bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Immuotherapy of Muc1 Positive Carcinomas with Genetically Engineered Human T Cells.
Authors: Chinnasamy Nachimuthu , Shaffer James , Chinnasamy Dhanalakshmi 
Published: October 2019

Abstract
Mucin1 (Muc1), a tumor-associated antigen, is overexpressed in many adenocarcinomas including breast, pancreas, ovary, prostate, colon, and in multiple myeloma. Therefore, tumor associated Muc1 is an attractive target for immunotherapy. Several types of immunotherapeutic approaches targeting Muc1 are currently being tested in preclinical and clinical settings. A major limitation of vaccination strategies involving tumor antigens is the lack of induction of sufficient number of antigen-specific effector T cells systemically to achieve objective clinical response. In an effort to redirect activated T cells towards tumor cells, we constructed lentiviral vectors expressing chimeric receptors consisting of a novel single chain variable domain (scFv) of a monoclonal antibody against Muc1 combined with various cytoplasmic signaling domains such as CD3 Zeta, CD28 and OX40. Human peripheral blood T cells were lentivirally transduced with chimeric immune receptors in order to redirect them towards Muc1 positive tumor cells. A sufficiently high level of transduction (>80) was achieved without any positive selection. Transduced T cells were stimulated and expanded over a period of 10–15 days in the presence of IL-2. Gene-modified T cells efficiently recognized Muc1 expressing tumor target cells in an MHC-independent manner as demonstrated by antigen-specific tumor cell cytolysis. Furthermore, transduced T cells showed antigen-specific proliferation and secreted interferon gamma upon ligation with Muc1 on tumor cells. These results indicate that generation of large numbers of antigen specific T cells for clinical application is possible through the use of this chimeric immune receptor gene transfer strategy. This approach might be an attractive strategy in a minimal residual disease setting complementing traditional therapies based on surgery, radiation and/or chemotherapy. Therefore, present study suggests a promising new strategy for cancer immunotherapy using gene-modified T cells.
Figure Figure
Successful Reversion of Refractory Paroxysmal Nocturnal Hemoglobinuria (PNH) by Allogeneic Peripheral Blood Stem Cell Transplantation.
Authors: Pang Ying , Feng Ying , Chen Ruizhen , Ye Xu 
Published: October 2019

Abstract
Objective: To observe the safety and effect of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) on hematopoietic reconstitution of refractory paroxysmal nocturnal hemoglobinuria(PNH)and reversion of hemolysis.
Methods: A 20 years old female patient diagnosed with PNH complicated with cerebral infarction underwent allo-PBSCT. The donor was the patient’s 18 years old biological brother. Six loci on HLA-A, B, and DRB1 were completely matched with those of the recipient. Four days after the administration of G-CSF (250 μg/day) to the recipient, peripheral blood stem cells (PBSCs) were collected from the donor for 2 consecutive days. A total volume of 112 ml was harvested. A median nucleated cell (MNC) count of 6.2×108/kg with 2.4×106 /kg of CD34+ cells were actually administered to the recipient. The standard conditioning regimen was busulfan/cyclophosphamide (BU/CY). The recipient was started on intravenous infusion (IV) of cyclosporine A (CSA) on Day -1 and a plasma concentration of 150–250 ng/L was maintained. IV methotrexate (MTX) 10mg/m2 was given on Days +1, +3, +6, and +11. Oral mycophenolate mofetil(MMF)was administrated from Days +1 to +28 for prophylaxis of acute graft-versus-host disease (GVHD). If the concentration of hemoglobin (Hb) decreased below 70 g/L and/or platelet count (BPC) below 15×109 /L, the recipient was transfused with 60Co 25cGy irradiated and leuko-depleted red blood cells (RBCs) and/or single-donor platelets. Starting from Day +3, G-CSF was given to the recipient until white blood cells (WBC) increased to above 3.0× 109 /L. EPO and Interleukin-11 were also administrated to stimulate the proliferation of the progenitors of erythrocytes and megakaryocytes.
Results: DNA-STR on Day +33 indicated a complete chimerism in the recipient. Chromatin bodies were observed as 46XY on Day +45. CD55/CD59 expression on the membranes of leucocytes and erythrocytes, hemolysis index, and coagulation parameters returned to normal. The patient has been relapse-free for one year since the time of discharge.
Conclusion: 1. When conventional therapy with hormone and immunosuppressant becomes unsuccessful to control PNH, allo-PBSCT may be an alternative measure with promising effect. 2. In comparison to the reduced dose regimen, the standard dose regimen of BU/CY shown lower rate of relapse. 3. To decrease the mortality rate related to transplantation, allo-PBSCT needs to be considered as early as possible for refractory paroxysmal nocturnal hemoglobinuria.
A Case of SAA with Secondary Hemochromatosis: Can Continuous Iron Chelation Reverse Both Bone Marrow and Multiple Organ Failures?.
Authors: Park Soo-Jeong , Han Chi-Wha 
Published: October 2019

