bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Study of Alemtuzumab in the Treatment of Plasma Cell Disorders.
Authors: Simpson Lijo , Kumar Shaji , Allred Jacob , Lacy Martha , Dispenzieri Angela , Hayman Suzanne , Zeldenrust Steven , Rajkumar S. Vincent , Lust John A. , Greipp Philip R. , Gertz Morie Abraham , Witzig Thomas E. 
Published: April 2020

Abstract
Background: While the therapeutic armamentarium for plasma cell disorders have expanded recently with introduction of thalidomide, lenalidomide and bortezomib, these diseases are still incurable and more agents are needed. We have previously demonstrated expression of CD 52 on plasma cells in MM, MGUS and AL amyloidosis. Based on this data we conducted a Phase II Study of Campath (Alemtuzumab; Monoclonal Anti-CD52 Antibody) in Primary Systemic Amyloidosis and Relapsed or Refractory Multiple Myeloma.
Methods: The study was an IRB approved, Phase II protocol, with a two stage design and interim analysis at 14 patients, to assess the efficacy and toxicity of Alemtuzumab. The regimen involved a dose escalation during week one (Day I 3 mg SQ; Day II 10 mg SQ; Day III 30 mg SQ; then 30 mg SQ three times a week for a planned total of 17 additional weeks). All patients received concurrent Co-Trimoxazole, Fluconazole and Valacyclovir prophylaxis. The planned accrual was 32 patients.
Results: A total of 14 patients were accrued, 8 patients with MM and 6 patients with AL. There were 8 females and 6 males in the study. The median age was 62 years (range: 50–78) years. The patients were heavily pretreated with the median number of treatments being 4. There were 5 grade 3–4 toxicities (CMV viremia (2 pts), skin rash (2 pts), and febrile neutropenia (1 pt)). Seven patients had evidence of disease progression and were removed from study. One patient completed the treatments with a mixed response. One patient had a sudden death while on study. The median duration of therapy was 6 weeks (range 3 weeks to 17 weeks). The accrual was stopped after 14 patients when the interim analysis showed a lack of anti-tumor efficacy and significant toxicity.
Conclusion: This phase II study in patients with relapsed / refractory myeloma or amyloidosis demonstrated no evidence of clinical activity with use of Campath. In addition it was also associated with significant toxicity in this population. We do not recommend use of campath as a primary treatment modality in these patients. The lack of efficacy despite demonstrated expression of CD52 on clonal plasma cells once again highlights the need for combining treatments with multiple mechanisms in order to improve the response and outcome in these patients. Whether it can synergize with other therapies at lower doses without significant toxicity remains unknown.
The Feature of Distribution and Clonality of TCR Vα and Vβ Repertoire in Cord Blood.
Authors: Chen Shaohua , Li Yangqiu , Yang Lijian , Cen Dongzhi , Chen Si , Li Chuang 
Published: April 2020

Abstract
Analysis of T cell receptor (TCR) Vα and Vβ repertoire is one of the sensitive methods to understand the distribution and clonality of T cells from different samples, which is used to identify clonal expansion T cells that response to tumor associated antigens. Cord blood has been used successfully as a source of hematopoietic stem cells for transplantation. Recently, stem cells transplantation was demonstrated more important as immunotherapy against malignance cells. And cord blood T cells are resourceful for production the specific CTL to use in leukemia immunotherapy. But the feature of distribution and clonality of TCR Vα and Vβ subfamily T cells in cord blood is not yet clearly defined. In the present study, the CDR3 of 29 TCR Vα and 24 Vβ subfamily genes were analyzed in T cells from 10 cases of cord blood, which obtained at delivery from full-term healthy pregnancies, using RT-PCR and genescan technique. Peripheral blood of nine cases healthy adult volunteers served as controls. The results showed that 15–19 of 29 Vα and 9–15 of Vβ subfamily T cells could be identified in the most cases, whereas only 2–4 of Vα subfamilies expressed was found in 3 cases. The most frequently expressed Vα subfamilies were Vα 3 and Vα 10 (100%), Vα 4, 5, 6, 8, 12, 15, 17 and Vα 21 (70%), Vα1, 13, 25, and Vα26 (60%), with a lower expression rate found in Vα16, 24 and Vα 28 (10%). Vα 9 and Vα 29 were not detected in both CB and healthy adults. In analysis of TCR Vβ repertoire, Vβ3, 5, 8 and Vβ9 genes could be identified in all samples, Vβ7 and Vβ13 could be found in 90% of samples, whereas Vβ4, 6, 11, 12, 18, 23 and Vβ24 were absent in all samples, which could be detected in normal peripheral blood samples. Genescan analysis showed that all PCR products of TCR Vα and Vβ subfamilies from cord blood displayed a Gaussian distribution of CDR3 lengths (multi-peaks), which are corresponding to polyclonal rearrangement pattern, except for tow cases, which displayed oligoclonal peak in Vα 24 or Vα28 respectively. In contrast, some Vα subfamily products from 8 of 9 cases of healthy adult volunteers contained at least an oligoclonal peak in different Vα subfamilies respectively, however, multi-peaks were found in all PCR products of TCR Vβ from normal peripheral blood. In conclusion, more than 20% of TCR Vα or Vβ subfamily T cells were absent in cord blood. The majority of TCR Vα and Vβ subfamily T cells in cord blood displayed polyclonality. Occasional oligoclonal peaks are identified in some cases.
