bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of MYD88 L265P and Whim-like CXCR4 Mutation in Patients with IgM Monoclonal Gammopathy
Authors: Cao Xinxin , Meng Qi , Cai Hao , Su Wei , Sun Jian , Zhou Daobin , Li Jian 
Published: October 2019

Abstract
Objectives The presence of IgM monoclonal gammopathy can occur in a broad spectrum of diseases, including Waldenstrom macroglobulinemia (WM), various B cell non-Hodgkin's lymphoma (NHL), monoclonal gammopathy of undetermined significance (MGUS), and so on. MYD88 L265P and WHIM-like CXCR4 mutation are highly prevalent in WM. However, the data is lacking in other IgM monoclonal gammopathy related diseases (IgM-RD). Therefore we investigated MYD88 L265P and WHIM-like CXCR4 mutation in various IgM-RD.
Methods Patients with sIFE confirmed IgM monoclonal gammopathy and had enough material for DNA extraction between January 2008 and May 2016 at Peking Union Medical College Hospital were enrolled in this cohort. Bone marrow samples or paraffin-embedded tumor tissues were collected. We performed Real-time allele-specific-polymerase chain reaction (AS-PCR), AS-PCR and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutation.
Results Ninety-three patients (51 male and 42 female patients) were included in this retrospective study. Median age at diagnosis was 62 years (range, 30-84 years). As for the type of light chain, 65 patients were IgM kappa (69.9%), 28 patients were IgM lambda (30.1%). The median level of serum IgM was 7.9g/L (range, 0.6-104.0g/L). There were 32 patients (34.4%) diagnosed with WM, 5 patients (5.4%) diagnosed with smoldering WM (sWM), 38 patients (40.9%) diagnosed with B cell NHL and 9 patients (9.7%) were diagnosed with MGUS. We outlined the main diagnosis, clinical characteristics and MYD88 L265P, WHIM-like CXCR4 mutation of the 93 patients in Table 1. MYD88 L265P mutation was detected in 30/32 (93.8%) patients with WM, 2/5 (40%) with sWM, 4/9 (44.4%) with IgM-MGUS, 6/14 (42.9%) with diffuse large B cell lymphoma (DLBCL), 2/6 (33.3%) with marginal zone lymphoma (MZL), 3/5 (60%) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 1/7 (4.3%) with mucosa-associated lymphoid tissue lymphoma (MALT), 1/2 (50%) with mantle cell lymphoma (MCL), 1/1 patients with primary amyloidosis (AL) and 1/1 patients with Castleman disease (CD). WHIM-like CXCR4 mutation was detected 7/32 (21.9%) patients with WM, 1/5 (20%) with sWM and 1/14 (7.1%) with DLBCL.
Conclusion IgM monoclonal gammopathy is most frequently found in WM, but it contains a broad spectrum of diseases. MYD88 L265P mutation is highly prevalent in WM and IgM MGUS, and the prevalence of MYD88 mutation in IgM related NHL is higher than that in not specified NHL reported in the literature. WHIM-like CXCR4 mutation is common in WM, but rare in other IgM-RD.

Disclosures
No relevant conflicts of interest to declare.
Evaluation of the Risk of Hepatitis B Reactivation Among Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors
Authors: Benjamini Ohad , Zlotnick Maya , Ribakovsky Elena , Kedmi Meirav , Duek Adrian , Merkel Drorit , Leiba Merav , Danylesko Ivetta , Shem-Tov Noga , Yerushalmi Ronit , Shimoni Avichai , Avigdor Abraham , Nagler Arnon , Volchek Yulia 
Published: October 2019

