bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in Human Growth Factors Induced by Non-Human Cell Expression.
Authors: Pilkington Glenn , Marks Denese , Crofts Linda , Domagala Teresa , Liddell Kate , Russell-Jones Greg 
Published: October 2019

Abstract
Expression of recombinant human proteins in cells from different species, including bacteria, yeast, insect, mouse, hamster or primates, imparts species-specific changes post-translation. The impact of these species-specific differences in post-translational modifications (PTMs) can be far-reaching, resulting in effects ranging from inaccurate quantitation of proteins in serum to in-vivo immunogenicity (Porter, J Pharm Sci 90: 1–11, 2001) or even autoimmunity to the patient’s own native protein (Ryan et al., Int Immunopharmacol 4:647–55, 2006). Currently, most human proteins are still produced from bacteria, including several of the World Health Organization international growth factor standards. For example, present-day clinical grade recombinant human growth factors such as G-CSF, IL-4 and GM-CSF are manufactured from bacteria. The expression of human proteins that naturally exhibit a high degree of glycosylation, such as GM-CSF, in bacterial cells has major implications for immunoassays and therapeutics. Since bacterial cells do not glycosylate human proteins, exposure of cryptic or masked epitopes, normally buried on the native protein, can result in generation of antibodies that bind falsely in immunoassays and can cause reduced potency or adverse reactions in patients. The expression of recombinant human proteins in non-human mammalian cells can result in non-natural epitopes due to the addition of non-human sugar structures. We have expressed several human growth factors in human cells and have demonstrated differences in their immunoreactivity patterns when compared to the same recombinant proteins expressed in non-human cells. These changes in the biological properties of the proteins are likely related to differences in glycosylation and other PTMs unique to proteins expressed in human cells. We have demonstrated that expression of human growth factors in human cells may have significant benefits for the accuracy of native human protein assays and the therapeutic efficacy of human growth factors.
Chronic Refractory Anemia with Sideroblastic Bone Marrow: A Study of Four Cases
Authors: BJÖRKMAN SVEN ERIK 
Published: October 2019

Abstract
Four cases of severe refractory anemia with an enormous increase of demonstrable free iron in the normoblasts are reported. Three cases were of unknown etiology and of benign course but in the fourth the anemia was probably related to rheumatoid arthritis or to the onset of myeloblastic leukemia. The significance of the sideroblastic bone marrow in these cases is discussed and the opinion expressed in the literature—that it indicates a defect in hemoglobin synthesis is subscribed to. Thus, it is believed that the anemia in these cases is due to degenerative changes in the bone marrow which also have some morphologic manifestations. The disturbance of marrow activity is probably best reflected in the reticulocyte counts.
Homozygous Hemoglobin C Disease in Siblings: Further Comment on Intraerythrocytic Crystals
Authors: WHEBY MUNSEY S. , THORUP OSCAR A. , LEAVELL BYRD S. 
Published: October 2019

Abstract
1. Two Negro brothers with homozygous hemoglobin C disease are reported. In one splenectomy was performed.
2. Intraerythrocytic crystals in smears of peripheral blood were demonstrated only in the patient who had splenectomy. The crystals could not be found in re-examination of bone marrow preparations of this patient that were made prior to splenectomy.
3. Absence of the spleen may be a necessary factor for the formation of these crystals.
4. The presence of homozygous C disease is compatible with a normal life span.
Atypical Familial Hemolytic Anemia
Authors: SMILEY R. K. , DEMPSEY H. , VILLENEUVE P. , CAMPBELL J. S. , BEST BARBARA 
Published: October 2019

Abstract
1. The genetic, clinical and hematologic features of an atypical chronic hemolytic anemia in two siblings of a French Canadian family have been described.
2. The anemia is normocytic, normochromic and not associated with any characteristic morphologic abnormality of the red cells.
3. Slight increases in osmotic and incubated mechanical fragility, as well as a more definite increase in aumtohemolysis were found which could not be demonstrated after splenectomy.
4. The survival time of normal red cells was shortened before splenectomy in one patient. Normal red cell survival was demonstrated in both patients after splenectomy.
5. The features which differentiate this hemolytic anemia from hereditary spherocytosis are discussed.
6. French or French Canadian ancestry has been noted in some of the reported patients most similar to our own.
7. The association of this type of hemolytic anemia with blood group A has been confirmed in our patients.
8. Splenectomy decreased the severity of the hemolytic process in both patients. This benefit may have resulted from removal of an extracorpuscuar hemolytic mechanism.
Sickle-Cell Anemia in South Turkey. A Study of Fifteen Cases in Twelve White Families
Authors: AKSOY MUZAFFER 
Published: October 2019

