bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Link between PI 3′ Kinase/p38 Map Kinase Pathway in Dasatinib (BMS354825) Mediated Effect in BCR-ABL Expressing Cells.
Authors: Lumby Crystal , Singh VeerPal , Reddy Shrisha , Sivess-Franks Sue , Dowell Jonathan , Verma Amit , Parmar Simrit 
Published: October 2019

Abstract
Background: Dasatinib (BMS354825), a dual Src/Abl tyrosine kinase inhibitor, exhibits potent antileukemic effects in vitro and in vivo. Despite the well-established role of BMS354825 in the treatment of imatinib-resistant chronic myelogenous leukemia (CML), the molecular mechanisms that result in generation of antileukemic responses remain unknown.
Methods: BCR/ABL (wild type and those carrying mutations: E255K, H396P, Y253F, M351T and T315I) expressing murine BAF3 cell lines were exposed to varying concentrations of BMS354825 for variable times to evaluate for effect on phosphorylation/activation of p38 MAP Kinase and PI3′ Kinase pathway in presence or absence of pharmacologic inhibitors of p38 MAP Kinase and mTOR respectively.
Results: In the present study we provide evidence that BMS354825 induces phosphorylation of the p38 MAP Kinase, and activation of its kinase domain, in BCR-ABL expressing cell lines except for those carrying T315I mutation. We also identify the kinases MapKapK-2 which is upregulated in response to BMS354825 as shown by increased phosphorylation of hsp27. Importantly, pharmacological inhibition of p38 MAP Kinase by SB203580 reverses the growth inhibitory effects of BMS354825 on primary leukemic CFU-GM progenitors from patients with CML (see figure). Moreover, SB203580 leads to impairment of the BMS354825 mediated antiproliferative effects in both wild type and mutated CML lines except for those carrying T315I. On the other hand, BMS354825 leads to dephosphorylation of p70S6 Kinase and its downstream effector pathway including down regulation of ribosomal S6. We also report that the pharmacological inhibition of mTOR by Rapamycin augments the growth inhibitory effects of BMS354825 on primary leukemic CFU-GM progenitors from CML patients (see figure). Furthermore, pharmacologic inhibition of p38 MAP Kinase by SB203580 led to reversal of the BMS354825 mediated dephosphorylation of p70 S6 Kinase demonstrating that it maybe downstream of p38 MAP Kinase activation. Altogether, our data establish that activation of the p38 MAP Kinase signaling cascade plays an important role in the generation of the effects of BMS354825 on BCR-ABL expressing cells.
Conclusion:
We have identified a novel crosstalk mechanism between the p38 MAPK and the PI3′ Kinase pathway which is unique to the effect of BMS354825 in CML. p38 MAP Kinase pathway may play an important role in developing of resistance to BMS354825 in CML. mTOR inhibition may augment effect of BMS354825 in CML and its role in combination with BMS354825 should be explored in resistant disease.
Figure Figure
Vitamin D Receptor (VDR) Polymorphisms in Chronic Lymphocytic Leukaemia (CLL) Patients.
Authors: Kwa Faith , Kapuscinski Miroslav , Cole-Sinclair Merrole 
Published: October 2019

Abstract
Chronic Lymphocytic Leukaemia (CLL) is a lymphoproliferative disorder in which leukaemic B cells are arrested in the G0/G1 phase of the cell cycle, resulting in their prolonged lifespan. The clinical course of CLL is highly variable with survival ranging from a few months to decades. Thus, a good prognostic tool is needed to help predict the course of the disease. The pathogenesis of CLL is unknown but it has been associated with the “escape” of B cells from apoptosis, possibly due to overexpression of anti-apoptotic genes and downregulation of pro-apoptotic genes. The expression of these genes is influenced by alterations in chromatin structure through a change in DNA methylation (chromatin remodelling) mediated by multi-protein complexes. The Vitamin D receptor (VDR), which forms part of one such chromatin remodelling complex, has been shown to be linked to the susceptibility to and outcome of other malignancies (e.g. prostate cancer). We hypothesised that VDR polymorphisms (FokI, TaqI, BsmI and ApaI) may be linked to CLL pathogenesis and/or might be a marker of CLL progression, given the immunomodulatory actions of Vitamin D. The genotypes of 34 patients with CLL were determined by either allele-specific PCR (FokI) or PCR/restriction digestion analysis (TaqI, BsmI and ApaI). Clinical data including disease stage (Rai), other prognostic markers (e.g. lymphocyte doubling time) and therapy status were recorded. Statistical analysis including Wilcoxon, Chi-square and Spearman correlation tests were performed. Initial analysis-to-date has not shown significant difference in allelic distribution between CLL patients and a healthy control population. There was no statistically significant association between the 4 VDR polymorphisms and the clinical parameters of CLL (all p>0.05). A larger cohort of CLL patients is currently under study to determine any such potential correlation.
Fifth Succesfully Retreatment with Alemtuzumab in Patient with Chronic Lymphocytic Leukemia.
Authors: Egyed Miklos , Kollar Balazs , Karadi Eva , Rajnics Peter , Magyarlaki Tamas , Kereskai Laszlo 
Published: October 2019