Abstract

Background: Immunosuppressive therapy is a known risk factor for hepatits B reactivation. The highest risk is reported in hematologic patients treated with anti-CD20 monoclonal antibodies, glucocorticoids and hematopoietic stem cell transplantation. Currently, treatment with tyrosine kinase inhibitors (TKIs) in the vast majority of chronic myeloid leukemia (CML) patients is life-long. Recently healthcare professionals were advised to test for hepatitis B infection before initializing therapy with TKIs and closely monitor HBV carriers. The risk is considered class effect with all TKIs and recommendations are based on case reports.
Aim: The aim of the current study was to evaluate the risk of hepatitis B reactivation in patients with CML treated with TKIs.
Methods: The records of patients with CML treated with TKIs from a single center were systematically reviewed for hepatitis B serology and serum biochemistry.
Results: One hundred eighty one patients diagnosed with CML between the years 1983 and 2016 were evaluated. The median age at diagnosis was 49.7 years (range 18-89), 117/181 (65%) males, with median duration of follow up with TKI therapy of 5.3 years (range 0.4 to 33 years). Over a total of 1195 years of therapy with TKIs no cases of HBV reactivation were identified. Among 114 patients with hepatitis serology, 11 patients (10%) had evidence of prior resolved HBV infection (HBsAg negative/anti-HBc positive). Two of them had anti-HBs positive serology, one had negative PCR for HBV DNA and other two patients received lamivudine prophylaxis. Only one patient had HBsAg positive serology. None of the patients with positive hepatitis serology had clinical or biochemistry evidence of hepatitis B reactivation. The 67 patients without available hepatitis serology had normal liver transaminases at 6 months of TKI therapy and at last day of follow up, confirming that no overt hepatitis B reactivation occurred.
Conclusions: We evaluated hepatitis B reactivation in a rather large cohort of CML patients, treated with TKIs. Although there were no cases of HBV reactivation during long term follow up, it should be emphasized that even a low incidence may exert a significant risk due to the long duration of treatment in a chronic disease with lifelong therapy. Our study infers that patients with serology of prior resolved HBV infection are at low risk for hepatitis B reactivation. Larger cohorts of patients with positive hepatitis B serology in a multicenter long term evaluation should be performed in order to address current recommendations for patients' safety and concerns.

Disclosures
No relevant conflicts of interest to declare.
Non-Transferrin-Mediated Iron Delivery
Authors: Knutson Mitchell 
Published: October 2019

Abstract
In iron overload conditions such as thalassemia major and hereditary hemochromatosis, the iron-carrying capacity of plasma transferrin is exceeded, giving rise to non-transferrin-bound iron (NTBI). NTBI is taken up preferentially by the liver, and to a lesser extent, the kidney, pancreas, and heart. How NTBI is taken up by various tissues has been elusive. We recently demonstrated that the plasma membrane metal-ion transporter SLC39A14 (ZIP14) mediates NTBI uptake and iron loading of the liver and pancreas, but not the kidney, heart or most other tissues¹ Given that the heart is particularly susceptible to iron-related toxicity, we are currently investigating the contribution of other iron transporters to iron loading of this organ. Possible alternative cardiac iron importers include L-type and T-type calcium channels, divalent metal transporter 1 (DMT1), and SLC39A8 (ZIP8). To examine the role of DMT1 and ZIP8 in cardiac iron metabolism, we generated mice with cardiomyocyte-specific disruption of DMT1 (Dmt1heart/heart) or ZIP8 (Zip8heart/heart). The mice were then crossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis characterized by high circulating levels of NTBI. Dmt1heart/heart mice were found to have cardiac non-heme iron concentrations that were 30% lower (P<0.01) than those of wild-type littermate controls at 6 weeks of age. Interestingly, however, double mutant Hjv-/-; Dmt1heart/heart mice accumulated more cardiac non-heme iron (3.9X control) than did single-mutant Hjv-/- mice (2.3X control) at 6 weeks of age. Cardiac-specific disruption of Zip8 did not affect cardiac non-heme iron concentrations under basal conditions or when mice were crossed with Hjv-/- mice. Collectively, these data indicate that DMT1 and ZIP8 are dispensable for iron loading of the heart in a mouse model of hemochromatosis. Our data additionally suggest that DMT1 may play a role in normal cardiac iron metabolism.
Reference:Jenkitkasemwong S, Wang C, Coffey R, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis.Cell Metabolism.2015; 22(1):138-150.

