bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Disparities between Primary Versus Secondary MGUS in Veteran Patients.
Authors: Malani Ashok , Singh Jaswinder , Pabla Maninder , Patel Vijay , Kambhampati Suman 
Published: April 2020

Abstract
Background: Monoclonal gammopathy of unknown significance (MGUS) is characterized by low levels of a monoclonal protein (M protein) in the serum or urine that is produced by a single clone of plasma cells. Though published evidence indicates that the incidence of MGUS increases with age, the clinical differences between young versus older MGUS patients are not completely understood. We investigated the age-dependent clinical characteristics of veteran patients with MGUS.
Objective: To identify age-dependent disparities in the clinical characteristics of veteran patients with primary versus secondary MGUS.
Methods: A retrospective chart review of 327 MGUS patients seen at the Kansas City Veteran Affairs Medical Center over the last 20 years was performed. “Primary” MGUS was defined as presence of monoclonal immunoglobulin protein (M-spike) in the absence of multiple myeloma (MM), primary amyloidosis, or leukemia/lymphoma. In this report, we use the term “Secondary” MGUS when an M-spike is associated with HIV, or non-HIV-infections, and/or autoimmune diseases. In the final analysis, we broadly subdivided patient with MGUS into age-group ≤ 55 years and ≥ 55 years.
Results: Of the total 327 patients, 14% (44/327) belonged to the age group ≤ 55 years. In our analysis, “Secondary” MGUS was more prevalent in patients ≤ 55 years (30/44; 68%) as compared to that in the ≥ 55 years age group (25/283; 8.5%; p-value &lt;0.0001). In the veteran population, the majority of patients ≤ 55 years age had hepatitis C-associated “Secondary” MGUS (45%). HIV-associated MGUS was also more prevalent in the younger age group (4/44; 9%) as compared to age ≥ 55 years (0/283). Secondary MGUS co-existing with autoimmune disorders was comparatively more common in the younger age group than the older patients (13.6% versus 4.5%; p-value &lt;0.05). IgA subtype was surprisingly not seen in MGUS patients with age ≤ 55 years. Most importantly, MGUS transformation into MM was not seen even after a prolonged follow-up of 20 years in the younger age group of patients.
Conclusion: MGUS in young patients (age ≤ 55 years) is often found in conditions associated with chronic antigenic stimulation or immunosuppression, such as chronic hepatitis B or C, HIV infections, and autoimmune diseases. We thus recommend that young patients (age ≤ 55 years) with MGUS undergo testing for hepatitis B/C, HIV infection if there is a possible history of exposure to these viruses. Our analysis also suggests that these so-called “secondary” MGUS are benign disorders.
Recombinant Human Mannose-Binding Lectin (rhMBL) Binds to Human and Mouse Cancer Cells and Elicits Antitumor Activity in a MBL Knockout Mouse Model of Murine Cancer.
Authors: Sapra Puja , Kraft Patricia , Mehlig Mary , Zhang Zhihua , Greenberger Lee M. , Horak Ivan D. 
Published: April 2020

Abstract
Mannose-binding lectin (MBL), a human plasma protein, plays a role in innate immune defense. MBL recognises microorganisms through surface carbohydrate structures leading to either direct opsonisation or activation of complement system. Since MBL deficiency is associated with increased susceptibility to infections in immunosuppressed individuals, e.g., during chemotherapy induced neutropenia, replacement therapy with recombinant human MBL (rhMBL) may be beneficial in this patient group. MBL has also been shown to bind to cancer cell lines. Therefore, we hypothesized that MBL binding to cancer cells may lead to direct opsonisation or activation of the innate immune system leading to cell kill. In this study, we aim to determine the binding and therapeutic efficacy of rhMBL in cancer cells and animals models respectively. The in vitro binding of rhMBL was evaluated on human cancer cell lines by flow cytometry using a specific anti-MBL antibody. rhMBL demonstrated binding to 6 of 7 cancer cells lines tested. These included human ovarian (OVCAR-3, SK-OV-3), pancreatic (MiaPaCa-2), colorectal (COLO-205), lymphoma (Daudi) and murine melanoma (B16-F0) cancer cells. The binding of rhMBL appeared to be specific since it was partially inhibited by 100mM mannose, 100mM N-acetyl glucosamine, 20mM mannan, use of Ca2+-free buffer or with 10mM EDTA. The antitumor effects of rhMBL were evaluated in MBL knockout (MBL/KO) transgenic mice, which lack both MBL-1 and MBL-2 genes, and corresponding MBL wildtype mice injected subcutaneously with B16-F0 mouse melanoma cells. MBL wildtype mice injected with B16-F0 mouse melanoma cells did not develop subcutaneous tumors. However, MBL/KO mice had robust tumor growth suggesting that MBL deficient individuals may be more susceptible to development of cancers.