Abstract
Before the introduction of Alemtuzumab, the prognosis of fludarabine-refractory chronic lymphocytic leukemia (CLL) was very poor. This humanised anti-CD52 monoclonal antibody was found to be effective in CLL patients with additional high-risk prognostic markers. In our case report, we present the courses of treatment with Alemtuzumab in a CLL patient with del q11, elevated ZAP-70 and CD38 levels. He was first admitted to our department because of CLL in 1996. He received high dose Chlorambucil, later fludarabine courses between 1996–2002. Because of early disease progression five courses of Alemtuzumab were administered between 2003–2007. The treatment resulting nodal partial remission lasting about 10–11 months. No CTC 3–4 grade side effects were registered, nor hospitalization was necessary. The patient responded favorably to each course of repeated therapy with single agent Alemtuzumab, suggesting, that Alemtuzumab retraitment is the choice of therapy for fludarabine refractory CLL patients.
Newly Diagnosed Multiple Myeloma Patients with 1q21 Amplification Treated by Autologous Stem Cell Transplantation Have Shorter Progression-Free Survival Interval.
Authors: Nemec Pavel , Greslikova Henrieta , Kuglik Petr , Filkova Hana , Zaoralova Romana , Vranova Vladimira , Smejkalova Jana , Vidlakova Petra , Oltova Alexandra , Hajek Roman 
Published: October 2019

Abstract
Amplification of chromosome band 1q21 as well as increased expression of CKS1B gene in this area is a frequently mentioned prognostic factor for patients with multiple myeloma (MM). Total 39 newly diagnosed multiple myeloma patients (median age: 56 years) enrolled in Faculty Hospital Brno, Brno, Czech Republic, were examined for 1q21 amplification status. All patients received 4 cycles of vincristine, adriamycin and dexamethasone (VAD) as induction and one course melphalan 200mg/m2 followed by autologous stem cell transplantation (ASCT). The median follow-up from treatment start was 16.1 (range: 2.2–44.0) months. All the “end-point” intervals and treatment responses were assigned by IMWG criteria. Plasma cells were identified by cytoplasmic light-chain immunofluorescence followed by fluorescence in situ hybridisation (cIg-FISH). Amplification of 1q21 (Amp(1q21)) was assigned utilizing labelled BAC clone (RP11-205M9) DNA probe. Cut-off level for Amp(1q21) was established to 10% of total amount of cells with additional signals detected. Amp(1q21) was found in 41% (16/39) patients. Clinical parameters valid for patients with Amp(1q21) versus patients lacking Amp(1q21) were as follows: overall response rate (ORR) achieved 87.5% (14/16) vs. 91.3% (21/23) patients (p=0.404); overall survival (OS) median was 22.4 months vs. not yet reached (p=0.022); time to progression (TTP) median was 16.1 months vs. not yet reached (p=0.010); progression-free survival (PFS) median was 15.6 months vs. 25.2 months (p=0.023) and duration of response (DOR) median was 15.9 months vs. not yet reached (p=0.048). There were found statistical significant difference in all named “end-point” intervals (OS, TTP, PFS and DOR) between patients with/without Amp(1q21) but not in ORR. In conclusion, patients with Amp(1q21) treated by ASCT have significant shorter PFS median (15.6 months) when compared with patients lacking Amp(1q21) with PFS median 25.2 months (p=0.023). This findings is in accordance with previously published work (Chang et al., 2006).
Hepatocyte Growth Factor Expression in Bone Marrow Microenvironment Is Critical for Progression of MGUS to Myeloma.
Authors: Ramasamy Karthik , Schey Stephen , Mufti Ghulam J. , Farzaneh Farzin , Calle Yolanda 
Published: October 2019

