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Purpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers.Experimental Design: Three patients were vaccinated with 1.0 × 108 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro.Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent.Conclusion: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR.

Supplementary Figure 1. Frequency of myeloid derived suppressor cells in the peripheral blood in patients pre and post vaccination with p53MVA

Objective. To investigate the relationship between quantitative parameters of echocardiography and vascular endothelial function in patients with chronic heart failure (CHF) and the predictive value of short-term major adverse cardiovascular events (MACE). Methods. From February 2018 to February 2020, 86 CHF patients in our hospital were selected as the observation group, and 46 healthy subjects were selected as the control group during the same period. Quantitative parameters of echocardiography (left ventricular ejection fraction (LVEF), left ventricular short-axis shortening rate (FS), and ratio of peak flow velocity between early and late mitral valve diastole (E/A)) and endothelial function indexes (endothelin-1 (ET-1)/nitric oxide (NO)) were compared between the two groups. The correlation between quantitative parameters of echocardiography and vascular endothelial function in patients with CHF was analyzed. A logistic regression equation was used to analyze the risk factors of MACE in patients with CHF. The receiver operating characteristic curve (ROC) was used to analyze the predictive value of quantitative parameters of echocardiography and NO/ET-1 for the risk of MACE in patients with CHF. Result. LVEF, FS, and NO/ET-1 in the observation group were lower than those in the control group, while E/A was higher than that in the control group ( P < 0.05 ). In CHF patients, LVEF and FS were positively correlated with NO/ET-1, while E/A was negatively correlated with NO/ET-1 ( P < 0.05 ). Logistic regression analysis showed that the decrease of LVEF, FS, NO/ET-1, and E/A were risk factors for MACE ( P < 0.05 ) after adjusting for age, body mass index, and cardiac function grading. The AUC value of short-term MACE predicted by quantitative parameters of echocardiography and NO/ET-1 combined was 0.883, with a corresponding sensitivity of 86.21% and specificity of 73.13%. Conclusion. Quantitative parameters of echocardiography in CHF patients are related to vascular endothelial function, and their combination can effectively predict the risk of MACE in the near future, providing reference for clinical treatment.

PURPOSE To explore the short-term changes after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) in patients with hypertrophic obstructive cardiomyopathy (HOCM), using quantitative analysis of two-dimensional speckle tracking imaging (2D-STI). METHODS This prospective self-controlled study included 30 HOCM patients treated with PIMSRA. The study for each patient spanned over at least 1 year. Interventricular septal thickness and the left ventricular outflow tract peak pressure gradient (LVOT-PG) were measured through echocardiography, and 2D-STI was used to evaluate the left ventricular (LV) systolic function and synchrony. Cardiac function was assessed using the New York Heart Association's (NYHA) functional classification for cardiac disease, and through the serum levels of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Biomarkers procollagen type I carboxy-terminal propeptide (PICP) and matrix metalloproteinases-2 (MMP-2) were detected for noninvasive assessment of myocardial fibrosis. RESULTS The patients' interventricular septal thickness, LVOT-PG, NYHA class, and plasma PICP and MMP-2 levels at the first month postoperatively were significantly lower than before operation (all P

BackgroundPathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2,MSH6andPMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes.MethodsAmong 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance ofTCLRin combination within silicopredictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed.ResultsCompared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (pTCLRalone. Models leveragingin silicoscores as prior probabilities accurately classified >76.7% variants. AddingTCLRas quantitative evidence in an MVP model (MVP +TCLRPred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLRPredresulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.ConclusionOur study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.

