bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies on Copper Metabolism
Authors: CARTWRIGHT G. E. , GUBLER C. J. , BUSH J. A. , WINTROBE M. M. 
Published: October 2019

Abstract
1. The morphology of the erythrocytes has been studied in 22 normal swine, 65 swine deficient in copper, and 16 swine deficient in iron. The mean values (± the standard deviation) for the volumes of packed red cells in the three groups were 42 ± 2.5, 21 ± 6.6, and 21 ± 6.1 ml/100 ml., respectively. The mean values for the mean corpuscular volumes were 55 ± 3.1, 43 ± 7.1, and 36 ± 5.3, respectively. The mean values for the mean corpuscular hemoglobin concentrations were 33 ± 1.1, 29 ± 2.3, and 28 ± 3.0, respectively.
2. The addition of 11 water-soluble B vitamins, 4 fat-soluble vitamins, ascorbic acid, and minerals (with the exception of copper) to the copper-deficient milk diet did not prevent or delay the development of anemia, modify the morphology of the red cells or alter the degree of hypoferremia.
3. The normoblasts in the marrow of a copper-deficient pig were similar morphologically to those in the marrow of a pig deficient in iron.
4. The intravenous administration of one Gm. of iron, given prior to the development of copper-deficiency, did not delay or prevent the development of anemia.
5. It is concluded that the anemia of copper-deficiency in swine is morphologically similar to the anemia due to iron deficiency in swine.
A Sign of Severe Radiation Injury Observed in the Erythrocyte Sedimentation of Dogs
Authors: SACHER GEORGE A. 
Published: October 2019

Abstract
Erythrocyte sedimentation curves are analyzed by determining the constants of a linear relation between logarithm of sedimentation distance and logarithm of time that obtains for the initial part of the sedimentation process. The sedimentation curves obtained from dogs exposed to x-rays, or injected with radiostrontium or plutonium were analyzed in this manner. The pathologic sedimentation curves fall into two groups. Dogs that received sublethal dosages of x-ray, radiostrontium or plutonium showed a response (phase I response) in which decreased slope of the log-log line is associated with increased intercept. Dogs that received dosages in or beyond the LD50 range showed, during the period of maximum acute death rate, a further increase in intercept associated with an increase in slope (phase II response). An increased slope indicates an increased rate of rouleau growth. It is inferred that the phase I response is due to decreased hematocrit and the phase II response to an increased titer of an agglutinating principle.
Studies on the Anemia of Disseminated Malignant Neoplastic Disease. II. Study of the Life Span of the Erythrocyte
Authors: HYMAN GEORGE A. , GELLHORN ALFRED , HARVEY JANE L. 
Published: October 2019

Abstract
1. A study of the life span of the erythrocyte in patients with advanced neoplastic disease was performed by transfusing blood from 23 hospitalized patients into 53 healthy volunteers.
2. The Ashby technic for red cell labeling was used alone in 16 instances, Cr51 technic in 52 instances, and a combination of the 2 technics in 8 instances.
3. Normal or nearly normal life spans were suggested by the slopes of curves in 15 instances where whole blood from patients was transfused into volunteers.
4. Some shortening of the life span of the patient’s red cells was noted when these cells, separated from the plasma, were transfused into volunteers or back into patients, possibly related to the handling during plasma removal.
5. Control studies using either Cr51 or Ashby labeling technic indicated a normal life span of approximately 120 days in the volunteers employed could be achieved by each method.
6. Values obtained with Cr51 were so similar to those using Ashby labeling that the easier Cr51 technic is recommended for future studies.
7. The normal erythrocyte transfused into patients with neoplastic disease may have a moderate to considerably shortened life span.
8. These studies seem to demonstrate an absence of an intrinsic defect in the erythrocytes of patients with neoplastic disease, and further favor the presence of a hemolytic plasma factor of considerable importance in the pathogenesis of the anemia of cancer.
Studies on the Biosynthesis of Heme In Vitro by Avian Erythrocytes
Authors: GOLDBERG A. , ASHENBRUCKER HELEN , CARTWRIGHT G. E. , WINTROBE M. M. 
Published: October 2019

