bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper Deficiency Secondary to Bariatric Surgery Mimicking Myelodysplasia.
Authors: Doshi Vaishali R. , Thertulien Raymond 
Published: October 2019

Abstract
Introduction: Bariatric Surgery is promoted as a successful method for weight loss and is performed with increasing frequency. The benefits and the short term risks of the surgical procedure are well understood. However, its long term pathophysiological consequences are still for the most part unknown. They may include metabolic changes that result in malnourishment and malabsorption. Deficiency disorders of iron, B-12 and folate are commonly encountered. However hematological problems from copper deficiency due to malabsorption have not been well studied.
Background: Copper and Iron are essential trace elements through their functions as co-factors in numerous biochemical reactions. Hephaestin, a transmembrane copper-dependent ferroxidase, is necessary for effective iron transport from intestinal enterocyte into the circulation. Copper is hence required for iron absorption. Copper enzymes such as superoxide dismutase and cytochrome oxidase have an essential role in red cell development and heme maturation.
Patients and Method: We present data on five patients referred for treatment of myelodysplasia whose evaluation revealed copper deficiency and low ceruloplasmin level. All five patients were female and had undergone gastric bypass surgery for weight reduction. The hematological features included pancytopenia, erythroid hyperplasia and dysplasia with increased blasts mimicking erythroleukemia, multilineage dysplasia with ring sideroblasts, bilineage megakaryocytic and erythroid dysplasia. One patient presented with neutropenia and anemia with a normal bone marrow; she was found to have copper deficiency. No cytogenetic abnormalities were observed and the patients had normal B-12 and folate. Copper gluconate was started at 20 mg/day by mouth, with weekly monitoring, till normal levels were reached. Patients were subsequently maintained at 5–10 mg/day with regular monitoring. Upon repletion of copper, all the patients recovered with normalization of the bone marrow and peripheral counts.
Discussion: We conclude that Gastric bypass especially Roux-en-Y gives rise to copper deficiency due to malabsorption in the duodenum and can present as pseudomyelodysplasia. We consider measurement of copper and ceruloplasmin levels an important component of the evaluation of patients presenting with myelodysplasia with normal cytogenetics, especially after gastric bypass.
Chronic Lymphocytic Leukaemia Patients with a Biallelic Deletion of 13q14 Have a More Favourable Profile of Prognostic Factors Compared with Cases That Have a Monoallelic 13q14 Deletion.
Authors: Pettitt Andrew R. , Emmens Chloe J. , Lin Ke , Harris Robert J. 
Published: October 2019

Abstract
Deletion of 13q14 is a common finding in CLL and is associated with a good prognosis when it occurs in the absence of del 17p13, del 11q23 and trisomy 12. In contrast, the latter chromosomal abnormalities, together with unmutated IgVH genes, CD38 expression and p53 dysfunction, are associated with an adverse clinical outcome. Unlike del 17p13 and del 11q23, which usually affect only one allele, del 13q14 can affect one or both alleles in a given case. It was therefore of interest to compare cases of CLL harbouring a monoallelic 13q deletion (13q+/−) with those cases harbouring a biallelic 13q deletion (13q−/−). FISH data including 13q14 status were available for 103 newly diagnosed cases of CLL presenting to the Royal Liverpool University Hospital between March 2002 and June 2005. 18 cases had a biallelic 13q deletion and 32 had a monoallelic 13q deletion, while 53 cases had no 13q deletion (13q+/+). As compared with 13q+/− and 13q+/+ cases, 13q−/− cases had a lower frequency of unmutated IgVH genes (8% v 32% and 46% respectively), CD38 positivity (14% v 32% and 29%), p53 dysfunction (13% v 34% and 30%), deletion of 17p13 (0% v 9% and 8%), deletion of 11q23 (0% v 13% and 6%) and trisomy 12 (0% v 13% and 23%). The combined frequency of 17p deletion, 11q deletion and trisomy 12 among cases with 13q−/−, 13q+/− and 13q+/+ was 0%, 31% and 35% respectively (P = 0.0085). At least one of the above adverse prognostic factors was found in 33% of 13q−/− cases, 82% of 13q+/− cases and 80% of 13q+/+ cases (P = 0.0084). There was no difference in sex or clinical stage between the 3 groups, although patients with 13q−/− tended to be older than those with 13q+/− (68.1 v 61.3 years, P = 0.0720). After a median follow-up of 18 months (range 1–39 months), no difference in treatment-free or overall survival was observed between the 3 groups but only 7 of the 50 evaluable patients had received treatment and only 3 had died. In conclusion, CLL patients with biallelic deletion of 13q14 appear to have a more benign form of the disease than do patients with a monoallelic 13q deletion. The latter have a profile of prognostic factors indistinguishable from that of patients with no 13q deletion. This suggests that the overall favourable prognosis associated with 13q deletion is probably attributable to the subset of cases in which both alleles are deleted.
