Wac'inyeya: Hope Among American Indian Youth.

This article examines what gives American Indian youth hope. The project included 56 rural tribal youth in focus groups across a Northern Plains reservation. The participants completed a Youth Personal Balance Tool to provide perspective on the balance according to a medicine wheel model of their lives. The focus groups asked questions from a strengths-based perspective about what gives them hope and how they could show others they were hopeful. The project culminated with the youth developing creative representations of hope and presenting these projects to family and community.

Principles and popularity: the interplay of moral norms and descriptive norms in the context of volunteerism.

Can a moral norm be manipulated and if so, how does a manipulated moral norm interact with a descriptive norm to impact on behavioural intentions? The present research addressed these questions in three studies. Study 1a and 1b demonstrated the validity of a manipulation designed to activate a moral norm for volunteer activity. In Study 2, activating a moral norm for volunteering strengthened intentions to volunteer and inhibited intentions to conform to a descriptive norm. Conceptual and applied implications of activating a moral norm are discussed.

The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody.

T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti-PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1(+) MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

What makes a caseload (un)manageable? School-based speech-language pathologists speak.

PURPOSE: Large caseload sizes and a shortage of speech-language pathologists (SLPs) are ongoing concerns in the field of speech and language. This study was conducted to identify current mean caseload size for school-based SLPs, a threshold at which caseload size begins to be perceived as unmanageable, and variables contributing to school-based SLPs' feelings of caseload manageability. METHOD: Approximately 2,000 public-school-based SLPs from across the country were solicited to participate in an online, Web-based survey between April and May of 2007. Of those SLPs who were contacted, 634 full-time SLPs from 49 states completed the survey. The data were evaluated using descriptive statistics and logistic regression. RESULTS: The mean caseload size for SLPs in this study was 49 students. At the caseload range of 41-50 students, approximately 60% of the SLPs perceived their caseload size as unmanageable. Logistic regression revealed caseload size, years of experience, and extent of collaboration as significant predictors of an SLP's likelihood of feeling that his or her caseload size is manageable. CONCLUSIONS: Caseload size continues to be an area of concern for school-based SLPs, and efforts to address this problem must continue in order to prevent long-term struggles with SLPs' dissatisfaction, shortages, and turnover. Policy, research, and clinical implications are discussed.

Effects of induction with novel agents versus conventional chemotherapy on mobilization and autologous stem cell transplant outcomes in multiple myeloma.

Multiple myeloma (MM) is the top indication for high-dose chemotherapy (HDC) with autologous stem cell transplantation (SCT), a strategy which improves progression-free survival and potentially overall survival (OS). Novel induction regimens incorporating the immunomodulatory (IMID) agents, such as thalidomide and lenalidomide and the proteosome inhibitor bortezomib improve response rates and survival for newly diagnosed patients. Recent data temper enthusiasm for these treatments by illustrating difficulty in some circumstances with mobilizing CD34(+) hematopoietic stem cells for subsequent HDC/SCT. We compare conventional induction regimens with novel agent-based induction strategies and the associated effects on stem cell mobilization and HDC/SCT outcome in 224 patients. Although patients exposed to novel agent inductions collected generally fewer CD34(+) cells than patients induced with chemotherapy, these differences did not translate into adverse consequences with subsequent HDC/SCT. We show that an improvement in OS after HDC/SCT may be related to induction therapy with novel agents as opposed to chemotherapy. Our data extrapolate on prior work and expand on ongoing controversies about optimal induction regimens for patients with MM planned for subsequent HDC/SCT and optimal sequencing of therapies.

Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels.

TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the C-terminal nudix domain. We also show that oxidative/nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.

Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7.

TRPM7 is a polypeptide with intrinsic ion channel and protein kinase domains whose targeted deletion causes cells to experience growth arrest within 24 hr and eventually die. Here, we show that while TRPM7's kinase domain is not essential for activation of its channel, a functional coupling exists such that structural alterations of the kinase domain alter the sensitivity of channel activation to Mg(2+). Investigation of the relationship between Mg(2+) and the cell biological role of TRPM7 revealed that TRPM7-deficient cells become Mg(2+) deficient, that both the viability and proliferation of TRPM7-deficient cells are rescued by supplementation of extracellular Mg(2+), and that the capacity of heterologously expressed TRPM7 mutants to complement TRPM7 deficiency correlates with their sensitivity to Mg(2+). Overall, our results indicate that TRPM7 has a central role in Mg(2+) homeostasis as a Mg(2+) uptake pathway regulated through a functional coupling between its channel and kinase domains.

NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved mitochondrial ADP-ribose pyrophosphatase.

We have recently characterized the protein product of the human NUDT9 gene as a highly specific ADP-ribose (ADPR) pyrophosphatase. We now report an analysis of the human NUDT9 gene and its potential alternative transcripts along with detailed studies of the enzymatic properties and cell biological behavior of human NUDT9 protein. Our analysis of the human NUDT9 gene and twenty-two distinct cloned NUDT9 transcripts indicates that the full-length NUDT9 alpha transcript is the dominant form, and suggests that an alternative NUDT9 beta transcript occurs as the result of a potentially aberrant splice from a cryptic donor site within the first exon to the splice acceptor site of exon 2. Computer analysis of the predicted protein of the NUDT9 alpha transcript identified an N-terminal signal peptide or subcellular targeting sequence. Using green fluorescence protein tagging, we demonstrate that the predicted human NUDT9 alpha protein is targeted highly specifically to mitochondria, whereas the predicted protein of the NUDT9 beta transcript, which is missing this sequence, exhibits no clear subcellular localization. Investigation of the physical and enzymatic properties of NUDT9 indicates that it is functional as a monomer, optimally active at near neutral pH, and that it requires divalent metal ions and an intact Nudix motif for enzymatic activity. Furthermore, partial proteolysis of NUDT9 suggests that NUDT9 enzymes consist of two distinct domains: a proteolytically resistant C-terminal domain retaining essentially full specific ADPR pyrophosphatase activity and a proteolytically labile N-terminal portion that functions to enhance the affinity of the C-terminal domain for ADPR.