Study of Mechanisms Underlying Fetal Transplantation Tolerance: Relative Organ Distribution of B Cells and CD45 Isoform Expression Patterns.
Authors: Skopal-Chase Jessica L. , Pixley John S. , Bhat Anupama S. , Torabi Alireza , Aiazzi Nicole M. , Thain David S. , Zanjani Esmail D. 
Published: April 2020

Abstract
Transplantation of hematopoietic stem cells into fetal sheep early in gestation (day (d) 55) (term gestation = 145d) results in long-term multi-lineage hemopoietic chimerism. We have proposed that the fetus is immunologically receptive at this time. However, our understanding of the mechanisms underlying this establishment of fetal tolerance remains poorly defined. We hypothesized that examination of developmental events in fetal immune ontogeny might provide insights into mechanisms underlying fetal tolerance formation. To this end we have previously reported the early appearance of cells phenotypically consistent with T regulatory cells (CD4+/CD25+) and multilineage expression of the CD45 isoform CD45R early in gestation (d40–65). Here, we extend our observations on B lineage cell distribution and relative CD45 isoform expression during gestation. The two commercially-available ovine CD45 antibodies are CD45 (immunoprecipitates proteins of MW 225, 210, and 190 kD, (Immunology.1985; 55:347–353)) and CD45R (immunoprecipitates a single protein of MW 220 kD (Cell. Immunol.1987;110:46–55)). Using dual-color flow cytometry, cells from fetal thymus, intestine, lung, spleen, bone/bone marrow, and peripheral blood (PB) were analyzed for expression of surface IgM, CD45 and CD45R from d39 to two days after birth. Surface IgM+ cells in the thymus were observed to be as high as 28% at d39 of gestation (uniformly CD45R+/CD45−). This rapidly dissipated to less than 1% after d65 of gestation, although IgM+ cells were observed as late as two days after birth. All IgM+ cells expressed CD45R in all organs tested but relative CD45 expression varied by gestational age and organ. Subsequent sampling noted rapid onset of CD45 coexpression on &gt;70% of detectable thymic surface IgM+ cells throughout gestation. Similarly, splenic IgM+ cells co-expressed high levels of CD45 while PB IgM+ cells had delayed CD45 expression (beyond d65). Bone/bone marrow showed variable coexpression of CD45 throughout gestation. By contrast, surface IgM+ cells in lung and intestine maintained CD45R expression without coexpression of CD45 prior to birth. We have previously reported humoral tolerance to retroviral vector transgene products transplanted at d55–60 (Blood.2001; 97:3417–3423). Further understanding of CD45 isoform expression patterns and relative organ distribution of surface IgM+ cell populations during the time of immune receptivity in the sheep may provide insight into fetal transplantation tolerance.
Unique MicroRNA Profiles in Childhood Acute Lymphoblastic Leukemia.