Identification and Purification of Hodgkin Cells from Lymph Nodes Involved by Classical Hodgkin Lymphoma by Flow Cytometry and Flow Cytometric Cell Sorting.
Authors: Fromm Jonathan R. , Kussick Steven J. , Wood Brent L. 
Published: October 2019

Abstract
The diagnosis of classical Hodgkin lymphoma (CHL) has historically been made in tissue sections, as attempts to identify the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of CHL by flow cytometry (FC) have been largely unsuccessful. As HRS cells are known to be ringed (“rosetted”) by benign/reactive T cells, we hypothesized that in cell suspensions the HRS will be bound to T cells (forming T cell rosettes), and that consequently the rosettes would have a composite T-cell/HRS immunophenotype by FC (CD3+/CD15+/CD20−/CD30+/CD45+). We further hypothesized that specific antibodies to the adhesion molecules known to be involved in T cell/HRS cell binding (CD2 and LFA-1 on the T cell, and CD54 and CD58 on the HRS cell) might result in “naked” (unbound) HRS cells, enabling us to use FC to identify HRS cells with the expected immunophenotype (CD3−/CD15+/CD20−/CD30+/CD45−). Our initial FC studies of the HRS cell line L1236 demonstrated that CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, but not CD3 or CD20, were brightly expressed on these cells and may be useful in identification of HRS in authentic cases of CHL involving lymph nodes. In mixing experiments, L1236 cells spontaneously bound normal T cells, analogous to T cell rosetting of HRS cells in CHL; these interactions could be blocked specifically using a cocktail of unlabeled antibodies to CD2, LFA-1, CD54, and CD58. Among 27 lymph nodes involved by CHL, this novel FC method, in which 250,000 to 500,000 total lymph node cells were evaluated, and in which up to ten cellular antigens were assessed simultaneously, enabled HRS cells to be identified in 89% of cases. 82% of these cases demonstrated interactions between HRS cells and T cells that could be disrupted with blocking antibodies. None of 29 non-CHL neoplasms, and none of 23 reactive lymph nodes, demonstrated HRS populations by FC. The proportions of cases where the HRS population showed expression of CD15, CD30, CD40, CD71, CD86, CD95, and HLA-DR, and absence of CD3 and CD20 was similar to that described previously in tissue sections by immunohistochemistry. Interestingly, in contrast to the findings in tissue sections, by FC the non-rosetted HRS cells of most CHL cases (73%) demonstrated detectable expression of CD45, usually at a low level. Finally, cell sorting experiments confirmed that (1) populations identified by FC have the cytomorphology of HRS cells, (2) HRS/T cell rosettes can be detected by FC, and (3) these rosettes can disrupted by the blocking antibody cocktail. This FC technique offers a potential alternative to immunohistochemistry in confirming the diagnosis of CHL and, through cell sorting, provides a means of rapidly purifying HRS cells.
53BP1 Is Targeted to Sites of DNA Breaks within the Immunoglobulin Heavy Chain Locus and Promotes Class Switch Recombination.
Authors: Manis John , Walsh Nicole , Carpenter Phil , Dutt Shilpee 
Published: October 2019

Abstract
The maintenance of genomic integrity relies on the cellular response to chromosomal damage from both exogenous (e.g. ionizing radiation) and endogenous (e.g. oxidative stress) sources. Various members of the DNA damage-sensing pathway including ATM, H2AX, 53BP1, and MDC1 are necessary to orchestrate the repair of DNA breaks. B cells undergo several programmed DNA alterations during their development: V(D)J recombination, Somatic Hypermutation (SHM), and Class Switch Recombination (CSR). We have previously shown that 53BP1 is relatively dispensable for V(D)J recombination and SHM. In contrast, class switch recombination is largely blocked to all isotypes indicating that regulated DNA breaks in B cells are regarded differentially by the DNA damage response machinery. 53BP1 is thought to promote the joining of DNA ends during CSR thus preventing translocations that could potentially lead to lymphoma. To better understand the damage response to CSR induced DNA breaks, a chromatin immunoprecipitation strategy and a combined immunofluorescence/FISH method was used to examine the components that assemble at IgH switch (S) regions during CSR. H2AX was found at S regions specifically targeted to undergo CSR after in vitro stimulation of B cells, and to a lesser degree, at adjacent S regions that were not activated for a switch event. H2AX was also found at S regions in switch activated 53BP1-deficient B cells. In contrast, 53BP1 was found primarily at S regions specifically targeted for CSR, and not at the adjacent S regions. Moreover, the localization of 53BP1 to S regions appeared to be in part, independent of DNA breaks, and potentially reliant on specialized DNA structures that are generated during CSR. These findings support a differential role for the various components of the DNA damage response program during CSR and have implications for understanding mechanisms of lymphomagenesis.
