bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Incidence of Varicella Herpes Zoster with Use of Bortezomib in Chinese Patients.
Authors: Tong Yin , Qian Jie Jing , Li Ying , Meng Hai Tao , Jin Jie 
Published: April 2020

Abstract
Bortezomib has been used for patients with refractory and relapsed multiple myeloma, non-Hodgkin lymphoma and leukemia in recent years. It has several complications. Here we report the complication of varicella herpes zoster after using bortezomib, which has higher incidence in Chinese patients. Ten patients were treated with bortezomib in our hematology centre. Among them, seven patients had refractory and relapsed multiple myeloma, two patients had refractory lymphoma (one of T cell lymphoma and one of mantle cell lymphoma) and one patient had refractory acute myeloblastic leukemia. All the patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Patients of multiple myeloma received dexamethasone simultaneously. The combination with liposomal doxorubicin was used on the patients of lymphoma. The patient of acute myeloblastic leukemia received bortezomib in combination with Amsacrine. After one cycle, 6 patients with multiple myeloma responded to treatment (four near complete remission, two partly remission). Two patients with lymphoma reached PR. The patient with leukemia had no response. A remarkable observation in our treatment was the high incidence of varicella herpes zoster. Six out of ten patients developed varicella herpes zoster. Among the six patients, two patients had previous infection of the zoster virus before. Most of the patients had the varicella herpes zoster infection after the complete of one cycle of bortezomib and were disappeared within one month by the use of antiviral treatment. The incidence of varicella hepers zoster after bortezomib was around 13% as reported. But the higher incidence of varicella herpes zoster were observed in our patients. Six of ten patients (60%) developed varicella zoster virus infection during treatment. We considered that the Chinese patients may be more liable to varicella zoster virus infection. And further observations should be made in the future. Prophylactic antiviral medication might be used in predisposed patients who receive bortezomib.
Zoledronic Acid for the Prevention of Bone Lesions in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS).
Authors: Berenson James R. 
Published: April 2020

Abstract
Recent studies have shown that approximately 5% of individuals over the age of 70 years have a monoclonal gammopathy and are at high risk for developing myeloma or a related lymphoproliferative disorder. Patients with monoclonal gammopathy of undetermined significance (MGUS) are at high risk for developing new fractures, particularly vertebral compression fractures. Currently, there is no treatment for this patient population. Among patients with advanced multiple myeloma, zoledronic acid has demonstrated efficacy in reducing skeletal complications. Therefore, a multicenter phase II trial is ongoing to evaluate zoledronic acid for patients with MGUS and a high risk for fractures. A total of 80 patients with MGUS and a T-score of less than −1.0 who have not received intravenous bisphosphonates within the past 2 years or oral bisphosphonates for more than 3 months within the past 2 years are eligible for enrollment. Eligible patients may not have had a change in hormonal therapy within 6 months of study entry. Patients will receive 4 mg zoledronic acid infused over 15 minutes at 0, 6, and 12 months. The primary endpoint is the change in bone mineral density (BMD) in the lumbar spine 1 month following the last infusion of zoledronic acid. Secondary endpoints include the mean change from baseline hip BMD, number of patients with new fractures, changes in serum M protein levels, number of patients who develop myeloma or other related malignancies, and safety of zoledronic acid in this patient population. The study commenced recruitment in 2004 and has enrolled 52 patients to date. Enrollment is continuing and expected to be complete by the end of 2006. This study may provide further support for the use of zoledronic acid in patients with MGUS who are at high risk for fracture development and currently do not receive any treatment.
Cord Blood Nucleated Cells Induce Delayed Proliferative and Cytotoxic T Cell Alloreactivity.