Abstract
Hepatocyte growth factor (HGF) augments proliferation, survival and increases migration of plasma cells in vitro and in addition it induces haemangiogeneis and lymphangiogenesis. C-met (HGF receptor) is expressed on plasma cells and HGF is constitutively elevated in serum of patients with myeloma (MM) and MGUS patients. We investigated the distribution of HGF in bone marrow biopsies to better understand its role in progression of monoclonal gammopathy.
Materials and methods: Bone marrow trephines were analysed by immunohistochemistry of paraffin embedded bone marrow (BM) trephine specimens. Trephines were dewaxed without antigen retrieval. Plasma cell enumeration was done using CD38 staining (Novocastra, UK). HGF (Goat antihuman IgG, R&D systems) staining was performed using Vectastain® ABC kit with DAB reactivity. Slides were analysed using an Optical microscope (Zeiss Standard 20, Germany).
Results: Archived BM specimens of MM (n= 7), MGUS (n= 5) and normal controls (n=6) were stained in duplicate. Trephines were graded from Grade 1–3 (weak, moderate, strong) based on the intensity of staining. The localisation of staining to paratrabecular, perivascular and intertrabecular areas was analysed. Interstitial and cytoplasmic staining patterns were analysed. HGF staining localised to paratrabecular regions was observed in all normal individuals with staining intensity of Grade 1–2 in 3/6(50%) and Grade 3 in 3/6(50%). In 4/5(80%) patients with MGUS a distinct intertrabecular pattern of staining was observed in discrete regions, where plasma cells were localised. Intensity of staining was Grade 2 in 3/5(60%) and Grade 3 in 2/5(40%) MGUS patients. Plasma cell percentages were between 5–20% in MGUS patients. In MM patients we found a correlation between the plasma cell counts and the degree of HGF staining. In 2/7 (28.5%) patients plasma cell percentages ranged between 5% and 15% and Grade 1–2 discrete paratrabecular staining was observed with none or low perivascular staining. In 5/7 (71.5%) MM patients plasma cell percentages were >20% and Grade 3 confluent staining with interstitial and cytoplasmic location of HGF was observed. In addition, patients with Grade 3 staining presented a strong perivascular localisation of HGF.
Conclusion: HGF distribution in bone marrow microenvironment of MGUS and MM patients is non random. We observed that MGUS patients have a discrete intertrabecular pattern and MM patients have a confluent interstitial pattern of staining with strong perivascular localisation. Other groups have shown that high HGF levels increase angiogenesis. We hypothesise that HGF localisation and pattern of distribution in BM microenvironment leads to neo angiogenesis and progression from MGUS to MM. Ongoing studies are evaluating this hypothesis.
The mTOR Inhibitor RAD001 (Everolimus) Inhibits Myeloma Tumor Growth In Vivo and Enhances the Anti-MM Effects of Bortezomib and Arsenic Trioxide.
Authors: Campbell Richard A. , Sanchez Eric , Steinberg Jeffrey , Share Michael , Wang Joseph , Li Mingjie , Leuchter Richard , Chen Haiming , Shalitin Dror , Pang Shen , Said Jonathan , Berenson James R. 
Published: October 2019

