Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells

<p>Abstract</p> <p>Background</p> <p>Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.</p> <p>Results</p> <p>Here we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.</p> <p>Conclusions</p> <p>BMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.</p

LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers

Towards long-tailed, multi-label disease classification from chest X-ray: Overview of the CXR-LT challenge

Many real-world image recognition problems, such as diagnostic medical imaging exams, are "long-tailed" \unicode{x2013} there are a few common findings followed by many more relatively rare conditions. In chest radiography, diagnosis is both a long-tailed and multi-label problem, as patients often present with multiple findings simultaneously. While researchers have begun to study the problem of long-tailed learning in medical image recognition, few have studied the interaction of label imbalance and label co-occurrence posed by long-tailed, multi-label disease classification. To engage with the research community on this emerging topic, we conducted an open challenge, CXR-LT, on long-tailed, multi-label thorax disease classification from chest X-rays (CXRs). We publicly release a large-scale benchmark dataset of over 350,000 CXRs, each labeled with at least one of 26 clinical findings following a long-tailed distribution. We synthesize common themes of top-performing solutions, providing practical recommendations for long-tailed, multi-label medical image classification. Finally, we use these insights to propose a path forward involving vision-language foundation models for few- and zero-shot disease classification

Galectin 7 leads to a relative reduction in CD4+ T cells, mediated by PD-1

Abstract The role of glycan-binding proteins as an activator of immune regulatory receptors has gained attention recently. We report that galectin 7 reduced CD4+ T cell percentage in both in vitro culture and mouse tumor models. Immunohistochemical staining of esophageal cancer patient samples showed a lower percentage of CD4+ cells in the galectin 7 high area. The lack of CD4+ T cell depletion by galectin 7 in PD-1 knockout mice supports the role of PD-1 in mediating the effects of galectin 7. The binding assays demonstrate that galectin 7 binds to the N-glycosylation of PD-1 on N74 and N116 sites and leads to the recruitment of SHP-2. NFAT suppressive activity of galectin 7 was abrogated upon overexpression of the dominant negative SHP-2 mutant or inhibition of PD-1 by siRNA. Glycosylation of PD-1 has been reported to play a critical role in surface expression, stability, and interaction with its ligand PD-L1. This report further expands the significance of PD-1 glycosylation and suggests that galectin 7, a glycan-binding protein, interacts with the immune regulatory receptor PD-1 through glycosylation recognition

Characterization of Mesenchymal Stem Cells from Human Vocal Fold Fibroblasts

OBJECTIVES/HYPOTHESIS: Mesenchymal stem cells (MSCs) originally isolated from bone marrow (BM), are fibroblast-looking cells that are now assumed to be present in the stromal component of many tissues. MSCs are characterized by a certain set of criteria, including their growth culture characteristics, a combination of cell surface markers, and the ability to differentiate along multiple mesenchymal tissue lineages. We hypothesized that human vocal fold fibroblasts (hVFF) isolated from the lamina propria meet the criteria established to define MSCs and are functionally similar to MSCs derived from BM and adipose tissue. STUDY DESIGN: In vitro study. METHODS: hVFF were previously derived from human vocal fold tissues. MSCs were derived from adipose tissue (AT), and BM of healthy donors based on their attachment to culture dishes and their morphology and expanded in culture. Cells were analyzed for standard cell surface markers identified on BM-derived MSCs and the ability to differentiate into cells of mesenchymal lineage (i.e., fat, bone, and cartilage). We investigated the immunophenotype of these cells before and after interferon-gamma (INF-gamma) stimulation. RESULTS: hVFF displayed cell surface markers and multipotent differentiation capacity characteristic of MSCs. Furthermore, these cells exhibited similar patterns of expression of human leukocyte antigen and costimulatory molecules, after stimulation with INF-gamma compared to MSCs derived from BM and AT. CONCLUSIONS: Based on our findings, hVFF derived from lamina propria have the same cell surface markers, immunophenotypic characteristics, and differentiation potential as BM- and AT-derived MSCs. We propose that vocal fold fibroblasts are MSCs resident in the vocal fold lamina propria

Thiol-ene Michael-type formation of gelatin/poly(ethylene glycol) biomatrices for three-dimensional mesenchymal stromal/stem cell administration to cutaneous wounds