Treatment of MBL/KO mice with 75 μg MBL/mouse (q2dx5) resulted in 63% tumor growth inhibition compared with the control mice (P&lt;0.05). Moreover, MBL/KO mice treated with rhMBL had a significant prolongation of life span compared with the control group (P&lt;0.05). In conclusion, rhMBL binds to mouse and human tumor cells and inhibits tumor cell growth in a MBL/KO murine melanoma model. This phenomenon may not take place in MBL-deficient individuals, and these individuals may thus be more susceptible to development of tumors. Replacement therapy with rhMBL in these individuals may have anticancer effects. rhMBL should thus be further evaluated for prevention and treatment of infection complications in MBL deficient immunocompromised patients as well as potential anticancer therapy.
Induction of Potentially Protective HIV-Specific T-Cell Responses In Vitro by Gag mRNA-Electroporated Dendritic Cells.
Authors: Berneman Zwi N. , Van Gulck Ellen R. , Heyndrickx Leo , Ponsaerts Peter , Van Tendeloo Viggo F.I. , Vanham Guido 
Published: April 2020

Abstract
Human immunodeficiency virus type 1 (HIV-1) infection is characterized by dysfunction of HIV-1-specific T-lymphocytes. In order to suppress the virus and delay evolution to AIDS, antigen-loaded antigen-presenting cells, including dendritic cells (DC) might be useful to boost and broaden HIV-1-specific T-cell responses. Monocyte-derived DC from 15 untreated (“naive”) and 15 highly active anti-retroviral therapy (HAART)-treated HIV-1-infected patients were electroporated with codon-optimized (“humanized”) mRNA encoding consensus HxB-2 (hHxB-2) Gag protein. These DC were co-cultured for 1 week with autologous peripheral blood leucocytes (PBL). Potential expansion of specific T-cells was measured by comparing ELISPOT responses of PBL before and after co-culture, using a pool of overlapping peptides, spanning the HxB-2 Gag. Expansion of specific PBL after co-culture was noted for T cells producing interferon (IFN)-gamma, interleukin (IL)-2 and perforin (Wilcoxon signed rank test p&lt;0.05, except for IL-2 in naive patients). From all HIV-1-seropositive persons tested, 12 HAART-treated and 12 naive patients match in absolute number of CD4+ T-cells. A comparison of the increase of the response between day 0 and after 1 week of stimulation between those two groups showed that the response was higher in HAART-treated subjects for IFN-gamma and IL-2 but not for perforin in comparison to untreated subjects. Examining purified CD4+ and CD8+ T-cells after co-culture revealed that HxB-2 Gag peptides induced IFN-gamma in both subsets, that IL-2 was only secreted by CD4+ T-cells and that perforin was dominantly secreted by CD8+ T-cells. Remarkably, the perforin response in the treatment-naive persons was negatively correlated with the peripheral blood absolute CD4+ and CD8+ T-cell count (respectively R=0.618, p=0.014; and R=0.529, p=0.043). Furthermore, the nadir absolute CD4+ T-cell count in HAART-treated subjects was positively correlated with the IL-2 response (R=0.521, p=0.046) and negatively correlated with the perforin response (R=0.588, p=0.021). In conclusion, DC from HAART-treated and therapy-naive subjects, electroporated with hHxB-2 gag mRNA have the capacity to induce secondary T-cell responses. In an earlier study (Van Gulck ER et al. Blood2006;107:1818–1827), we already demonstrated ex vivo that CD4+ and CD8+ T-cells from non-treated HIV-1-infected subjects can be directly triggered by DC electroporated with autologous proviral-derived gag mRNA. Taken together, our results open the perspective for a DC immunotherapy for HIV disease.
C-Reactive Protein Binds to FcγRII and Impairs the Differentiation and Function of Dendritic Cells.