Abstract
1. Fifteen cases of sickle-cell anemia in twelve white families in southern Turkey are reported.
2. In all these cases of sickle-cell anemia and their families, there was no suggestion of anything Negroid in their features or coloring.
3. The hereditary trait of these patients has been investigated. In 53 healthy members of twelve families 37 persons had sickle-cell traits.
4. With the exception of case 12, both parents of all cases had sickle-cell trait.
5. The possible explanations of the frequent occurrence of sickle-cell anemia and the fairly high incidence of sickle-cell trait in this white community have also been considered.
Detection of p57KIP2 Gene Methylation Is Useful Marker for Minimal Residual Disease in Diffuse Large B Cell Lymphoma.
Authors: Hagiwara Kazumi , Nagai Hirokazu , Yokozawa Toshiya , Kato CHiaki , Hamaguchi Motohiro , Hotta Tomomitsu , Horibe Keizo 
Published: October 2019

Abstract
Background: The t(14;18)(q32;q21) translocation, which causes a BCL2/IgH gene rearrangement, is a characteristic chromosomal abnormality found mainly in B cell lymphomas, and its detection and quantification is useful for monitoring of minimal residual disease (MRD) in follicular lymphoma (FL). However, in diffuse large B cell lymphoma (DLBCL), the frequency of this rearrangement is relatively low. We revealed that the promoter region of p57KIP2 gene is frequently methylated in B cell lymphomas. Aberrant DNA methylation in the promoter regions of genes is known as the major mechanism for inactivation of tumor suppressor genes, so the detection of the methylation is expected to be used as a promising tumor specific marker. Therefore, we investigated the possibility of p57KIP2 gene promoter methylation as a biomarker for MRD detection in B cell lymphoma, especially in DLBCL.
Methods: We analyzed lymphoid cell line DNA, tumor DNA from 64 patients with DLBCL, and 4 patients with FL. The bisulfite-modified DNA was used as a template for conventional methylation-specific PCR (MSP) and real-time quantitative MSP (Q-MSP).
Results: In clinical samples (tumor DNA), p57KIP2 gene methylation was detected by Q-MSP in 73% (47/64) DLBCL, and 50% (2/4) FL. Using cell line DNA, which was fully methylated in promoter region of p57KIP2 gene, we determined the detection limit of Q-MSP assay. The methylated DNA could be detected in the presence of a 1000-fold excess of unmethylated DNA by Q-MSP. We could validate the level of methylated DNA in each sample by Q-MSP evaluating the p57KIP2/b-actin ratio. The sensitivity to detect MRD in bone marrow by this method was found to be equivalent to real time quantitative PCR for BCL2/IgH major breakpoint region.
Conclusion: The methylation of p57KIP2 gene is detected at high frequency in DLBCL. This biomarker is thought to be conventional and widely applicable to the detection of MRD in DLBCL.
Bone Marrow Biopsy for the Staging of Diffuse Large B-Cell Lymphoma: Is It Necessary Bilateral Trephine Biopsy?.
Authors: Bellesso Marcelo , Velasques Rodrigo D. , Pracchia Luis F. , Beitler Beatriz , Aldred Vera L. , Chamone Dalton , Kutner Jose M. , Pereira Juliana 
Published: October 2019

Abstract
In this retrospective analysis we study the usefulness of bilateral rather than unilateral iliac trephine biopsies in demonstrating Diffuse Large B-Cell Lymphoma (DLBCL) in the bone marrow (BM). A total of 28 DLBCL cases with BM infiltration were investigated with bilateral iliac trephine biopsy during staging. Our propose was to evaluate the incidence of unilateral BM involvement, and we compare the BM biopsy size with negative and positive BM infiltration. In 28 cases studied it was analyzed 70 BM fragments. These fragments were reviewed separately by pathologist about size and infiltration. In this group, 6 cases (21.4%) were unilaterally positive. The median number of fragment per case was 2.5; the median size of BM fragment was 11.01 mm (± 5.12) and BM fragment per case was 27.53mm. It was not found difference between size BM fragment in negative or positive fragments 11,57mm (±5.2) versus 10.95mm (±5.1), p>0.05, respectively. In 24 cases it was possible to compare negative and positive BM infiltration with age, sex, LDH and computerized tomography (CT) staging. In addition, it was not found difference between unilateral and bilateral BM infiltration about LDH and age, and CT. (Table 1).
Conclusion: Although in unilateral infiltration cases did not change risk factor in International Prognostic Index (stage III–IV) by CT, we conclude that bilateral trephine biopsy is superior to unilateral, because bilateral biopsy could increase by 21,4% the detection of BM involvement by DLBCL, without difference between the size in negative versus positive fragments.
Table 1. Distribution of Unilateral and Bilateral Bone Marrow infiltration by categories Unilateral infiltration (%) Bilateral infiltration (%) Age < 60 21% 50% Age ≥ 60 4% 25% Sex Male 16% 29% Sex Female 8% 47% CT staging I–II - 35% CT staging III–IV 26% 39% LDH Normal 8% 34% LDH Elevated 16% 42%
A Comparative Study of Diffuse Large B-Cell Lymphoma (DLBCL) between African Americans and Caucasians: Single-Center Experience at the University of Alabama at Birmingham (UAB).
Authors: The Angelina , Li Yufeng , Reddy Vishnu , Davis Randall , Baird Melissa , Foran James 
Published: October 2019