Abstract
1. A method, based on the uptake of radioiron into heme, is described for the measurement of heme synthesis in a hemolysate of chicken erythrocytes.
2. The addition of glycine, δ-aminolevulinic acid, porphobilinogen or protoporphyrin 9 to the system augmented heme synthesis.
3. Citrate potentiated heme synthesis in the presence of glycine, but had no effect when porphobilinogen was added. Succinate, in the presence of glycine did not enhance heme synthesis.
4. The addition of coproporphyrin I or III, or uroporphyrin I or III, did not augnment the uptake of radioiron into heme. The addition of mesoporphyrin 9 or hematoporphyrin 9 enhanced the uptake of radioiron. These studies are iterpreted as suggesting that protoporphyrin, but not uroporphyrin or coproporphyrin, is a precursor of heme. For reasons discussed, further work will be necessary to determine if mesoporphyrin and hematoporphyrin are precursors of protoheme.
5. The synthesis of heme was inhibited by the addition of malonate or lead. Evidence is presented that both of these substances affected heme synthesis at several different levels, particularly the formation of δ-aminolevulinic acid and the incorporation of iron into protoporphyrin.
6. Plasma extracts from chickens, made anemic by bleeding or by the administration of phenylhydrazine, did not potentiate heme synthesis.
7. Normal, nonreticulated, human erythrocytes failed to synthesize heme in the presence of glycine, δ-aminolevulinic acid, porphobilinogen on protoporphyrin 9.
Hematologic Observations on Patients with Sickle Cell Anemia Sustained at Normal Hemoglobin Levels by Multiple Transfusions
Authors: CHAPLIN HUGH , KEITEL HANS G. , PETERSON RALPH E. 
Published: October 2019

Abstract
(1) Three sickle cell patients were sustained at normal hemoglobin levels for 3-4 months by means of repeated transfusions of fresh blood.
(2) In response to transfusions, there was a decline in reticulocytes to normal levels during the first 5-7 days of observation. During periods in which the hemoglobin was maintained at high-normal or super-normal levels, the reticulocyte values were depressed below the normal range. A distinct reticulocyte response was observed when the hemoglobin declined to approximately 11.0 Gm. per cent following cessation of transfusions.
(3) Employing anti-M differential agglutination, a simple exponential decline was observed in the number of sickle cells in each patient’s circulation during the period of sustained normal hemoglobin concentration.
(4) The continued production of new sickle cells during the first week of observation complicated the interpretation of the differential agglutination data, but provided indirect evidence for the presence of an especially short-lived proportion of the patient’s cells. Support for this concept was derived from the radioactive iron utilization studies performed in Case 1.
Long Term Disease Free Survival in Patient with Linfoplasmocytic Lymphoma and Regression of Associated Severe Renal Failure after Treatment with Bortezomib.
Authors: Abbadessa Antonio , Monaco Giuseppe , Troiano Mario , Liguori Lucia , Focarile Elisa , Vigliotti Maria Luigia , Iaccarino Salvatore 
Published: October 2019