Disclosures
No relevant conflicts of interest to declare.
Innate Immune Signaling in Regulation of Immunity
Authors: Trinchieri Giorgio 
Published: October 2019

Abstract
Innate resistance, as an integral part of inflammation, and adaptive immunity participate in oncogenesis and tumor surveillance. For a long time, innate resistance was considered a primitive nonspecific form of resistance to infections that was eclipsed by the potent and specific acquired immunity of higher organisms. More recently, it has been recognized that innate resistance is not only the first line of defense against infections but also sets the stage and is necessary for the development of adaptive immunity. Advances in cancer biology have revealed that the defensive mechanisms of innate resistance and inflammation are indeed manifestations of tissue homeostasis and control of cellular proliferation that have many pleiotropic effects on carcinogenesis and tumor progression and dissemination. The interaction of innate and adaptive immunity with carcinogenesis and tumor progression is complicated and results in effects that either favor or impede tumor progression. Innate immune receptors both sense and regulate the composition of the microbiota, the large number of commensal microorganisms that colonize the barrier surfaces of all multicellular organisms, including those of humans. The microbiota affects many functions of our body and the two together comprise one metaorganism. Microbial imbalance particularly in the gut plays a critical role in the development of multiple diseases, such as cancer, autoimmune conditions and increased susceptibility to infection. Alteration in innate immune signaling and immunity may change the composition of the microbiota affecting tumor initiation both at the barrier sites (e.g. in the gut) and systemically. The commensal microbes not only may affect the development and progression of cancer but they have also important effects on the response to cancer therapy. Mostly through their interaction with innate receptors, commensal microorganisms modulate the ability of the organism to respond to cancer immunotherapy and chemotherapy by affecting the threshold of response of tumor-associated myeloid cells and their ability to sustain anti-tumor immunity.

Disclosures
No relevant conflicts of interest to declare.
Megaloblastic Anemia Probably Caused by Defective Utilization of Folinic Acid
Authors: HAURANI FARID I. , WANG GEORGE , TOCANTINS L. M. 
Published: October 2019

Abstract
A 12 year old negro girl was studied who presented a picture of megaloblastic anemia refractory to physiologic doses of vitamin B-12 and to folic acid. However, remission could be induced and maintained by pharmacologic doses of vitamin B-12 (1000 µg. per week), by folinic acid or by a combination of vitamin C (or homocysteine) and folic acid. Folinic acid determinations and the clinical response to various metabolites indicated the existence of a metabolic defect in the utilization of folinic acid. The hereditary nature of this defect was suggested by the fact that two siblings might have had a similar condition.
The Role of the Kidney in the Production of the Erythropoietic Factor
Authors: NAETS JEAN-PIERRE 
Published: October 2019

Abstract
The role of the kidney in production of erythropoietin was investigated. Dogs were made anemic by phlebotomy and were then subjected to bilateral nephrectomy, ureter ligation or ureter section. Erythropoietic stimulating activity in the dog plasma was judged by measuring the incorporation of Fe59 into the red cells of starved rats. No erythropoietic activity could be found in the dog plasma 24 and 48 hours after nephrectomy, but erythropoietic activity was found after ligation of the ureters.
THE HEMATOLOGIC RESPONSE IN DOGS TO THE ADMINISTRATION OF ANTI SPLEEN SERUM
Authors: MIALE JOHN B. 
Published: October 2019

Abstract
1. Intravenous injection into dogs of rabbit anti-dog-spleen serum in doses of 0.04 cc./10 Kg. results in a significant increase in the mononuclear cells of the peripheral blood.
2. The rise in circulating mononuclears occurs promptly, with 24-48 hours, and is sustained, generally for 20 days.
3. A large dose of the same serum, 5.4 cc./10 Kg., exerted an opposite effect, poducing a significant decrease in circulating mononuclears.
4. The possible significance of these findings is discussed.
DEVELOPMENT OF INCLUSION BODIES CONTAINING RIBOSE NUCLEIC ACID IN MYELOMA CELLS AFTER INJECTIONS OF STILBAMIDINE. DETERMINATION OF STILBAMIDINE IN MYELOMA TISSUE
Authors: SNAPPER I. , MIRSKY A. E. , RIS H. , SCHNEID B. , ROSENTHAL M. 
Published: October 2019