Relative Value of CD38 and ZAP-70 Versus Immunoglobulin Mutation Status in Predicting Early Disease Progression in Chronic Lymphocytic Leukemia.
Authors: Rassenti Laura Z. , Neuberg Donna S. , Huynh Lang , Wierda William G. , Gribben John G. , Brown Jennifer R. , Flinn Ian W. , Rai Kanti R. , Byrd John C. , Kay Neil E. , Greaves Andrew W. , Kipps Thomas J. 
Published: October 2019

Abstract
We assessed the relative value of CD38 in predicting the need for early treatment in 307 patients with chronic lymphocytic leukemia (CLL) previously characterized for ZAP-70 and immunoglobulin heavy-chain-variable region gene (IgVH) mutational status (NEJM2004, 351;9;893–901). Recursive partitioning by maximally selected chi-square analyses of flow cytometry and clinical data identified the optimal cut-off for designating a CLL sample as CD38+ was at 34%, which was highly similar to the conventional cut-off of 30%. Since these cut-offs identified highly similar cohorts of CD38+ CLL patients (e.g. 32.2% (99/307) vs. 35.5% (109/307)) we chose to use 30% as the cut-off for this analysis. We used the logrank test to compare CD38 expression-status to the time from diagnosis to therapy (TTT), initiated per established NCI-Working Group guidelines. Patients with CLL cells that were CD38-negative by this criterion had a median TTT of 7.8 years; whereas, patients with CD38+ CLL cells had a median TTT of 3.7 years (p<0.0001). There was a significant association between expression of CD38 and ZAP-70 or use of unmutated IgVH genes (p < 0.0001). The median level of CD38 among cases that used mutated IgVH was 4.0%, compared to 27.4% among cases that used unmutated IgVH (p < 0.0001). The median level of CD38 among ZAP-70-negative cases was 5.3% (range from 0.1% to 99.5%), compared to 27.2% among ZAP-70-positive cases (range from 0.1% to 99.4%) (p < 0.0001).
We explored the TTT based only on flow cytometric parameters (CD38 and ZAP-70) and investigated whether addition of mutation status significantly altered our predictions. For most patients, the knowledge of CD38 and ZAP-70 provided a reliable means for predicting the TTT and the knowledge of the IgVH mutation status did not substantially alter the prediction. Only in 41 cases (14% of the total), where the CLL cells were CD38+ but negative for ZAP-70, was the prediction significantly improved by inclusion of IgVH mutation status. The median TTT of this group of 41 patients was 7.8 years. Addition of mutation status identified a subgroup of 20 patients with unmutated IgVH genes for whom median TTT was estimated at 4.6 years; 21 patients with mutated IgVH genes had a median TTT of 8.4 years. For patients with CLL cells that were CD38-negative and either negative or positive ZAP-70, stratification via IgVH mutation status did not identify subgroups within each of these categories that had significantly different median TTT. We conclude that knowledge of CD38 and ZAP-70, as assessed by the CRC, can reliably predict TTT in most patients with CLL. For the 14% of cases that are CD38+ but negative for ZAP-70, determining the IgVH mutation status may provide added value in predicting the time from diagnosis to initial therapy.
The 13q and 11q B-Cell Chronic Lymphocytic Leukemia Deleted Regions Derive from a Common Ancestral Region in the Zebrafish on Linkage Group 9.
Authors: Auer Rebecca L. , Riaz Sophia , Cotter Finbarr E. 
