Physical Pictures of Transport in Heterogeneous Media: Advection-Dispersion, Random Walk and Fractional Derivative Formulations

The basic conceptual picture and theoretical basis for development of transport equations in porous media are examined. The general form of the governing equations is derived for conservative chemical transport in heterogeneous geological formations, for single realizations and for ensemble averages of the domain. The application of these transport equations is focused on accounting for the appearance of non-Fickian (anomalous) transport behavior. The general ensemble-averaged transport equation is shown to be equivalent to a continuous time random walk (CTRW) and reduces to the conventional forms of the advection-dispersion equation (ADE) under highly restrictive conditions. Fractional derivative formulations of the transport equations, both temporal and spatial, emerge as special cases of the CTRW. In particular, the use in this context of L{\'e}vy flights is critically examined. In order to determine chemical transport in field-scale situations, the CTRW approach is generalized to non-stationary systems. We outline a practical numerical scheme, similar to those used with extended geological models, to account for the often important effects of unresolved heterogeneities.Comment: 14 pages, REVTeX4, accepted to Wat. Res. Res; reference adde

Children\u27s experiences of companion animal maltreatment in households characterized by intimate partner violence

Cruelty toward companion animals is a well-documented, coercive tactic used by abusive partners to intimidate and control their intimate partners. Experiences of co-occurring violence are common for children living in families with intimate partner violence (IPV) and surveys show that more than half are also exposed to abuse of their pets. Given children\u27s relationships with their pets, witnessing such abuse may be traumatic for them. Yet little is known about the prevalence and significance of this issue for children. The present study examines the experiences of children in families with co-occurring pet abuse and IPV. Using qualitative methods, 58 children ages 7–12 who were exposed to IPV were asked to describe their experiences of threats to and harm of their companion animals. Following the interviews, template analysis was employed to systematically develop codes and themes. Coding reliability was assessed using Randolph\u27s free-marginal multirater kappa (kfree = .90). Five themes emerged from the qualitative data, the most common being children\u27s exposure to pet abuse as a power and control tactic against their mother in the context of IPV. Other themes were animal maltreatment to discipline or punish the pet, animal cruelty by a sibling, children intervening to prevent pet abuse, and children intervening to protect the pet during a violent episode. Results indicate that children\u27s experiences of pet abuse are multifaceted, potentially traumatic, and may involve multiple family members with diverse motives

Perfusion Assessment in Laparoscopic Left-Sided/Anterior Resection (PILLAR II): A Multi-Institutional Study

BackgroundOur primary objective was to demonstrate the utility and feasibility of the intraoperative assessment of colon and rectal perfusion using fluorescence angiography (FA) during left-sided colectomy and anterior resection. Anastomotic leak (AL) after colorectal resection increases morbidity, mortality, and, in cancer cases, recurrence rates. Inadequate perfusion may contribute to AL. The PINPOINT Endoscopic Fluorescence Imaging System allows for intraoperative assessment of anastomotic perfusion.Study DesignThis is a prospective, multicenter, open-label, clinical trial that assessed the feasibility and utility of FA for intraoperative perfusion assessment during left-sided colectomy and anterior resection at 11 centers in the United States.ResultsA total of 147 patients were enrolled, of whom 139 were eligible for analysis. Diverticulitis (44%), rectal cancer (25%), and colon cancer (21%) were the most prevalent indications for surgery. The mean level of anastomosis was 10 ± 4 cm from the anal verge. Splenic-flexure mobilization was performed in 81% and high ligation of the inferior mesenteric artery in 61.9% of patients. There was a 99% success rate for FA, and FA changed surgical plans in 11 (8%) patients, with the majority of changes occurring at the time of transection of the proximal margin (7%). Overall morbidity rates were 17%. The anastomotic leak rate was 1.4% (n = 2). There were no anastomotic leaks in the 11 patients who had a change in surgical plan based on intraoperative perfusion assessment with FA.ConclusionsPINPOINT is a safe and feasible tool for intraoperative assessment of tissue perfusion during colorectal resection. There were no anastomotic leaks in patients in whom the anastomosis was revised based on inadequate perfusion with FA

High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma.