Abstract
Background: SEER data indicate that African Americans (AA) have a lower incidence of DLBCL but a higher mortality rate than Caucasians (C). To investigate this, we conducted a single-center analysis of AA and C patients with DLBCL at UAB. UAB is a primary care facility and the main tertiary referral center in Alabama. It is located in Jefferson County where the average African American population of 39% is nearly triple the national average.
Methods: After IRB approval, patients diagnosed with DLBCL from 1995 to 2007 were identified from pathology, referral, and UAB tumor registry databases. Baseline demographic data including race, age at diagnosis, stage, treatment administered, response to treatment, and survival were extracted. Serum LDH levels and performance status were not consistently available in medical records and therefore not included in the final analysis. Patients with monomorphic post-transplant lymphoproliferative disease and primary CNS lymphoma were excluded. Associations between race and stage, treatment (first-line rituximab, anthracycline, or combination therapy), response, and outcome were analyzed using Chi-squared or Cochran Mantel-Haenszel statistical analysis.
Results: A total of n=309 (n=32 AA and n=277 C) patients were identified. AA patients were diagnosed at a significantly younger age than C patients [median age 49 (range: 22–90) vs. 61 (range: 16–91), respectively; p=0.0131]. AA patients also presented with advanced stage disease (Ann Arbor stage III–IV) more frequently (69% vs. 52%, p=0.046). No difference in extranodal disease presentation or in complete response rate to first-line therapy was noted. As expected, those with early stage disease, age <60, and those given first-line rituximab +/− anthracycline therapy had superior survival regardless of race. No difference in overall survival was seen between AA and C patients (p=0.1306). However, AA patients had an inferior survival to C patients when the analysis was restricted to patients who received either first-line treatment with rituximab (p=0.0658), anthracycline (p=0.0188), or combination (p=0.0196).
Figure Figure
Conclusions: Compared to C patients, AA patients were diagnosed with DLBCL at a significantly younger age, more advanced stage, and had worse survival despite first-line rituximab +/− anthracycline therapy. This single-center experience confirms SEER data and suggests a possible difference in tumor biology or treatment effect, although potential socioeconomic factors can not be excluded.
Marqibo (Vincristine Sulfate Liposomes Injection (OPTISOME™) Demonstrates Activity in Patients with Relapsed and Refractory Peripheral T-Cell Lymphoma.
Authors: Rodriguez M. Alma , Winter Jane N. , Lu Biao , Huang Gary , Choy Gavin S. , Deitcher Steven R. 
Published: October 2019

