bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermediate-Dose Interleukin-2 Demonstrates Activity in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma.
Authors: Foss Francine M. , Higgins Beth 
Published: April 2020

Abstract
Interleukin-2 (IL-2) has demonstrated activity as an antineoplastic and biomodulatory agent, but its activity in hematologic malignancies has not been fully defined. Cutaneous T-cell lymphoma (CTCL) has been characterized as a disorder of mature clonal CD4+CD7− cells with a predominantly Th2 cytokine profile and a blunted response to Th1 and Fas-associated apoptosis. Durable responses have been reported in several advanced CTCL patients in prior studies using high dose IL-2, but the capacity of IL-2 as an immune modulator to upregulate Th1 cytokine secretion and to facilitate a cytotoxic T-cell response in CTCL has not been studied. To further explore the activity of IL-2 to restore a Th1 phenotype and to induce an antitumor response in CTCL, we treated 11 patients with advanced or refractory CTCL with intermediate dose IL-2 (11 MIU subcutaneously daily x 4 days for 6 weeks with 2 weeks rest). The median age was 60 (range 55–72) among 6 females and 5 males. Disease was stage IB-IIA in 4, IIB in 2, III-IVB in 5, and 7 had circulating Sezary cells. Four had evidence of significant lymphadenopathy on CT scans. The mean prior therapies was 3, with 4 patients having received 3 or more systemic cytotoxic therapies. Five patients had prior electron beam irradiation, and 5 had prior biological therapies, including IFN in 3, bexarotene in 4, and interleukin-12 in one. The median cycles administered was 2 (range 1–8). Two patients were discontinued for toxicity, one with grade 3 constitutional symptoms and one who had severe underlying cardiovascular disease and developed bilateral lower extremity deep venous thromboses. Overall, therapy was well tolerated with grade 3 fatigue in 3 patients and grade 2 eosinophilia in one. Response data includes: 4 patients with partial response, including 3 with Sezary syndrome and one with diffuse plaque stage disease; 3 patients with stable disease; 2 patients with progressive disease; 2 patients discontinued before completing one cycle and were inevaluable for response. One patient with diffuse pruritis, erythroderma and circulating Sezary cells completed 8 cycles of therapy and had a complete response in the skin but persistence of a low number of Sezary cells in the blood. Immunophenotypic analysis of circulating lymphocytes revealed an overall increase in CD4+CD25+ cells during therapy, suggesting a direct immunomodulatory effect of IL-2. In summary, our experience with intermediate dose IL-2 demonstrates that the therapy was well tolerated and was associated with biological activity in patients with extensive and refractory CTCL, with responses noted in 3 of 7 patients with Sezary syndrome. Based on our results, we intent to explore the biomodulatory effects of IL-2 on both normal T-cells and Sezary cells to attempt to define the role of IL-2 as a single agent or in combination with other biological agents in patients with CTCL.
Results of a Phase II Trial of Oral Bexarotene Combined with Interferon Alfa-2b for Patients with Cutaneous T-Cell Lymphoma (CTCL).