Abstract
The cytoplasm of myeloma cells is rich in ribose nucleic acid. The basophilic inclusion bodies which develop in myeloma cells under the influence of stilbamidine contain ribose nucleic acid. The myeloma tissue of patients treated with stilbamidine contains appreciable amounts of stilbamidine.
There is reason to believe that the nucleoproteins of myeloma cells differ from the nucleoproteins of other cells. This could explain why stilbamidine reacts with the nucleoproteins of myeloma cells only, and not with the nucleoproteins of other cells.
THE ERYTHROPOIETIC ACTIVITY OF CHOLINE CHLORIDE IN MEGALOBLASTIC ANEMIAS
Authors: DAVIS L. J. , BROWN ALEXANDER 
Published: October 2019

Abstract
1. The effect of the administration of choline chloride has been observed in 10 cases of megaloblastic anemia of various types.
2. Choline was without effect in a case of untreated Addisonian pernicious anemia which subsequently responded to parenteral liver therapy.
3. Choline was also without effect in a case of nutritional megaloblastic anemia, in a case of megaloblastic anemia of pregnancy, and in two cases of megaloblastic anemia associated with the sprue syndrome. All these cases had proved refractory to injections of potent liver extract before the choline was given, and all responded to subsequent oral liver or folic acid therapy.
4. A significant erythropoietic response to choline occurred in two cases resembling Addisonian pernicious anemia which were refractory to parenteral liver extracts.
Secondary responses followed the administration of choline in two other cases of Addisonian pernicious anemia and in a case of megaloblastic anemia of pregnancy, all of which had already responded to injections of liver extract.
5. The significance of these observations is discussed. It is concluded that choline possesses no direct erythropoietic activity, but that under certain circumstances it may potentiate the effect of liver extracts.
It is suggested that refractory megaloblastic anemias may be divided into two groups. In one, represented by well known syndromes associated with defective absorption or pregnancy, the lack of response to parenteral liver extracts is not corrected by choline. In the other, represented by two cases simulating Addisonian pernicious anemia, choline is effective in overcoming, partially or completely, the refractoriness to parenteral liver therapy. Consideration is given to the view that the refractoriness of this group results from hepatic dysfunction.
6. The most satisfactory method of administering choline probably consists of intravenous injections in daily doses of 1 gram. Larger doses given intravenously are frequently accompanied by unpleasant side effects, while oral administration appears to be relatively less effective.
7. It seems unlikely that choline will be of practical value in the treatment of refractory megaloblastic anemias, for which oral liver preparations provide the most certain and effective treatment. It is possible, however, that choline may be of use in cases complicated by severe hepatic disease.
SUCCESSFUL TREATMENT OF LIVER-REFRACTORY ANEMIA WITH SYNTHETIC LACTOBACILLUS CASEI FACTOR
Authors: WALDENSTRÖM JAN 
Published: October 2019

Abstract
Four cases of liver-refractory macrocytic anemia are described. Three were treated with folic acid perorally and reacted well.
The first was an instance of nontropical sprue with atrophy of the spleen that was diagnosed clinically and confirmed at postmortem examination. The megaloblastic anemia also became completely refractory to crude liver extracts and liver digested with gastric juice.
The second case was successfully treated with liver extracts for twelve years. After that time she suddenly became refractory with severe leucopenia. Folic acid in large doses had an excellent effect and the patient has kept relatively normal blood values for about a year without further treatment of importance. It should be noted that the morbid condition of the tongue could not be influenced by folic acid.
The third case should probably be classified as idiopathic steatorrhea. Folic acid gave a full remission of the macrocytic anemia.
The fourth case resembled typical pernicious anemia more closely, as a histamine-fast achlorhydria was present. This patient had been refractory to liver treatment but reacted well to folic acid in ordinary doses.
The fifth case was a typical instance of idiopathic stcatorrhea with probable atrophy of the spleen. She had a moderate anemia that was refractory to liver extracts. Folic acid perorally and intramuscularly neither influenced the anemia nor the fecal fat.
In a series of cases of uncomplicated pernicious anemia, the immediate response to folic acid in doses of 20 to 30 mg. daily was good. Full remissions as regards hemoglobin and erythrocytes could be expected with a total dosage of 400 to 600 mg.
Certain cases of pernicious anemia refractory to liver extract may respond to folic acid. This indicates that the two substances probably have different mechanisms of action.
THE RELATION OF THERAPY IN PERNICIOUS ANEMIA TO CHANGES IN THE NERVOUS SYSTEM. EARLY AND LATE RESULTS IN A SERIES OF CASES OBSERVED FOR PERIODS OF NOT LESS THAN TEN YEARS, AND EARLY RESULTS OF TREATMENT WITH FOLIC ACID
Authors: BETHELL FRANK H. , STURGIS CYRUS C. 
Published: October 2019

