Backpack weight and back pain reduction: effect of an intervention in adolescents.

BACKGROUND: To assess if an educational intervention is effective to reduce backpack weight and back pain in schoolchildren. METHODS: We designed an intervention study in schoolchildren aged between 12 and 16 years aimed to reduce the weight of backpacks and back pain. The intervention was multifaceted, including an educational intervention with practical examples, advising on performing sports, postural habits, leaflets, stickers, and so on. The comparison group did not receive any intervention. RESULTS: A total of 1668 schoolchildren took part in the study. We observed a high prevalence of carrying heavy backpacks, with 66-80% of schoolchildren carrying backpacks surpassing 10% of their body weight. Back pain prevalence was 30%. We observed that the intervention was significant in reducing the backpack weight in first-year schoolchildren but not in second-year. The intervention was also significant in reducing back pain in third-year schoolchildren but only in girls. CONCLUSION: This study shows that an inexpensive intervention directed to reduce the backpack weight and back pain might have a positive effect in schoolchildren.

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells.

BACKGROUND: Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. METHODS: We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. RESULTS: At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. CONCLUSION: Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. TRIAL REGISTRATION: Clinicaltrials.gov NCT00442130. FUNDING: NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells.

CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker.

Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients.

PURPOSE: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance. EXPERIMENTAL DESIGN: We assessed whether leukemia neoantigens could be generated from drug-resistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML). RESULTS: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC(50) < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC(50) = 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8+ T cells were detected in two imatinib-resistant HLA-A3+ CML patients concurrent with an effective anti-CML response to further therapy. CONCLUSIONS: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens.

School children's backpacks, back pain and back pathologies.

OBJECTIVE: To investigate whether backpack weight is associated with back pain and back pathology in school children. DESIGN: Cross-sectional study. SETTING: Schools in Northern Galicia, Spain. PATIENTS: All children aged 12-17. INTERVENTIONS: Backpack weight along with body mass index, age and gender. MAIN OUTCOME MEASURES: Back pain and back pathology. RESULTS: 1403 school children were analysed. Of these, 61.4% had backpacks exceeding 10% of their body weight. Those carrying the heaviest backpacks had a 50% higher risk of back pain (OR 1.50 CI 95% 1.06 to 2.12) and a 42% higher risk of back pathology, although this last result was not statistically significant (OR 1.42 CI 95% 0.86 to 2.32). Girls presented a higher risk of back pain compared with boys. CONCLUSIONS: Carrying backpacks increases the risk of back pain and possibly the risk of back pathology. The prevalence of school children carrying heavy backpacks is extremely high. Preventive and educational activities should be implemented in this age group.

Novel myeloma-associated antigens revealed in the context of syngeneic hematopoietic stem cell transplantation.

Targets of curative donor-derived graft-versus-myeloma (GVM) responses after allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility Ags (mHAgs) complicates the elucidation of multiple myeloma (MM)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GVM-associated Ags because donor immune responses in this setting should exclusively target unique tumor Ags in the absence of donor-host genetic disparities. Therefore, in the present study, we investigated the development of tumor immunity in an HLA-A0201(+) MM patient who achieved durable remission after myeloablative syngeneic HSCT. Using high-density protein microarrays to screen post-HSCT plasma, we identified 6 Ags that elicited high-titer (1:5000-1:10 000) Abs that correlated with clinical tumor regression. Two Ags (DAPK2 and PIM1) had enriched expression in primary MM tissues. Both elicited Ab responses in other MM patients after chemotherapy or HSCT (11 and 6 of 32 patients for DAPK2 and PIM1, respectively). The index patient also developed specific CD8(+) T-cell responses to HLA-A2-restricted peptides derived from DAPK2 and PIM1. Peptide-specific T cells recognized HLA-A2(+) MM-derived cell lines and primary MM tumor cells. Coordinated T- and B-cell immunity develops against MM-associated Ags after syngeneic HSCT. DAPK1 and PIM1 are promising target Ags for MM-directed immunotherapy.

Phenotypic and functional delineation of murine CX(3)CR1 monocyte-derived cells in ovarian cancer.