Authors: Mahmud Dolores , Chunduri Sandeep , Abbasian Javaneh , Maciejewski John , Iqbal Ronak , Rondelli Damiano 
Published: April 2020

Abstract
Transplantation of HLA-mismatched nucleated cells from cord blood (CB) has reduced risks of graft rejection and severe acute graft-versus-host disease. In this study we analyzed the in-vitro alloantigen presenting capacity of cord blood nucleated cells. CB mononuclear cells (MNCs) or immunomagnetically-selected CD34+ cells, or CD14+ monocytes, were irradiated and tested as stimulators of allogeneic blood T cells in primary (stimulator:responder ratio = 1:1) or secondary (stimulator:responder ratio = 1:2) mixed leukocyte culture (MLC), or in cytotoxic T-lymphocytes (CTL) assays. CB-MNCs failed to induce allogeneic T cell proliferation in 6-days primary MLC, whereas CD34+ or CD14+ cells stimulated brisk T cell responses. A suppressive effect of CB-MNCs was ruled out since CD3+ cell-depletion of CB-MNCs did not restore CB immunogenicity and the addition of increasing doses of CB-MNCs did not inhibit T cell alloreactivity to CD34+ cells. Despite allogeneic T cells were unresponsive to CB-MNCs after primary and secondary MLC, T cell anergy was ruled out since T cells that were unresponsive after primary MLC proliferated potently in secondary MLC stimulated with CB CD34+ cells, and even more with CB monocyte-derived dendritic cells (Mo-DC) generated in-vitro with GM-CSF and IL-4. Interestingly, after co-culture with irradiated allogeneic T cells for 6 days, CB-MNCs showed a greater proportion of CD86+ cells and elicited allo- T cell proliferation. In addition, allo-CTL activity was induced by CB-MNCs only after restimulating effector cells for 3–4 weeks (26±7% lysis of antigen-specific PHA-blast at 50:1 E:T ratio), and was comparable to CTL activity induced after 1 week by Mo-DC generated from the same CB. When T cell effectors were stimulated by combining two incompatible cord blood MNCs mixed together, CTL activity was then detected after 4 weeks against both of them regardless of the CB:CB cell ratio. These results show an impaired allo-APC activity of CB-MNCs, without suppressive or tolerogenic activity. These findings might partially explain the initial engraftment of combined HLA mismatched CB grafts in vivo, however they also suggest that a delayed T cell response may occur due to CB-derived APCs activating CTLs.
FGFR3 Activates RSK2 To Mediate Hematopoietic Transformation through Both Tyrosine Phosphorylation of RSK2 and Activation of the MEK/ERK Pathway.
Authors: Kang Sumin , Dong Shaozhong , Gu Ting-lei , Cohen Michael S. , Lonial Sagar , Khoury H. Jean , Gilliland D. Gary , Taunton Jack , Polakiewicz Roberto D. , Chen Jing 
Published: April 2020

Abstract
Reccurent chromosomal translocation t(4;14)(p16.3;q32.3) that frequently occurs in patients with multiple myeloma is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3), which sometimes contains the activation mutations such as K650E (TDII). To better understand the signaling properties of oncogenic FGFR3, we performed a mass spectrometry-based phospho-proteomics study to identify potential downstream signaling effectors that are tyrosine-phosphorylated due to expression of FGFR3. RSK2 (p90 ribosomal S6 kinase 2) was found to be specifically tyrosine-phosphorylated at Y488 and Y529 in hematopoietic Ba/F3 cells transformed by TEL-FGFR3 fusion, which is associated with t(4;12)(p16;p13) peripheral T-cell lymphoma. In addition, RSK2 was highly tyrosine-phosphorylated in t(4;14)-positive human myeloma cell lines expressing constitutively activated FGFR3 mutants. We found that expression of leukemogenic FGFR3 variants resulted in activation of RSK2 through the MEK/ERK pathway. The current model suggests that inactive ERK binds to the C-terminus of RSK2 in quiescent cells, prior to ERK-dependent phosphorylation and activation of RSK2 when ERK is activated. Interestingly, we found that FGFR3-dependent tyrosine phosphorylation at Y529 regulates the ERK-dependent activation of the serine/threonine kinase RSK2. Co-immunoprecipitation experiments revealed that substitution of Y529 significantly decreased inactive ERK binding to RSK2. This disrupted ERK-RSK2 association consequently attenuated phosphorylation and activation of RSK2 by ERK activated by FGFR3, in both in vitro kinase assays and an RSK2-specific CREB mediated transcription assay. Moreover, inhibition of RSK2 by specific siRNA or an RSK inhibitor fmk effectively induced apoptosis in FGFR3 transformed murine Ba/F3 and t(4;14) human myeloma cells, suggesting RSK2 is a critical signaling effector in FGFR3-induced hematopoietic transformation. Together, these data support a novel two-step model that leukemogenic FGFR3 activates RSK2 to mediate transformation signals by promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK. Thus, RSK2 may represent an alternative therapeutic target in the treatment of diverse human malignancies associated with dysregulated FGFR3.
