From the ECM to the Cytoskeleton and Back: How Integrins Orchestrate T Cell Action

T lymphocytes constitute a highly dynamic tissue type. During the course of their lives, they travel through a variety of physiological environments and experience a multitude of interactions with extracellular matrix components and other cells. In order to do this, they must receive many environmental cues, and translate these signals into the appropriate biological actions. Particularly dramatic are the cytoskeletal shape changes a T cell must undergo during the processes of leaving the bloodstream, migrating through tissues, and encountering antigen. In this review, we highlight the role of integrins in providing a link between the extracellular environment and cytoskeletal regulation and how these receptors help to orchestrate T cell migration and antigen recognition

Alcohol-related Discussions during General Medicine Appointments of Male VA Patients Who Screen Positive for At-risk Drinking

OBJECTIVE: This study describes primary care discussions with patients who screened positive for at-risk drinking. In addition, discussions about alcohol use from 2 clinic firms, one with a provider-prompting intervention, are compared. DESIGN: Cross-sectional analyses of audiotaped appointments collected over 6 months. PARTICIPANTS AND SETTING: Male patients in a VA general medicine clinic were eligible if they screened positive for at-risk drinking and had a general medicine appointment with a consenting provider during the study period. Participating patients (N = 47) and providers (N = 17) were enrolled in 1 of 2 firms in the clinic (Intervention or Control) and were blinded to the study focus. INTERVENTION: Intervention providers received patient-specific results of positive alcohol-screening tests at each visit. MEASURES AND MAIN RESULTS: Of 68 visits taped, 39 (57.4%) included any mention of alcohol. Patient and provider utterances during discussions about alcohol use were coded using Motivational Interviewing Skills Codes. Providers contributed 58% of utterances during alcohol-related discussions with most coded as questions (24%), information giving (23%), or facilitation (34%). Advice, reflective listening, and supportive or affirming statements occurred infrequently (5%, 3%, and 5%, of provider utterances respectively). Providers offered alcohol-related advice during 21% of visits. Sixteen percent of patient utterances reflected “resistance” to change and 12% reflected readiness to change. On average, Intervention providers were more likely to discuss alcohol use than Control providers (82.4% vs 39.6% of visits; P = .026). CONCLUSIONS: During discussions about alcohol, general medicine providers asked questions and offered information, but usually did not give explicit alcohol-related advice. Discussions about alcohol occurred more often when providers were prompted

Ecotourists' perception of ecotourism experience in lower Kinabatangan, Sabah, Malaysia

This paper presents the empirical findings of an exploratory qualitative study which looks at ecotourists' perceptions of ecotourism experiences in Sabah, Malaysia in order to identify the expressive dimensions that describe the quality of their experience. In-depth interviews were conducted with European ecotourists who stayed at two ecolodges in Sukau. Positive and negative experiences were identified from an analysis of the expressive dimensions of their service experience. The findings show that the ecotourists' experience is multidimensional. Respondents place particular emphasis on the ecotourism activities in which they physically engage at the sites and the natural environment in which they are located; their interaction with the site service staff; socialisation with other ecotourists, and the information acquired during the visit. The six expressive dimensions describing the positive experience are consistent with previous research. The study explores understanding of ecotourists' experience in the ecotourism environment - an under-researched area. The paper points out that the evaluation of quality of experience appears to involve both attributes - functional elements that are provided by the service suppliers and affective/emotional elements that are brought about by the ecotourists themselves

Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate <b>1</b> (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of <b>20</b> (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead <b>1</b> culminated in the discovery of clinical development candidate <b>8h</b>, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models

Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window

p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido­[2,3-<i>d</i>]­pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery

Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window

p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido­[2,3-<i>d</i>]­pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery