bluuebunny/crossref_metadata_2025_split huggingface dataset:
HSP27 Protects Malignant Hematopoietic Cells Against VP-16-Induced Apoptosis through Modulation of P38 and C-JUN.
Authors: Schepers Hein , Geugien Marjan , van der Toorn Marco , Bryantsev Anton L. , Kampinga Harm H. , Vellenga Edo 
Published: April 2020

Abstract
In the present study, expression and function of Heat Shock Protein 27 (HSP27) was analyzed in acute myeloid leukemia (AML), since HSP27 expression is linked to unfavourable prognosis. HSP27 protein was predominantly expressed in monocytic blasts (M4-M5, 91%, N = 11) and absent in myeloid leukemic blasts (M1-M2, N = 5). A similar lineage restricted expression was observed in normal hematopoietic cells: high expression in normal CD34+ cells and monocytes, and absent in granulocytes. To study the functional role of HSP27, RNA interference (RNAi) studies were performed in the leukemic TF-1 cell line. These experiments demonstrated a twofold increase in VP-16-induced apoptosis after HSP27 siRNA. In contrast, CD95 Fas-induced apoptosis remained the same, as a result of CD95 Fas-mediated upregulation of HSP27. Additional investigations demonstrated that the increased VP-16-induced apoptosis after HSP27 RNAi, was associated with an enhanced phosphorylation of p38 and c-Jun. This VP-16-induced phosphorylation was subsequently followed by the release of cytochrome c into the cytoplasm, which increased twofold after siRNA treatment. These results indicate that HSP27 plays an important role in the protection against VP-16-induced apoptosis through the modulation of p38 and JNK activation, probably through interference with DAXX-mediated ASK1 activation. This was further underscored by co-immunoprecipitation studies, demonstrating complex formation of DAXX and HSP27 in an ASK1-dependent manner. However, in the investigated AML samples, VP-16-mediated apoptosis correlated moderately with HSP27 expression, although HSP27 was highly expressed and phosphorylated and activated in primitive monocytic AML blasts. This is likely due to the co-expression of p21Waf1/Cip1, which is in the majority of the monocytic AML M4-M5 blasts constitutively localised in the cytoplasm and interferes with apoptosis via the DAXX-ASK1-dependent pathway. Preliminary data indicate that overexpression of a cytoplasmic form of p21 is able to reduce the VP-16-induced apoptosis after RNAi for HSP27 as compared to controls, suggesting a predominant anti-apoptotic role of p21 over HSP27. In summary, we demonstrate a role for HSP27 in the survival of leukemic cells by modulation of the DAXX/p38/JNK apoptosis pathway. This survival advantage can further be promoted by the co-expression of cytoplasmic localised p21Waf1/Cip1 protein, indicating that strategies in AML treatment should be focused on targeting multiple signal transduction pathways.
Leukemia Inhibitory Factor: A Newly Identified Chemoattractant and Regulator of Metastasis of Rhabdomyosarcomas and Neuroblastomas to Bone Marrow.
Authors: Wysoczynski Marcin , Jankowski Kacper , Miekus Kasia , Kucia Magda , Janowska-Wieczorek Anna , Ratajczak Janina , Ratajczak Mariusz Z. 
Published: April 2020

Abstract
Rhabdomyosarcomas (RMS) and neuroblastomas (NBS) are tumors that originate in skeletal muscle and neural tissue respectively, and frequently metastasize/infiltrate bone marrow (BM). We have recently demonstrated a crucial role for the stromal-derived factor (SDF)-1- CXCR4 axis in RMS and NBS metastases to BM (Blood2002:100, 2597). However, our recent studies with the CXCR4 antagonist T140 suggest involvement of other factor(s) besides SDF-1 that direct the motility/metastasis of these cells. Based on the fact that the gp-130 receptor signaling cytokine Leukemia Inhibitory Factor (LIF) plays an important role in trafficking of normal muscle and neural cells and the development of muscle and neural tissue we hypothesized that LIF could be this missing chemoattractant that is involved in directing metastasis of RMS and NBS cells to the BM environment. Supporting this notion we found that LIF is secreted by BM stroma cells and LIF-R (a gp130 receptor family member) is expressed at the protein level on several human RMS and NBS cell lines as determined by FACS analysis. Next, we found that LIF-R is functional on RMS and NBS cells, mediates phosphorylation of MAPKp42/44, PI-3K-AKT, and JAK-STAT pathways and activation of small GTP-ase - Rac-1, and both RMS and NBS cells are chemoattracted by LIF. Furthermore, LIF increases adhesion of RMS and NBS cells to stroma and endothelium and upregulated expression of angiopoietic factors such as VEGF and IL-8. Finally we found that LIF-mediated responses were specifically inhibited by anti-LIF-R blocking antibodies. In conclusion, we present evidence for first time that LIF-LIF-R (cytokine-gp130 signaling receptor axis) may direct metastasis and enhance the invasive potential of human solid tumor cells. Hence molecular targeting of LIF or LIF-R may become a new antimetastatic strategy to improve therapeutic outcome from pediatric sarcomas. Molecular strategies aimed at inhibiting the LIF-LIF-R axis, and the SDF-1-CXCR4 axis, for example, by the use of small-molecule inhibitors, could lead to the development of new anti-metastatic therapies that could complement the conventional radio- or chemotherapy in preventing the dissemination of RMS and NBS cells into bone marrow and lymph nodes. This is currently being tested in animal models in our laboratory.
Crosstalk between Breast Cancer Cells and Bone Marrow Endothelium Require the Engagement of PI3K/AKT Signaling.
Authors: Brandao Joana G. , Barata Joao T. , Nunes Raquel , Nadler Lee M. , Cardoso Angelo A. 
Published: April 2020

Abstract
The presence of breast cancer cells in the patient’s bone marrow (BM) at diagnosis is associated with resistance to treatment, disease relapse and poor prognosis. Identification of the factors implicated in the homing, survival and latency of breast cancer cells in the BM should contribute to the design of more efficient therapeutic strategies for breast cancer. There is evidence that breast cancer can recruit endothelial progenitors from the BM. Also, other epithelial tumors seem to preferentially adhere to BM endothelial cells. Therefore, we hypothesized that BM endothelium may play a significant role in the biology of breast cancer cells residing in the BM. Co-cultures in Matrigel showed that breast cancer cells interact with BM endothelium to form heterotypic multicellular networks. Moreover, breast cancer cells migrate towards BM endothelium assembled as capillary-like structures, but not to structures of BM mesenchymal stem cells or BM stroma. This migration was abrogated by pertussis toxin-mediated blockade of chemokine receptor signaling, suggesting the involvement of endothelium-secreted chemokine(s). We then evaluated the impact of breast cancer cells in the survival and proliferation of BM endothelium. All breast cancer lines tested (n=4) promoted the proliferation of BM-derived endothelial cells. This effect is mediated through the engagement of the PI3K/Akt pathway (phosphorylation of Akt at Ser437 and Thr308, and activation of its downstream substrates GSK3β, PRAS-40 and FKHRL1) since its specific blockade abrogated the stimulatory effects of breast cancer on BM endothelium. We next determined whether, reciprocally, BM endothelium impacts on breast cancer cell survival. These experiments were performed in serum-free media to enhance dependency of breast cancer cells from microenvironmental stimuli. In all cases tested, BM endothelium promoted survival/proliferation of breast cancer cells. This stimulation was accompanied by the engagement of the PI3K/Akt pathway in breast cancer cells and, in three of the four lines, the phosphorylation of Erk1/2. These effects were also observed for breast cancer cells that showed constitutive activation of Akt (MCF-7 and ZR-75-1 cells). Specific blockade of PI3K/Akt abrogated the BM endothelium-promoted survival of breast cancer cells, thus demonstrating the critical role of this pathway. These studies show that crosstalk between BM endothelial cells and breast cancer cells may impact on the survival of both cell types. These findings provide new light on the mechanisms that may facilitate the development of a tumor-permissive BM microenvironment in breast cancer, and the creation of breast cancer-supporting BM niches. Importantly, this study implicates BM endothelium as a therapeutic target in breast cancer and suggest that blockade of PI3K/Akt may impact the outcome of patients with metastatic breast cancer.
Risk-Adapted Therapy in Adults Previously Untreated Hodgkin’s Lymphoma (HL) with ABVD Followed by Involved Field Radiotherapy (IFRT).
Authors: Pavlovsky Santiago , Corrado Claudia S. , Pavlovsky Miguel A. , Giunta Mario , Zoppegno Lucia , Prates Virginia , Lastiri Francisco , Cerutti Ider , Narbaitz Maria C. , Rudoy Silvia , Cavagnaro Fernando , Kurchan Alejandra , Palomino Elsa , Campo Cesar 
Published: April 2020

Abstract
Background: The present goal for the treatment of HL is to develop a combined modality therapy with high response rate, disease-free survival (DFS) and overall survival (OSV) with minimal toxicity.
Methods: On December 1996, the GATLA started a non randomized protocol for 15 to 75 years old (median 28) patients previously untreated. Patients with clinical stage I, II, IIIA without bulky tumor (&lt; 10 cm mass or &lt; 1/3 thoraxic diameter) (low risk) received 3 cycles of ABVD followed by IFRT 25 Gy to all node areas of more than 2 cm at diagnosis. A total of 46 out of 218 patients (21%) with low risk who failed to achieve complete remission (CR) after 3 cycles of ABVD were included as high risk completing 6 cycles of ABVD. Patients with clinical stage IIIB and IV or all other stages with bulky disease or persistance lymph nodes areas after 3rd cycle of ABVD (high risk) received 6 cycles of ABVD followed by IFRT 30 Gy to residual areas after the third cycle of ABVD or bulky areas at diagnosis. The dose of ABVD was the standard; Adriamycin 25 mg/m2, Bleomycin 10 IU/m2, Vinblastine 6 mg/m2 and Dacarbacine 375 mg/m2 all IV on day 1 and 15 of each 28 days cycles. Patients who achieved partial remission (PR) were salvage with other regimen mainly ESHAP x 3 cycles followed by high dose therapy with autograft rescue.
Results: A total of 171 (99%) out of 172 patients with low risk achieved CR. One 74 year old patient died of pneumonia after the third ABVD. A total of 187 (85%) of 219 patients with high-risk achieved CR, 25 PR, and 7 failed to respond (FR) (P&lt;0,001). The estimate DFS at 60 months was 92% and 67% (P&lt; 0.001), while the OS was 98% and 89% (P=0.004) for low and high risk respectivelly. Of the 25 patients with PR, all received second line therapy followed in 15 by an autograft. Twelve patients are in CR, 5 are in PR, 2 in progressive disease and 6 died. Of the seven who FR, four died of PD an three are alive with the disease. One patient developed a MDS/AML after relapsing from an autograft and 8 months after having been rescued with BEACOPP. Five other second cancer (1 ovary, 2 NHL, 1 lung, 1 colon) appeared after treatment, two died and 3 remain in CR of their HL. Using the IPI HL 165 patients (48%) have scored 0–1, 145 (43%) scored 2–3, and 30 (9%) scored 3–4. The rate of CR was 96%, 88% and 87% respectively (P&lt;0.016). The EFS at 60 months was 89%, 72% and 55% respectively (P=0.004). The OSV was 98%, 89% and 86% (P=0.037).
Conclusions: We can conclude by saying that with risk-adapted therapy, 92% of the 391 patients achieved CR, with a CR + PR response of 98%. A total of 78% are event-free and 93% are alive at 60 months with remarkable low-toxicity.
G-CSF Administration Increases Pulmonary Toxicity for Hodgkin’s Disease Patients Treated with Bleomycin-Containing Chemotherapy.
Authors: Martin William G. , Habermann Thomas M. , Colgan Joseph P. , Ristow Kay M. , Ansell Stephen M. 
Published: April 2020

Abstract
Background: In Hodgkin’s Disease (HD), G-CSF has been used to maintain maximum dose intensity by avoiding neutropenia and treatment delays. Pre-clinical data and anecdotal reports have shown an association between G-CSF administration and bleomycin pulmonary toxicity (BPT). This complication may cause access morbidity and have a detrimental impact on survival in this otherwise good prognosis population. We embarked on a retrospective analysis to determine if G-CSF increased the incidence of this complication or had an impact on outcomes.
Methods: We reviewed all patients managed for HD at Mayo Clinic, Rochester, from January 1986 to February 2003. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence for an infectious etiology. Patients who received G-CSF support with one or more of their bleomycin-containing chemotherapy cycles were considered as being treated with G-CSF.