Abstract
A 24-year-old male patient with hemochromatosis due to multiple packed red blood cell transfusions, was referred to our emergeny center for a treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at the age of 11 and had developed a transfusional hemochromatosis after 5 years of multiple blood transfusions. He had dilated cardiomyopathy with ejection fraction of 4 % requiring diuretics and digitalis, multiple endocrine dysfunctions (hypothyroidism, hypoparathyroidism with hypocalcemia, cataract, and intracranial calcifications, diabetes, and gonadal dysfunction), liver dysfunction, generalized bleeding, and skin pigmentation (Fig.1-left). A total volume of packed red blood cell transfusion before deferoxamine therapy was about 96,000 ml and the number of transfused units of platelet concentrates were innumerable. He had received regular iron chelation therapy (continous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3–4 weeks) for 7 years after multiple organ failures. His cytopenias and organ dysfunctions (heart, liver and skin) began to recover progressively in 2002, after four years of deferoxamine therapy. He had had complete normal ranges of his peripheral blood cell counts, heart size, and liver function two years ago (Fig.1-right & Fig.2). He has not received any transfusions for the last four years. This finding suggests that continuous deferoxamine infusion may play a role in immune regulation in addition to iron chelation effect.
Figure 1. Posteroanterior chest radiographs reveal a marked cardiomegaly with right pleural effusion before the treatment (left) and a normalized heart after the deferoxamine therapy (right). Figure 1. Posteroanterior chest radiographs reveal a marked cardiomegaly with right pleural effusion before the treatment (left) and a normalized heart after the deferoxamine therapy (right). Figure 2. Hemoglobin changes and clinical course. Figure 2. Hemoglobin changes and clinical course.
Retrospective Review of Patients of Southeast Asian Descent with Persistent Hyperferritinemia Who Are Negative for Hereditary Hemochromatosis.
Authors: Yenson Paul R. , Tsang Peter W.K. , Li Charles , Chung Henry , Yoshida Eric M. 
Published: October 2019

Abstract
Background and Methods. Isolated hyperferritinemia is a common clinical finding. However, known HFE mutations C282Y and H63D have not been well-described in the Asian population. As well, evaluation of hyperferritinemia in the Asian population is confounded by chronic hepatitis B infection. We performed a retrospective case review of 79 patients of Southeast Asian ethnicity referred to three subspecialists in a tertiary care teaching hospital from January 1997 until July 2006 for assessment of hyperferritinemia. A subset of patients may represent a novel syndrome of isolated hereditary hyperferritinemia.
Results. 35 patients had identifiable secondary causes for their hyperferritinemia. 4 had clinical or biopsy proven iron overload consistent with hemochromatosis. 40 had isolated hyperferritinemia. Of the 35 patients with secondary causes, 26 had liver disease; 16 with viral hepatitis. Other causes included hematologic disorders (10), malignancy (2) and inflammatory arthritis (2). On liver biopsy, 8 patients showed no increase in stainable iron while 10 showed mild-moderate increase. 7 patients were negative for C282Y and H63D mutations. Of the 40 cases of isolated hyperferritinemia, 38 had normal liver enzymes. 2 had liver biopsies showing mild increase in stainable iron. 9 patients underwent C282Y and H63D genotyping with 1 patient being H63D heterozygous. 8 index patients had first-degree relatives with hyperferritinemia. 3 families were identified with more than 2 members affected, suggestive of a possible hereditary hyperferritinemia syndrome.
Conclusion. Hyperferritinemia appears to be relatively common in Asians but classic hemochromatosis is not. Liver disease is a frequent cause of hyperferritinemia in the Asian population. We have, however, discovered a small group of healthy patients with no evidence of liver disease and isolated hyperferritinemia that in some cases appears to be familial. This has not been previously reported.
Re-Organization of Cardiac Band 3 (cAE1) in Neonatal Cardiomyocytes Submitted to Alkali Loading.
Authors: Baratti Mariana O. , Lima Paulo R.M. , Alberto Daniella C. , Borges Luciene , Franchini Kleber G. , Costa Fernando F. , Saad Sara T.O. 
Published: October 2019

