bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Tolerance with a High Purity Plasma Derived Factor VIII Containing Von Willebrand Factor in Haemophilia A Patients with High Responding Inhibitors.
Authors: Polack Benoit , Beurrier Philippe , Rothschild Chantal , Orsini Frédérique , Faradji Albert , Liennhard Anne , Fressinaud Edith , Goudemand Jenny 
Published: October 2019

Abstract
We report on 8 patients with severe haemophilia A and high responding anti-factor VIII (FVIII) inhibiting antibody in whom immune tolerance (IIT) was induced with a high purity plasma derived FVIII containing 14 to 20 IU/ml of von Willebrand factor (VWF) as a stabiliser. Their median ages at the diagnosis of the inhibitor was 10.6 months and ranged from 5 months to 9 years. At the onset of IIT, the median age was 1 year and 9 months and ranged from 9 months to 24.5 years. The median cumulative exposure days (CED) was 18.5 days and varied from 8 to 81 days when inhibitor was detected. The maximum level of inhibitor reached from 10 to 500 Bethesda Units (BU) with a median of 22.5 BU. Before inhibitor diagnosis 6 patients had received plasma derived high purity FVIII and 2 had received recombinant FVIII. The treatment schedule started with 50 IU/kg to 200 IU/kg FVIII every day. The time to reach an inhibitor level <1 BU was available for 5 patients; its median was 142 days and varied from 75 to 216 days. The treatment was considered successful when either the recovery or the half life of FVIII was normalized. The outcome was successful in 7 out of the 8 patients (87.5 %) who are now receiving FVIII concentrates either on demand or prophylactically. The last patient was considered as a partial success since the titre of his inhibitor was 0.8 BU and he could be treated by FVIII concentrates when needed. No definite IIT failure was observed in this cohort of patients. Since all the patients are by now back to FVIII treatment we can consider having a 100% success in IIT in this small cohort of patients. Therefore, despite the size of our cohort of patients, our study shows that high purity FVIII stabilized by VWF is an effective drug for the eradication of anti-FVIII inhibitors through induction of immune tolerance.
Patients data
Patient Age at FVIII 1st infussion Age at inhibitor diagnosis CED at inhibitor diagnosis Age at IIT Inhibitor max.titre (BU) Time (d) <1 BU IIT results N.A.; not available 1 9m 1y 9 1y 3m 52 93 Success 2 2d 4y 3m 81 4y 3m 21 N.A. Success 3 8y 10m 9y 33 24y 6m 30 N.A. Success 4 8m 10m 28 1y 8m 24 75 Success 5 8m 8.5m 8 9m 14.5 - Partial success 6 1y 1m 1y 10m 21 3y 1m 10 142 Success 7 6m 9m 10 11m 20 216 Success 8 4m 5m 16 1y 9m 500 176 Success
HIV Envelope Protein gp120 Stimulates Expression of Specific Chemokines in Lymphatic Endothelial Cells.
Authors: Zhang Xuefeng , Wang Jian Feng , Groopman Jerome E. 
Published: October 2019

Abstract
Lymphoid organs are the major anatomical home of HIV, where the virus replicates during both the acute and chronic phases of infections. In this regard, there are significantly more infected cells in lymph nodes (LNs) than in circulating blood, and these infected cells are a major reservoir of infectious HIV. Certain chemokines like CCL19 (MIP-3β) and CCL21 (SLC) play key roles in immune cell trafficking to LNs. They induce specific homing of naïve T cells and dendritic cells into the T cell zone of secondary lymphoid organs. There, the T cells become activated by the dendritic cells. A network of channels composed of lymphatic endothelium exists in LNs that provides a route for this dendritic cell and T cell movement. To date, how this lymphatic endothelium may contribute to the pathogenesis of HIV infection has not been studied. This prompted us to investigate whether HIV may alter immune cell trafficking via interaction with this lymphatic network. Lymphatic endothelial cells (LEC) were separated from primary dermal microvascular endothelial cells. The phenotype of LEC was confirmed by immunostaining with specific lymphatic markers including VEGFR-3, LYVE-1, and podoplanin. Since HIV envelope proteins are presented to endothelial cells in the microenvironment, we studied the effects of X4 gp120 on LEC. Using a pathway specific cDNA array, we detected enhanced expression of a restricted repertoire of chemokines in LEC upon HIV-1 gp120 stimulation. Gp120 upregulated expression of the chemokine genes GRO-α, GRO-γ, MIP-3β, and SDF-1α and β in LEC. These chemokines can act to enhance T cell and dendritic cell homing to LNs. Furthermore, we also detected GRO-α, SDF-1, and SLC proteins in culture supernatants of the gp120-treated LEC. We did not observe upregulation of the chemokines RANTES and MCP-1 upon gp120 stimulation. Since dendritic cells mediate the HIV infectivity of CD4+ T cells by presenting HIV particles, our study suggests that HIV-1 gp120-induced production of a restricted repertoire of chemokines in LEC may accelerate the trafficking of infected dendritic cells to LNs and foster HIV infection in this reservoir.
Abbreviated Treatment with Short-Course Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Is Highly Effective in AIDS-Related Lymphoma (ARL).
Authors: Dunleavy Kieron , Little Richard , Gea-Banacloche Juan , Grant Nicole , Steinberg Seth , Yarchoan Robert , Pittaluga Stefania , Jaffe Elaine , Janik John , Wilson Wyndham H. 
Published: October 2019