Abstract
Background. We describe a case of lymphoplasmocytic lymphoma, refractory to conventional treatments and complicated with bone lesions and acute renal failure, completely regressed after therapy with bortezomib. Case report. Woman, 48 years old, in march 1994 receives diagnosis of lymphoplasmocytic lymphoma, refractory to conventional chemotherapy (chlorambucil, CHOP, fludarabine), immunotherapy (rituximab), radiotherapy. She comes to our attention in november 2005 for disease’s progression, associated to severe renal failure (sieric creatinine=3.65 mg/dl; creatinine clearance = 17.52 ml/min), caused by serious monoclonal proteinuria (21500 mg/24h). We decide to use dexamethazone (20 mg) and bortezomib at a reduced dose (1mg/m2 twice a week on days 1,4,8,11, for eight cycles). At the end of second cycle with bortezomib, there is a conspicuous reduction of proteinuria (350 mg/24h) with partial recovery of renal function (sieric creatinine = 1.7mg/dl; creatinine clearance=23.68ml/min) Because of severe neurologyc toxicity (convulsion, peripheric neuropathy) and appearance of herpetic lesions, we decide to suspend treatment with bortezomib. After eleven months from the end of treatment with bortezomib, PET total-body, shows only a moderate hypercaptation on the anterior segment of lower lobe of right lung. At a follow-up of 20 months renal function results clearly improved (sieric creatinine = 1.4 mg/dl; creatinine clearance=44.57 ml/min) with normalization of proteinuria (104 mg/24h).
Discussion. Renal faillure in course of lymphoplasmocytic lymphoma is a not frequent event. It is due to amount of paraprotein on endothelial side of glomerular basal membrane. Generally standard treatments not improves the renal failure. The therapeutic activity of the antiproteosome in myeloma and in different lymphomas is currently well documented (O’Connor et al, JCO2005, 23 (4):676–684; K. Anderson et al, JCO2006 Annual Meeting Proceedings Part I. Vol 24 (18S): 7504). Other authors have demonstrated the renal repair (A. K. Malani et al, Acta Haematologica2006;116 (4):255–258).
Conclusion. bortezomib, proteosome inhibitor, can be used to improve not only myeloma and lymphoma course but also to repair renal failure, when caused by paraprotenemia/paraproteinuria.
Systematic Profiling and Novel Targets of the Bcr-Abl Kinase Inhibitors Imatinib, Nilotinib and Dasatinib.
Authors: Hantschel Oliver , Rix Uwe , Buerckstuemmer Tilmann , Schmidt Uwe , Kneidinger Michael , Bennett Keiryn L. , Kaupe Ines , Ellmeier Wilfried , Valent Peter , Superti-Furga Giulio 
Published: October 2019

Abstract
The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia (CML). Since imatinib resistance has become a major clinical problem in recent years, two second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL and targeting imatinib-resistant CML clones were developed. To predict potential side effects and novel medical uses we generated comprehensive drug-protein interaction profiles for all three drugs. We have used an unbiased chemical proteomics approach to detect drug-binding proteins directly from lysates of CML cells. Our studies yielded four major findings:
The interaction profiles of the three drugs displayed strong differences and only a small overlap covering the ABL kinases. Dasatinib bound in excess of thirty Tyr− and Ser−/Thr−kinases, including major regulators of the immune system suggesting that dasatinib might have a particular impact on immune function. Despite the high specificity of nilotinib the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations representing the first non-kinase target of these drugs.
In addition, we have concentrated on the promiscuous binding profile of dasatinib: Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. The kinase activity of Btk and Tec, but not of Itk, was inhibited by nanomolar concentrations of dasatinib in vitro and in cultured cells. We identified the gatekeeper residue as the critical determinant of dasatinib susceptibility. Mutation of Thr-474 in Btk to Ile and Thr-442 in Tec to Ile conferred resistance to dasatinib, while mutation of the corresponding residue in Itk (Phe-435) to Thr sensitized the otherwise insensitive Itk to dasatinib. The configuration of this residue may be a predictor for dasatinib sensitivity across the kinome. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Furthermore, dasatinib inhibited histamine release in primary human basophils and secretion of pro-inflammatory cytokines in immune cells. The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer new therapeutic opportunities for inflammatory and immunological disorders.
Activity of Circulating Proteasomes Correlates with Clinical Behavior in Patients with Chronic Myeloid Leukemia.
Authors: Ma Wanlong , Kantarjian Hagop , Donahue Amber , Zhang Xi , O’Brien Susan , Jilani Iman , Estey Elihu , Estrov Zeev , Cortes Jorge , Keating Michael , Giles Francis , Albitar Maher 
Published: October 2019