Objective: To evaluate the clinical efficacy of percutaneous coronary intervention (PCI) on patients with acute myocardial infarction (AMI) complicated with multiple organ dysfunction syndrome (MODS). Methods: A total of 216 patients with AMI complicated with MODS enrolled from January 2016 to March 2018 were divided into a PCI group (n=98) and a drug treatment group (n=118). The baseline clinical data, the incidence of each dysfunction organ, the number of dysfunctional organs and the mortality were compared between the two groups. Results: The number of patients with ST-segment elevation AMI in the PCI group was higher than in the drug treatment group, and the rate of patients with non-ST-segment elevation AMI was lower than in the drug treatment group (P0.05). The recanalization rate in PCI group was much higher than that in the drug treatment group (P

Objective: To evaluate the clinical efficacy of percutaneous coronary intervention (PCI) on patients with acute myocardial infarction (AMI) complicated with multiple organ dysfunction syndrome (MODS). Methods: A total of 216 patients with AMI complicated with MODS enrolled from January 2016 to March 2018 were divided into a PCI group (n=98) and a drug treatment group (n=118). The baseline clinical data, the incidence of each dysfunction organ, the number of dysfunctional organs and the mortality were compared between the two groups. Results: The number of patients with ST-segment elevation AMI in the PCI group was higher than in the drug treatment group, and the rate of patients with non-ST-segment elevation AMI was lower than in the drug treatment group (P0.05). The recanalization rate in PCI group was much higher than that in the drug treatment group (P

Many in silico predictors of genetic variant pathogenicity have been previously developed, but there is currently no standard application of these algorithms for variant assessment. Using 4,094 ClinVar-curated missense variants in clinically actionable genes, we evaluated the accuracy and yield of benign and deleterious evidence in 5 in silico meta-predictors, as well as agreement of SIFT and PolyPhen2, and report the derived thresholds for the best performing predictor(s). REVEL and BayesDel outperformed all other meta-predictors (CADD, MetaSVM, Eigen), with higher positive predictive value, comparable negative predictive value, higher yield, and greater overall prediction performance. Agreement of SIFT and PolyPhen2 resulted in slightly higher yield but lower overall prediction performance than REVEL or BayesDel. Our results support the use of gene-level rather than generalized thresholds, when gene-level thresholds can be estimated. Our results also support the use of 2-sided thresholds, which allow for uncertainty, rather than a single, binary cut-point for assigning benign and deleterious evidence. The gene-level 2-sided thresholds we derived for REVEL or BayesDel can be used to assess in silico evidence for missense variants in accordance with current classification guidelines.

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher’s exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86–1.36, p = 0.21–0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.

To observe and analyze the clinical efficacy and ultrasound detection results of treatment of hypertensive patients with heart disease with valsartan combined with hydrochlorothiazide. The 160 hypertensive patients with heart disease who were treated in our hospital were selected as study subjects and randomly divided into study group and reference group, each with 80 patients. Where, the reference group was solely treated with valsartan, while the study group received hydrochlorothiazide treatment on this basis. The therapeutic effects of the two groups were observed and analyzed. Comparison of the overall treatment efficacy and incidence of adverse reactions between the two groups showed that the study group had more significant advantages than the reference group, P0.05; in comparison of systolic blood pressure and diastolic blood pressure after treatment between the two groups, the study group had higher improvement degree than the reference group, P0.05; ultrasonic ECG inspection showed that the study group was superior to the reference group with better recovery in indexes including left ventricular mass index, left ventricular posterior wall thickness, left ventricular ejection fraction, P0.05. The combination of Valsartan and hydrochlorothiazide for hypertensive patients with heart disease can significantly improve the treatment effect and significantly reduce the incidence of adverse reactions. Therefore, it is worthy of popularization and application.

Modern systems are increasingly dependent upon and interacting with each other, and become interdependent networks. These interdependent networks may exhibit some interesting and even surprising behaviors due to the interdependency and the interplay between the constituent systems. In this article we focus on two important phenomena, namely cascading failure in cyber-physical systems (CPS) and information cascade in coupled social networks. Specifically, cascading failures may occur in CPS that exhibit functional interdependency between two constituent systems (e.g. smart grid); information cascade may happen in multiple social networks that are coupled together by so-called multi-membership individuals. This article explores these two types of cascading effects in interdependent networks by reviewing existing studies in the literature. We review different models in the literature to study the two types of cascading effects in interdependent networks, and highlight the key findings from these studies.