Abstract
In ARL, rituximab may slightly improve CHOP response but is associated with greater toxicity (Proc Am Soc Hem102:1488, 2003). We hypothesized that the addition of rituximab to DA-EPOCH may increase fractional tumor cell kill and allow fewer treatment cycles and lower immune suppression. Patients received DA-EPOCH-R (E=etoposide 50 mg/m2/d, O=vincristine 0.4 mg/m2/d and H=doxorubicin 10 mg/m2/d all CIV d 1–4 (96 hours); C=cyclophosphamide 750 mg/m2 IV d5; P=prednisone 60 mg/m2 PO qd d1–5 and R=rituximab 375 mg/m2 IV d1 and 5) with G-CSF. Prophylactic IT MTX x 6 was administered. HAART was discontinued before and recommenced after DA-EPOCH-R. Unlike our previous study of DA-EPOCH in ARL (BLOOD101:4653, 2003) where the dose of C was lower and based on CD4 cell count, all patients on this study received full dose C on cycle 1 with subsequent reduction if the ANC nadir was < 500/mm3 for ≥ 2 days. Patients received 1 cycle beyond CR, based on CT and PET, for a minimum of 3 cycles. Characteristics of 21 patients include median (range) age 39 (9–61) years; IPI 3 (0–4); ECOG PS 2 (1–4); CD4 212 (0–674) cells/mm3 and HIV viral load 53100 (0– 286472) RNA copies/mL. Additionally, male sex 17 (81%); LDH> nl 15 (71); stage IV 15 (71%) and histology with diffuse large B-cell 9 (90%) and Burkitt’s lymphoma 2 (10%). The 18 patients who completed treatment (2 TE; 1 NE) received a median (range) of 3 (3–5) cycles. Responses are CR/CRu 15 (83%); PR 1 (6%) and NR 2 (11%). At 19 mos median follow-up, overall PFS and OS are both 77%, and both 90% in patients with CD4 > 100 cells/mm3. Treatment outcome of DA-EPOCH-R is similar to DA-EPOCH (CR 74% and PFS 73% at 53 months) but with significantly shorter treatment (median cycles 3 vs. 6). Toxicity on 57 cycles include ANC < 500/mm3 on 27 (47%); platelets < 50,000/mm3 on 15 (26%) and; fever/neutropenia on 20 (35%) cycles. DA-EPOCH-R produced a median (range) CD4 cell decrement of 64 (−541 to + 239) cells/mm3 compared to 189 (−973 to +19) with DA-EPOCH. Hematological toxicity is higher with DA-EPOCH-R compared to DA-EPOCH with ANC < 500/mm3 47% vs 30% and fever/neutropenia 35% vs. 13%, respectively, likely due to higher C dose intensity and/or rituximab. Other toxicities are similar. Abbreviated DA-EPOCH-R is equivalent to DA-EPOCH x 6 and appears to produce less CD4 cell loss. Accrual continues.
Figure Figure
Adolescents with Hodgkin Lymphoma Treated on Adult and Pediatric Protocols Have Distinct Therapeutic Outcome.
Authors: Mottl Alexis A. , Fisher Susan G. , Fisher Richard I. , Constine Louis S. , Friedberg Jonathan W. 
Published: October 2019