Published: October 2019

Abstract
Loss of the long arm of chromosomes 11 and 13 are the most consistent cytogenetic abnormalities for patients with B-cell chronic lymphocytic leukemia (B-CLL). They suggest the presence of as yet unidentified tumor suppressor genes within well defined minimal deleted regions (MDRs). The use of small vertebrate organisms, such as the zebrafish, as models of diseases associated with chromosomal deletions enables the functional analysis of potential causative genes. Hemopoiesis is well conserved between the zebrafish and human and conserved synteny exists between the two genomes. In this study, the evolutionary conservation between the zebrafish and human genome is investigated for the 13q14 and 11q22-23 regions deleted in B-CLL. Zebrafish orthologs have been identified and radiation hybrid (RH) mapping performed to confirm their chromosomal location and define regions of conserved synteny.We have identified 38 zebrafish orthologs of the human genes in the MDRs in zebrafish cDNA and the syntenic regions for the human deletions in the zebrafish genome. The 13q14 region was syntenic with two main regions in the zebrafish genome, namely linkage group 1 (LG1) and LG9. The majority of zebrafish orthologs to 11q22-23 were found on LG5, LG15 and LG21. One syntenic region, LG9, in the zebrafish genome is of potential interest. Analysis of the smallest critical region of deletion in B-CLL for both 11q22-23 and 13q14 reveals that the human gene equivalents are contained within an area of 22.02 cR on LG9 (approximately 3260 kb). Within LG9, orthologs to two genes to human chromosome 11, three to human chromosome 13 and two chromosome 13 microRNAs (mir-15a and mir-16-1) were identified. The critical region on zebrafish LG9 maps to the MDR for both human chromosomes, suggesting a common ancestry for the B-CLL tumor suppressor genes. This is further supported by analysis of the chicken genome where the same 5 genes from 13q14 and 11q22-23 (C13orf1, RFP2, FLJ11712, FDX1, ARHGAP20) lie within a 10.04 Mb region on chromosome 1. In addition, TILLING for knock-outs of genes in this region of zebrafish embryos will allow analysis of their in vivo potential for lymphoproliferation and may define prime causative genes for B-CLL within human chromosomes 11q and 13q by reverse genetics. Our study provides an explanation for involvement of both 11q and 13q in B-CLL and the potential to develop animal models for this common lymphoproliferative disorder.
Risk Factors of Treatment Related Mortality during Autologous Stem Cell Transplant in Patients with Light Chain Associated Amyloidosis (AL).
Authors: Leung Nelson , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Kumar Shaji , Gertz Morie Abraham 
Published: October 2019

Abstract
Background: High dose melphalan followed by autologous stem cell transplant (ASCT) is an effective treatment of immunoglobulin light chain amyloidosis (AL). However, the high treatment related mortality (TRM, death before day 100) remains a serious concern and is the major drawback of this therapy. A better understanding the risk factors contributing to TRM could help physicians choose the most appropriate therapy for these patients. We performed a retrospective study to identify risk factors that contribute to TRM after ASCT in AL patients.
Methods: All patients who underwent ASCT for AL at our institution from 7/96 to 12/04 were studied. Data were collected on age, sex, septal thickness, glomerular filtration rate (GFR), B2M, CRP, proteinuria, albumin, cardiac troponin T (cTnT) and alkaline phosphate.
Results: A total of 218 patients underwent ASCT for AL during this time period. One patient refused consent for this study. Pretransplant cTnT was available on 161 (73.9%) patients. The overall TRM rate for the 217 patients was 12.4%. By univariate analysis, septal thickness, GFR, albumin, alkaline phosphatase and cTnT were found to be associated with TRM. In the multivariate analysis, only albumin, alkaline phosphatase and cTnT remained independent predictors of TRM. Cutoffs were identified using receiver-operator characteristic (ROC) curve. The cutoff for albumin was 2.85 g/dL, 249 U/L for alkaline phosphatase and 0.02 ng/mL for cTnT. The percentage of patients with low albumin, elevated cTnT and alkaline phosphatase were 51.1%, 20.5% and 12.4% respectively. The TRM rate of patients with low albumin was 18.0%, 27.3% for elevated cTnT and 29.6% for high alkaline phosphatase. Risk of TRM increased significantly with each additional risk factor (Table).
Discussion: In our AL population, low serum albumin, elevated alkaline phosphatase and cTnT were independent risk factors of TRM after ASCT. Patients with 2 or more risk factors are at significant risk of TRM during ASCT. In these high risk patients, alternative therapy should be considered in order to avoid excessively high incidence of TRM.
Treatment Related Mortality by Number of Risk Factors Risk Factors 0 1 2 3 Rate of TRM 1.8% 8.4% 35.0% 66.0% Odds Ratio 5.0 29.1 108.0
Phase I Study of BB-10901 (huN901-DM1) in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma.
Authors: Chanan-Khan Asher Alban , Jagannath Sundar , Schlossman Robert L. , Fram Robert J. , Falzone Richard M. , Ruberti Mary F. , Welch Samantha K. , DePaolo Dawn , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Background: BB-10901 is a humanized monoclonal antibody that binds with high affinity to CD56 and is covalently linked to a novel cytotoxic maytansinoid DM1. Once bound to CD56, the conjugate is internalized and releases DM1. CD56 is expressed on a variety of tumor types such as small cell lung carcinoma, neuroendocrine tumors and hematological malignancies including multiple myeloma (MM) and acute leukemia. About 70% of MM patients have evidence of CD56 expression. Based on our preliminary results that BB-10901 has significant in vitro and in vivo anti-myeloma activity in a murine model, we have now initiated a phase I clinical study.
Objectives: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and pharmacokinetics (PK) of BB-10901 given on a weekly schedule.
Methods: Relapsed or relapsed/refractory MM patients who have failed at least one prior therapy and have CD56 expressing myeloma received a single IV infusion of BB-10901 on 2 consecutive weeks every 3 weeks. Subjects are enrolled in cohorts of 3 at each dose level. The starting dose was 40 mg/m2/week based on experience from a prior phase I trial in solid tumors.
Results: Five patients have received BB-10901, 3 at 40 mg/m2/week and 2 at 60 mg/m2/week. No patients have experienced DLTs and no serious adverse events related to study drug were observed. In addition, no patients have experienced serious hypersensitivity reactions or evidence of HAHA or HADA formation. Our preliminary PK findings demonstrate that there is no evidence of accumulation of BB-10901. Detailed PK analysis and updated toxicity and efficacy data will be presented. Immunohistochemistry performed on marrow aspirates about 24 hours after huN901-DM1 infusion at 40 mg/m2 confirmed the presence of huN901-DM1 on myeloma cells in the marrow. Two patients treated at 60 mg/m2/week and who had failed multiple prior therapies including bortezomib, thalidomide and/or lenalidomide demonstrated anti-tumor response with a decrease in M proteins of 90% and 33%, respectively. Both patients received a fifth cycle of therapy and one continues on study.
Conclusions: This phase I study provides preliminary evidence of safety and clinical activity of BB-10901 in patients with CD56-positive MM who have failed established MM treatments. Targeting of BB-10901 to myeloma cells in the marrow was confirmed. The MTD is not yet defined and enrollment is ongoing.
JAK2 Inhibitors for the Treatment of Myeloprolifertive Disorders.
Authors: Hood John , Cao Jon , Hanna Ehab , Lohse Dan , Mak Chi Ching , McPherson Andrew , Noronha Glenn , Renick Joel , Zheng Binqi , Zhu Hong , Soll Richard 
Published: October 2019

Abstract
The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia has been conclusively linked to a single mutation in JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution of phenylalanine for valine at amino residue 617 leads to constitutive activation of JAK2V617F in a majority of these MPD cases. Assays in several laboratories indicate that between 90–100% of patients with polycythemia vera harbor this allele. Because the JAK2.V617F gain-of-function mutant affects such a large patient population, pharmacologically targeting the mutated JAK2 is highly clinically relevant. In order to address this unmet clinical need we designed and synthesized a series of structurally novel compounds for their capacity to inhibit JAK2.V617F. Compounds were identified which potently inhibited JAK2 enzyme, with enzymatic IC50s as low as 1 nM. Subsets of this group were subsequently identified which were highly selectivity against undesirable off-target kinases, including up to 100X selectivity versus the highly homologous JAK3 kinase. Compounds were then advanced into in vitro assays in JAK2.V617F transformed cell lines in which compounds were identified with proliferation EC50s as low as 60 nM (representative compounds listed in Table below). Compounds from this series were subsequently shown to be orally available and efficacious in rodent models of MPD driven disease.
Conclusion: TargeGen has synthesized a series of JAK2.V617F inhibitors with promising potency, selectivity and pharmaceutical properties for utility in the treatment of myeloproliferative disorders.
Representative JAK2 Inhibitors Compound Primary Target Selectivity Profile Cell EC50 JAK2 IC50 JAK2 vs JAK3 (X-fold selectivity) BaF3:JAK2.V617F TG101192 3.8 15 140 TG101209 6 28 279 TGs101348 12.5 83 297 JAK Inhibitor I (Calbiochem) 10 1.5 320