CHARACTERIZATION OF ERBB4 EXPRESSION IN OSTEOSARCOMA

ERBB4 (Her-4) is a member of the ERBB family of Class I receptor tyrosine kinases. ERBB4 is unique within the ERBB family for alternate splicing in its juxtamembrane and cytoplasmic regions, which produces four juxtamembrane isoforms and two cytoplasmic isoforms. The cleavable juxtamembrane isoforms, Jm-a and Jm-d, can undergo proteolytic cleavage and produce an 80-kDa cytoplasmic fragment referred to as “p80,” which has been demonstrated to enhance cellular survival and malignant behavior in many solid tumors [44]. ERBB4 was almost exclusively 80 kDa in size and localized to the nucleus in primary tumors and metastases in studies characterizing ERBB4 expression in osteosarcoma, indicating that ERBB4 may be cleaved to enhance malignant behavior in osteosarcoma. ERBB4 protein was significantly up-regulated from monolayer to sphere cultures in osteosarcoma, leading to the hypothesis that there would be an up-regulation of the cleavable isoforms Jm-a and Jm-d from monolayer to sphere cultures of osteosarcoma. The first aim of this thesis was to measure if the proportion of cleavable juxtamembrane isoform expression in osteosarcoma tumor spheres from monolayer culture. All cell lines on the panel showed a significant increase in expression, by proportion or up-regulation, of at least one of the cleavable juxtamembrane isoforms Jm-a or Jm-d in sphere culture. We hypothesized that there would be a significant reduction of lung metastases with shRNA specific for Her-4 in osteosarcoma cells in xenograft mice. Immunohistochemical staining for ERBB4 was performed on sections of lungs from the experimental mice injected with CCH-OS-O cells with shRNA against ERBB4 and controls, with adjacent sections stained with vimentin as a counterstain for total osteosarcoma metastases. There were significant reductions in formation of ERBB4-negative macrometastases (\u3e 200 microns) in ERBB4 control mice and of ERBB4-negative micrometastases (6 cells-200 microns) in ERBB4 control and ERBB4 knockdown mice over two experiments. There was not a significant difference in the numbers of oligometastases (1-5 cells) in ERBB4 knockdown and control mice. Taken together, the immunohistochemistry suggests that ERBB4 expression may be important to metastatic progression, or formation of detectable foci, in osteosarcoma

Failure of Working Memory Training to Enhance Cognition or Intelligence

Fluid intelligence is important for successful functioning in the modern world, but much evidence suggests that fluid intelligence is largely immutable after childhood. Recently, however, researchers have reported gains in fluid intelligence after multiple sessions of adaptive working memory training in adults. The current study attempted to replicate and expand those results by administering a broad assessment of cognitive abilities and personality traits to young adults who underwent 20 sessions of an adaptive dual n-back working memory training program and comparing their post-training performance on those tests to a matched set of young adults who underwent 20 sessions of an adaptive attentional tracking program. Pre- and post-training measurements of fluid intelligence, standardized intelligence tests, speed of processing, reading skills, and other tests of working memory were assessed. Both training groups exhibited substantial and specific improvements on the trained tasks that persisted for at least 6 months post-training, but no transfer of improvement was observed to any of the non-trained measurements when compared to a third untrained group serving as a passive control. These findings fail to support the idea that adaptive working memory training in healthy young adults enhances working memory capacity in non-trained tasks, fluid intelligence, or other measures of cognitive abilities.</p

Failure of Working Memory Training to Enhance Cognition or Intelligence

Fluid intelligence is important for successful functioning in the modern world, but much evidence suggests that fluid intelligence is largely immutable after childhood. Recently, however, researchers have reported gains in fluid intelligence after multiple sessions of adaptive working memory training in adults. The current study attempted to replicate and expand those results by administering a broad assessment of cognitive abilities and personality traits to young adults who underwent 20 sessions of an adaptive dual n-back working memory training program and comparing their post-training performance on those tests to a matched set of young adults who underwent 20 sessions of an adaptive attentional tracking program. Pre- and post-training measurements of fluid intelligence, standardized intelligence tests, speed of processing, reading skills, and other tests of working memory were assessed. Both training groups exhibited substantial and specific improvements on the trained tasks that persisted for at least 6 months post-training, but no transfer of improvement was observed to any of the non-trained measurements when compared to a third untrained group serving as a passive control. These findings fail to support the idea that adaptive working memory training in healthy young adults enhances working memory capacity in non-trained tasks, fluid intelligence, or other measures of cognitive abilities.National Institutes of Health (U.S.) (Blueprint for Neuroscience Research (T90DA022759/R90DA023427)United States. Defense Advanced Research Projects Agency (government contract no. NBCHC070105)United States. Dept. of Defense (National Defense Science and Engineering Fellowship)Massachusetts Institute of Technology (Sheldon Razin (1959) Fellowship

Enterococcus raffinosus Infection with Atypical Hemolytic Uremic Syndrome in a Multiple Myeloma Patient after Autologous Stem Cell Transplant

Autologous hematopoietic stem cell transplant (AHSCT) is the standard of care in the treatment of multiple myeloma worldwide. Infections are one of the most common complications of the chemotherapy regimen and AHSCT. Thrombotic microangiopathies are one of the rare but potentially life-threatening complications of infections associated with AHSCT. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (HUS) are two most common type of thrombotic microangiopathies. The HUS is classically related to diarrheal illness such as with E. coli strain O157: H7 that produce Shiga-like toxins. But it has never been described with Enterococcus raffinosus urinary tract infections (UTI). Here we are describing a case of atypical HUS associated with Enterococcus raffinosus UTI in a patient with multiple myeloma after AHSCT. The management of atypical HUS especially after AHSCT is challenging. Eculizumab, a humanized monoclonal antibody against complement protein C5, and thrombomodulin have emerging role in the management of some cases, but more studies are needed to define evidence-based management of this condition