The Molecular Characteristics of T-Cell Receptor Repertoire of Clonal Expansion of T Lymphocytes in Leukemia Patients after Haploidentical Bone Marrow Transplantation.
Authors: Fu YueWen , Wu De Pei , Feng YuFeng , Chang WeiRong , Zhu ZiLin , Zhu Ping 
Published: April 2020

Abstract
The clinical and experimental results indicated that the T cell immune reconstitution was slow after haploidentical hematopoietic stem cell transplantation and existed high rate of GVHD and infection. This study was to analyze the molecular characteristics of T cell clones during immune reconstitution in leukemia patients after haploidentical bone marrow transplantation (H-BMT). Reverse transcriptase-polymerase chain reaction (RT-PCR) amplified 24 subfamily genes of TCRVB from peripheral blood lymphocytes of nine leukemia patients underwent H-BMT, five normal donors as control. The PCR products were further analyzed by genescane to evaluate the clonality of VB subfamily and characteristics of CDR3 and usage rate in VB subfamily. The monoclonal bands which associated with GVHD obtained and sequenced. Compared the sequences of TCRVB CDR3 gene repertoire with other sequences associated with GVHD had been reported before. In +10~+19m, the usage of TCRVB subfamilies still restricted. It can detected that some VB subfamilies were missing, others expanded in monoclonal or oligoclonal. 4 patients in stable condition showed that 9~14 VB subfamilies expressed and more than 50 percent were polyclone. In other 5 patients which have GVHD or CMV-pp65(+), the usage of TCRVB decreased obviously(p&lt;0.05), the express of CDR3 were monoclonal or oligoclonal, only 30 percent were polyclonal. No common monoclone VB subfamilies expressed. After treatment and GVHD controled, the usage of VB subfamilies was increased and CDR3 polymorphism increased in 2 patients. Analyzed the sequences associated with GVHD and found that none of the clones appeared to share any similarity in amino acid motif. In +10~+19m, the usage of TCRVB subfamilies still skewing. In stable condition, there were 9~14 VB subfamilies expressed and dominated by polyclones, in active condition, the express of VB subfamilies decreased and dominated by monoclones or oligoclones. A group of CDR3 molecules related to GVHD showed no common amino acid motif.
High Anti-Tumor Activity of Natural Killer Cells after Non-Myeloablative Conditioning and Allogeneic Stem Cell Transplantation.
Authors: Fischer Lars , Penack Olaf , Stroux Andrea , Gentilini Chiara , Thiel Eckhard , Uharek Lutz 
Published: April 2020

Abstract
Background: It is hypothesized that enhanced graft-versus-leukemia activity of natural killer (NK) cells contributes to the clinical efficacy of non-myeloablative allogeneic hemotopoietic stem cell transplantation (HSCT). We compared NK cell cytotoxic activity after transplantation with full and reduced dose regimens with normal values obtained from healthy volunteers.
