With the aim of producing a 3D representation of tumors, imaging and molecular annotation of xenografts and tumors (IMAXT) uses a large variety of modalities in order to acquire tumor samples and produce a map of every cell in the tumor and its host environment. With the large volume and variety of data produced in the project, we developed automatic data workflows and analysis pipelines. We introduce a research methodology where scientists connect to a cloud environment to perform analysis close to where data are located, instead of bringing data to their local computers. Here, we present the data and analysis infrastructure, discuss the unique computational challenges and describe the analysis chains developed and deployed to generate molecularly annotated tumor models. Registration is achieved by use of a novel technique involving spherical fiducial marks that are visible in all imaging modalities used within IMAXT. The automatic pipelines are highly optimized and allow to obtain processed datasets several times quicker than current solutions narrowing the gap between data acquisition and scientific exploitation.

The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene–gene interactions that influence central dopaminergic systems. (JINS, 2011, 17, 1–7)

Elderly patients with cancer face unique physical and psychiatric challenges in coping with their illness. Optimal psychosocial therapy for older cancer patients requires recognizing certain enhanced psychological capacities such as coping better with illness, which is associated with older age. This strength can be combined with the most appropriate cognitive coping strategies to develop a model intervention. This paper describes such a model, which integrates Erik Erikson's eighth and final psychosocial developmental life stage, in which the task is to achieve ego integrity (equanimity) or to experience despair (sadness, regrets), with Susan Folkman's cognitive coping paradigm, which utilizes reappraisal. This theoretical model addresses older cancer patients who are struggling with depression, isolation, and despair related to aging and illness, and utilizes cognitive reappraisal in a group setting to foster relatedness, acceptance of illness, and a sense of meaningful integration.

“Chemobrain” is the phenomenon of cognitive decline some patients may experience after chemotherapy. Current research indicates the cognitive domains that may be most impacted by chemotherapeutic agents are visual and verbal memory, attention, and psychomotor functioning. These cognitive deficits can have an effect on a patient's ability to make informed treatment decisions, pursue occupational or academic pursuits, and his or her overall quality of life. The potential mechanisms that cause this disruption remain largely unknown, although contributing factors could be vascular injury and oxidative damage, inflammation, direct injury to neurons, autoimmune responses, chemotherapy-induced anemia, and the presence of the apolipoprotein E ε4 (APOE ε 4) gene. Interventions to help alleviate the symptoms of chemobrain could include nonpharmacologic treatment such as antioxidants and cognitive-behavioral therapy. In addition, patients may benefit from pharmacologic treatment such as recombinant human erythropoietin and psychostimulant drugs such as methylphenidate. It is important to note that the proposed therapeutics treat the symptoms of chemobrain based on the hypothesized mechanisms. Therefore, a detailed understanding of the mechanisms that cause chemobrain, as well as a comprehension of what specific cognitive domains are impacted, is crucial in developing more specific treatments to improve patients' cognitive functioning and overall quality of life.

This article investigates how participants in broadcast news interviews display their orientations to a social distribution of knowledge regarding newsworthy events and actors. Interviewers treat the nature, grounds, and limits of interviewees' knowledge as accountable matters. The article employs single-case and quantitative analyses to show that, in and through the design of their questions, interviewers distinguish between (i) interviewees as subject-actors who are responsible for direct, first-hand knowledge of their own conduct; and (ii) interviewees as commentators who, on the basis of indirect, second-hand knowledge, are entitled to opinions about third parties' conduct. This distinction serves as a basis for the production of interviewees' responses as talk that expresses either matters of fact or points of opinion. The article examines how these aspects of question design establish relevancies for interviewees' responses and, ultimately, shape news content.

In 1964 the late Harvey Sacks began to present his now-famous lectures on conversation at UCLA (Sacks 1992, vol. 1). By the decade's end, as he continued his lectures at UC Irvine (Sacks 1992, vol. 2), the first published instance of the work that had come to be known as Conversation Analysis (Schegloff 1968) introduced this developing perspective to a broader public. In the early 1970s Sacks and Schegloff, along with their colleague Gail Jefferson, pursued their research on the organization of talk-in-interaction and published a number of articles that remain foundational (e.g. Schegloff & Sacks 1973, Sacks et al. 1974).

In the mid-1960s, the late sociologist Harvey Sacks initially developed the concept of “membership categorization devices” as a means of analyzing how people identify, describe, and refer to one another. In his now canonical treatment of a child's story, “The baby cried. The mommy picked it up,” Sacks (1972) explored the possibilities for formal analyses of references to and descriptions of persons, as implemented in written texts and talk-in-interaction.

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 Å. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S′1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S′1 pocket. The largest differences occur in the loop forming the “top” of this pocket. The occupation of these nonpeptidic inhibitors in the S′1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.