Authors: Schotte Diana , Chau Jacqueline C.K. , Sylvester Giselle , Liu Gwen , Peters Susan T.C.J.M. , Pieters Rob , Den Boer Monique L. , Chen Chang-Zheng 
Published: April 2020

Abstract
MicroRNAs (miRNAs), an abundant class of ~22-nt endogenous regulatory RNAs that control gene expression at the posttranscriptional levels, have been implicated to play roles in the normal hematopoiesis and pathogenesis of leukemias. To identify “leukemic miRNAs”--miRNAs that may be oncogenes or tumor suppressors in human leukemias, we systematically cloned miRNAs from the blast cells of childhood acute lymphoblastic leukemia (ALL) patients with either a poor prognostic mixed-lineage leukemia rearrangement phenotype (MLL) or a prognostically more favorable precursor B-cell ALL phenotype (B-ALL). We have identified 87 known and 43 new human mature miRNAs, which potentially encoded by 101 known and 94 new human miRNA genes, respectively. Many newly identified miRNAs are not conserved in mouse, suggesting that systematic miRNA cloning analysis can facilitate the discovery of many novel human leukemia specific miRNAs. Interestingly, quantification of miRNA expression by real-time PCR analyses revealed that miRNAs are generally expressed at higher levels in MLL and B-ALL leukemia cells when compared to that in normal CD34+ bone marrow cells. We selected 21 highly differentially expression miRNA candidates and determined their expression in a larger group of 14 MLL patients and 16 B-ALL patients. We found that 9 miRNAs, including 4 newly identified miRNAs, were significantly differentially expressed (p &lt; 0.05) between MLL and B-ALL subtypes. These findings demonstrate that the expression of both known and newly identified miRNA genes differs in genetically and prognostically different subgroups of ALL and normal CD34+ progenitor cells, suggesting that systematic miRNA cloning analyses and subsequent expression profiling analysis may facilitate the identification of specific signatures for leukemia classification and tumor suppressors or oncogenes that contribute to the pathogenesis of MLL and B-ALL.
Safety and Efficacy of Anti-Fibrinolytics in Orthopedic Surgery: A Meta-Analysis of Randomized Trials.
Authors: Kagoma Yoan K. , Nematullah Adeela , Lim Wendy P. , Crowther Mark A. 
Published: April 2020

Abstract
Background: Minimizing blood transfusions following elective orthopedic procedures is desirable given the risks associated with transfusion, including cost, infection, and allergic reactions. Anti-fibrinolytic agents may reduce perioperative blood loss but are used infrequently possibly due to a lack of data supporting their efficacy and concerns about increased risks for venous thromboembolism (VTE). We performed a meta-analysis to determine whether anti-fibrinolytic agents reduce perioperative blood loss in patients undergoing total hip replacement (THR) or total knee arthroplasty (TKA).
Data sources: MEDLINE (1966 to May Week 3 2006), EMBASE (1980 to 2006 Week 21), Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials (the latter four databases to May 29, 2006) were searched. Additional trials were identified by manual searches. Authors and/or pharmaceutical companies were contacted if required. Study selection was based on the following criteria: prospective randomized clinical trials in which tranexamic acid, epsilon-aminocaproic acid, or aprotinin were administered. Two independent reviewers abstracted transfusion requirements, total blood loss, and venous thromboembolism. Study quality was assessed using the Jadad Quality Assessment scale. Data was pooled using the Mantel-Haenszel method and a random effects model.
Results: In 25 studies involving 1332 patients, the weighted mean difference (WMD) in total blood loss in patients treated with anti-fibrinolytic agents compared to patients receiving placebo was −409.50 mL (95%CI, −548.17 to −270.82; P&lt; 0.00001, I2 = 89.6%). In 1557 patients, the relative risk (RR) for transfusion was 0.52 (95%CI, 0.42 to 0.64; P&lt;0.00001, I2 = 58.0%). VTE did not appear to be increased in patients who received anti-fibrinolytic agents (RR 0.972 (95%CI, 0.885 to 1.06).
Conclusions: Patients undergoing TKR or THA who receive anti-fibrinolytic agents appear to have reductions in blood loss and need for transfusion. Whether these medications increase VTE risk cannot be determined due to limited data. Study characteristics were heterogeneous and the optimal timing, dose, and type of anti-fibrinolytic therapy have yet to be determined. Further studies in this area are warranted.
Protease Signaling in Severe Systemic Inflammation.