Fluorescence-activated cell sorting (FACS) is an essential tool for studies requiring isolation of distinct intestinal epithelial cell populations. Inconsistent or lack of reporting of the critical parameters associated with FACS methodologies has complicated interpretation, comparison, and reproduction of important findings. To address this problem a comprehensive multicenter study was designed to develop guidelines that limit experimental and data reporting variability and provide a foundation for accurate comparison of data between studies. Common methodologies and data reporting protocols for tissue dissociation, cell yield, cell viability, FACS, and postsort purity were established. Seven centers tested the standardized methods by FACS-isolating a specific crypt-based epithelial population (EpCAM+/CD44+) from murine small intestine. Genetic biomarkers for stem/progenitor (Lgr5 and Atoh 1) and differentiated cell lineages (lysozyme, mucin2, chromogranin A, and sucrase isomaltase) were interrogated in target and control populations to assess intra- and intercenter variability. Wilcoxon's rank sum test on gene expression levels showed limited intracenter variability between biological replicates. Principal component analysis demonstrated significant intercenter reproducibility among four centers. Analysis of data collected by standardized cell isolation methods and data reporting requirements readily identified methodological problems, indicating that standard reporting parameters facilitate post hoc error identification. These results indicate that the complexity of FACS isolation of target intestinal epithelial populations can be highly reproducible between biological replicates and different institutions by adherence to common cell isolation methods and FACS gating strategies. This study can be considered a foundation for continued method development and a starting point for investigators that are developing cell isolation expertise to study physiology and pathophysiology of the intestinal epithelium.

We study the diffusion behavior of real-time information in an overlaying social-physical network. Typically, real-time information is valuable only for a limited time duration and needs to be delivered before its deadline, indicating that real-time information is more likely to spread among friends within a “social proximity.” With this insight, we consider a physical information network which consists of many cliques and assume that real-time information can spread quickly within a clique. Conjoint to this physical information network, there are online social networks where the information can propagate via websites such as Facebook, Twitter, Youtube, etc. Capitalizing on the theory of inhomogeneous random graph, we analytically characterize the size of information epidemic. One interesting finding is that a larger size online social network, with the same degree distribution, may not necessarily yield a larger size of information epidemic in this overlaying social-physical network. In fact, under certain conditions, the size of information epidemic could even decrease with the growing size of the online social network. This is in stark contrast to that in a single network.

Preservation of cell quality during shipment of human pancreatic islets for use in laboratory research is a crucial, but neglected, topic. Mammalian cells, including islets, have been shown to be adversely affected by temperature changes in vitro and in vivo, yet protocols that control for thermal fluctuations during cell transport are lacking. To evaluate an optimal method of shipping human islets, an initial assessment of transportation conditions was conducted using standardized materials and operating procedures in 48 shipments sent to a central location by eight pancreas-processing laboratories using a single commercial airline transporter. Optimization of preliminary conditions was conducted, and human islet quality was then evaluated in 2,338 shipments pre- and postimplementation of a finalized transportation container and standard operating procedures. The initial assessment revealed that the outside temperature ranged from a mean of −4.6 ± 10.3°C to 20.9 ± 4.8°C. Within-container temperature drops to or below 15°C occurred in 16 shipments (36%), while the temperature was found to be stabilized between 15°C and 29°C in 29 shipments (64%). Implementation of an optimized transportation container and operating procedure reduced the number of within-container temperature drops (£15°C) to 13% ( n = 37 of 289 winter shipments), improved the number desirably maintained between 15°C and 29°C to 86% ( n = 250), but also increased the number reaching or exceeding 29°C to 1% ( n = 2; overall p < 0.0001). Additionally, postreceipt quality ratings of excellent to good improved pre- versus postimplantation of the standardized protocol, adjusting for preshipment purity/viability levels ( p < 0.0001). Our results show that extreme temperature fluctuations during transport of human islets, occurring when using a commercial airline transporter for long distance shipping, can be controlled using standardized containers, materials, and operating procedures. This cost-effective and pragmatic standardized protocol for the transportation of human islets can potentially be adapted for use with other mammalian cell systems and is available online at http://iidp.coh.org/sops.aspx .

