genotype data of other horse breeds. We identified a number of regions showing interesting patterns of polymorphisms. For instance, the region containing the MC1R locus associated with chestnut coat color may have been targeted by selection for a different mutation much earlier on than the recent selection for chestnut color. We also identified regions that show signatures of selection specific to Thoroughbreds. In addition, we found that intense inbreeding early in the history of the Thoroughbred breed and also before the formation of the breed has a significant impact on the genomic architecture of modern Thoroughbreds. Our study demonstrates that the horse 670k array can be utilized to gain important insight into the domestication process of horses and to understand the genetic basis of the phenotypic diversity in horses.
Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in ...cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma.
The incidence of prostate cancer is much lower in Asian than Western populations. Given that environmental factors such as dietary habits may play a major role in the causation of prostate cancer and ...the high consumption of green tea in Asian populations, this low incidence may be partly due to the effects of green tea. The JPHC Study (Japan Public Health Center-based Prospective Study) was established in 1990 for cohort I and in 1993 for cohort II. The subjects were 49,920 men aged 40–69 years who completed a questionnaire that included their green tea consumption habit at baseline and were followed until the end of 2004. During this time, 404 men were newly diagnosed with prostate cancer, of whom 114 had advanced cases, 271 were localized, and 19 were of an undetermined stage. Green tea was not associated with localized prostate cancer. However, consumption was associated with a dose-dependent decrease in the risk of advanced prostate cancer. The multivariate relative risk was 0.52 (95% confidence interval: 0.28, 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (ptrend = 0.01). Green tea may be associated with a decreased risk of advanced prostate cancer.
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