Authors: Straus David J. , Duvic Madeleine , Kuzel Timothy , Horwitz Steven , Demierre Marie-France , Myskowski Patricia , Maignan Kathleen , Steckel Steven 
Published: April 2020

Abstract
Bexarotene, a synthetic retinoid ligand for the retinoid X receptor (RXR), is a highly active agent in the treatment of relapsed or refractory CTCL with a response rate of ~45% (Arch Dermatol137: 581–93, 2001; J Clin Oncol19: 2456–71, 2001). Interferon alfa has a similar response rate although the doses and responses in the literature have varied. Promising results have been reported with combinations of retinoids and interferon alfa, including bexarotene (J Am Acad Dermatol50: 375–9, 2004). To explore this combination, a phase II trial was designed in which patients with CTCL were treated with bexarotene 300 mg/m2/day for at least 8 weeks. If less than a complete response was seen at this time, interferon alfa-2b at a dose of 3 million units escalated to 5 million units subcutaneously 3 times weekly was added for another 8 weeks. Responding patients could continue treatment beyond 16 weeks. Twenty-two patients with CTCL were enrolled in the trial: median age 58 years (22–79); 9 males, 13 females, TNM stages: IB (3), II (7), III (4), IV (8). One patient had no prior treatment; the rest had relapsed or refractory disease with a mean of 49 months from initial diagnosis to enrollment. Four patients had previously received bexarotene and 2 interferon alfa. Seventeen patients completed 16 weeks of treatment and are assessable for response, 1 has not completed 16 weeks and 4 received less than 16 weeks (1 early death, 1 non-compliant, 1 withdrawal of consent because of side effects, and 1 myocarditis, probably not treatment-related). Using reproducible objective criteria for response utilized in the single agent bexarotene trials cited above (Primary Endpoint Classification), 6 of 17 patients achieved a partial response and 1 a complete response (objective response rate 41%, 95% confidence intervals 18%–67%). Three of the 6 partial responses occurred with bexarotene alone at 8 weeks. Median duration of response was 2.7 months, range 1.1–7.6 months. Reversible grade 3 or 4 toxicities seen in more than 1 patient were hypercholesterolemia (2 pts.), hypertriglyceridemia (4 pts.), neutropenia (3 pts.), lymphopenia (2 pts.) and elevated AST in 2 patients. Lipid lowering agents were used in all patients. Six patients died, all of progressive disease from 1.6–29.9 months following initiation of treatment. The major response rate for the combination of bexarotene and interferon alfa is similar to that for bexarotene alone. Despite the wide confidence intervals that indicate that a small advantage might be missed by not increasing accrual, the clinical usefulness of this combination is limited by the inconvenience of interferon injections. Further trials in CTCL are planned combining bexarotene with other agents, including active cytotoxics.
Cbl Regulates CXCR4-Mediated Chemotaxis and CXCR4 Receptor Internalization.
Authors: Lane Heather C. , Anand Appakkudal R. , Fernandis Aaron Z. , Ganju Ramesh K. 
Published: April 2020

Abstract
CXCL12-induced and CXCR4-mediated chemotaxis plays a critical role in the trafficking of lymphocytes, which modulates inflammatory and immune responses. The CXCR4 receptor is down-modulated by its ligand CXCL12, which has been shown to inhibit HIV entry into the cells. However, the molecular mechanisms that regulate CXCL12-induced chemotaxis and down-modulation of the CXCR4 receptor are not well known. We have previously shown that CXCL12 induces the tyrosine phosphorylation of the signaling molecule Cbl and its association with the tyrosine phosphatase SHP2. In the present investigation, we have further explored the role of Cbl in CXCR4-mediated chemotaxis and CXCR4 down-modulation. Cbl, a 120 kd protein that contains a tyrosine kinase binding domain (TKB), can function as an adaptor molecule by binding to various proteins. It also contains a RING finger domain and has been shown to negatively regulate signaling by directing the ubiquitination and degradation of signaling molecules. We found that CXCR4 L1.2 cells overexpressing wild-type Cbl or G306E-Cbl (deletion in the TKB domain) showed reduced migration to CXCL12, only 50% of the vector control. Cells overexpressing 70Z-Cbl (deletion in the RING finger domain) showed no difference in migration as compared to the vector control. We next examined CXCR4 expression in these cells by FACS analysis. We found that cells overexpressing wild-type Cbl and G306E-Cbl had approximately 60% CXCR4 receptor expression as compared to the vector control, while the cells overexpressing 70Z-Cbl had no difference in receptor expression. Cells were then internalized by stimulation with CXCL12 or HIV gp120, and after 2 hours approximately 80% of the vector control cells had internalized, as compared to approximately 90% of the cells overexpressing wild-type Cbl and G306E-Cbl, and 60% of the cells overexpressing 70Z-Cbl. Overexpression of wild-type Cbl or G306E-Cbl slightly increased internalization of the CXCR4 receptor, while 70Z-Cbl impeded this process. This indicates that wild-type Cbl enhances internalization, while the G306E mutation in the tyrosine kinase binding domain has no effect on this function of Cbl. Our results suggest that the RING finger domain of Cbl is important for internalization of the CXCR4 receptor. In addition, we observed that there was no difference in the phosphorylation of Erk 1/2 between the vector control cells and those overexpressing wild-type Cbl, 70Z-Cbl, or G306E-Cbl after stimulation with CXCL12, indicating that these changes in migration and receptor expression act in a MAPK-independent pathway. Taken together, these studies suggest that Cbl plays an important role in CXCR4-mediated chemotaxis and the CXCR4 internalization process. These results may lead to better understanding of HIV pathogenesis and inflammatory responses mediated by CXCR4.