In this paper, we study distributed scheduling in multihop multiple-input-multiple-output (MIMO) networks. We first develop a "MIMO-pipe" model that provides the upper layers a set of rates and signal-to-interference-plus-noise ratio (SINR) requirements that capture the rate-reliability tradeoff in MIMO communications. The main thrust of this paper is then dedicated to developing distributed carrier sense multiple access (CSMA) algorithms for MIMO-pipe scheduling under the SINR interference model. We choose the SINR model over the extensively studied protocol-based interference models because it more naturally captures the impact of interference in wireless networks. The coupling among the links caused by the interference under the SINR model makes the problem of devising distributed scheduling algorithms very challenging. To that end, we explore the CSMA algorithms for MIMO-pipe scheduling from two perspectives. We start with an idealized continuous-time CSMA network, where control messages can be exchanged in a collision-free manner, and devise a CSMA-based link scheduling algorithm that can achieve throughput optimality under the SINR model. Next, we consider a discrete-time CSMA network, where the message exchanges suffer from collisions. For this more challenging case, we develop a "conservative" scheduling algorithm by imposing a more stringent SINR constraint on the MIMO-pipe model. We show that the proposed conservative scheduling achieves an efficiency ratio bounded from below.

There is a growing need to develop variant prediction tools capable of assessing a wide spectrum of evidence. We present a Bayesian framework that involves aggregating pathogenicity data across multiple in silico scores on a gene-by-gene basis and multiple evidence statistics in both quantitative and qualitative forms, and performs 5-tiered variant classification based on the resulting probability credible interval. When evaluated in 1,161 missense variants, our gene-specific in silico model-based meta-predictor yielded an area under the curve (AUC) of 96.0% and outperformed all other in silico predictors. Multifactorial model analysis incorporating all available evidence yielded 99.7% AUC, with 22.8% predicted as variants of uncertain significance (VUS). Use of only 3 auto-computed evidence statistics yielded 98.6% AUC with 56.0% predicted as VUS, which represented sufficient accuracy to rapidly assign a significant portion of VUS to clinically meaningful classifications. Collectively, our findings support the use of this framework to conduct large-scale variant prioritization using in silico predictors followed by variant prediction and classification with a high degree of predictive accuracy.

The purpose of the study was to evaluate the feasibility and safety of two cycles of high-dose chemotherapy (HDT) followed by autologous hematopoietic SCT (HSCT) in patients with poor prognosis Ewing family of tumors (EFT). Twenty patients with primary metastatic bulky disease or recurrent EFT were enrolled to a treatment protocol with two cycles of HDT and HSCT. Patients tolerated well the first (n=20) and second (n=13) cycles, with limited and predictable toxicities. Only one (5%) TRM occurred during the second cycle. Myeloid engraftment occurred at the median of 11 days after both cycles. At 3 years, the overall and EFS were 45% (confidence interval; CI 0.22, 0.69) and 47% (CI 0.25, 0.70), respectively, for the entire group and 58% (CI 0.30, 0.86) for patients who completed two cycles. Dose intensification with two cycles of HDT and HSCT is feasible and safe, with low and acceptable treatment-related morbidity and mortality. Adding a second course of therapy does not impair engraftment. However, only 65% of the patients were able to proceed to the second cycle. Further studies are required to define the optimal mode of delivery of HDT and HSCT in treatment of advanced EFT.

The success of human pancreatic islet transplantation in a subset of type 1 diabetic patients has led to an increased demand for this tissue in both clinical and basic research, yet the availability of such preparations is limited and the quality highly variable. Under the current process of islet distribution for basic science experimentation nationwide, specialized laboratories attempt to distribute islets to one or more scientists based on a list of known investigators. This local decision making (LDM) process has been found to be ineffective and suboptimal. To alleviate these problems, a computerized Matching Algorithm for Islet Distribution (MAID) was developed to better match the functional, morphological, and quality characteristics of islet preparations to the criteria desired by basic research laboratories, i.e., requesters. The algorithm searches for an optimal combination of requesters using detailed screening, sorting, and search procedures. When applied to a data set of 68 human islet preparations distributed by the Islet Cell Resource (ICR) Center Consortium, MAID reduced the number of requesters that (a) did not receive any islets, and (b) received mis-matched shipments. These results suggest that MAID is an improved more efficient approach to the centralized distribution of human islets within a consortium setting.

