Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED(50) = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED(50) = 0.5nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.     

Juvenile hyaline fibromatosis: a case report

Juvenile hyalinefibromatosis (JHF) is a rare autosomal recessive (4q21) genodermatosis characterized by a triad of cephalic fibrous outgrowths, gingival hypertrophy and flexion contractures. This paper presents a case report of juvenile hyaline fibromatosis.     

Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor

Donor lymphocyte infusions (DLIs) induce effective graft-versus-tumor responses in patients with multiple myeloma who relapse after allogeneic hematopoietic stem-cell transplantation. The graft-versus-myeloma response is presumably mediated primarily by donor T cells, but recent studies have also demonstrated the presence of antibodies specific for a variety of myeloma-associated antigens in patients who achieve complete remission after DLI. One of the B-cell antigens identified in these studies was B-cell maturation antigen (BCMA), a transmembrane receptor of the tumor necrosis factor (TNF) superfamily that is selectively expressed by mature B cells. The present studies were undertaken to characterize the functional significance of antibodies to BCMA in vivo. Using transfected cells expressing BCMA, antibodies in patient serum were found to react with the cell-surface domain of BCMA. Post-DLI patient serum was able to induce complement-mediated lysis and antibody-dependent cellular cytotoxicity (ADCC) of transfected cells and primary myeloma cells expressing BCMA. BCMA antibodies were only found in post-DLI responders and not in other allogeneic transplant patients or healthy donors. These results demonstrate that BCMA is a target of donor B-cell immunity in patients with myeloma who respond to DLI. Antibody responses to cell-surface BCMA may contribute directly to tumor rejection in vivo.     

Continuous absence of metaphase-defined cytogenetic abnormalities,especially of chromosome 13 and hypodiploidy,ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.     

Angiotensin-converting enzyme in organs of air-breathing fish

Angiotensin-converting enzyme (ACE) was measured in tissue homogenates from the African lungfish and six species of air-breathing teleosts (Heteropneustes fossilis, Clarias batrachus, Channa gachua, Anabas testudineus, Notopterus chitala, and Monopterus cuchia) using a standard spectrophotometric assay. In most species, the highest levels of ACE activity were found in the respiratory organs (gills and/or accessory respiratory organs). ACE was also found in heart and kidney tissues from most species and occasionally in liver. Converting enzyme was not found in skin or skeletal muscle from any species and only in blood from H. fossilis and brain from C. batrachus. Captopril, a potent inhibitor of mammalian ACE, inhibited enzymatic activity from all tissues except C. gachua heart and liver and A. testudineus heart. As fish make the transition from aquatic to aerial respiration the gill microcirculation is usually reduced in size and the accessory respiratory organs become elaborated and occupy a more central position in the vascular tree. The presence of ACE in accessory respiratory organs of air-breathing fish appears to greatly enhance the metabolic efficiency of this enzyme on circulating substrates.     

Is problem-based learning an ideal format for developing ethical decision skills?

Ethical decision making is a complex process, which involves the interaction of knowledge, skills, and attitude. To enhance the teaching and learning on ethics reasoning, multiple teaching strategies have to be applied. A medical ethical reasoning (MER) model served as a framework of the development of ethics reasoning and their suggested instructional strategies. Problem-based learning (PBL), being used to facilitate students' critical thinking, self-directed learning, collaboration, and communication skills, has been considered effective on ethics education, especially when incorporated with experiential experience. Unlike lecturing that mainly disseminates knowledge and activates the left brain, PBL encourages “whole-brain” learning. However, PBL has several disadvantages, such as its inefficiency, lack of adequately trained preceptors, and the in-depth, silo learning within a relatively small number of cases. Because each school tends to utilize PBL in different ways, either the curriculum designer or the learning strategy, it is important to maximize the advantages of a PBL session, PBL then becomes an ideal format for refining students' ethical decisions and behaviors.