Abstract
Band 3 was initially described as the first member of the anion exchanger family (AE1). It is an integral membrane protein, initially characterized in erythrocytes. The AE family is encoded by four genes, AE1, AE2, AE3 and AE4. Three AE1 isoforms have been described up to now: erythroid (eAE1), kidney (kAE1), and cardiac (cAE1). Increased expression and activity of AE1 and AE3, as well as of the Na+/H+ exchanger have been demonstrated in hypertrophic myocardium of rats. A physical association of band 3 with cardiac actin has been previously described by our group, using yeast two hybrid screening. It has also been suggested that this binding occurs in the intercalated disc, a site of cell-cell contact and attachment of the sarcomere to the plasma membrane. In the present study, immunolocalization analysis by confocal laser scanning microscopy was used to investigate the band 3 re-organization in neonatal cardiomyocytes (Wistar rats 1 to 2-day-old) submitted to different stimuli, such as pH changing or mechanical stretch (a model leading to cardiac hypertrophy). In the untreated cells, band 3 was dispersedly distributed in the cytoplasm, preferentially in the perinuclear region. On the other hand, when these cells were submitted to cyclic stretch (2 hours), band 3 appears between actin filaments, in the sarcomeric units. Similar distribution was showed in cardiac cells submitted to alkali loading (pH 8.9 for 2 hours). However, in experiments where the culture medium was pH 6.8, band 3 was dispersed in the cytoplasm, but was not concentrated in the perinuclear region. Intracellular pH (pHi) is a major regulator of diverse cellular processes including metabolic pathways, Ca2+ homeostasis, cell contractility, cell excitability and cell death; a rise in pHi activates Cl−/HCO3− exchanger. On the other hand, the mechanical stretch stimulates a rapid secretion of Angiotensin II, rise of pHi and activation of intracellular signaling molecules such as protein kinase C and tyrosine kinases. These processes induce cell proliferation, cardiac hypertrophy and reorganization of actin cytoskeleton. The demonstration of reorganization of band 3 and its localization in the sarcomeric units after these stimuli suggest that band 3 is involved in the cardiac hypertrophy physiopathology. Band 3 could function as an anchorage for the contractile apparatus, as well as in the transport of anions in the myocardium, which are well described processes in normal erythrocytes.
CobaSorb, a New Non-Radioactive Vitamin B12 Absorption Test.
Authors: Hvas Anne-Mette , Morkbak Louise , Nexo Ebba 
Published: October 2019

Abstract
After diagnosing vitamin B12 deficiency, the cause of the deficiency has to be clarified. For many years Schillings test was used for this purpose. However, Schillings test has almost disappeared from the marked. Recently, a new vitamin B12 absorption test, CobaSorb, was introduced. CobaSorb is based on oral intake of non-radioactive vitamin B12 followed by measurement of an increase in holotranscobalamin (holoTC) 24 hours later. In the present study, we further explored the design of CobaSorb to identify the best marker for reflection of vitamin B12 absorption and to determine the duration of the test. Seventy-eight healthy individuals (age 21–81 years, 40 males) were included and three oral doses of 9 microgram vitamin B12 per day were administered for 5 successive days. Non-fasting blood samples were collected on days 1 to 5 before administration of vitamin B12 and in the morning day 8. Plasma cobalamins were assayed on the Advia Centaur (Bayer A/S, Germany), and holoTC was measured by an in-house sandwish ELISA after removal of the apoTC with vitamin B12 coated beads. Baseline levels were 151–528 pmol/L for plasma cobalamins and 19–33 pmol/L for holoTC. We found a significant positive association between age and baseline holoTC (p=0.03), whereas no association was found between baseline plasma cobalamins and age (p=0.55). Baseline levels were not associated with sex. Because a vitamin B12 absorption test is relevant only in individuals with borderline or low levels of holoTC or plasma cobalamins, we analysed in detail the pattern of absorption in those having baseline levels below the 75% percentiles. We used a change greater than 2×CVday-to-day in holoTC (22%) and plasma cobalamins (12%) to indicate a change caused by absorption of vitamin B12. Among individuals with a baseline holoTC below the 75% percentile (<75 pmol/L, n=57), the increase in holoTC from baseline (day 1) to day 3 was > 22% for 56 (98%). Only 41 (72%) of the individuals with baseline plasma cobalamins below the 75% percentile (<335 pmol/L, n=57) had an increase in plasma cobalamins >12% from day 1 to day 3. We concluded that in healthy individuals with baseline holoTC <75 pmol/L, vitamin B12 absorption was well reflected by an increase in holoTC-but not plasma cobalamins-after 2 days administration of oral vitamin B12. We suggest that future use of CobaSorb is done based on this design.
Clinical Observation of Combination Therapy of Anti-Thymocyte Globulin Cyclosporine A, Hemopoietic Growth Factor and Androgen for 47 Severe Aplastic Anaemia Cases.
Authors: Shen JianPing , Zhou YuHong , Zheng Zhiying , Chen Junfa , Lin Shengyun , Shen YiPing , Hu ZhiPing , Luo Xiusu , Ye BaoDong , Yu LongXi 
Published: October 2019