Metaplastic carcinoma of the breast, a neoplasm with both epithelial and mesenchymal elements, represents less than 1 per cent of all breast cancer. We reviewed the records of all patients diagnosed with localized metaplastic breast cancer from 1991 to 2003 at our institution. We identified 21 patients. Mean primary tumor size was 4.62 cm. Eight patients (38%) had axillary node involvement at presentation. All the tumors were high grade. Only two (10%) of the tumors were hormone receptor positive. Seventeen (81%) of the patients received adjuvant chemotherapy, and 12 (57%) of the patients received radiation. Ten (29%) patients suffered a local recurrence. With a mean follow-up of 46 months, the 5-year disease-free and overall survival was 42 per cent (95% CI: 20% to 65%) and 71 per cent (95% CI: 46% to 96%), respectively. Stage-specific overall survival was 100 per cent, 83 per cent, and 53 per cent for stages I, II, and III, respectively. By multivariate analysis, there was no impact on recurrence or survival with regard to size, age, menopausal status, nodal status, histologic subtype, adjuvant therapy, or extent of surgery. Metaplastic breast cancer is a unique neoplasm that tends to present at an advanced stage and has a propensity for local recurrence. When stratified by stage, however, survival appears similar to that of adenocarcinoma of the breast, and these tumors should be treated as such.

Widespread use of screening mammography has resulted in a remarkable increase in the incidence (or detection rate) of ductal carcinoma in situ (DCIS). Axillary lymph node involvement in DCIS is reported to occur at a frequency of 1–12 per cent. Over the past few years, however, there has been increasing emphasis on axillary sampling, limited axillary dissection, and the potential role of sentinel lymph node biopsy. The clinical relevance of axillary lymph node biopsy or dissection remains unanswered. This retrospective analysis was performed on 171 patients who underwent treatment for DCIS at a tertiary care center over a period of 14 years. Clinical and tumor factors were evaluated, and the local, axillary, and systemic recurrence rates were noted. No axillary recurrences from the primary DCIS diagnosis were noted in the entire group of 171 patients. During a mean follow-up of 70 months, 10 patients (6%) developed recurrence in the ipsilateral breast. Six of these recurrences were in the form of DCIS, whereas, four recurred as invasive cancers. Nine patients developed a new primary (seven DCIS and two invasive) in the same breast but in a different quadrant. Two patients with ipsilateral invasive disease also developed systemic disease and eventually died of disease. During the same period, 10 patients (6%) developed DCIS, and seven patients (4%) developed invasive cancer in the contralateral breast. The data show that the risk of axillary recurrence in pure DCIS is, at most, extremely low and support the position that nodal sampling or dissection is unwarranted.

This article presents a six-rule algorithm for the reconstruction of multiple minimum-recombinant haplotype configurations in pedigrees. The algorithm has three major features: First, it allows exhaustive search of all possible haplotype configurations under the criterion that there are minimum recombinants between markers. Second, its computational requirement is on the order of O(J(2)L(3)) in current implementation, where J is the family size and L is the number of marker loci under analysis. Third, it applies to various pedigree structures, with and without consanguinity relationship, and allows missing alleles to be imputed, during the haplotyping process, from their identical-by-descent copies. Haplotyping examples are provided using both published and simulated data sets.

Purpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. Experimental Design: Three patients were vaccinated with 1.0 × 108 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro. Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent. Conclusion: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR.

Cancer risk prediction models are important in identifying individuals at high risk of developing cancer, which could result in targeted screening and interventions to maximize the treatment benefit and minimize the burden of cancer. The cancer-associated genetic variants identified in genome-wide or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients. In this article, we review the cancer risk prediction models that have been developed for popular cancers and assess their applicability, strengths, and weaknesses. We also discuss the factors to be considered for future development and improvement of models for cancer risk prediction.