Results: A retrospective review identified 141 patients with HD treated with a bleomycin-containing regimen. The mean age of patients at diagnosis was 34 years. Fifty four percent were males. The histology was nodular sclerosing in 85%. The Hasenclever index was 0 in 15%, 1 in 35%, 2 in 24%, 3 in 16%, 4 in 9%, and ≥ 5 in 1%. The G-CSF and non G-CSF groups were balanced for poor prognosis risk factors including Hasenclever index. Frontline chemotherapy included ABVD in 57%, MOPP-ABV(D) in 33%, COPP-ABV in 8%, BEACOPP in 3%, and Stanford V in 2%. Forty one percent of patients received radiation. The 5-year overall survival (OS) and progression free survival (PFS) for all patients were 87% and 79% respectively. G-CSF was administered to 52% (74/141) of patients. BPT occurred in 18% of patients (25/141). A higher rate of BPT was observed in patients receiving G-CSF, 26% (19/74) versus 9% (6/67) in non G-CSF patients (p=0.0141). In this population, G-CSF administration was the only factor associated with an increased risk of BPT. There was no difference between the two groups for BPT associated risk factors including radiation, bleomycin dose, renal insufficiency, smoking history, and underlying lung disease. Additionally these risk factors showed no correlation with the development of BPT. The mortality from BPT was 4.2% (6/141) in all patients and 24% (6/25) in patients who developed the pulmonary syndrome. Of the 6 patients who died acutely, 83% (5/6) received G-CSF. CR rates were equal between the G-CSF and non G-CSF groups at 92% and 94% respectively. Five year OS and PFS were equal between the G-CSF and non G-CSF groups at 82% versus 89% (p=0.473) and 74% versus 84% (p=0.152) respectively.
Conclusion: G-CSF administration increases the incidence of pulmonary toxicity in HD patients treated with bleomycin based chemotherapy. The major impact was on treatment related morbidity as 5-year OS and PFS were equal between the G-CSF and non G-CSF groups.
New Animal Models Reveal Stage-Specific Hematopoietic Functions for the BMP Signaling Pathway.
Authors: Evans Todd , Gupta Sunny , McReynolds Lisa M. 
Published: April 2020

Abstract
Genetic analyses in mouse and zebrafish demonstrate that a conserved BMP signaling pathway is essential for normal development of the embryonic vascular and hematopoietic systems. However, it has not been clear which aspects of hemato-vascular development are regulated by the pathway beyond the initial specification of embryonic mesoderm. We present new animal models for studying BMP signaling at specific stages of both embryonic and adult hematopoiesis. First, we developed approaches to modulate BMP signaling conditionally at specific stages of development in transgenic zebrafish. For this purpose we adapted the Crelox system to express a dominant-negative BMP receptor in cells derived from specific progenitor populations, with subsequent analysis of hematopoietic and vascular development using GFP reporter strains of fish. For example, we find that BMP signaling is required in LMO2+ cells for the normal development of both hematopoietic and vascular systems. Yolk sac vasculature and trunk angiogenesis are both disrupted, and primitive erythropoiesis is also impaired, when these cells express the mutant receptor. In contrast, BMP signaling is apparently no longer required in primitive erythroid cells once they have activated expression of the GATA-1 gene. In a second approach, we studied hematopoiesis in zebrafish mutants for Smad5, which is an intracellular mediator of BMP signaling. For example, homozygote piggytail (pgy) mutant embryos live until day 3–5, yet the fish have little to no blood and no circulation. Surprisingly, we find that key hematopoietic regulatory genes including GATA-1, GATA-2, SCL, and LMO2 are expressed in the pgy mutant fish, but that their patterns of expression are altered. Thus, the progenitor cells initiate a hematopoietic program but fail to differentiate. We also established adult pgy fish that carry a GATA1::GFP transgene, to facilitate the analysis of adult-stage blood cell profiles using flow cytometry. Blood cell populations were monitored under normal conditions and following phenylhydrazine-induced hemolytic anemia in wild-type and pgy/+ fish. Preliminary results indicate that pgy/+ adult fish are able to mount an erythropoietic response to hemolytic anemia. However, the kinetics are altered, specifically in the transition from the proerythroblast to the polychromatophilic erythroblast stage. In summary, we present data using novel animal models disrupted for normal BMP signaling, and demonstrate roles for this pathway at specific stages of differentiation for both embryonic and adult hematopoiesis.
Antibody Response to Pneumococcal Polysaccharide Vaccination Predicts Pneumococcal Disease in Splenectomized Patients with Hematological Diseases.