Abstract
The mammalian target of rapamycin (mTOR) is an intracellular protein that acts as a central regulator of multiple signaling pathways (IGF, EGF, PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation, survival and angiogenesis in cancer. mTOR is a critical component of the PI3K/Akt pathway, a key cell survival pathway that is dysregulated in many cancers including multiple myeloma (MM). mTOR is an important therapeutic target because it is a “rate-limiting” bottleneck in the key signaling pathway that regulates cell survival, proliferation, and angiogenesis. RAD001 (everolimus) is a novel oral mTOR pathway inhibitor. Recent data suggests that RAD001 has direct effects on tumor cell proliferation and may have antiangiogenic activity due to inhibition of tumoral VEGF production and effects on vascular endothelial and smooth muscle cell biology. We first evaluated the in vivo effects of single agent RAD001 in mice bearing the human MM tumor LAGλ-1. Tumor-bearing mice receiving RAD001 at 3, 10, or 30 mg/kg once daily five times per week (M-F) via oral gavage showed marked inhibition of tumor growth at all doses (P<0.0001) and reduction of paraprotein levels (P<0.0001) compared to mice receiving placebo. Next, we evaluated the in vivo anti-MM effects of RAD001 in combination with arsenic trioxide (ATO) and RAD001 in combination with bortezomib. Each severe combined immunodeficient (SCID) mouse was implanted with a fragment (2 – 4 mm3) of the LAGλ-1 tumor into the left hind limb muscle. The tumors were allowed to grow for 10 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups. Tumor-bearing mice received RAD001 at 1, 3, or 10 mg/kg once daily five times per week via oral gavage, ATO (3 mg/kg) once daily five times per week via intraperitoneal injection, bortezomib (0.5 mg/kg) once daily twice weekly via intravenous injection, or a placebo. Mice receiving RAD001/ATO combination therapy exhibited decreased hIgG levels and tumor volume compared to those mice receiving single agent and placebo therapy. Additionally, those mice receiving the RAD001/bortezomib combination treatment displayed similar MM tumor growth inhibition including decreased hIgG levels and tumor volume as the RAD001/ATO-treated mice. These preliminary in vivo results are encouraging with combination RAD001+ATO and RAD001+bortezomib therapy for the treatment of MM and additional studies are being performed to further optimize the clinical development of RAD001 in combination with other anti-MM treatments for patients with MM.
Complete Remission Achievement during Long-Term Maintenance with Bortezomib Based Therapy in Multiple Myeloma: A Case Report.
Authors: Crescenzi Sabrina Leonetti , Piccioni Anna Lina , Bagnato Antonino , Venditti Adriano 
Published: October 2019

Abstract
The treatment of multiple myeloma (MM), a B-cell neoplasm characterized by a clonal expansion of plasma cell in the bone marrow, remains unsuccessful in a significant proportion of patients. The majority of MM patients fail to achieve a complete response (CR) with standard therapy. Bortezomib is a new drug that has been shown to induce a complete response (CR) in 10% of pre-treated patients and continues to show benefit in relapsing/refractory myeloma treatment. We report a case of 72 year-old women with IgAl and IgGK MM who resulted refractory to two different line therapies. Patient was diagnosed with MM in March 2005 following the admission to our clinic for bone pain and weight loss. Laboratory blood tests were: total protein 9,4 gr/dl; IgAl and IgGK monoclonal spike (IgG: 917; IgA: 2990, IgM<17, Ks: 253, ls: 997 gr/dl); Beta2 microglobulin 2,7 mg/L; Ca 9,7 mg/dl. Mild pancytopenia was found. No renal failure and significant proteinuria were observed, Bence Jones were negative. Bone scans revealed diffuse lytic lesions to spine with a vertebral fracture (D12). Bone marrow biopsy showed 60% of plasma cells, with atypical characteristics. Initial treatment consisted of melphalan, prednisone and pamidronate that were given for a total of four cycles. Patient achieved a stable disease according to International Myeloma Working Group criteria. Then the patient underwent idarubicine based regimen without any response indicating refractory MM. In November 2005, a 3-week cycle schema with Bortezomib (1,3 mg/m2 i.v. on day 1,8,11), Melphalan (10 mg PO on day 1,3,5) and Dexamethasone (4 mg i.v. on day 1,8,11,15) was started. The patient achieved a partial response (PR) after 8 cycles of this combination therapy .No therapy related Grade 3–4 neuropathy and trombocytopenia were observed. The patient experienced a mild HZV reinfection. In June 2006, a maintenance regimen with Bortezomib (1,3 mg/m2 i.v. on day 1,8) Melphalan (6 mg PO on day 4,11) and Dexamethasone (4 mg i.v. on day 1,8,15) was initiated considering the positive response and the absence of toxicity from the primary previous therapy. Each cycle was repeated every three weeks for a total of 16 courses, until June 2007. Efficacy assessment (including bone marrow biopsy) was performed every three months and showed a sustained decrease in plasma cell infiltration and a persistent reduction of M serum protein.Very Good PR and CR were achieved after 10 and 16 maintenance courses, respectively. This case demonstrates that a Bortezomib-based regimen is effective and feasible in refractory MM and, interestingly, supports the hypothesis that a long-term maintenance therapy may improve the quality of response. This treatment approach should be evaluated in a larger patient cohort and in prospective randomised trials.
TEL-AML1 Dysregulates the TGFβ Pathway: A Basis for Pre-Leukaemic Stem Cell Selection.
Authors: Ford Anthony , Palmi Chiara , Bueno Clara , Knight Deborah , Cardus Penny , Hong Dengli , Cazzaniga Giovanni , Enver Tariq , Greaves Mel 
Published: October 2019