Methods&Material: Using a flow cytometric assay that detects CD107a expression after coincubation with leukemia cell lines as a marker for NK cell degranulation we prospectively quantified and characterized NK cells mediating anti-tumor activity in patients after HSCT. Mononuclear cells (MNC) were isolated from peripheral blood of 17 healthy individuals and 31 patients transplanted with G-CSF mobilized peripheral blood stem cells at day +30. MNC were incubated with leukemia cell lines HL60 and K562 (effector/target ratio 1:1) and expression of CD107a was measured after 3 hours. The absolute number of degranulating (CD107a+) NK cells was calculated.
Results: Thirty one patients (five with ALL, four with NHL, one with Aplastic Anemia and 21 with AML) were enrolled, of whome 22 were transplanted from a matched related donor, seven from a matched unrelated donor, and two from a haploidentical donor. Nine patients had been transplanted after conditioning with 2 Gy TBI only, whereas 22 patients had received various conventional dose regimens. NK cell counts at day +30 after HSCT with conventional conditioning were comparable to normal values, but percentage and number of degranulating cells were significantly reduced (2.4% and 7/μl vs. 6.2% and 18/μl; p&lt;0.0001 and p=0.0003). In contrast, in patients after 2 Gy TBI the percentage of degranulating NK cells was comparable to healthy donors (7.6%; p=0.9), and interestingly, absolute numbers of all and of degranulating NK cells (41/μl; p=0.004) were higher than normal values and consequently higher than in patients with conventional dose conditioning.
Conclusions: Using this new method we were able to exactly quantify tumor-reactive NK cells after HSCT in a feasible way. We found a high cytotoxic activity of NK cells towards leukemia cell lines in patients undergoing non-myeloablative conditioning with 2Gy TBI. Further studies to determine the clinical impact of these findings are needed.
Rapamycin Induces Balb/C Murine CD4+CD25+Foxp3+ T Cells Proliferations.
Authors: Yang Mingzhen , Wu De Pei , Yuan Yanhui , Cen Jiannong , Chang Weirong , Zhu Ziling 
Published: April 2020

Abstract
Rapamycin(RAPA) is an immunosuppressive agent, it inhibits T lymphocyte activation and proliferation by suppressed antigen and cytokine(interleukin-2, interleukin-4 and interleukin-15), it was always used to treat autoimmune disease and graft versus host disease. RAPA can selectively expand mice CD4+CD25+FoxP3+ regulatory T cells in vitro, in this study, we demonstrated RAPA induce mice CD4+ CD25+FoxP3+ regulatory T cells proliferation in vivo. Balb/C mice were used between 8–10 weeks of age, weight was 20±2g, RAPA was given to Balb/C murine 0.4mg/day intragastric administration according to man dose, the same mice of age and weight were given with steriled water as the control, all mice were kept under specific pathogen-free conditions. Drinking water and food were steriled. After three weeks, peripheral blood was collected and spleen cells were prepared, CD4+CD25+T cells were detected with FCM(CD4-pcy5, CD25-FITC), the relative levels of foxp3 mRNA were determined by real-time quantitative RT-PCR in total splenocytes. The CD4+CD25+T cell of peripheral blood of experimental group and control group was (9.24±4.16)% and (4.32±1.26)%, respectively (P&lt;0.01), and CD4+CD25+T cell of experimental mice splenocytes was (22.99±10.59)%, while control group was (7.37± 2.91)% (P&lt;0.01). real-time quantitative RT-PCR showed that the levels of foxp3 mRNA of experimental mice splenocytes was 6 folds than control group(P&lt;0.01). CD4+CD25+T cells and CD+CD25−T cells were enriched with CD4+CD25+T regulate cells isolation kits from experimental Balb/C mice, we used mixed leukocyte reaction for CD4+CD25+T cells suppressor function. The CD4+CD25+T cells can inhibit the proliferation of CD4+CD25−T cells and inhibition ratio was about 50%. Our result demonstrated that RAPA can induce Balb/C murine CD4+CD25+Foxp3+T cells proliferation in vivo, which suggested RAPA could increase CD4+CD25+Foxp3+T cells on the autoimmune disease and graft versus host disease treatment.