In the last decade, percutaneous angioplasty (PTA) has been used with increasing frequency to treat infrainguinal atherosclerotic lesions. In hopes of better delineating the role of PTA, we undertook a retrospective analysis of infrainguinal PTA in one hospital over a 7-year period. The charts of all patients receiving infrainguinal PTA from 1989 to 1996 were reviewed. Demographics, site and type of lesion, and results of treatment were recorded. Survival curves were plotted using the Kaplan-Meier method following current Society of Vascular Surgery/International Society for Cardiovascular Surgery (SVS/ISCVS) guidelines. Differences in times to first failure were tested using the log rank method. Failures were documented by duplex ultrasound. All patients requiring repeat intervention underwent contrast angiography. In selected patients with stenotic lesions3 cm, infrainguinal PTA may be an appropriate initial treatment modality. However, 5-year patency rates are significantly lower than those achieved by saphenous vein grafting. The efficacy of the procedure is markedly decreased when used to treat arterial stenoses3 cm in length as well as occlusions, and surgical revascularization may be a more appropriate initial therapeutic procedure.

We describe a multiple regression approach to nonparametric linkage analysis in sibships incorporating multiple genetic loci, environmental covariates, and interactions. The covariance in trait residuals between sib pairs is treated as the dependent variable, regressed upon identical-by-descent sharing probabilities and interaction effects, using generalized estimating equations to allow for the correlations among multiple sib pairs within a sibship. Individual covariates can also be introduced in the model for the trait means. An application to the GAW11 simulated data revealed linkage with each of the four simulated loci, as well as gene x environment interactions of E1 with loci C and D and gene x gene interactions among the cluster of loci A, B, and D.

The interaction between smoking and oral contraceptive (OC) use with respect to thrombogenesis was investigated by studying the effects of OC and smoking on urinary prostacyclin (PGI 2 ) and thromboxane A 2 (TxA 2 ) metabolite levels in smokers and nonsmokers. Sixty healthy women, aged 19–32 years, who were not taking any hormonal treatment for at least 3 months before initiating the study, were divided into three equal groups: OC users who smoked (N = 20), OC users who did not smoke (N = 20), and a control group of 10 smokers and 10 nonsmokers. Each OC treatment group was randomized to receive either norethindrone (NET) acetate (1 mg)/ethinyl estradiol (EE 2 ) (35 μg) (N = 10) or NET acetate (1 mg)/EE 2 (20 μg) (N = 10) daily for 3 months. Overnight urine collections and fasting blood samples were obtained at baseline and at the end of the 3-month study. Serum levels of NET and EE 2 , as well as urinary levels of cotinine and the stable metabolites of PGI 2 and TxA 2 , namely 6-keto-prostaglandin F 1α (6-keto-PGF 1α ) and thromboxane (TxB 2 ), respectively, were measured by specific immunoassays. Analysis of pre- to posttreatment changes in mean urinary 6-keto-PGF 1α and TxB 2 levels for each subgroup, as determined by smoking status and EE 2 dose, showed no statistically significant differences. Also, no significant differences were found in each subgroup with respect to changes in the 6-keto-PGF 1α /TxB 2 ratios. Large intersubject variability in urinary 6-keto-PGF 1α and TxB 2 levels were observed in all subgroups. The results of this study indicate that both low-estrogen–dose compounds, when used by smokers or nonsmokers, did not significantly alter the ratio of PGI 2 to TXA 2 metabolites, compared with pretreatment. However, the small number of subjects and the large intersubject variability in this study make it difficult to determine if there is a significant difference between the 20- and 30-μg EE 2 doses.

BACKGROUND Reactivation of chronic hepatitis B virus (HBV) infection with the development of fulminant hepatitis induced by withdrawal of chemotherapy and/or corticosteroids (CS) is well known. However, less is known about liver dysfunction in patients with hepatitis C virus (HCV) who are undergoing chemotherapy. Thus, the authors conducted this study to determine whether chemotherapy for HCV positive patients with hematologic malignancies is associated with hepatic injury. METHODS Thirty-three consecutive HCV positive patients were studied. Twenty-six had B-cell lymphoma, two had Hodgkin's disease, two had acute myeloblastic leukemia (AML), two had chronic myelocytic leukemia, and one had multiple myeloma. HCV infection was detected by anti-HCV antibodies (enzyme immunoassay) and HCV RNA (reverse transcription polymerase chain reaction). In 28 of 33 patients, CS were used as part of the chemotherapy regimens. Liver function tests (LFTs) were evaluated prior to chemotherapy, a mean of 19 days after each cycle of chemotherapy, and during the follow-up period after the completion of chemotherapy. Mean follow-up was 14 months (range, 7-26 months). RESULTS Twenty-seven of 33 patients (82%) were positive for both anti-HCV and HCV RNA, 5 for HCV RNA only, and 1 for anti-HCV antibodies only. Fourteen patients (42%) had normal pretreatment LFTs. During treatment, 18 patients (55%) (7 with normal and 11 with abnormal pretreatment transaminase levels) had mild-to-moderate increases of alanine aminotransferase (ALT) (median, 156 U/L; range, 59-491) and aspartate aminotransferase (AST) (median, 121; range, 45-243), which occurred 2-3 weeks after the withdrawal of chemotherapy without associated hyperbilirubinemia. Only one patient with baseline ALT and AST of 182 IU/L and 117 IU/L had a severe "flare" of hepatitis C, with peak ALT and AST of 491 IU/L and 243 IU/L. No patient developed fulminant hepatitis or died of liver-related causes. Posttreatment levels of transaminases were not significantly different from pretreatment levels. Abnormal pretreatment transaminase levels did not predict further increase during treatment. CONCLUSIONS Significant hepatic dysfunction is uncommon among HCV infected patients treated with chemotherapy for hematologic malignancies. Cancer 1998;83:1224-1230. © 1998 American Cancer Society.

We evaluated 85 human immunodeficiency virus (HIV)-negative patients with tuberculosis for clinical features and CD4 cell counts. Thirty-seven patients had low CD4 cell counts (mean +/- SD, 341 +/- 116 cells/microL), and 48 patients had normal CD4 cell counts (mean +/- SD, 830 +/- 254 cells/microL). CD4 cell counts were most strongly correlated with total lymphocyte counts (r = 0.84). If total lymphocyte count was excluded, depressed CD4 cell counts were significantly associated with low serum albumin levels, extensive pulmonary disease, low body-mass index, and low hematocrit. Of these four variables, multivariate linear discriminant analysis revealed that the serum albumin level was the best single predictor of low CD4 cell counts and that the other three variables did not improve predictive value. Because these four variables are markers of severe tuberculosis, these findings suggest that disease severity is associated with greater depression of the total lymphocyte and CD4 cell counts. The CD4 cell counts returned to normal levels in most patients after 1 month of therapy.

Background There is accumulating experimental, epidemiological, and clinical evidence of an association between antioxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis. Methods and Results CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of ≥100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of ≥250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P =.03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found. Conclusions Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

This paper studies risk-aware day-ahead scheduling and real-time dispatch for plug-in electric vehicles (EVs), aiming to jointly optimize the EV charging cost and the risk of the load mismatch between the forecasted and the actual EV loads, due to the random driving activities of EVs. It turns out that the inclusion of the load mismatch risk in the objective function complicates the risk-aware day-ahead scheduling and indeed the optimization problem is nonconvex. A key step is to utilize the hidden convexity structure to recast it as a two-stage stochastic linear program, which can be solved by using the L-shaped method. Further, we develop a distributed risk-aware real-time dispatch algorithm, where the aggregator only needs to compute the shadow prices for each EV to optimize its own charging strategy in a distributed manner. We show, based on real data, that the proposed risk-aware day-ahead scheduling algorithm can reduce not only the overall charging cost, but also the peak demand of EV charging.

An association between hospital volume and postoperative mortality has been identified for several oncologic surgical procedures. Our objective was to analyze differences in surgical outcomes for patients with rectal cancer according to hospital volume in the state of California. A cross-sectional study from 2000 to 2005 was performed using the state of California Office of Statewide Health Planning and Development database. Hospitals were categorized into low (≤30)-, medium (31–60)-, and high (>60)-volume groups based on the total number of rectal cancer operations performed during the study period. Overall, 7,187 rectal cancer operations were performed. Of the 321 hospitals in the study cohort, 72 % (n = 232), 20 % (n = 65), and 8 % (n = 24) were low-, medium-, and high-volume hospitals, respectively. Postoperative mortality was significantly lower- in high-volume hospitals (0.9 %) when compared to medium- (1.1 %) and low-volume hospitals (2.1 %; p

