Analysis Oof Existing Business Models for Startup Projects

The analysis of existing business models for startup project, the necessity of searching the optimal model based on the input parameters

Anemia in cancer patients

Anemia is a common feature in c.40% of patients at the time of cancer diagnosis and in more than half of patients undergoing anticancer therapy. Cancer-related anemia does have an unfavourable impact on the functional capacity of the relevant tissue and organs. Its pathogenesis is complex and often difficult to identify. Symptoms related to cancer and chemotherapy-induced anemia may have a negative impact on the quality of life and may influence treatment efficacy, disease progression and even survival. Moreover, anemia causing tumor hypoxia leads to tumor progression through the increase of local tumor expansion and spreading of metastases. Tumor hypoxia directly or indirectly confers resistance to irradiation, some chemotherapeutic drugs, and photodynamic therapy. Therapeutic alternatives in cancer patients with anemia include the substitution of the lacking agents, red blood cell (RBC) transfusions, iron supplementation, and erythropoiesis-stimulating agents (ESAs). Using ESAs reduces the need for red blood cell transfusions, decreases the risk of post-transfusion adverse reactions, and improves the quality of life for cancer patients with chemotherapy-induced anemia. The immediate administration of RBC transfusions is justified in patients with hemoglobin (Hb) under 7–8 g/dL and/or severe anemia-related symptoms (even at higher Hb levels) and who require immediate Hb and symptom improvement. Therefore, clinical evidence supports the need to closely monitor Hb level in cancer patients. Anemia should be corrected to improve chemo- and radiosensitivity and the quality of life

The levels of sMUC-1 in patients with multiple myeloma

Mucins have been shown to be aberrantly overexpressed in various diseases including cystic fibrosis, asthma, and cancer. Recent studies have uncovered the roles of these mucins in the pathogenesis of cancer. The presence of MUC-1 has also been detected on the cell surface of multiple myeloma (MM) cells in peripheral blood and showed direct correlation with tumor mass. In this study, we evaluated the levels of soluble MUC-1 (sMUC-1) in 50 new MM patients and correlated this with the levels of sMUC-1 after treatment. High levels of sMUC-1 were found in 20/50 (40%) MM patients, and in 2/50 (4%) healthy individuals (p = 0.001). According to the ISS, we found significant differences of mean sMUC-1 levels between the first stage of the disease (0.63 ± ± 0.26) and the third (0.93 ± 0.24; p = 0.03), but not with the second stage (0.80 ± 0.22; p = 0.08). Our study confirmed the correlation between elevated sMUC-1 and high elevated lactate dehydrogenase (p = 0.03) and the level of IgG in groups of patients with MM IgG at every stage of disease (p = 0.001). We showed for the first time that levels of sMUC-1 after treatment, in a group of patients with initially elevated levels of MUC-1, were statistically lower than in a group of patients with initially lower levels of sMUC-1 (21% vs. 42,6%; p = 0.05). At 37 months median of follow-up, we found a statistically significant difference between patients with normal versus elevated sMUC-1 in terms of progression-free survival (median 12 months vs. 8.1 months; p = 0.03). (<i>Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 654–658</i>

A Proliferation-Inducing Ligand and B-Cell Activating Factor Are Upregulated in Patients with Essential Thrombocythemia

A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines belonging to the tumor necrosis factor family which play an essential role in B-cell maturation, differentiation, and survival. Recent evidence indicates their importance in hematological disorders; however, their function in essential thrombocytosis (ET) pathogenesis remains elusive. Therefore, we aimed to analyze the role of APRIL and BAFF in megakaryocytopoiesis in ET patients. We observed elevated levels of APRIL and BAFF in the plasma of ET patients compared with healthy controls, while no differences were found among patients with different JAK2(V617F) statuses. In addition, APRIL levels were positively associated with the number of platelets and WBC count. In the bone marrow, APRIL but not BAFF levels were higher in ET patients with the JAK2(V617F) mutation; however, JAK2(V617F)-negative patients showed slightly reduced levels of BAFF. In ET patients, we showed that the differentiation of CD34+ progenitor cells towards megakaryocytes induces the expression of both APRIL and BAFF. More importantly, APRIL neutralization significantly reduced platelet production. In conclusion, our data provide evidence that blocking APRIL signaling, which acts as an autocrine growth factor for terminal megakaryocytopoiesis, inhibits platelet production in ET patients, regardless of the status of JAK2(V617F) mutation