Immune Mobilization of Autologous Peripheral Blood Progenitor Cells: IL-2 with GM-CSF and G-CSF Results in Effective Mobilization without Delay in Engraftment.
Authors: Hill John M. , Wu Jia-Yan , Webber Susan M. , Sharlin Ortal , Kendall Melinda , McGregor David , Ernstoff Marc J. , Szczepiorkowski Zbigniew M. , Meehan Kenneth R. 
Published: April 2020

Abstract
We initiated an immune mobilization trial in an attempt to mobilize cytotoxic effector cells, along with CD34+ hematopoietic progenitor cells. A Prospective Phase I trial was initiated using dose escalation of IL-2, in combination with GM-CSF and G-CSF. IL-2 began on Day 0 and continued as a daily SQ injection for 11 days. On Day 7, GM-CSF (7.5 mcg/kg/d) and G-CSF (5 mcg/kg/d) were initiated for 5 days (Days 7–11). On Day 11, leukapheresis was started if the peripheral blood CD34 + cell count was &gt; 5 cells/mcl. The endpoint of collection was ≥ 3 × 106 CD34+ cells/kg. After collection, patients received melphalan (200 mg/m2) followed by infusion of cryopreserved stem cells. Post-transplant GM-CSF began on Day +5 and terminated once the ANC reached 5000 cells/mcl. To date, 9 patients have been treated (myeloma, n = 8; NHL, n = 1) and 7 patients are evaluable. Six patients received IL-2 at Dose Level 1 (6 × 105 IU/m2/d). The remaining 3 patients received IL-2 at Dose Level 2 (1 × 106 IU/m2/d). The MTD of IL-2 has not been reached. One patient (NHL) was removed from the study due to progressive disease. The remaining 8 patients completed the regimen. Toxicities have been mild and have included Grade 2 fever (n=1) on Dose Level 2. All patients were successfully mobilized. The median number of CD34+ cells/kg and MNC/kg collected were 3.4 × 106 (range 2.8 – 4.4 × 106/kg) and 9.5 × 108 (range 0.4 – 1.7 × 109), respectively. Two large volume leukaphereses were required (median; range 1 – 3). Following transplant, the ANC recovered on Day 13 (median; range: 10 – 14 d) and platelets recovered on Day 12 (median; range 0 – 13 d). These preliminary results demonstrate that immune mobilization and collection of an adequate number of hematopoietic progenitor cells is feasible without suppression of hematopoiesis. Toxicities are minimal but the MTD of IL-2 has not yet been reached. Post-transplant engraftment is not delayed. As patient accrual continues, we are currently evaluating the qualitative and quantitative components of the collected cells, including Th1 vs. Th2 cells and the types of dendritic cells mobilized.
Engineering a Disulfide Bond To Stabilize the Calcium Binding Loop of Activated Protein C Eliminates Its Anticoagulant but Not Protective Signaling Properties.
Authors: Bae Jong-Sup , Yang Likui , Manithody Chandrashekhara , Rezaie Alireza R. 