Abstract
The ubiquitin-proteasome pathway is implicated in the pathogenesis of many malignancies and is an important regulator of cell proliferation, apoptosis, DNA repair, and the stress response. Free circulating proteasomes have been reported in the plasma and sera of cancer patients. We measured proteasome peptidase activity in the plasma of patients with chronic myeloid leukemia (CML) and correlated these findings with clinical behaviour. Plasma samples from apparently healthy volunteers (n = 92) and patients in the chronic (n = 104) or accelerated/blast phase (n = 56) of CML were analysed with fluorogenic kinetic assays. Using peptide-AMC (7-amino-4-methylcoumaran) substrates, we measured the three reported proteasome enzymatic activities: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L). All proteasome activities were significantly higher in CML patients than in healthy volunteers. Extensive characterization of proteasome activities revealed correlations between levels or ratios of specific peptidase activities and disease phase, progression, aggressiveness, and survival. High Ch-L activity correlated with shorter survival in both CP (P=0.037) and Acc/Bl phase (P=0.047). Patients in CP and a ratio of Cas-L: Tr-L activity >1.48 had significantly shorter survival (P=0.03). Cas-L: Tr-L activity ratio was predictor of survival in Acc/Bl patients as a continuous variable. These findings suggest that proteasome activity in the plasma of CML patients reflects disease activity and can be used as a biomarker for predicting clinical behavior. Studies exploring the role of proteasome inhibitors in CML are therefore warranted.
Rituximab and 2-Chlorodeoxyadenosine in Hairy Cell Leukemia as First Line Treatment: A Faster Way to Remission. Report of Five Cases.
Authors: Farina Giuliana , Giordano Giulio , Papini Stefano , Zappacosta Bruno , Carbone Arnaldo , Guerriero Massimiliano , Storti Sergio 
Published: October 2019

Abstract
Background Hairy-Cell leukaemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder that accounts for about 2% of all leukaemias. Although the disease is generally indolent in its natural course, the majority of patients requires treatment for life-threatening infections due to pancytopenia or symptomatic splenomegaly. Remarkable progresses have been made in the treatment of HCL. Prior to the advent of nucleoside analogues, which are currently the standard initial treatment, interferon and splenectomy were the most effective therapies. Treatment with purine analogs (PNA) such as 2-chlorodeoxyadenosine (2-CdA) is associated with excellent remission rate and long-term survival. Recently, immunotherapeutic approaches which use monoclonal antibodies, like rituximab, have increased the number of therapeutic options for HCL and offer promising salvage strategies for patients who relapse or who are refractory to treatment with purine analogues. Previously rituximab, used in patients relapsing or refractory to CdA and for elimination of MRD after treatment with PNA, showed hematological CR and good MRD eradication. Patients and treatment We analysed, in a retrospective study, five consecutive patients M/F 4/1, 4 with HCL and one with HCLVariant treated at the diagnosis with one rituximab administration at the dose of 375mg/mq and 2CdA at the dose of 0.14 mg/mq/day s.c. for 5 days. Their median age was 70 years (range 41–71). All patients showed splenomegaly and thrombocytopenia (median platelet count was 65000 with range 49000–88000), four of these presented neutropenia (median count was 435/mmc with range 430–800/mmc) and one patient was severely anemic (Hb < 8 g/dl).
Results None of the patients had severe therapy-related side effects. Four patients showed febrile cutaneous rash, although received prophyilaxis with acyclovir. The median time of recovery for neutrophil count >1500/mmc was 20 days (range 15–38) for platlets count> 100000/mmc was 21days (12–21), and hemoglobin level> 8g/dl was 31.5 days(27–36). Our median follow up at today was 264 days(range 40–570). At this time all patients are in hematological and morphologic complete remission.
Conclusions The use of Rituximab together with 2CDA in first line therapy is safe and feasible. Moreover when Rituximab is used in such setting, median time of recovery in neutrophils and platelets count is significatively shorter than that obtained after therapy with 2CdA alone (8 and 4 weeks respectively). A longer follow-up is needed to evaluate the long-term results of the treatment.
Monoclonal Immunoglobulins of Alpha-2 Mobility on Protein Electrophoresis: A Case Series.
Authors: Chari Ajai , Eisenberger Andrew , Pesce Michael 
Published: October 2019