Authors: Qian Jianfei , Yang Jing , Wang Siqing , Zhang Liang , Hong Sungyoul , Han Xiaohong , Yi Qing 
Published: April 2020

Abstract
Human C-reactive protein (CRP) is an acute-phase protein, and elevated levels of CRP are present in patients with infections, inflammatory diseases, necrosis such as myocardial infarction, or malignancies including multiple myeloma (MM), lymphoma, and carcinoma. CRP has many biological functions and is involved in host defense, regulation of inflammation, and modulation of autoimmune diseases. Although our current understanding of CRP interaction with complement and Fcγ receptors (FcγR) has elucidated a regulatory role of CRP in these disease situations, it is not clear whether CRP affects the function of immune cells such as dendritic cells (DCs). In this study, we investigated the effect of CRP on DC differentiation, maturation, and function. CD14+ monocytes isolated from human peripheral blood mononuclear cells were cultured in RPMI-1640 medium supplemented with GM-CSF and IL-4 for 5 days to generate immature DCs (imDCs), and were further treated with IL-1β and TNF-α for 2 additional days to produce mature DCs (mDCs). CRP (5–100 μg/mL) was added to the cultures during DC differentiation (on days 0 and 3) or maturation (on day 5). The presence of CRP in cultures reduced imDC cell yields in a dose-dependent manner. Significantly lower cell yields were detected in cultures with 5 to 10 μg/mL CRP. Compared with untreated controls, CRP treatment (10 μg/mL) led to inhibited surface expression of DC-related molecules HLA-ABC, CD1a, CD40, and CD54; increased secretion of IL-6, IL-8, and IL-10; reduced production of TGF-β by imDCs; and decreased secretion of IL-12 by mDCs. Furthermore, the function of CRP-treated DCs was also impaired, evident by the markedly decreased ability of imDCs to phagocytose apoptotic cells and to uptake and present soluble antigen to antigen-specific T cells. Compared with untreated controls, CRP-treated mDCs had reduced capacity at activating allospecific T cells, which consequently secreted significantly lower amounts of IFN-γ, IL-2, and TNF-α compared with T cells activated by normal mDCs. Western blot analysis showed that CRP treatment led to inhibited phosphorylation of ERK and p38 MAPKs, and inhibited NFκB activity in the differentiating cells. Monocytes and DCs all express FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), and the expression of FcγRII, but not FcγRI and FcγRIII, were upregulated on CRP-treated DCs. The detrimental effects of CRP on DCs were abrogated by blocking antibody against CRP and by antibody against FcγRII, but not against FcγRI or FcγRIII. These results indicate that CRP affected DC differentiation via binding to cell surface FcγRII. Taken together, this study demonstrates for the first time that CRP at high concentrations has detrimental effects on in vitro differentiation and function of DCs. Further studies will be needed to examine the clinical and biological relevance of this observation.
A 17q25.3 Duplication Defines a New Dosage-Sensitive Congenital Neutropenia Locus and Implicates SOCS3 as a Candidate Gene for Cases Unexplained by ELA2 Mutation.
Authors: Mealiffe Matthew E. , Le Doan , Duan Zhijun , Papadaki Helen , Eliopoulos George , Badolato Raffaele , Horwitz Marshall S. 
Published: April 2020

Abstract
We have investigated the etiology of congenital neutropenia in a girl with de novo duplication of chromosome 17q25.3. She presented during the first year of life with neutropenia, episodic hypothermia, failure to thrive, and other congenital abnormalities. Peripheral blood karyotype demonstrated 46,XX,add(17)(q25.3), and molecular cytogenetic studies confirmed interstitial duplication of chr17-derived material. We excluded ELA2 mutation (the most common cause of hereditary neutropenia) and reasoned that the neutropenia and other medical problems most likely were the result of the chromosomal abnormality. In the duplicated 17q25.3 region, SOCS3 emerged as a promising candidate gene responsible for neutropenia, because SOCS3 is a well-characterized negative regulator of G-CSF-receptor signaling and, in murine conditional knockout models, acts as a physiologic negative regulator of granulopoiesis. As we had previously demonstrated that mutations of the Gfi1 transcriptional repressor are a rare cause of human neutropenia, we searched for potential Gfi1 binding sites in the SOCS3 promoter and noted a total of five, and chromatin immunoprecipitation analysis validated occupancy of the SOCS3 promoter by Gfi1 in Jurkat, HL-60, and U937 cells. Thus, several lines of evidence suggested SOCS3 as a plausible neutropenia gene. We confirmed that SOCS3 is indeed duplicated in this patient by both FISH and quantitative genomic PCR. In an effort to identify other patients with SOCS3-related neutropenia, we sequenced both exons of SOCS3 in a total of 66 patients with severe congenital neutropenia (SCN) or cyclic neutropenia (CN) and 94 patients with chronic idiopathic neutropenia of adults (CINA) in whom ELA2 mutations were absent. No coding mutations were detected, but we did identify several variants in the SOCS3 promoter and 5′- and 3′- UTRs, including a single base pair substitution (+1779AtoG) in the 3′-UTR in a SCN patient and deletion of a single G (-1318delG) occurring in a six-G tract immediately adjacent to a predicted STAT binding site in a highly conserved region of the SOCS3 promoter (found in heterozygous and homozygous form in several patients with CN and SCN). The 3′-UTR alteration was absent in 270 control chromosomes and is located within a predicted binding site for miR-449 that is well-conserved across mammalian species. In sum, we have identified a patient with congenital neutropenia and a de novo duplication of 17q25.3 defining a new candidate locus for congenital neutropenia, and the evaluation to date suggests that SOCS3 is a promising dosage sensitive candidate gene in this interval that additionally could be a key target in neutropenia associated with Gfi1 mutations.