Abstract
Introduction: New and more effective agents are needed to improve treatment outcomes for patients with relapsed and refractory peripheral T-cell lymphoma (PTCL). Marqibo is a novel formulation of vincristine (VCR) encapsulated in sphingomyelin/cholesterol liposome called OPTISOME. In preclinical studies, OPTISOME technology has been shown to provide targeted, increased, and sustained delivery of VCR to tumor cells compared to non-encapsulated VCR or VCR encapsulated in conventional liposomes.
Methods: PTCL patients from two multi-center phase 2 studies of Marqibo in relapsed and refractory lymphoid malignancies are integrated for safety and efficacy evaluation. In both studies, Marqibo (2.0 mg/m2 without dose capping IV over 60 minutes) was administered every 14 days for up to 12 cycles or until toxicity or progressive disease was observed. The primary efficacy endpoint of the 2 studies was the objective response rate (ORR) defined as the percentage of patients whose best response was complete response (CR), complete response unconfirmed, or partial response (PR). Best response was determined according to the International Workshop Response Criteria. Secondary endpoints included adverse event evaluation, time to progression (TTP) and overall survival (OS).
Results: Six (3M/3F) patients diagnosed with PTCL received at least one dose of Marqibo. At baseline, the median age was 59 years (range, 34–86). All six patients had aggressive disease and most were heavily pretreated. The median number of prior lines of chemotherapy and immunotherapy regimens was 3 (range, 1–6) and four patients (66.7%) had received prior autologous bone marrow transplant. All patients had prior exposure to neurotoxic therapy: platinum compounds (33.3%), taxanes (16.7%) and VCR (100%). All patients had achieved a CR or PR to their frontline therapy and 50% (3/6) had achieved a CR or PR to their last line of therapy prior to receiving Marqibo. Patients received a median of 4 cycles of Marqibo (range, 1–9). Median cumulative dose of Marqibo was 7 mg/m2 (range, 2–17.4). The most commonly reported adverse event was peripheral sensory neuropathy (3 of 6 patients) and all of Grade 1 severity. Three patients had PR, 1 patient had stable disease, 1 patient experienced disease progression, and 1 patient was unevaluable. Median OS and TTP were 194 and 70 days, respectively.
Conclusions: These preliminary results suggest encouraging activity and tolerability of Marqibo in heavily pre-treated relapsed and refractory PTCL patients. Given the high proportion of exposure to neurotoxic agents preceding Marqibo, the low grade neurotoxicity noted following Marqibo is a favorable finding.
Rituximab Maintenenance Therapy Prolongs Event Free Survival in Patients with CD20+ B-Cell Non-Hodgkin-Lymphoma.
Authors: Witzens-Harig Mathias , Hensel Manfred , Schmier Johann W. , Neben Kai , Benner Axel , Dreger Peter , Kuhn Christian , Schmidt-Wolf Ingo , Kraemer Alwin , Ho Anthony D. 
Published: October 2019

Abstract
Clinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy in patients with CD20+ B-cell Non-Hodgkins-Lymphoma. After completion of standard treatment patients were randomized to either observation or maintenance therapy with rituximab (375 mg/m2) every 3 months for 2 years. Patients after first line therapy as well as relapse patients were included in the study. Patients with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Patients with aggressive lymphoma with residual tumor mass were examined with positrone emission tomography (PET) and qualified for randomization if PET showed no signs of tumor activity. Patients with indolent lymphoma qualified for the study if at least a partial response (PR) was achieved. After recruitment of 172 patients a planed interim analysis was performed. Complete data sets of 162 patients (pts) with CD20+ B-cell Non-Hodgkins-Lymphoma were evaluable for analysis. Histological subtypes included diffuse large cell lymphoma (69 pts), follicular lymphoma (41 pts), mantle cell lymphoma (18 pts), primary mediastinal lymphoma (15 pts), marginal zone lymphoma (9 pts), Burkitt’s lymphoma (3 pts), immunocytoma (2 pts), primary intestinal lymphoma (1 pt), hairy cell leukemia (1 pt), chronic lymphocytic leukemia (1 pt) and unclassified B-cell lymphoma (2 pts). The interim analysis showed that event free survival was significantly prolonged in the rituximab maintenance group compared to the observation group (p<0.05). However, no difference in overall survival between the two groups was observed so far. Two patients in the treatment group developed WHO grade III adverse events (1 leucopenia, 1 infection). Both pts recovered shortly after appropriate treatment. We conclude that rituximab maintenance therapy is feasable, safe and well tolerated in patients with CD20+ B-cell Non-Hodgkins-Lymphoma and may prolong event free survival in this patient population.
Bortezomib, Pegylated-Lyposomal-Doxorubicin and Dexamethasone Followed by Melphalan 100 mg/m2 in Elderly Newly Diagnosed Patients: An Interim Analysis.
Authors: Palumbo Antonio , Avonto Ilaria , Patriarca Francesca , Crippa Claudia , Petrucci Maria T. , Rossini Fausto , Corradini Paolo , Liberati Anna M. , Giuliani Nicola , Pescosta Norbert , Falco Patrizia , Larocca Alessandra , Omedè Paola , Offidani Massimo , Fanin Renato , Boccadoro Mario 
Published: October 2019