Abstract
Protein electrophoresis (PEP) separates proteins based on mobility through support media such as agarose into five general regions: albumin, alpha-1, alpha-2, beta, and gamma. Monoclonal and polyclonal immunoglobulins typically migrate in the gamma or beta regions. Between April 1990 and July 2007 at Columbia University Medical Center, we identified and then retrospectively reviewed 15 patients with monoclonal proteins of alpha-2 mobility repeatedly on serum PEP (see figure). Immunofixation identified the paraprotein as IgA kappa in 7 patients, IgA lambda in 2, IgG lambda in 2, free kappa light chain in 4, free lambda light chain in 2, and one IgG lambda. In the urine, of the 14 patients who had PEP performed, 6 patients had serum concordant light chains (5 kappa and 1 lambda) also migrating in the alpha 2 region, however, for 5 other patients migration was either in the beta or gamma regions. Published case reports of monoclonal proteins with atypical mobility patterns are reviewed. The median age of our patients was 66 years and there were 9 males. 10 patients had multiple myeloma, 5 had monoclonal gammopathy of undetermined significance (MGUS), and 1 had lambda AL amyloidosis. This is the largest case series ever described of patients with monoclonal proteins migrating in alpha 2 region and illustrates the importance of immunofixation in screening patients for plasma cell dyscrasias. Possible explanations for this unusual migration pattern include protein complex formation with other plasma components, high carbohydrate content, or given the IgA predominance noted, properties of the IgA immunoglobulin such as polymerization.
Figure Figure
Safety and Efficacy of Bortezomib and Dexamethasone (BD) in Multiple Myeloma as First-Line, Second-Line or Third-Line Treatment.
Authors: Li Juan , Huang Beihui , Zhao Ying , Zheng Dong , Luo Shaokai 
Published: October 2019

Abstract
Purpose: To compare efficacy and safety of BDbortezomib and dexamethasone in multiple myeloma as first-line, second-line or third-line treatment.
Patients and methods: 18 patients(pts) treated with BD (bortezomig 1.3mg/m2 on d 1,4,8,11 and dexamethasone 20mg on d 1–4 in a 21-day cycle). Responses were evaluated by the criteria of EBMT but a nCR was included. Adverse events were graded by the WHO criteria.
Results: The median age was 52.5 years, and 13 (72.2%) were male. Ig subtypes were IgG, (8 pts, 44.4%), IgA (4 pts, 22.2%), light chain (2 pts, 11.1%), and IgD (1 pts, 5.9%). Durine/Salmon staging: IIA 5.9% (1/18), IIB 5.9% (1/18), IIIA 72.2% (13/18), IIIB16.6% (3/18). BD was administered in first-line (4 pts, 22.2%), second-line (7 pts 38.9%) and third-line (7 pts, 38.9%). The median number of BD cycles was 2.5 (range, 1–6 cycles). 17 pts could be evaluated, overall response was 88.3%, including CR in 2 pts (11.7%), nCR in 5 pts (29.4%), PR in 7 pts (41.2%), MR in 1 pts(5.9%), NC in 1 pts(5.9%), PD in 1 pts(5.9%). Pts in the first-line group received a response of 100%(4/4), including nCR in 1 pts (25.0%), PR in 2 pts (50.0%), MR in 1 pts(25.0%). The second-line group received a response of 100%(7/7), including CR in 1 pts(14.3%), nCR in 3 pts (42.9%), PR in 3 pts (42.9%). Those received BD as third-line or more got a response of 66.7% (4/6), including CR in 1 pts(16.7%), nCR in 1 pts (16.7%), PR in 2 pts (33.3%). Aderse events included diarrhea 44.4% (8/18; grade IV: 2/18), thrombocytopenia 44.4% (8/18; grade III–IV: 7/18), fatigue 44.4% (8/18; grade IV: 1/18), peripheral neuropathy 33.3% (6/18, grade II:1/18), pyrexia 22.2%, infection 16.7% (3/18), headache 11.1%(2/18), parageusis 11.1%(2/18), hypotension 5.9%(1/18), hypoglycemia 5.9%(1/18) while combining with glipizide. The median time to minimum counts of platets was 14 days. The median time to most serious peripheral neuropathy appeared after treatment of 3 cycles. In 1 pts the therapy was disrupted by toxicity.
Conclusion: BD demonstrated better response as first-line or second-line therapy than as third or more line therapy. Toxicities were torelated and manegable. There were no treatment related deaths.