Transgenic GATA1ie3.9int - DAPK2 Mice Exhibit Low-Grade Anemia, Deficient Stress Erythropoiesis, and Compromised Erythroblast Survival.
Authors: Fang Jing , Menon Madhu P. , Zhang Diya , Tschan Mario , Torbett Bruce , Pramanik Nayani , Houde Estelle , Wojchowski Don M. 
Published: April 2020

Abstract
Death-associated protein kinases (DAPKs) include DAPK-1, DAPK-2, ZIPK and death receptor associated kinase 1 & 2 (DRAK-1 and -2). DAPK-1 and -2 are highly homologous in their shared serine-threonine kinase domains, and calmodulin and phospho-serine regulatory regions. DAPK1 is cytoskeletally associated via ankyrin repeats, and modulates a p19ARF/p53 pathway. DAPK2 is cytoplasmic, less widely distributed, and is expressed predominantly in erythroid cells. Hypothesized effects of DAPK2 on erythroblast formation presently were tested by preparing and studying several independent lines of GATA1ie3.9int-DAPK2 transgenic mice. At steady-state, hematocrits in GATA1ie3.9int-DAPK2 mice were mildly yet significantly decreased (while other lineages were essentially unaffected). Reticulocyte production also was modestly increased, and spleen morphologies were altered. During hemolytic anemia, however, DAPK2 mice exhibited comparably sharp deficiencies in stress erythropoiesis including prolonged decreases in hematocrits (as observed in repeated experiments at varied phenylhydrazine dosing). The basis for this stress-associated erythropoietic defect due to DAPK2 was investigated further in primary bone marrow erythroid progenitor cells ex vivo. A stage-specific defect in erythroblast formation was discovered specifically at KitnegCD71highTer119neg stage. Later stage CD71highTer119pos DAPK2-erythroblasts also were somewhat under-represented (but perhaps as a consequence of decreased KitnegCD71high pools.) In addition, DAPK2-progenitors gave rise to increased frequencies of Annexin V positive apoptotic erythroblasts. These first-time analyses of DAPK2 function in a relevant primary cell model reveal negative regulation of stage-specific erythroblast pool selectively during stress erythropoiesis, and in part via pro-apoptotic mechanisms.
Phenotypic Changes of Hematopoietic Stem Cells and Stromal Cells by Aberrant Expression of GATA−2; Possible Role for the Development of Aplastic Anemia.
Authors: Okitsu Yoko , Harigae Hideo , Takahashi Shinichiro , Minegishi Naoko , Suzuki Norio , Kameoka Junichi , Yamamoto Masayuki , Sasaki Takeshi 
Published: April 2020

Abstract
(Introduction) Aplastic anemia (AA) is characterized by a fatty bone marrow and the reduced number of hematopoietic stem cell (HSC)s, resulting in peripheral pancytopenia. Several clinical studies have reported that the expression of transcription factor GATA−2 is significantly decreased in CD34 positive cells in AA, suggesting that downregulation of GATA−2 in HSCs may cause the reduction of number of HSCs in AA. Of note, GATA−2 has been shown to be essential for the maintenance of immaturity of preadipocytes as well as HSCs. If GATA−2 functions in the differentiation of stromal preadipocytes in bone marrow, GATA−2 may be involved in the formation of a fatty bone marrow in AA. In order to explore the role of GATA−2 for development of AA, phenotypic changes of HSCs and stromal preadipocytes by aberrant expression of GATA−2 were examined in this study.