Mesenchymal stromal/stem cells (MSCs) are considered promising cellular therapeutics in the fields of tissue engineering and regenerative medicine. MSCs secrete high concentrations of immunomodulatory cytokines and growth factors, which exert paracrine effects on infiltrating immune and resident cells in the wound microenvironment that could favorably promote healing after acute injury. However, better spatial delivery and improved retention at the site of injury are two factors that could improve the clinical application of MSCs. In this study, we utilized thiol-ene Michael-type addition for rapid encapsulation of MSCs within a gelatin/poly(ethylene glycol) biomatrix. This biomatrix was also applied as a provisional dressing to full thickness wounds in Sprague-Dawley rats. The three-way interaction of MSCs, gelatin/poly(ethylene glycol) biomatrices, and host immune cells and adjacent resident cells in the wound microenvironment favorably modulated wound progression and host response. In this model we observed attenuated immune cell infiltration, lack of foreign giant cell (FBGC) formation, accelerated wound closure and re-epithelialization, as well as enhanced neovascularization and granulation tissue formation by 7 days. The MSC entrapped in the gelatin/poly(ethylene glycol) biomatrix localized cell presentation adjacent to the wound microenvironment and thus mediated the early resolution of inflammatory events and facilitated the proliferative phases in wound healing. © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.Link_to_subscribed_fulltex

Dental caries prevalence of medieval Korean people

Objectives: Prevalence and distribution of dental caries in medieval Korean society were evaluated. Materials and methods: Two thousand and nine hundred teeth samples of 126 individuals collected from 16th to 18th century Korean tombs. Results: Preservation status of sample was good. The prevalence of ante- and postmortem tooth loss was 4.4% and 14.2%, respectively. The total caries prevalence was 3.9%. The tooth surface most frequently affected by dental caries was occlusal (4.5%), followed by approximal (2.1%), buccal (1.5%), and lingual (1.1%) surfaces. Discussion: The prevalence of dental caries in Joseon Dynasty skeleton collection was lower than have been found in other collections of similar chronology. The low consumption of refined sugar in medieval Korean society might be a possible explanation, though the technical limitations inherent in such comparison studies preclude definitive conclusions.Esclassan R, 2009, ARCH ORAL BIOL, V54, P287, DOI 10.1016/j.archoralbio.2008.11.004Kim MJ, 2008, INT J OSTEOARCHAEOL, V18, P614, DOI 10.1002/oa.962SHIN MH, 2008, MUMMIES SCI WORLD MU, P105Caglar E, 2007, ARCH ORAL BIOL, V52, P1136, DOI 10.1016/j.archoralbio.2007.05.010Arnold WH, 2007, INT J OSTEOARCHAEOL, V17, P52, DOI 10.1002/oa.859Wesolowski V, 2006, MEM I OSWALDO CRUZ, V101, P139VODANOVIC M, 2005, ARCH ORAL BIOL, V50, P669Oyamada J, 2004, ANTHROPOL SCI, V112, P235, DOI 10.1537/ase.040309HILL SK, 2003, J FORENSIC NEUROPSYC, V3, P1Duyar I, 2003, HOMO, V54, P57Elvery MW, 1998, AM J PHYS ANTHROPOL, V107, P211Keenleyside A, 1998, AM J PHYS ANTHROPOL, V107, P51Watt ME, 1997, ARCH ORAL BIOL, V42, P601Whittaker DK, 1996, ARCH ORAL BIOL, V41, P55OSULLIVAN EA, 1993, CARIES RES, V27, P147VARRELA TM, 1991, ARCH ORAL BIOL, V36, P553KERR NW, 1990, J DENT RES, V69, P857KERR NW, 1988, ARCH ORAL BIOL, V33, P143MOLNAR S, 1985, AM J PHYS ANTHROPOL, V67, P51BROTHWELL DR, 1981, DIGGING BONES, P71WHITTAKER DK, 1981, ARCH ORAL BIOL, V26, P237TURNER ICG, 1979, AM J PHYS ANTHROPOL, V51, P619CORBETT ME, 1976, CARIES RES, V10, P401MOORE WJ, 1975, CARIES RES, V9, P163LUNT DA, 1974, ARCH ORAL BIOL, V19, P431KANG HJ, 1974, HAEHENGCHONGJAEMOORE WJ, 1973, CARIES RES, V7, P139MOORE WJ, 1971, CARIES RES, V5, P151KEYES PH, 1968, J AM DENT ASSOC, V76, P1357HARDWICK JL, 1960, BRIT DENT J, V108, P9CLEMENT AJ, 1956, BRIT DENT J, V101, P4BEGG PR, 1954, AM J ORTHOD DENTOFAC, V40, P298*MIN HLTH WELF FAM, KOR NAT OR HLTH SURV