Ovarian tumor progression is marked by the peritoneal accumulation of leukocytes. Among these leukocytes, an immunosuppressive CD11b(+)CD11c(+) population has been identified in both human and ovarian tumors. The use of transplantable models of murine ovarian tumors has demonstrated that this population promotes ovarian tumor growth, whereas elimination of this population has been shown to inhibit ovarian tumor progression. Despite the demonstrated importance of these cells to ovarian tumor progression, the mechanisms by which these cells are recruited to the peritoneal tumor are largely unknown. Therefore, this study analyzes the mechanisms these cells use to migrate to the peritoneum with the goal of therapeutically blocking their recruitment and subsequent immunosuppressive activity. Recent studies have identified that CX(3)CR1, Gr-1, and CCR2 delineate phenotypic and functional murine monocyte subsets. Here, we report that CX(3)CR1(lo)Gr-1(hi) cells dominate the population of peritoneal CD11b(+) leukocytes early in murine tumor development; however, the CX(3)CR1(hi) population of cells present in the peritoneum dramatically increases in both total numbers and percentage during tumor progression. Functional analyses reveal that both of these CX(3)CR1 subsets are immunosuppressive to naive CD8(+) and CD4(+) T-cell responses. Importantly, we demonstrate that CCR2 is a critical functional facilitator of leukocyte recruitment to the ovarian tumor microenvironment, and its genetic deletion results in a reduced tumor burden compared with wild-type mice. These results demonstrate that subsets of immunosuppressive leukocytes are recruited to the ovarian tumor environment through the CCR2 pathway, which offers a viable therapeutic target to inhibit their migration to the tumor site.

Pivotal Advance: Toll-like receptor regulation of scavenger receptor-A-mediated phagocytosis.

Class-A scavenger receptors (SR-A) and TLR mediate early immune responses against pathogenic bacteria. SR-A and TLR molecules are expressed on phagocytes and interact with common ligands from Gram-negative and Gram-positive bacteria; however, the contribution of TLR activity to SR-A-mediated phagocytosis has not been assessed directly. Herein, we provide genetic and functional evidence that ligand- and TLR-specific stimuli synergize with SR-A to mediate bacterial phagocytosis. Although complete loss of SR-A (SR-A(-/-)) is known to impair bacterial clearance, here we identify the first deficiency attributable to SR-A heterozygosity: SR-A(+/-)TLR4(+/-) cells and mice are impaired significantly in the clearance of Gram-negative Escherichia coli. This phenotype is specific to the TLR signaling event, as SR-A(+/-)TLR4(+/-) cells are not deficient for the clearance of Gram-positive Staphylococcus aureus bacteria, which contain cell-surface TLR2 ligands but lack TLR4 ligands. We demonstrate that this is a global, phagocytic mechanism, regulated independently by multiple TLRs, as analogous to the SR-A(+/-)TLR4(+/-) deficit, SR-A(+/-)TLR2(+/-) cells are impaired for S. aureus uptake. In support of this, we show that SR-A(+/-)MyD88(+/-) cells recapitulate the phagocytosis defect observed in SR-A(+/-)TLR4(+/-) cells. These data identify for the first time that TLR-driven innate immune responses, via a MyD88 signaling mechanism, regulate SR-A-dependent phagocytosis of bacteria. These findings provide novel insights into how innate immune cells control SR-A-mediated trafficking and are the first demonstration that subtle changes in the expression of SR-A and TLRs can substantially affect host bacterial clearance.

Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression.

The predominant leukocyte population present in both human and murine peritoneal ovarian tumors is the Vascular Leukocyte (VLC). VLCs are recruited en masse to the ovarian tumor microenvironment whereupon they promote tumor progression. Importantly, the presence of VLCs is requisite for peritoneal ovarian cancer progression: selective elimination of VLCs inhibits tumor burden and ascites accumulation. Despite the critical importance of VLCs to ovarian tumors, their derivation and the mechanisms by which they facilitate tumor progression are not well understood. Here we demonstrate in vivo that the murine ID8 ovarian tumor model can usurp the host peritoneal macrophage pathway to elicit and recruit VLCs. Moreover, we demonstrate that VLCs express CD11b and Gr-1, a characteristic phenotype shared amongst heterogeneous populations of leukocytes referred to as myeloid-derived suppressor cells (MDSCs). In accord with their MDSC phenotype, both murine and human VLCs express arginase-1 (ARG1). Importantly, we demonstrate that the VLCs suppress both CD8(+) and CD4(+) T cells responses and that this immunosuppression is ARG1-dependent, since blockade of VLC ARG1 activity with nor-NOHA reversed the immunosuppression. These data further characterize the tumor-associated leukocytes in ovarian cancer and provide insights into the mechanisms by which they promote tumor growth.