Abstract
Seventy patients with pernicious anemia have been observed for periods of not less than ten years. The clinical course in these cases has been analyzed with particular reference to changes in the neurologic status.
Most of the patients, whether treated with oral preparations of stomach or liver, or parenteral crude or refined liver extracts, showed significant improvement of their neurologic manifestations. The period of improvement was limited, essentially, to the first year of therapy.
Thirty-six members of the series received treatment regularly and were maintained consistently in complete hematologic remission. Fifteen of the patients did not adhere to an optimal therapeutic regimen, and their blood values were frequently abnormal, although definite relapses did not occur. In the former group there were no instances of development or progression of neural lesions. In the latter such adverse changes as did occur were transient and reversible on resumption of adequate therapy. Nineteen patients in the series suffered clinical and hematologic relapses after their initial response to intensive therapy. The end results in this group were not so favorable, but nevertheless serious progression of spinal cord involvement was rarely observed. The apparent infrequent occurrence of pronounced changes is attributed to the short duration of the relapses and to the relatively mild degree of nervous system involvement present when the diagnosis of pernicious anemia was made. It may be assumed that patients with more extensive neural disease who suffered relapses, progressed to a fatal termination.
The observations reported in no way justify the conclusion that irregular or sub-optimal therapy is without serious risk. They are presented in order to indicate what the long-term clinical results may be in the case of patients with pernicious anemia, who frequently fail to adhere to an ideal therapeutic regimen.
The early results of treatment with synthetic folic acid, as observed in a series of 15 patients, indicate that both the hematologic and neurologic response to this form of therapy is much less predictable than is the case with stomach or liver preparations. It is suggested that disturbance of folic acid metabolism is not the sole cause of either the hematologic or the neurologic manifestations of pernicious anemia, but that inability to utilize folic acid effectively may play a part in the development of both myeloid and neural abnormalities.
THE DEVELOPMENT AND PROGRESSION OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD IN PATIENTS WITH PERNICIOUS ANEMIA TREATED WITH SYNTHETIC PTEROYLGLUTAMIC (FOLIC) ACID
Authors: Ross J. F. , BELDING H. , PAEGEL B. L. 
Published: October 2019

Abstract
1. Twenty-one patients with pernicious anemia were maintained on synthetic folic acid (pteroylglutamic acid) therapy alone for periods ranging from eight to seventeen months. Satisfactory blood levels were maintained in all cases receiving daily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred within six months in a case treated with monthly injections of 30 mg.
2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute combined degeneration of the spinal cord.
3. Ten patients showed a significant improvement in blood values for a few months after substitution of folic acid for liver extract. With one exception these subsided after six or more months to pre-folic acid levels comparable with those previously maintained with liver extract alone.
4. These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone.
5. A previously untreated patient with severe subacute combined degeneration of the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy.
6. Eleven patients developed, or showed progression of, subacute combined degeneration of the spinal cord during folic acid treatment. Neurologic disease developed in most of these patients when the peripheral blood was normal.
7. One patient showed an extremely explosive onset and rapid progression of neural disease. The progression of the disease was rapid in 3 other cases.
8. The institution of liver extract therapy in adddition to folic acid in 5 patients who developed subacute combined degeneration during folic acid maintenance therapy failed to prevent progression of the disease in 4 cases, and only partially arrested the disease in the fifth, in which improvement occurred more rapidly when folic acid was discontinued.
9. Subacute combined degeneration occurred with greater frequency in patients on large daily doses of folic acid than it did in patients with small or intermittent doses.
10. The possibility is discussed that folic acid in large daily doses may actually precipitate or aggravate neurologic disease.
11. It is suggested that folic acid may interfere with the metabolism of 1(+) glutamic acid in the central nervous system and possibly disturb the formation or function of acetylcholine.