Abstract
Hodgkin Lymphoma (HL) is a B cell malignancy, highly curable in the modern era (1989–2004). It is the most common cancer in the 15–19 age range. In the United States, adolescents with de novo HL may be treated on either pediatric or adult protocols. To identify outcomes of adolescents with HL, we conducted a comprehensive literature review and statistical analysis of all treatment trials (N > 50 pts) published in the past 15 years. Trials were selected for their relevance to treatment and disease outcome in adolescents with the following search criteria: Hodgkins disease, therapy, treatment, adolescents (13–18 years), and adults (19–44 years). The search retrieved 120 randomized control trials and 57 Phase II trials. 117 trials were eliminated due to inappropriate histology, non-clinical endpoints, topic reviews or otherwise not meeting established criteria. 79 studies were eligible for analysis. 15 pediatric treatment protocols (13 multi-center, 7 randomized) met established criteria. 7 identified the number of adolescents on trial (N=958/2675; 36%). Only 3 of these studies evaluated adolescent outcome; one trial demonstrated an inferior event-free survival for the adolescent subgroup vs. all children (72.0% vs. 89.0%; p-value 0.006, Chi Square Test). 57 adult treatment studies (39 multi-center, 44 randomized) were reviewed. 7 identified the number of adolescents on trial (N=422/2522; 17%). Only one provided information on adolescent outcome, which experienced a superior overall survival compared with the entire population (86.0% vs. 73.1%; p-value 0.030, Chi Square Test). None of the trials with both pediatric and adult subjects (7 multi-center, 4 randomized) provided information on the adolescent subgroup. In comparing pediatric and adult trials, we found remarkable differences in therapeutic approaches (all pediatric studies included XRT as a treatment component compared to 58% of adult studies) and in trial design (77% of adult studies were randomized compared to 47% of pediatric studies; p-value 0.0234, Fishers Exact Test). The adolescent population with HL is significantly understudied despite reasonable clinical trial participation and relatively high prevalence. In fact, only 4 published trials provided outcome information on adolescents with HL; in 2, outcome was statistically different from the rest of the study population, suggesting this subgroup may benefit from a specialized treatment approach. It is critical for future treatment trials to analyze results of the adolescent population to determine whether unique biological features, therapeutic practices, or host factors contribute to prognosis and outcome.
Assessment of the Economic Value of the Intercept Blood System for Platelets in Belgium.
Authors: Moeremans Karen , Warie Hans , Annemans Lieven , Digneffe Toon , Toté Jacques , Corash Laurence 
Published: October 2019

Abstract
Objectives: Despite transfusion safety measures, a residual risk of infection remains. New emerging pathogens continue to threaten blood safety, requiring novel approaches to prevent transmission as from the time of emergence. INTERCEPT Blood System for platelets (IBSP) inactivates different types of pathogens including viruses, bacteria and parasites, aiming at eliminating the residual risk of screened infections, the risk of other existing pathogens and the risk of transmitting emerging pathogens. The objective was to evaluate the potential incremental cost-effectiveness ratio (ICER) associated with implementing IBSP in Belgium.
Methods: A decision model compares a “world with IBSP” to a “world without IBSP”. It calculates lifetime costs and “quality adjusted life years” (QALYs) following platelet transfusion in patients with different oncological and surgical indications, taking into account disease specific life expectancy and the potential impact of transfusion transmitted infections. Transfusion safety data were obtained from Belgian Red Cross, costs from Belgian health insurance. The health economic consequences of HIV, HCV and HBV transmission were modelled on the basis of clinical and economic literature. In addition a HCV-like emerging pathogen was simulated at different risk levels based on current and historical hepatitis, HIV and West Nile Virus transmission data. Different scenarios for additional benefits (elimination of current safety measures) were considered.
Results: A wide range of ICERs was observed, highly sensitive to the risk of emerging pathogen transmission, underlying disease and age. In the most conservative scenario with emerging risk of 1/100,000 and no additional benefits, the ICER ranged from 3,355,308€/QALY to 165,051€/QALY. The mean threshold of emerging infection risk for dominance of IBS ranged from 1/1,074transfusions to 1/2,277transfusions depending on additional benefits.
Conclusion: Considering the high value society places on prevention of accidental injury, and the ICER of recent implementations in transfusion medicine (NAT testing: up to €2.3 million/lifeyear), IBSP can be considered cost-effective and even a dominant strategy taking into account the potential risk of emergence of a new pathogen in the future.
Tumor Cell Apoptosis Induced after Treatment with Adenovirally Expressed TRAIL in Vivo.
Authors: Wang Jishi , Fang Qin , Wu Yingya , Hu Xiaoyan , Abraham N.G. 
Published: October 2019