Authors: Niessen Frank , Ahamed Jasimuddin , Andrade-Gordon Patricia , Ruf Wolfram 
Published: April 2020

Abstract
The tissue factor (TF) pathway drives disseminated intravascular coagulation in sepsis. Although extensive in vitro data demonstrate proinflammatory effects of protease activated receptor (PAR) signaling, it remains unclear whether PAR signaling plays a significant role in severe systemic inflammation. In a murine model of severe, 75–90% lethal endotoxemia, we addressed the interplay between intravascular coagulation activation (based on thrombin-antithrombin complexes) and inflammatory exacerbation (based on inflammatory cytokines IL6, IL1b and MCP1) downstream of PAR signaling. TF cytoplasmic domain deleted mice displayed increased TF expression in macrophages and enhanced systemic coagulation activation. However, these mice resolved inflammation earlier than wild-type controls. Thus, intravascular coagulation activation per se does not predict survival. Rather, genetic deletion of PAR2 demonstrated that PAR2 signaling increased survival in TF cytoplasmic domain-deleted mice. PAR2 deficiency alone initially attenuated inflammatory cytokine production, but did not prevent progressive exacerbation of coagulation and inflammation, further evidence for protective PAR2 signaling in advanced, severe endotoxemia. In contrast, PAR1-deficiency had no effect on initial inflammation and coagulation, but at late stages attenuated inflammation and prolonged survival. In addition, PAR1-deficiency produced a synergistic survival benefit with TF cytoplasmic domain deletion. These experiments show that coagulation protease signaling both regulates and amplifies severe systemic inflammation. Strategies to target TF cytoplasmic domain signaling may therefore be beneficial to reduce sepsis lethality in combination with therapeutic blockade of proinflammatory PAR1 signaling.
Activation-Induced Cytidine Deaminase Acts as a Mutator in BCR-ABL1-Transformed Acute Lymphoblastic Leukemia Cells.
Authors: Feldhahn Niklas , Klein Florian , Hofmann Wolf-Karsten , Rowley Janet D. , Jumaa Hassan , Müschen Markus 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) cells are derived from B and T cell precursors and typically carry rearranged immunglobulin (Ig) or T cell receptor (TCR) variable (V) region genes devoid of somatic mutations. The Philadelphia chromsome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Here we show that oncogenic BCR-ABL1 kinase activity induces aberrant somatic hypermutation in Ph-positive ALL cells. Under physiological conditions, somatic hypermutation is restricted to mature germinal center B cells and depends on expression of the DNA-deaminating enzyme AID. Comparing Ph-positive and Ph-negative ALL cells, AID expression was found in 24 of 28 Ph-positive but only 3 of 80 Ph-negative ALLs. As shown by RT-PCR and Western blot, expression of AID in Ph-positive ALL cells reached similar levels as in germinal center B cells.
Forced expression of BCR-ABL1 in Ph-negative ALL cells and usage of the BCR-ABL1-kinase inhibitor STI571 revealed that BCR-ABL1 kinase activity is required and sufficient to induce aberrant expression of AID in Ph-positive ALL. Consistent with aberrant AID expression in Ph-positive ALL, Ig VH region genes were mutated in most Ph-positive but unmutated in Ph-negative cases. Of note, also non-Ig genes including BCL6 and MYC harbored somatic mutations in Ph-positive but not Ph-negative ALL cells. Likewise, Ph-positive T cell lineage ALL cells express AID and carry somatically mutated TCRβ V region genes. As demonstrated by ligation-mediated PCR, AID introduced DNA-single-strand breaks also within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to both inhibition of BCR-ABL1 kinase activity and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.
Escape from Suppression: Tumor-Specific Effector Cells Out-Compete Regulatory T Cells Following Stem Cell Transplantation.