(Method) First, to analyze phenotypic changes of HSCs by decreased expression of GATA-2, lineage negative, sca-1 positive, c-kit positive (LSK) cells were sorted both from wild-type and GATA-2 haplodeficient mice (kindly provided Dr SH Orkin), and the gene expression profile was compared by cDNA array. The difference of expression level on cDNA array was confirmed by RQ-PCR. Next, in order to examine the role of GATA-2 in the differentiation of stromal preadipocytes, the GATA-2-GFP expression vector was transfected into TBR343, a mouse stromal preadipocyte cell line, and GFP positive cells were sorted. The differentiation capacity of these GATA-2 overexpressing TBR343 cells was compared to that of control cells. In addition, GATA-2 expression was suppressed by using siRNA in TBR343, and the phenotypic change was also examined.
(Results) By comparing the gene expression profile, the expression levels of cyclin D1, D3, p21, E2F, c-Myc were found to be decreased in GATA-2 haplodeficient LSKs, suggesting GATA-2 down-regulation in HSCs may inhibit the cell cycle progression. When GATA-2 was overexpressed in TBR343, the oil drop formation and adipocyte-specific gene expression was significantly suppressed. Conversely, When GATA-2 was suppressed in TBR343 by siRNA, the oil drop formation and adipocyte-specific gene expression was significantly accelerated, suggesting that decrease of GATA-2 expression accelerates the differentiation of stromal preadipocytes.
(Conclusion) These results suggest that suppression of GATA-2 in the bone marrow leads to an inactive cell cycle of HSCs and the accumulation of mature adipocytes, which may contribute to the expression of the representative features of AA, a fatty bone marrow and the reduced number of HSCs.
HematideTM, a Synthetic Peptide-Based Erythropoiesis Stimulating Agent (ESA), Assessed for Correction of Anemia in Oncology Patients Receiving Chemotherapy.
Authors: Pickering Lisa M. , Cwiertka Karel , Jassem Jacek , Petera Jiri , Pettengell Ruth , Ramlau Rodryg , Vorlicek Jiri , Vyzula Rostislav , Andresen Corina , Chang Stephen , Duliege Anne-Marie , Leong Robert , Stead Richard , Harper Peter G. 
Published: April 2020

Abstract
Introduction: Hematide™, a novel synthetic PEGylated peptidic compound, binds to and activates the erythropoietin receptor. It is being developed for the treatment of anemia associated with chronic kidney disease and cancer.
Objective: To assess the subcutaneous (SC) Hematide™ dose required to increase hemoglobin (Hgb) by ≥1 g/dL in anemic cancer patients on chemotherapy. Safety, PD and PK assessment of Hematide™ are also planned.
Method: In an ongoing phase 2, openlabel, multicenter, dosefinding study, Hematide™ is being given SC in 15 patient cohorts every 3 wks for 4 doses. The initial dose is 0.10 mg/kg. Entry criteria include confirmed solid tumor malignancy or lymphoma, ≥9 weeks of chemotherapy, baseline (BL) Hgb ≥8 and &lt;11 g/dL, and adequate iron, folate, and B12 stores.
Results: Preliminary results are presented for the 1st cohort. Mean body weight for the 8 female and 7 male patients was 67.8Kg. Nine out of 15 patients completed 12 weeks follow-up. Six patients terminated early for non-study drug related SAEs (2), remission of cancer (1), or transfusions (3, Hgb values posttransfusion excluded from this report) . Week 7: 10 patients completed Week (Wk) 7 with data available. Their mean ± SD Hgb increased from BL by 1.6 ± 1.8 g/dL. Seven had a ≥1.0 g/dL Hgb increase (range 1.7–3.7 g/dL) at Wk 7. Of the remaining 3 patients, 2 had a Hgb increase of 1.65 and 1.1 g/dL, respectively at Wk 9; the 3rd had a Hgb increase of 1.7 g/dL at Wk 12. One patient with missing Wk 7 data had Hgb increases of 1.8 and 3.4 g/dL at Wk 6 and 9 respectively. Week 9: 11 patients had Wk 9 data that show a mean ±SD Hgb increase from baseline of 2.2 ±1.79 g/dL. Of these, 10 had Hgb increases of ≥1.0 g/dL (range 1.1–5.2 g/dL). The one patient who did not have ≥1.0 g/dL Hgb increase at Wk 9 had a Hgb increase of 1.7 g/dL at Wk 12. Four SAEs (none related to study drug) were reported in 3 patients.
Conclusion: Preliminary data from the 1st cohort indicate that Hematide™ given every 3 wks appears to be well tolerated and results in an increase in Hgb of ≥ 1g/dL by Wk 7 in the majority of this study population. Additional data will be presented as it becomes available.