Authors: Cherif Honar , Bjorkholm Magnus , Kalin Mats , Konradsen Helle B. , Landgren Ola 
Published: April 2020

Abstract
Patients with hematological diseases undergoing diagnostic or therapeutic splenectomy are at increased risk of acquiring fulminant pneumococcal infections. Vaccination is a straightforward option in reducing these infections. Certain patient subgroups showing inadequate immunological response to pneumococcal vaccination may be candidates for alternative prophylactic measures. We prospectively studied the antibody response to vaccination with 23-valent pneumococcal capsular polysaccharide vaccine (Pneumovax N) in splenectomized patients with hematological disorders in relation to clinical characteristics and pneumococcal disease. A total of 76 splenectomized patients (Hodgkin s lymphoma 26, indolent lymphoma 10, aggressive lymphoma 8, immune hemolytic anemia 6, immune thrombocytopenic purpura 22, and others 4) with a median age of 52 years (range 18–82) were included. Antibody titers were determined using an enzyme-linked immunosorbent assay before and 12 months after vaccination. A weak immunological response was observed in 27 (35%) patients (poor responders) and an adequate response in 49 (65%) (good responders). During the follow-up period of 5–9 years after vaccination and despite repeated revaccination in many cases, a total of 5 episodes of microbiologically verified pneumococcal infections were reported in poor responders, while only one episode was noted among good responders (p=.01). Underlying malignant hematological diseases were more frequent among poor responders than among good responders (p=.002). The distribution of patients according to age, gender, immunoglobulin levels, time between splenectomy and vaccination (&lt;1 year&gt;), time between preceding chemotherapy/radiotherapy and vaccination (&lt;6 months&gt;) and/or previous radiotherapy did not differ between poor and good responders. In conclusion, a significant number of splenectomized patients with hematological diseases respond poorly to pneumococcal vaccination and have a significantly increased risk of post-splenectomy pneumococcal infections despite vaccination. In the absence of clinical parameters that can reliably predict a poor antibody response, measurement of antibody titers 12 months after vaccination seems to be the most adequate method for identification of patients in this subgroup. Poor responders may be offered other prophylactic measures such as antibiotic prophylaxis and/or immunization with pneumococcal conjugate vaccines. Studies to further elucidate the last alternative are ongoing.
Phase I/II Trial of Dendritic Cells Pulsed with Telomerase.
Authors: Marten Angela , Sievers Elisabeth , Albers Peter , Muller Stefan , Franchy Christian , von Rucker Alexander , Strunk Holger , Schild Hans H. , Sauerbruch Tilman , Schmidt-Wolf Ingo G.H. 
Published: April 2020

Abstract
Human telomerase reverse transcriptase (hTERT) could be a potential target for immunotherapy in cancer patients because it is detectable in more than 85% of human tumors including renal cell carcinoma. Here, we present results of a clinical phase I/II trial using dendritic cells (DC) pulsed with hTERT-peptides in patients with progressive metastatic renal cell carcinoma. Patients received injections of hTert-peptides pulsed autologous DC intradermally and intratumorally. DC were generated from leukapheresis products and matured by addition of a cytokine cocktail. Beside toxicity and feasibility aspects, a complex immune monitoring was a major point of interest in this study. All ten patients were in progressive disease when entering the protocol. The dendritic cell vaccine was well tolerated, no toxicity was observed. Two patients showed a mixed response (MR) and one patient a stable disease (SD). Seven out of ten patients remained in progression. Clinical outcome was based on a comparison of CT scans before and after treatment, i.e. three months after entering the protocol. 2/8 patients showed DTH reactivity after vaccination. Interestingly, there was a significant increase in cytotoxic activity of effector cells from all responders (SD and MR patients) after the first vaccination. In most cases, effector cells of responders showed cytotoxic activity in contrast to those of non-responders. Most interestingly, all non-responders had shown no cytotoxic activity before treatment. In contrast, responders showed cytotoxic activity already before start of therapy. Therefore, cytotoxic activity might be used as a predictive marker in the future. With tetramer staining, we could detect higher amounts of tumor specific cytotoxic cells in responding patients compared to non-responders. Responders possessed increasing amounts of IFN-gamma producing immunological effector cells, tested by ELISpot assay. In summary, telomerase-pulsed DC could induce a tumor-specific immune response against renal cell carcinoma.