Suppression of Negative Immune Regulators PD-1 and PD-L1 Expression on Lymphocytes by Inflammatory Cytokines.
Authors: Zhong Xuemei , Bai Chunyan , Rothstein Thomas L. 
Published: April 2020

Abstract
The strength and duration of lymphocyte activation is determined by the net effect of positive and negative regulatory co-signaling molecules. The inhibitory receptor PD-1 and its ligand PD-L1 are both expressed on activated lymphocytes. Mice deficient of PD-1 or PD-L1 demonstrate lymphocyte hyperactivity and are prone to autoimmunity. We have shown that the expression and function of PD-1 on activated B lymphocytes can be down-regulated by certain inflammatory cytokines, rendering them resistant to PD-L1 mediated suppression. Here we further report that both PD-1 and PD-L1 expression on activated T lymphocytes can be down-regulated in a similar fashion. Thus, in addition to stimulating positive regulators, inflammatory cytokines may boost immune responses and break self-tolerance by inhibiting a negative regulator on T and B lymphocytes. Our findings may indicate a potential mechanism for the link between chronic inflammation and autoimmunity.
The Effect of Aging on Hematopoietic Stem Cell Homing and Engraftment.
Authors: Liang Ying , Van Zant Gary , Szilvassy Stephen J. 
Published: April 2020

Abstract
The efficiency with which hematopoietic stem (HSC) and progenitor cells (HPC) home to bone marrow (BM) critically impacts their engraftment after transplantation. Little is known about the effects of aging on this parameter. The present study was thus initiated to test the hypothesis that homing efficiency of HSCs and HPCs to the BM will vary with aging of the donor, recipient, or both. Young or old C57BL/6 BM cells were intravenously injected into lethally irradiated old or young Ly-5 congenic recipient mice. Three or 24 hours later, the numbers of HPCs or HSCs that could be recovered from the BM and spleen were assayed using an in vitro colony-forming cell assay or an in vivo limiting-dilution competitive repopulating unit (CRU) assay and compared to the number of such cells that were initially transplanted. The frequency of CRU in old BM was two-fold higher than that in young BM (~1 per 10,000 vs. 24,000 cells). However, old CRU homed less efficiently to young BM after 24 hours than did young HSCs (3% vs. 10%). The proliferative potential of individual HSCs (measured as the overall level of engraftment in mice transplanted with 1 CRU) did not change with donor age, but was reduced by advanced recipient age, and was also reduced by prior transplantation as observed previously. HSC differentiation potential (defined by the proportion of lymphocytes and myeloid cells in mice transplanted with 1 CRU) was also skewed toward myelopoiesis at the expense of lymphopoiesis with both donor and recipient age. Donor and recipient aging exerted similar effects on the 3 hour BM and spleen seeding efficiency of HPCs, both leading to a 40% decrease in BM homing, and a 5-fold decrease in spleen homing compared with young HPCs transplanted into young recipients. In terms of the rate of hematopoietic engraftment, advanced recipient age resulted in slower erythrocyte and platelet recovery, but moderately accelerated leukocyte regeneration compared with young cells transplanted into young recipients. Conversely, old donor cells exhibited faster leukocyte and platelet recovery, but erythrocyte recovery was essentially unchanged compared to young donor cells. In sum, these data suggest that primitive hematopoietic cells undergo intrinsic aging-related changes in homing efficiency, proliferation/differentiation potential, and engraftment capability that are also extrinsically affected by an older BM microenvironment. These findings have important implications for clinical stem cell transplantation where older individuals often serve as donors for elderly patients.
Repopulation Advantage of Blm−/− Cells in the Primary Recipients Can Be Reversed by Cisplatin Treatment.