Abstract
For therapy to severe aplastic anaemia (SAA), the effective and survival rate of combination regime using anti-thymocyte globulin (ATG), globulin, cyclosporine A (CsA), hemopoietic growth factor and androgen are similar to those of hemopoietic stem cell transplantation(HSCT). we have treated 236 cases of SAA from Oct. 1995 to Dec. 2005. 47of them took combination therapy mainly with ATG. The range of age was 10 to 56 (median age was 32). Of all the patients, totle effective rate was 84.5%, 41% achieved complete remission and 43.5% got partial remission. With the median follow-up time of 53 months, 41 patients are survival (87.2%),6 died, 3 relapsed, 4 patients stayed the same, 1 coincided with PNH. The combination therapy mainly with ATG began to work after 1 to 11months (median time was 2.5 months). If one can be treated in 6 months after diagnosis, the effective rate can be 95% after 3 months’ management, but if not, it was only 43%. For patients whose bone marrow hemopoietic cell >30% before treatment, the effective rate was 87.5%, but if it<5%, the effective rate was only 15%. No patients was severely affected by allergy or serum disease caused by ATG during treatment. By using infection preventing method of platelet transfusion and supporting treatment, most of the patients went through risk time and showed therapeutic reaction. We believe that the combination therapy mainly with ATG is safe and effective for SAA. It is considerable for SAA patients without HLA matched donors.
Uniform Approach Better Defines Natural History of Transient Myeloproliferative Disorder (TMD) in Down Syndrome (DS) Neonates: Outcomes from Children’ Oncology Group (COG) Study A2971.
Authors: Sharma Mukta , Alonzo Todd A. , Sorrell April , Gerbing Robert B. , Hilden Joanne M. , Arceci Robert J. , Massey Gita , Doyle John J. , Bayer Lisa , Perentesis John P. , Ross Julie , Smith Franklin O. , Brynes Russell , Hussong Jerry , Hathaway Lois , Gamis Alan 
Published: October 2019