Abstract
Tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) is a naturally occurring death inducing ligand that induces apoptosis preferentially in malignant cells as normal cells are protected by expression of decoy receptors. Activation of TRAIL-R1 and R2 leads to the recruitment of procaspase-8 to the receptor, through an adaptor protein FADD, leading to formation of the death inducing complex (DISC), which leads to activation of caspase 8 followed by caspase 3 activation resulting in apoptosis. Our previous in vitro studies indicated that TRAIL induces apoptosis in tumor cells but not in normal cells. In order to improve the delivery of TRAIL to tumor cells, we constructed a recombinant adenovirus pAd5CMV-NpA- TRAIL vector, the TRAIL transgene was placed under the control of the CMV promoter. Ad-CMV-EGFP was constructed and used as control. They were amplified in HEK 293 cells and the titer of both was 1–1.5x1010pfu/ml.
C57 mice were injected with the adenoviral vectors (200ul) in the tail vein. We examined the expression of EGFP in mice tissues from animals administered adenoviral pAd5CMV-NpA-EGFP vector, and the presence of the EGFP gene was examined in the heart, lung, liver, and kidney of the animals. The results showed that EGFP was detectable in these tissues. Positive signals were obtained 1 and 2 weeks after injection of adenoviral- EGFP construct, the highest tissue levels of EGFP were obtained 1 week after EGFP gene transfer. Western blots revealed strong EGFP expression in the tissues 5 days after Ad-CMVEGFP injection.
In a model for metastatic cancer, tail vein infusion of pAd5CMV-NpA- TRAIL (200ul) resulted in elimination of preestablished liver metastases. Intravenous injection of this vector caused increased TRAIL expressions in tissues in tumor-bearing melanoma C57 mice, which we attributed to factors released from apoptotic tumor cells. Liver histology analyzed at day 7–14 after virus injection did not show signs of hepatocellular damage. This new oncolytic vector represents a potentially efficient means for gene therapy of metastatic cancer. We found that TRAIL can systemically inhibit tumor growth and reduce the size of tumors. In addtion, we also investigated whether pretreatment of TRAIL can prevent the tumor formation in mice treated with B16 melanoma. Normal C57 mice that received 5 days of treatment of TRAIL prior to implanting tumors resulted in the inhibitoty effect on tumor growth when compared to control mice.
Blockade of Inhibitor Formation by B-Cell Delivered Tolerance to Immunodominant A2 and C2 Domains.
Authors: Lei Tei Chi , Scott David W. 
Published: October 2019

Abstract
A major impediment in the treatment of hemophilia is the formation of inhibitory antibodies, which occurs in approximately 25–30% of Hemophilia A patients treated with therapeutic Factor VIII (fVIII). We have focused on the development of a gene therapy protocol for tolerance induction, with an emphasis on the elimination of inhibitor production. Our lab has demonstrated that LPS-stimulated B-cell blasts, transfected with a retrovirus encoding an IgG-peptide fusion protein, such as fVIII domains, are tolerogenic in both normal and primed recipients. Last year, we reported (http://www.abstracts-on-line.com/abstracts/hemphiladelphia03; Scott and Lei 2003) that specific tolerance to the immunodominant epitopes in the C2 domain of fVIII (a major target of inhibitors) could be induced by our protocol. However, the immune response to full length fVIII was only modestly affected. Most inhibitory antibodies are reactive with conformational epitopes on the exposed surfaces of the A2, as well as the C2, domain of fVIII. Therefore, in this study, we inserted residues S2173-Y2332 of the C2 domain and S373-R740 of the A2 domain onto the IgG heavy chain backbone, respectively, to induce tolerance in hemophilic mice. Specific tolerance to each domain was induced by this protocol. Importantly, a combination of A2-IgG and C2-IgG expressing B cells induced tolerance to the full length fVIII molecule, a result which supports the dominance of these domains in the immune response to fVIII. Tolerance was manifested in terms of ELISA, T-cell proliferation and especially Bethesda Unit titers (95% reduction). Similar results were obtained even when treatment was initiated after priming injections of fVIII. In conclusion, this protocol offers great promise for prevention and potential reversal of this serious complication of fVIII replacement therapy. (Supported by HL61883 and a Laboratory Grant from the National Hemophilia Foundation).
Red Blood Cell Hemolysis and Suppression of Erythropoiesis Strongly Upregulate mRNA for Iron Binding Lipocalin (NGAL/24p3) in the Liver.
Authors: Necas Emanuel , Vokurka Martin , Krijt Jan 
Published: October 2019