Authors: Park Youngji , Luo Guangbin , Gerson Stanton 
Published: April 2020

Abstract
Deficiencies in DNA repair-related genes such RecQ DNA helicases lead to human genetic disorders such as Bloom’s syndrome, Werner’s syndrome, and Rothmund-Thomson syndrome characterized by premature aging and cancer predisposition. We hypothesized that deficiency in RecQ DNA helicases may lead to drug hypersensitivity and/or stem cell failure after serial transplantation. Several genotoxic agents were tested on the bone marrow cells isolated from Bloom (Blm)−/− and RecQ4−/− knockout mice and compared to wildtype bone marrow cells. RecQ4−/− bone marrow showed mild sensitivity to γ-ray irradiation and very mild sensitivity to cisplatin. RecQ4−/− bone marrow did not show sensitivity to etoposide. However, Blm−/− bone marrow cells did not show hypersensitivity to either γ-ray irradiation or etoposide treatment, implying each RecQ DNA helicase may have different roles for DNA repair and/or proliferation in bone marrow cells.
To assess how deficiency in RecQ DNA helicase affects hematopoietic stem cell function, serial transplantation capacity into lethally irradiated recipients was compared between bone marrow cells isolated from Blm−/− (Ly5.2) and wildtype (Ly5.1) mice. Competitive repopulating capacity was monitored by Ly5.1 / Ly5.2 marker analysis of peripheral blood every three weeks. There was no difference in early repopulating capacity between Blm−/− and wildtype in primary transplants at 3, 6 and 9 weeks post-transplantation (wt 46.6% ± 11.9% vs. Blm−/− 53.5% ± 11.9%, n=6, p=0.33 at 9 weeks post-transplantation). However, at 15 weeks post-transplantation, Blm−/− cells showed higher repopulation than wildtype bone marrow cells (wt 30.7 % ± 7.1 % vs. Blm−/− 69.3% ± 7.1%, n=3, p=0.003), implying Blm−/− cells might gradually accumulate a proliferative advantage over wildtype cells. To assess whether drug treatment may cause sensitivity in Blm−/− cells after transplantation, primary recipients of an equal mixture of Blm−/− and wildtype bone marrow were treated with 1 mg/kg cisplatin biweekly i.p. between 9 to 15 weeks post-transplantation and repopulation capacity was monitored. The repopulation advantage of Blm−/− cells in primary transplants was abolished by cisplatin treatment (wt 61.3 % ± 17.3 % vs. Blm−/− 38.7% ± 17.3%, n=3, p=0.19, in the cisplatin-treated cohort compared to wt 30.7 % ± 7.1 % vs. Blm−/− 69.3% ± 7.1%, n=3, p=0.003, in the control cohort). Thus, a proliferative advantage of progenitors is apparent in Blm−/− bone marrow, but lost after cisplatin-mediated DNA damage. This suggests that defective DNA repair of Blm−/− cell may promote deregulated proliferation of hematopoietic progenitors.
Marrow Derived Muscle Colonies Are a Clonal Phenomenon.
Authors: Abedi Mehrdad , Greer Deborah A. , Foster Bethany A. , Demers Delia A. , Colvin Gerald A. , Dooner Mark S. , Quesenberry Peter J. 
