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I. Hurricane Litigation A. Wind versus Water B. Negligent Levee Design versus Flood C. Hurricane Deductibles D. Valued Policy Laws II. Appraisal A. Scope B. Timeliness C. Binding Nature of [...]

I. Appraisal A. Scope B. Timeliness C. Binding Nature of Appraisal D. Nonrevocable II. Business Interruption--Civil Authority A. Necessary Suspension of Operations B. Assignment C. Civil Authority D. Period of [...]

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnasgene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2(PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2as a target for GC resensitization in relapsed pediatric T-ALL.

Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-β (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.

Issue: The insured homeowners were hauling home a new table and four chairs in their pickup truck. As they drove home on the highway, however, wind blew two of the [...]

Issue: The insured suffered loss to personal property that was being stored in a unit at a self-storage warehouse. The warehouse management company leases the unit to the insured under [...]

Leonard E. Murphy is counsel for the Property Loss Research Bureau in Downers Grove, Ill. Issue: The insured suffered loss to personal property that was being stored in a unit [...]

This research reports on a comparison between sex role attitudes in co-ed treatment programs and an all female treatment program. Eighty residents, sixty males and twenty females, and thirty-eight staff, twenty-two males and sixteen females, of Marathon House, the largest drug rehabilitation community in New England completed Spence and Helmreich's Attitudes toward Women Scale (AWS). The AWS was also administered to four staff and twelve residents at Caritas House, an all female therapeutic community in Rhode Island. The results from the AWS indicate that female staff at Marathon House and Caritas House have significantly more liberal attitudes toward women than the male staff at Marathon House. Female residents of both Houses have significantly more liberal attitudes on the AWS than male residents of Marathon House. Surprisingly, however, the female residents at Marathon House have almost identical scores on the AWS to female residents at Caritas House even though residents at Marathon House are exposed to the attitudes of both male and female staff, whereas residents at Caritas House are exposed only to the attitudes of an all female staff.

WWSSN seismograms for the Caucasus earthquake of May 14, 1970, and the Alma-Ata earthquake of June 5, 1970, were scaled formb using techniques employed by USSR (P amplitude during first 20 seconds) and USA (P amplitude during first few cycles). USSR seismograms will be used in a second phase of this study. Using both techniques, the scatter at each station formb (SPZ) was 0.0–0.3 with half of the stations having no scatter. The scatter among all of the stations was over 1 unit. Using both techniques, the scatter at each station formb (LPZ) was zero except for NUR on May 14. The scatter among all of the stations was 1 unit on May 14 and 0.4 on June 5. This preliminary study indicates the scaling techniques have no effect in computingmb (SPZ) andmb (LPZ) but the differences are more likely related to source functions, crust and upper mantle response functions, and instrumental band pass.