High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade

Discovering pathways by orienting edges in protein interaction networks

Modern experimental technology enables the identification of the sensory proteins that interact with the cells’ environment or various pathogens. Expression and knockdown studies can determine the downstream effects of these interactions. However, when attempting to reconstruct the signaling networks and pathways between these sources and targets, one faces a substantial challenge. Although pathways are directed, high-throughput protein interaction data are undirected. In order to utilize the available data, we need methods that can orient protein interaction edges and discover high-confidence pathways that explain the observed experimental outcomes. We formalize the orientation problem in weighted protein interaction graphs as an optimization problem and present three approximation algorithms based on either weighted Boolean satisfiability solvers or probabilistic assignments. We use these algorithms to identify pathways in yeast. Our approach recovers twice as many known signaling cascades as a recent unoriented signaling pathway prediction technique and over 13 times as many as an existing network orientation algorithm. The discovered paths match several known signaling pathways and suggest new mechanisms that are not currently present in signaling databases. For some pathways, including the pheromone signaling pathway and the high-osmolarity glycerol pathway, our method suggests interesting and novel components that extend current annotations

Entangled Stories: The Red Jews in Premodern Yiddish and German Apocalyptic Lore

“Far, far away from our areas, somewhere beyond the Mountains of Darkness, on the other side of the Sambatyon River…there lives a nation known as the Red Jews.” The Red Jews are best known from classic Yiddish writing, most notably from Mendele's Kitser masoes Binyomin hashlishi (The Brief Travels of Benjamin the Third). This novel, first published in 1878, represents the initial appearance of the Red Jews in modern Yiddish literature. This comical travelogue describes the adventures of Benjamin, who sets off in search of the legendary Red Jews. But who are these Red Jews or, in Yiddish, di royte yidelekh? The term denotes the Ten Lost Tribes of Israel, the ten tribes that in biblical times had composed the Northern Kingdom of Israel until they were exiled by the Assyrians in the eighth century BCE. Over time, the myth of their return emerged, and they were said to live in an uncharted location beyond the mysterious Sambatyon River, where they would remain until the Messiah's arrival at the end of time, when they would rejoin the rest of the Jewish people. This article is part of a broader study of the Red Jews in Jewish popular culture from the Middle Ages through modernity. It is partially based on a chapter from my book, Umstrittene Erlöser: Politik, Ideologie und jüdisch-christlicher Messianismus in Deutschland, 1500–1600 (Göttingen: Vandenhoeck & Ruprecht, 2011). Several postdoctoral fellowships have generously supported my research on the Red Jews: a Dr. Meyer-Struckmann-Fellowship of the German Academic Foundation, a Harry Starr Fellowship in Judaica/Alan M. Stroock Fellowship for Advanced Research in Judaica at Harvard University, a research fellowship from the Heinrich Hertz-Foundation, and a YIVO Dina Abramowicz Emerging Scholar Fellowship. I thank the organizers of and participants in the colloquia and conferences where I have presented this material in various forms as well as the editors and anonymous reviewers of AJS Review for their valuable comments and suggestions. I am especially grateful to Jeremy Dauber and Elisheva Carlebach of the Institute for Israel and Jewish Studies at Columbia University, where I was a Visiting Scholar in the fall of 2009, for their generous encouragement to write this article. Sue Oren considerably improved my English. The style employed for Romanization of Yiddish follows YIVO's transliteration standards. Unless otherwise noted, translations from the Yiddish, Hebrew, German, and Latin are my own. Quotations from the Bible follow the JPS translation, and those from the Babylonian Talmud are according to the Hebrew-English edition of the Soncino Talmud by Isidore Epstein

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles

Machine learning approaches offer the potential to systematically identify transcriptional regulatory interactions from a compendium of microarray expression profiles. However, experimental validation of the performance of these methods at the genome scale has remained elusive. Here we assess the global performance of four existing classes of inference algorithms using 445 Escherichia coli Affymetrix arrays and 3,216 known E. coli regulatory interactions from RegulonDB. We also developed and applied the context likelihood of relatedness (CLR) algorithm, a novel extension of the relevance networks class of algorithms. CLR demonstrates an average precision gain of 36% relative to the next-best performing algorithm. At a 60% true positive rate, CLR identifies 1,079 regulatory interactions, of which 338 were in the previously known network and 741 were novel predictions. We tested the predicted interactions for three transcription factors with chromatin immunoprecipitation, confirming 21 novel interactions and verifying our RegulonDB-based performance estimates. CLR also identified a regulatory link providing central metabolic control of iron transport, which we confirmed with real-time quantitative PCR. The compendium of expression data compiled in this study, coupled with RegulonDB, provides a valuable model system for further improvement of network inference algorithms using experimental data

Phase II trial of biochemotherapy with interferon α, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial

The therapeutic benefit of adding interferon α (IFNα) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNα, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNα plus dacarbazine over dacarbazine alone, we treated patients with an “induction” regimen of IFNα, 15 mU m −2 day −1 intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNα, 5 mU m −2  day −1 subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m −2  day −1 and cisplatin 33 mg m −2  day −1 for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNα and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%–20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42256/1/432-125-5-292_91250292.pd