An Application of the Multi-Level Heuristic for the Heterogeneous Fleet Vehicle Routing Problem

The Multi-Level heuristic is used to investigate the heterogeneous fleet vehicle routing problem (HFVRP). The initial solution for the Multi-Level heuristic is obtained by Dijkstra\u27s algorithm based on a cost network constructed by the sweep algorithm and the 2-opt procedure. The proposed algorithm uses a number of local search operators such as swap, 1-0 insertion, 2-opt, and Dijkstra\u27s Algorithm. In addition, in order to improve the search process, a diversification procedure is applied. The proposed algorithm is thentested on the data sets from the literature

Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts

Evidence on the association between mode of delivery and asthma at school age is inconclusive. We assessed the associations between specific modes of delivery and asthma in children from 9 European birth cohorts that enrolled participants between 1996 and 2006. Cohort-specific crude and adjusted risk ratios for asthma at ages 5–9 years were calculated using Poisson regression models and pooled. A sensitivity analysis was carried out in children born at term to reduce confounding due to perinatal factors. The study included 67,613 participants. Cohortspecific rates of cesarean delivery varied from 9.4% to 37.5%. Cesarean delivery, as opposed to vaginal delivery, was associated with an increased risk of asthma (adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.02, 1.46). Compared with spontaneous vaginal delivery, the adjusted risk ratio was 1.33 (95% CI: 1.02, 1.75) for elective cesarean delivery, 1.07 (95% CI: 0.94, 1.22) for emergency cesarean delivery, and 0.97 (95% CI: 0.84, 1.12) for operative vaginal delivery. In children born at term, the associations were strengthened only for elective cesarean delivery (aRR = 1.49, 95% CI: 1.13, 1.97). The large sample size allowed analysis of the associations between specific modes of delivery and asthma at school age. The increased risk of asthma associated with elective cesarean delivery, especially among children born at term, is relevant in counteracting the increasing use of this procedure, which is often performed without a clear medical indication.This work was supported by the European Community’s Seventh Framework Programme (FP7/2009–2013) under a grant agreement (grant 241604) and by the University of Turin and the San Paolo Foundation (Turin, Italy). Data collection was funded and the study teams of all participating birth cohorts were supported by local and/or national research organizations

Identification of biomarkers in ductal carcinoma in situ of the breast with microinvasion

<p>Abstract</p> <p>Background</p> <p>Widespread use of mammography in breast cancer screening has led to the identification of increasing numbers of patients with ductal carcinoma <it>in situ </it>(DCIS). DCIS of the breast with an area of focal invasion 1 mm or less in diameter is defined as DCIS with microinvasion, DCIS-Mi. Identification of biological differences between DCIS and DCIS-Mi may aid in understanding of the nature and causes of the progression of DCIS to invasiveness.</p> <p>Methods</p> <p>In this study, using resected breast cancer tissues, we compared pure DCIS (52 cases) and DCIS-Mi (28 cases) with regard to pathological findings of intraductal lesions, biological factors, apoptosis-related protein expression, and proliferative capacity through the use of immunohistochemistry and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method.</p> <p>Results</p> <p>There were no differences in biological factors between DCIS and DCIS-Mi, with respect to levels of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The frequency of necrosis and positive expression ratio of survivin and Bax were significantly higher in DCIS-Mi than in DCIS. In addition, apoptotic index, Ki-67 index, and positive Bcl-2 immunolabeling tended to be higher in DCIS-Mi than in DCIS. Multivariate analysis revealed that the presence of necrosis and positive survivin expression were independent factors associated with invasion.</p> <p>Conclusion</p> <p>Compared with DCIS, DCIS-Mi is characterized by a slightly elevated cell proliferation capacity and enhanced apoptosis within the intraductal lesion, both of which are thought to promote the formation of cell necrotic foci. Furthermore, the differential expression of survivin may serve in deciding the response to therapy and may have some prognostic significance.</p

Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA

Expression of hypoxia-inducible factor-1α and cell cycle proteins in invasive breast cancer are estrogen receptor related

BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. Previous studies showed that concentrations of its subunit HIF-1α, as a surrogate for HIF-1 activity, are increased during breast carcinogenesis and can independently predict prognosis in breast cancer. During carcinogenesis, the cell cycle is progressively deregulated, and proliferation rate is a strong prognostic factor in breast cancer. In this study we undertook a detailed evaluation of the relationships between HIF-1α and cell cycle-associated proteins. METHODS: In a representative estrogen receptor (ER) group of 150 breast cancers, the expression of HIF-1α, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, cyclin A, cyclin D(1), p21, p53, and Bcl-2 was investigated by immunohistochemistry. RESULTS: High concentrations (5% or more) of HIF-1α were associated with increased proliferation as shown by positive correlations with Ki-67 (P < 0.001) and the late S–G2-phase protein cyclin A (P < 0.001), but not with the G1-phase protein cyclin D(1). High HIF-1α concentrations were also strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression (P = 0.013). No association was found between p21 and HIF-1α (P = 0.105) in the whole group of patients. However, the subgroup of ER-positive cancers was characterized by a strong positive association between HIF-1α and p21 (P = 0.023), and HIF-1α lacked any relation with proliferation. CONCLUSION: HIF-1α overexpression is associated with increased proliferation, which might explain the adverse prognostic impact of increased concentrations of HIF-1α in invasive breast cancer. In ER-positive tumors, HIF-1α is associated with p21 but not against proliferation. This shows the importance of further functional analysis to unravel the role of HIF-1 in late cell cycle progression, and the link between HIF-1, p21, and ER

Differential expression of MUC genes in endometrial and cervical tissues and tumors

BACKGROUND: Mucin glycoprotein's are major components of mucus and are considered an important class of tumor associated antigens. The objective of this study was to investigate the expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8) in human endometrium and cervix, and to compare and quantitate the expression of MUC genes in normal and cancerous tissues. METHODS: Slot blot techniques were used to study the MUC gene expression and quantitation. RESULTS: Of the five-mucin genes studied, MUC1, MUC5B and MUC8 showed high expression levels in the normal and cancerous endometrial and cervical tissues, MUC2 and MUC5AC showed considerably lower expression. Statistically, higher levels of MUC1, MUC5B and MUC8 were observed in endometrial adenocarcinomas compared to normal tissues. In contrast, only MUC1 levels increased with no significant changes in expression of MUC5B and MUC8 in cervical tumors over normal cervical tissues. CONCLUSION: Endometrial tumors showed increased expression of MUC1, MUC5B and MUC8 over normal tissues. Only MUC1 appears to be increase, in cervical tumors. All the studied tissues showed high and consistent expression of MUC8 mRNA. Low to neglible levels of MUC2 and MUC5AC were observed in all studied endometrial and cervical tissues

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births

Background. Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings. We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers’ median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02–1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02–1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07–2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35–1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52–2.34] instead of OR 2.20 [95% CI 2.02–2.42] when reducing from 5–9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39–3.25] and OR 1.93 [95% CI 1.46–2.57] instead of OR 2.95 [95% CI 2.75–3.15] when reducing from ≥10 to 5–9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16–1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions. We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.This collaborative project received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle). EMP and LT were supported by grant R01ES022972 from the National Institutes of Health, USA. LC was supported by the National Institute for Environmental Health Sciences: P30ES007048, R21ES029681, R01ES029944, R01ES030364, R21ES028903. DAL works in a unit that receives UK MRC funding (MC_UU_12013/5) and is an NIHR senior investigator (NF-SI-0611-10196). ACS holds an FCT Investigator contract IF/01060/2015. RG received funding from the Dutch Heart Foundation (grant number 2017T013), the Dutch Diabetes Foundation (grant number 2017.81.002) and the Netherlands Organization for Health Research and Development (ZonMW, 543003109). VWVJ received grant from the European Research Council (Consolidator Grant, ERC-2014-CoG-648916)

Impact of maternal body mass index and gestational weight gain on pregnancy complications : an individual participant data meta-analysis of European, North American and Australian cohorts

Objective To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. Design Individual participant data meta-analysis of 39 cohorts. Setting Europe, North America, and Oceania. Population 265 270 births. Methods Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. Main outcome measures Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. Results Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. Conclusions Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity.Peer reviewe