Abstract
Bortezomib has been evaluated as induction regimen to improve cyto-reduction before autologous stem cell transplant. Combinations including bortezomib, doxorubicin and dexamethasone have shown encouraging results. Melphalan at 100 mg/m2 has been suggested as reduced-intensity conditioning regimen for elderly patients. In this prospective multicenter phase II study, bortezomib, pegylated-liposomal-doxorubicin and dexamethasone (PAD) followed by tandem melphalan 100 mg/m2 has been investigated in newly diagnosed patients aged 65–75 years. The induction regimen included four 21-day PAD cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11, pegylated-liposomal-doxorubicin 30 mg/m2 day 4 and dexamethasone 40 mg days 1–4, 8–11, and 15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3 g/m2) plus G-CSF were used to harvest stem cells. Patients were then conditioned with tandem melphalan 100 mg/m2 followed by stem cell infusion. A single interim analysis has been planned. Sixty-five patients have been enrolled in the study and 37 completed the induction cycles. Median age was 69 years; median β2-microglobulin 3 mg/L; median albumin 4.1 g/L; chromosome 13q deletion was detected by FISH in 35% of patients. After the 4 courses of PAD 97.1% of patients achieved at least a partial response (PR), 50% at least a very good partial response (VGPR), 11.8% an immunofixation negative complete remission (CR). After tandem melphalan 100 mg/m2, all patients achieved at least a PR, 80% at least a VGPR and 30% an immunofixation negative CR. After 4 cycles of PAD, grade 3–4 hematologic events were thrombocytopenia (13.5%) and neutropenia (8.1%); more frequent grade 3–4 non-hematologic toxicities were peripheral neuropathy (21.6%) and infections (10.8%). One early toxic death was reported (central nervous system bleeding) and two patients had to discontinue therapy due to pneumonia and HBV reactivation. Eighty-two percent of patients achieved successful stem cell harvest (>4 CD34+ cells/Kg). PAD is an effective induction approach, it may improve autologous transplant results in selected elderly patients. Updated results of the interim analysis will be presented at the meeting.
Predicting Structural and Serologic Modifications in Blood Group Antigens by Homology Modeling.
Authors: Westhoff Connie M. , Wylie Dwane E. 
Published: October 2019

Abstract
Homology modeling of blood group proteins offers the possibility of predicting the effect of amino acid changes on serologic phenotype and immunogenicity. The location of an amino acid change within known structural motifs, its phylogenetic conservation, and its proximity to known epitopes give insight into its potential effect on protein structure and, consequently, its clinical significance. We applied this approach to investigate the loss of membrane expression of the Dombrock blood group antigens in a patient with a single amino acid change and to investigate RhD alterations in weak D phenotypes. The Dombrock homology model was derived with rat ART2.2 crystal structure as template. For the RhD model, the crystal structure of the Rh-like-ammonia transporter from Nitrosomonas europaea was used. Protein alignment was derived with Clustal X, adjusted visually, and submitted to the Swiss Modeling server. Models were viewed with Deep View Swiss Pdb Viewer. The Dombrock null containes a Phe62Ser substitution. This Phe (F) residue is located in an FDDQY motif near the COOH terminus. This region of the protein also contains a HYYLT motif. These two motifs are highly conserved in the ART protein family and contribute several aromatic amino acids to this region of the molecule. Aromatic side chain interactions between these residues could contribute to the stability of the Do protein. In support, the distance in the ART2.2 crystal structure between Phe in FDDQY and His in HYYLT is 3.7 Å, which is the appropriate distance for aromatic side chain interactions. This is also the measured distance between these two residues in the Do model. Thus, protein modeling indicates that the Phe62Ser mutation disrupts important stacking interactions between Phe62 and His160. When amino acid changes causing weak D phenotypes were examined, some of those affecting expression of RhD were located near the vestigial transport channel. These include the Trp220Arg mutation (weak D Type 16). This Trp residue is part of the transport channel in Nitrosomonas and is conserved in Rh proteins of almost all species. Its role in maintaining Rh structure is indicated by the dramatic effect its modification has on protein and epitope expression. Additionally, Arg114Trp change (weak D Type 17), which is also near the channel, reduces D expression to only 66 antigen sites/cell. GlyXXXGly motifs stabilize interactions of adjacent alpha helices in membrane proteins. Evidence for a role in stabilization of RhD is revealed by the Gly282Asp mutation (weak D Type 15) which is part of such a motif. In addition, a D-epitope in loop 3 is near the 282Asp residue. Alteration of helical packing accompanied by epitope conformation could explain production of anti-D in patients with weak D Type 15. Homology modeling is an important tool for understanding the structure and serologic bases of blood group proteins and will continue to give important insight as more protein crystal structures become available.