Abstract
TEL-AML1 fusion is the most frequent, defined genetic abnormality in paediatric cancer and is usually an early or initiating and pre-natal event in childhood acute lymphoblastic leukaemia (ALL). Transformation results in the generation of a persistent pre-leukaemic clone, which converts to frank ALL post-natally (at 1-15years) following the acquisition of secondary genetic alterations. The mechanism by which the transcriptional dysregulation imposed by TEL-AML1 impacts on the pre-leukaemic phenotype and disease natural history is unknown. Using regulated expression of TEL-AML1, we show that, in murine progenitor cells, this protein blocks the TGFβ response pathway including the critical regulator of cell cycle inhibition, p27. This inhibition facilitates the selective expansion of otherwise more slowly expanding TEL-AML1 progenitor cells. The mechanism of action of TEL-AML1 appears to operate downstream of SMAD2/3 phosphorylation (by TGFβ signalling) and involves binding of a transcriptional repressor complex to TGFβ target genes. In transgenic Eμ TEL-AML1 mice, we show that early pro-B cells (but not pre-B cells) are selectively expanded and appear less sensitive to the inhibitory effects of TGFβ than equivalent wild-type cells. Finally, we show that expression of TEL-AML1 in human cord blood progenitor cells leads to the expansion of a candidate pre-leukaemic stem cell population with an early B lineage phenotype (CD34+/CD38-/CD19+) that has a selective growth advantage in the presence of TGFβ.
Association of Neurodevelopmental Abnormalities Is a Common Clinical Character in Japanese Patients with Severe Congenital Neutropenia Due to HAX1 Deficiency.
Authors: Okada Satoshi , Ishikawa Nobutsune , Shirao Kenichiro , Tsumura Miyuki , Satoh Takashi , Ohno Yoshinori , Yasunaga Shin’ichiro , Ohtsubo Motoaki , Takihara Yoshihiro , Kobayashi Masao 
Published: October 2019

Abstract
Severe congenital neutropenia (SCN) is characterized by early childhood onset of profound neutropenia and recurrent life-threatening infections. The bone marrow usually shows a reduced number of mature myeloid cells with an arrest at the promyelocyte-myelocyte stage. SCN includes a variety of hematological disorders caused by the different genetic abnormality. Genetic analysis in individuals with SCN indicates that 60% of cases are attributable to heterozygous mutation in ELA2, encoding neutrophil elastase. Recently, homozygous mutation in HAX1 encoding HAX1, mitochondrial protein associates with HS1 which is a substrate for Src family tyrosine kinase, was identified in individuals with autosomal recessive forms of SCN and the original Kostmann family in Sweden. In this study, we examined involvement of HAX1 and ELA2 in 17 Japanese cases with SCN. Ten patients had heterozygous mutations, including two novel mutations in ELA2. Five patients had homozygous or compound heterozygous mutations in HAX1. A homozygous single-base-pair substitution at nucleotide 256 (256C>T) HAX1 mutation causing a nonsense change R86X was detected in three patients. Two sibling cases showed compound heterozygous mutation of 256C>T and 59-bp deletion at nucleotide 376–434. This 59-bp deletion was a novel mutation leading to a frameshift and a premature stop codon at nucleotide 441–443 (R126fsX128). All heterozygous carriers had no detectable phenotype. HAX1 protein was undetectable in both homozygous and compound heterozygous patients by immunoblot analysis of leukocytes. Notably, all patients with HAX1 deficiency showed failure to thrive and mild to severe developmental delay. Further, three patients carrying homozygous R86X mutation had epilepsy. Two of three patients had complex partial seizures, and another had atypical absence. An Iranian patient carrying homozygous R86X mutation of HAX1 was described to show failure to thrive in the original report of HAX1 deficiency, and three of six cases of the original Kostmann family showed neurological deficits. In contrast, no SCN patients with a heterozygous mutation in ELA2 displayed the association of neurodevelopmental abnormalities. Thus, R86X mutation in HAX1 is a common abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities as well as severe myelopoietic defects. Because HAX1 is a ubiquitously expressed gene, further accumulation of the patients should be needed to characterize the clinical features of HAX1 deficiency.