Published: April 2020

Abstract
In addition to its potent anticoagulant activity, activated protein C (APC) also exhibits anti-inflammatory and cytoprotective properties. The latter properties of APC are thought to be responsible for its beneficial effect in treating severe sepsis patients. A higher incidence of bleeding due to its anticoagulant function has been found to be a major drawback of APC as an effective anti-inflammatory drug. Thus, there is intense interest in developing APC variants that have no anticoagulant activity, but have normal protective properties. In this study, we have prepared a protein C variant in which an engineered disulfide bond between two β-sheets has stabilized the functionally critical Ca2+-binding 70–80 loop of the molecule. The 70–80 loop of this mutant no longer binds Ca2+ and the activation of the mutant by thrombin has been enhanced 60–80-fold independent of thrombomodulin. The anticoagulant activity of the APC variant has been essentially eliminated as determined by both factor Va degradation and plasma-based clotting assays. However, the endothelial protein C receptor- and protease-activated receptor-1-dependent protective signaling properties of the APC variant have remained intact as determined by staurosporine-induced endothelial cell apoptosis, thrombin-induced endothelial cell permeability and TNF-α-mediated neutrophil adhesion and migration assays. These results suggest that modulation of the structure and/or activity of APC by Ca2+ is required for its anticoagulant, but not for its anti-inflammatory activity, thus the protein C variant may potentially be a safer drug for treating severe sepsis patients in both activated and zymogenic forms.
Predictive Markers for Acute Graft-Versus-Host Disease in the Peripheral Blood - Surface Receptor Profile Defines Alloreactive T Cells In Vivo.
Authors: Beilhack Andreas , Zeiser Robert , Schulz Stephan , Olson Janelle A. , Nishimura Ryosei , Leveson-Gower Dennis , Negrin Robert S. 
Published: April 2020

Abstract
Acute graft-versus-host disease (aGVHD) still results in high morbidity and mortality in patients undergoing allogeneic hematopoietic cell transplantation (aHCT). Early diagnosis of aGVHD remains difficult and is made based on clinical symptoms and histological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestations. Therefore, it is important to develop predictive assays to identify patients at risk of developing aGVHD for improved disease prevention.
Using bioluminescence imaging (BLI) we have recently demonstrated that aGVHD pathogenesis is tightly spatially and temporally regulated in a murine model across major histocompatibility barriers. Therefore, we asked whether insights in the timing of aGVHD initiation and effector phase could allow for the development of a diagnostic test whereby specific cell surface profiles can predict the onset of aGVHD.
FVB/N (H-2q, Thy1.1+, 4x106) or C57Bl/6 (H-2b, Thy1.1+, 4x106) splenocytes plus bone marrow (BM) cells (5x106) were transplanted into conditioned (2x400rad) allogeneic Balb/c (H-2d, Thy1.2+) or syngeneic (2x450rad) C57Bl/6 (H-2b, Thy1.2+) recipients. Allogeneic recipients developed the first clinical signs of aGVHD starting at day+6 which progressed rapidly to animal death typically by day+14. However, BLI revealed that aGVHD target organ infiltration had already occurred days earlier. On day+3 after aHCT, dividing (BrdU+) donor derived allogeneic T cells (Thy1.1+) were still confined to the T cell areas in secondary lymphoid organs. Between day+3 and day+4 T cells appeared in the red pulp of the spleen, indicating likely entry into the blood circulation. Thereafter, increasing aGVHD target organ infiltration became apparent. These findings prompted us to analyze peripheral blood (PB) samples from allogeneic vs. syngeneic recipients (day+1 to +6). Until day+3 after aHCT, no significant PB T cell numbers were detectable. However, by day+4 we found a dramatic increase of PB T cells (mostly CD4+, by day+5 mostly CD8+) that were CD44hi and expressed the homing receptors α4β7 integrin, αEβ7 integrin, CCR9, E-selectin ligand, P-selectin ligand, CCR5, and CXCR3 in allogeneic recipients, but not in syngeneic or BM controls. These T cell populations could be verified as clonally expanded (CFSElo) donor-derived alloreactive T cell subsets (Thy1.1+).
In summary, alloreactive T cells could be identified by the timed up-regulation of a panel of distinct homing receptors. Furthermore, the transition between aGVHD initiation and effector phase emerged as an early diagnostic window for the detection of alloreactive T cells in the peripheral blood days before aGVHD onset. Taken together, this approach could predict aGVHD in order to tailor immunosuppressive therapy for individual patients.