Abstract
TMD is solely found in DS infants in the first few months of life & is distinguished from congenital AML primarily by its spontaneous resolution. A2971, the largest study of TMD conducted to date, defines the natural history of this disorder by utilizing uniform observation & treatment guidelines. A total of 136 DS patients (pts) <90 days (d) of age were enrolled from 1999–2004 with median follow-up of 745d(0–2187). Pts were assigned to observation(n=110) or intervention(n=26) arms based upon clinical severity. Median age at diagnosis was 5d(0–58) with median hematologic values of WBC 32,800(4,800 – 259,100), hemoglobin 15(5–22.5), platelets 125K(10–958K), peripheral blasts 25%(0–92) & bone marrow blasts 15%(0–95). Hepatomegaly (HM) was seen in 59%, splenomegaly in 39%, & pleural or pericardial effusion in 10% & 19%. Pts required intervention due to hyperviscosity(11%), blast count >100,000/μl(25%), organomegaly(OM) with respiratory(resp) compromise(43%), CHF(11%), hydrops fetalis(21%), liver dysfunction(43%), renal dysfunction(14%), or DIC(25%). For pts who required intervention(n=29, 21%), 9 pts(31%) received leukopheresis/exchange transfusion (Leuk/Exch). 26(90%) pts received low-dose AraC (3.33 mg/kg/24 hrs continuous infusion on days 0–4) for OM, organ dysfunction causing resp compromise, or continued symptoms after Leuk/Exch. Among all pts, 3-year overall survival(OS) was 77 ± 8% & event-free survival(EFS) was 73 ± 9%. 28 deaths were noted (15 related, 12 unrelated to TMD or therapy, 1 unknown). Median time to TMD resolution (defined as resolution of peripheral/ bone marrow blasts, OM, effusions & organ dysfunction) was 46d(7–757). Peripheral blast resolution was attained in a median of 35d (2–147). To date, 16 pts (12%), including 4 treated with AraC, developed AML/MDS at a median time of 355d(118–888). We identified 3 distinct groups of TMD pts: low risk (without palpable HM or hepatic dysfunction, n=52, 38%), intermediate risk (HM with non-life threatening hepatic dysfunction, n=55, 40%), & high risk (WBC>100K or life threatening cardio-resp compromise due to TMD, n=29, 21%). The OS for low, intermediate & high risk groups was 92 ± 8%, 82 ± 11% & 49 ± 20% and EFS was 83 ± 11%, 64 ± 15% & 36 ± 19%, respectively(p<0.001 for low vs high & intermediate vs high risk groups for OS & EFS). WBC >100K (Hazards Ratio-HR 3.57, p=0.004) & presence of hepatomegaly (HR 3.6, p=0.009) were significant adverse risk factors for OS in univariate analyses. This study confirms that most TMD pts undergo spontaneous resolution of disease without intervention, further clarifies the natural history of TMD, & provides baseline comparisons for upcoming COG trials.
Effect of the Terminal Complement Inhibitor Eculizumab on Patient Reported Outcomes in Paroxysmal Nocturnal Hemoglobinuria (PNH): Phase III Triumph Study Results.
Authors: Brodsky Robert A. , Muus Petra , Dührsen Ulrich , Hill Anita , Bessler Monica , Coutre Steven , De Paz Raquel , Moskovits Tibor , Nakamura Ryotaro , Van den Neste Eric , Zanella Alberto , Quinn-Senger Kerry , Kroon Henk-Andre , Cella David 
Published: October 2019

Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which complement-sensitive RBCs are destroyed leading to chronic intravascular hemolysis. PNH patients suffer from diverse and serious hemolysis-induced morbidities leading to a poor quality of life (QoL). Fatigue in PNH patients may be disabling and levels are similar to anemic cancer patients. Fatigue is multifactoral, related to both the underlying anemia and hemolysis. Patients suffer from reduced global health status, patient functioning, pain and dyspnea. Treatment with the terminal complement inhibitor eculizumab reduces intravascular hemolysis and improves anemia. The impact of eculizumab treatment on levels of fatigue and other patient reported outcomes was prospectively examined in a double-blind placebo controlled study (TRIUMPH) using two distinct instruments, the FACIT-Fatigue and the EORTC QLQ-C30. Improvements in QoL were quantified using standardized effect sizes (SES), a measure of the magnitude of the clinical benefit in various instruments. Eculizumab treatment, as compared to placebo, was associated with a very large and significant improvement in fatigue as measured by the FACIT-Fatigue scale (SES=1.13, P<0.001) as well as the EORTC QLQ-C30 fatigue subscale (SES=1.12, P<0.001). Similarly, the percentage of patients achieving a pre-specified minimally important difference (MID) was 53.7% versus 20.5% of eculizumab- and placebo-treated patients, respectively (P=0.003) using the FACIT-Fatigue; 67.7% versus 24.4%, respectively (P<0.001) with the EORTC QLQ-C30. Treatment independent univariate analyses showed that reduction in intravascular hemolysis (decreased LDH levels) and improvement in anemia (increased hemoglobin levels) were both significantly associated with an improvement in fatigue. Further, multivariate analyses indicated that reduction in hemolysis was more predictive than improvement in anemia of an improvement in fatigue. Eculizumab treatment was also associated with significant improvements with moderate to large SES in the following EORTC QLQ-C30 subscales: global health status (0.87, P<0.001); role functioning (0.93, P<0.001); social functioning (0.57, P=0.003); cognitive functioning (0.78, P=0.002); physical functioning (1.01, P<0.001); emotional functioning (0.51, P=0.008); pain (0.65, P=0.002); dyspnea (0.69, P<0.001); and appetite loss (0.50, P<0.001). These data demonstrate that resolution of intravascular hemolysis with eculizumab treatment results in large and clinically meaningful improvements in patient reported outcomes including fatigue, global health status, patient functioning, and disease-related symptoms in PNH.