Authors: Mirmonsef Paria , Tan Gladys , Zhou Gang , Pyhel Tricia , Borrello Ivan M. , Levitsky Hyam 
Published: April 2020

Abstract
Autologous hematopoietic stem cell (HSC) transplantation is an accepted therapy for many hematological malignancies. High dose chemo-radiation reduces tumor burden but also ablates lymphohematopoiesis. Subsequent infusion of cellular grafts containing HSC and mature lymphocytes “rescues” the host from this otherwise lethal ablation, and initiates immune reconstitution. In many systems, tumor-specific T cells are functionally tolerant in the presence of established tumor. Paradoxically, however, the infusion of these lymphocytes into irradiated tumor-bearing syngeneic recipients unmasks effector function manifested as prolonged progression-free survival when compared to recipients treated with lymphocytes from non-tumor bearing donors. We have recently demonstrated that this tolerant tumor-specific T cell population from mice with established tumor is in fact a heterogeneous mixture of naive, effector, and regulatory T cells (Tregs), which as a whole are rendered functionally unresponsive through dominant suppression. The apparent reversal of tolerance in the post-transplant setting prompted a more detailed examination of the fate of these individual components during immune reconstitution. Here, we show that CD4+ T cells specific for a model tumor antigen are hyporesponsive to antigen when isolated from mice harboring an established systemic B cell lymphoma. Upon transfer into irradiated lymphoma-bearing mice, however, these cells undergo robust antigen-driven clonal expansion, and their ability to produce interferon gamma (IFNγ) is restored. Notably, in spite of the presence of tumor in the transplant recipients, tolerance to tumor antigen was not established in the early post-transplant period, even for mice receiving naive T cells in the graft. Tumor-specific CD4+CD25+Foxp3+ Tregs isolated from the donors were found to undergo a modest tumor-antigen-driven expansion in transplant recipients. When isolated from recipients, such cells maintained expression of Foxp3 and their capacity to suppress naive T cells when cultured in vitro. However, the presence of tumor-specific Tregs failed to significantly inhibit the expansion of naive or effector T cells specific for tumor in vivo, when examined 2 weeks post BMT. Indeed, the expansion of tumor-specific effector T cells significantly exceeded the expansion of Tregs, resulting in a nearly five-fold increase in the effector:Treg ratio. At the ratios present during this phase of immune reconstitution, the frequency of Tregs was insufficient to suppress effector cell function (proliferation and IFNγ production) when studied in vitro. This accounts for the reversal of tolerance identified in the population as a whole and its capacity to mediate tumor rejection.
A Signal Hierarchy Model of Alloreactive T Cell Trafficking for the Organ Manifestation in Acute Graft-Versus-Host Disease.
Authors: Beilhack Andreas , Schulz Stephan , Baker Jeanette , Beilhack Georg F. , Nishimura Ryosei , Landan Gilad , Baker Enosh M. , Herman Edward I. , Contag Christopher H. , Negrin Robert S. 
Published: April 2020

Abstract
Acute graft-versus-host disease (aGVHD) is caused by alloreactive effector T cells attacking the gastrointestinal tract, liver and skin after allogeneic hematopoietic cell transplantation (aHCT). The mechanism by which alloreactive T cells target these organs and not others remains elusive. Recently, we reported that different secondary lymphoid organs (SLOs), as alloreactive priming sites, can imprint distinct homing phenotypes on evolving alloreactive effector cells in vivo. However, preventing access to selected lymphoid organs (via the use of blocking antibodies or recipient mice lacking Peyer’s patches (PP), PP and lymph nodes (LN) or spleens) did not alter the aGVHD organ manifestation. These findings not only suggested a high redundancy of SLOs as induction sites of aGVHD, but also questioned whether homing instruction of alloreactive T cells by these sites can explain the mechanism of aGVHD target organ manifestation.
To test the homing instruction model we transplanted transgenic luciferase+ (luc+) FVB/N (H-2q, Thy1.1+) splenocytes into conditioned (2×400rad) Balb/c recipients (H-2d, Thy1.2+). On day+3 we isolated luc+ donor lymphocytes from peripheral LN, mesenteric LN, or spleens and transferred them into conditioned secondary allogeneic recipients. 16 hours later, bioluminescence imaging revealed that allogeneic luc+ T cells irrespective of their original priming site targeted the intestinal tract and liver. Subsequently, we compared aHCT of conditioned with non-conditioned secondary Balb/cRag−/− cγ-Chain−/− recipients.
Surprisingly, we found allogeneic luc+ T cells accumulating in SLOs in non-conditioned recipients in contrast to intestinal and hepatic tissues in conditioned recipients.
These in vivo findings establish that alloreactive effector cells migrate to aGVHD target tissues because of attraction to these sites rather than specific instruction by SLOs. Therefore, we propose a signal hierarchy model of alloreactive cell trafficking whereby inflammatory signal/ligand interactions dominate over organ-specific homing receptor/ligand interactions.