Abstract
A member of the lipocalin family of proteins, NGAL/24p3, was demonstrated to bind iron and was suggested to participate in a non-transferrin dependent iron transport mechanism capable to deliver iron to the cytoplasm (Kaplan 2002, Yang et al. 2003). Therefore, we have studied mRNA for NGAL/24p3 levels in the liver tissue during its loading with iron released from senescent and damaged red blood cells. Red blood cell hemolysis was induced in mice by administration of phenylhydrazine (PHZ). Suppression of iron reutilization for erythropoiesis was achieved by a total body sublethal irradiation (5 Gy). Samples of liver tissue were collected 16 hrs or 48 hrs after PHZ and 40 hrs after irradiation. Combined treatment consisted from irradiation followed by PHZ administration 40 hrs later. The irradiation suppressed 24 hrs incorporation of 59Fe into blood from 46,5 % in controls to 1.2 % in irradiated mice, indicating a significant suppression of erythropoiesis. PHZ administration alone decreased hematocrit from 44.7 % to 38.7 %, reflecting degree of the red blood cell hemolysis. The combined treatment by irradiation and PHZ resulted in the elevation of the liver iron content from 43.8 to 106.7 micrograms/g wet tissue 16 hours after PHZ, indicating a significant loading of the liver tissue with iron. All these treatments increased mRNA for NGAL/24p3 levels as determined by real-time PCR, significantly. After the combined treatment the increase reached almost three orders of magnitude. We further compared the response of NGAL/24p3 mRNA to the response of hepcidin and transferrin-1 receptor (TfR-1) mRNAs, both known to be sensitive to the liver iron content. Hepcidin mRNA increased significantly after the treatment with irradiation, PHZ, or combination of irradiation and PHZ but the increase was less pronounced compared to that of NGAL/24p3 mRNA. TfR-1 mRNA significantly decreased 48 hours after the combined treatment only. As an indicator of the acute phase response, the mRNA for interleukin-6 was determined and it did not change after the treatments used. The results demonstrate that mRNA for the putative iron transport molecule NGAL/24p3 was strongly upregulated by experimental maneuvers that lead to accumulation of iron in the liver tissue.
Initial Screening Transferrin Saturations, Serum Ferritin Concentrations, and HFE Genotypes in Whites and Blacks in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
Authors: Barton James C. , Acton Ronald T. , Dawkins Fitzroy W. , Adams Paul C. , Lovato Laura , Leiendecker-Foster Cathy , McLaren Christine E. , Reboussin David M. , Speechley Mark R. , Gordeuk Victor R. , McLaren Gordon D. , Sholinsky Phyliss , Harris Emily L. 
Published: October 2019

Abstract
We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks (9,788 men; 17,159 women) who reported no previous diagnosis of hemochromatosis or iron overload from a primary care-based sample of ~100,000 adults ≥25 years recruited from 5 Field Centers. Each underwent transferrin saturation (TfSat) and serum ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. We observed these mean TfSat and SF values and percentages of participants with elevated biochemical measurements (TfSat >50% and SF >300 ng/mL, men; TfSat >45% and SF >200 ng/mL, women):
Participants Mean % TfSat (95% CI) Elevated TfSat, % Participants Mean SF, ng/mL (95% CI) Elevated SF, % Participants White men 32.4 (32.3, 32.6) 7.05 150.9 (149.1, 152.8) 19.49 Black men 29.3 (29.1, 29.5) 4.03 178.4 (175.5, 181.3) 25.95 p Value <0.0001 <0.0001 <0.0001 <0.0001 White women 27.5 (27.3, 27.6) 6.62 63.0 (62.3, 63.7) 8.74 Black women 23.3 (23.1, 23.4) 3.04 68.3 (67.2, 69.4) 15.43 p Value <0.0001 <0.0001 <0.0001 <0.0001
In participants grouped by decade, mean TfSat was greater in white men than in black men, and in white women than in black women (all p<0.0001). Mean SF was greater in black men than in white men in all decades except 25–34 years, and in black women than in white women in decades ≥45 years. SF increased with age to ~45 years in white men and ~50 years in black men, and then decreased. In white women, SF rose with age until ~62 years and less rapidly to age ≥80. In black women, SF rose with age until ~62 years and then decreased. C282Y allele frequency was 0.0700 (95% CI: 0.0683, 0.0717) in whites and 0.0119 (0.0110, 0.0129) in blacks. H63D allele frequency was 0.1532 (0.1509, 0.1556) in whites and 0.0299 (0.0284, 0.0313) in blacks. Frequencies of genotypes with C282Y or H63D were greater in whites than in blacks (all p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y was 0.003 in whites and 0.00004 in blacks (p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks (p<0.0001). We conclude that: 1) the prevalence of elevated TfSat is higher in whites and the prevalence of elevated SF is higher in blacks; 2) SF levels increase with age; 3) HFE C282Y and H63D alleles occur more frequently in whites than in blacks; and 4) the prevalence of elevated TfSat and SF plus genotypes with two common HFE mutations is greater in whites than in blacks.