Published: April 2020

Abstract
We have previously established a model of plasticity of marrow to skeletal muscle that is based on transplantation of GFP positive marrow and cardiotoxin injury to the tibialis muscle. In these experiments, we have observed colonies of GFP positive muscle fibers, defined as 3 or more myocytes. We noted that individual GFP positive fibers showed marked heterogeneity of fluorescence. In sharp contrast, colonies of GFP+ cells, showed homogeneous fluorescence. This was confirmed by using confocal microscopy and by measuring the mean fluorescent intensity of the individual cells in the colonies. When the intensity of the green fluorescence in individual fibers was graded to dull, moderate or bright, in 95% of the colonies counted, showed homogenous intensity of green fluorescence while for single GFP fibers dispersed throughout the specimen the probability of 3 cells being the same color was only 14.12%. Therefore the probability of 95% of colonies to have a minimum of 3 homogenous fibers by random association is less than 0.0001. To show that colonies are not from clumps of cells injected into the muscle, we compared the number of the colonies in two different experimental setting where in both GFP positive marrow cells were injected intravenously after 900cGy of radiation followed by cardiotoxin injury to the muscle. Animals who received two cycle of G-CSF mobilization were compared with those who had lineage negative marrow cells directly injected into their muscle, one day after injury. The incidence of muscle colonies remained the same between the groups. The incidence increased in experiments with multiple cycles of mobilization and injury and also in mdx mouse that has spontaneous ongoing regeneration of its muscles. Cotransplantation of marrow cells from yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) transgenics into C57BL/6 mice followed by cardiotoxin injury showed colonies that were either from YFP or CFP cells. No mixed colonies were found. Transplantation of YFP marrow cells before injury followed by CFP cells after injury and vice versa showed colonies only from cells that were infused at the time of transplantation. Colonies were seen only in samples that received CD45, C-Kit and/or Sca positive marrow cells and not in those negative populations. These cells resulted in a GFP+ CD45 negative population 4 weeks after transplantation and produced Myf5+ and MyoD+ myoblasts three days after injury. These data suggests that marrow derived muscle colonies are a clonal phenomenon similar to CFU-S cells in recipient spleens after transplantation.
Monitoring of Bone Marrow Cell Homing in the Infarcted Human Myocardium by PET.
Authors: Hertenstein Bernd , Wollert Kai C. , Hofmann Michael , Meyer Gerd P. , Arseniev Lubomir , Gasner Arnold , Knapp Wolfram H. , Drexler Helmut 
Published: April 2020

Abstract
Intracoronary transfer of autologous bone marrow cells (BMCs) has been shown to promote recovery of left ventricular (LV) systolic function in patients with acute myocardial infarction. (BOOST Trial; Wollert et al. Lancet, 2004, 364 141-8). Although the mechanisms of this effect remain to be established, homing of BMCs to the infarcted LV is probably a crucial early event. We determined BMC tissue distribution after therapeutic application in nine patients with a first ST-elevation myocardial infarction, who had undergone stenting of the infarct-related artery (all male; median age 43 ys; range 36 – 66). The study was approved by the local ethics committee and all patients provided written informed consent. Time from symptom onset to percutaneous coronary intervention (PCI) was 8 h (3–27) and median maximum CK level was 1767 U/l. Cells were harvested from the posterior iliac crest during short anesthesia with etomidate and midazolam and subjected to 4% gelatine polysuccinate sedimentation to obtain a preparation of unfractionated BMCs. 2.5 ± 0,7 x 108 unfractionated BMCs (10% of the harvested cell number) were radiolabeled with 100 MBq 2′-[18F]-fluoro-deoxyglucose (FDG) and infused into the infarct-related coronary artery (i.c., n=3 patients) or injected via an antecubital vein (i.v., n=3 patients). In 3 additional patients, CD34pos cells were immunomagnetically enriched from unfractionated BMCs (Clinimacs, Miltenyi, Germany), labeled with FDG, and infused i.c. Cell transfer was performed 8±2 days after stenting. Following application of FDG labelled cells all patients received 20 ± 6 x 108 non-labeled BMCs i.c. (i.e. the cell dosage that improved cell function in the BOOST trial). More than 98% of the total radioactivity infused was cell-bound. Cell viability after FDG-labeling was 95±2%. Sixty minutes after cell transfer, all patients underwent 3D-positron emission tomography imaging. After i.c. transfer, 3.4±1.4% of FDG-labeled unfractionated BMCs were detected in the infarcted LV; the remaining activity was found primarily in the liver and spleen. After i.v. transfer, only background activity was detectable in the infarcted LV. After i.c. transfer of FDG-labeled CD34-enriched cells, 25±13% of the total activity was detectable in the infarcted LV. Unfractionated BMCs engrafted in the infarct center and border zone, CD34pos cell homing was more pronounced in the border zone. FDG-labeling can be used to monitor myocardial homing and tissue distribution of BMCs after therapeutic application. I.c. transfer is superior to i.v. application in terms of BMC homing in the the infarcted LV. CD34-enriched cells display a 7-fold higher retention in the infarcted LV as compared to unfractionated BMCs.