We consider a cyber-physical system consisting of two interacting networks, i.e., a cyber-network overlaying a physical-network. It is envisioned that these systems are more vulnerable to attacks since node failures in one network may result in (due to the interdependence) failures in the other network, causing a cascade of failures that would potentially lead to the collapse of the entire infrastructure. The robustness of interdependent systems against this sort of catastrophic failure hinges heavily on the allocation of the (interconnecting) links that connect nodes in one network to nodes in the other network. In this paper, we characterize the optimum inter-link allocation strategy against random attacks in the case where the topology of each individual network is unknown. In particular, we analyze the "regular" allocation strategy that allots exactly the same number of bi-directional inter-network links to all nodes in the system. We show, both analytically and experimentally, that this strategy yields better performance (from a network resilience perspective) compared to all possible strategies, including strategies using random allocation, unidirectional inter-links, etc., 13 pages, 6 figures. To appear in the Special Issue of IEEE Transactions on Parallel and Distributed Systems on Cyber-Physical Systems, 2012

We study the diffusion of information in an overlaying social-physical network. Specifically, we consider the following set-up: There is a physical information network where information spreads amongst people through conventional communication media (e.g., face-to-face communication, phone calls), and conjoint to this physical network, there are online social networks where information spreads via web sites such as Facebook, Twitter, FriendFeed, YouTube, etc. We quantify the size and the critical threshold of information epidemics in this conjoint social-physical network by assuming that information diffuses according to the SIR epidemic model. One interesting finding is that even if there is no percolation in the individual networks, percolation (i.e., information epidemics) can take place in the conjoint social-physical network. We also show, both analytically and experimentally, that the fraction of individuals who receive an item of information (started from an arbitrary node) is significantly larger in the conjoint social-physical network case, as compared to the case where the networks are disjoint. These findings reveal that conjoining the physical network with online social networks can have a dramatic impact on the speed and scale of information diffusion., 14 pages, 4 figures

We consider a cyber-physical system consisting of two interacting networks, i.e., a cyber-network overlaying a physical-network. In the event of attacks, due to the interdependence between the networks, node failures in one network may result in a cascade of failures affecting both networks - potentially leading to the collapse of the entire infrastructure. Robustness against such catastrophic failure hinges heavily on the allocation of the interconnecting links that connect nodes in one network to nodes in the other network for proper functioning. Assuming that no information about the degree distribution within each of the two constituent networks, we develop a “uniform” allocation strategy that allots inter-network links equally across all nodes. Our findings indicate that, from a network resilience perspective, uniform allocation of internetwork edges yields a significant gain compared to random allocation.

This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m2 per day for 5 days, melphalan 140 mg/m2 for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non–relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non–relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.

In recent years, industries have turned to the field of operations research to help improve the efficiency of production and distribution processes. Largely absent is the application of this methodology to biological materials, such as the complex and costly procedure of human pancreas procurement and islet isolation. Pancreatic islets are used for basic science research and in a promising form of cell replacement therapy for a subset of patients afflicted with severe type 1 diabetes mellitus. Having an accurate and reliable system for cell distribution is therefore crucial. The Islet Cell Resource Center Consortium was formed in 2001 as the first and largest cooperative group of islet production and distribution facilities in the world. We previously reported on the development of a Matching Algorithm for Islet Distribution (MAID), an automated web-based tool used to optimize the distribution of human pancreatic islets by matching investigator requests to islet characteristics. This article presents an assessment of that algorithm and compares it to the manual distribution process used prior to MAID. A comparison was done using an investigator's ratio of the number of islets received divided by the number requested pre- and post-MAID. Although the supply of islets increased between the pre- versus post-MAID period, the median received-to-requested ratio remained around 60% due to an increase in demand post-MAID. A significantly smaller variation in the received-to-requested ratio was achieved in the post- versus pre-MAID period. In particular, the undesirable outcome of providing users with more islets than requested, ranging up to four times their request, was greatly reduced through the algorithm. In conclusion, this analysis demonstrates, for the first time, the effectiveness of using an automated web-based cell distribution system to facilitate efficient and consistent delivery of human pancreatic islets by enhancing the islet matching process.