Increased methylation upstream of the MEG3 promotor is observed in acute myeloid leukemia patients with better overall survival

Abstract Background The delta-like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3(MEG3) locus (DLK1-MEG3 locus) plays a critical role in the maintenance and differentiation of hematopoietic stem cells. Accumulating evidence implicates the imprinted genes from this locus, DLK1 and MEG3, in the development and progression of acute myeloid leukemia (AML). However, the contribution of this locus to the treatment response of patients and their survival is unknown. Methods DNA methylation of select CG dinucleotide-containing amplicons (CpG sites) within the DLK1-MEG3 locus and within differentially methylated regions of other imprinted loci was assessed in the mononuclear cells of 45 AML patients by combined bisulfite restriction analysis. Methylation results were compared with patient response to first-round induction therapy and overall survival. Multivariable analysis was employed to identify independent prognostic factors for patient overall survival in AML. Results Increased methylation at CpG sites within the MEG3 promotor region was observed in AML patients having longer overall survival. In addition, patients with shorter overall survival had increased expression of DLK1 and MEG3, and methylation at the MEG3-DMR CpG site inversely correlated with MEG3 expression. Multivariable analysis revealed that methylation at CG9, a non-imprinted CpG site within the MEG3 promotor region which contains a CCCTC-binding factor (CTCF)-binding DNA sequence, is an independent prognostic factor for the overall survival of AML patients. Conclusions The results of our pilot study underscore the importance of the DLK1-MEG3 locus in AML development and progression. We identify CG9 methylation as an independent prognostic factor for AML patient survival, which suggests that distinct miRNA signatures from the DLK1-MEG3 locus could reflect varying degrees of cell stemness and present novel opportunities for personalized therapies in the future. These data provide a foundation for future studies into the role of higher-order chromatin structure at DLK1-MEG3 in AML

The Association between Immune Checkpoint Proteins and Therapy Outcomes in Acute Myeloid Leukaemia Patients

The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients’ survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data

Treatment and outcome patterns in European patients with Waldenström’s macroglobulinaemia: a large, observational, retrospective chart review

Background: Treatment options for Waldenström's macroglobulinaemia are heterogeneous, and no well established treatment standards exist. Although guidelines from the Eighth International Workshop on Waldenstrom's Macroglobulinemia were published in 2016, inconsistent awareness and budget constraints have prevented their widespread implementation, and real-life treatment patterns might differ across health-care systems. We aimed to generate information about treatment and outcome patterns for patients with Waldenström's macroglobulinaemia outside of clinical trials. Methods: In this large, observational, retrospective chart review, academic and community physicians in ten European countries were invited to retrospectively complete electronic records for patients with symptomatic Waldenström's macroglobulinaemia who had begun treatment after Jan 1, 2000, and before Jan 1, 2014, and had available clinical and biological data. The primary endpoints were reasons for treatment initiation, treatment choices, progression-free survival, and overall survival. We assessed the variables that affected choice of front-line therapy, progression-free survival, and overall survival in multivariate analyses. Findings: Electronic records were reviewed for 454 eligible patients. The most frequent reasons for starting front-line treatment were anaemia (in 328 [72%] patients) and constitutional symptoms (in 264 [58%] patients). Choice of therapy varied between front-line, second-line, and third-line approaches; age; and type of institution. In the front-line setting, 193 (43%) of 454 patients received monotherapy, 164 (36%) received chemoimmunotherapy, and 95 (21%) received other combination regimens (data on front-line treatment were missing for one patient, and another patient received only steroids). After front-line treatment, median progression-free survival was 29 months (95% CI 25–31), median overall survival was not reached (not reached–not reached), and 10-year overall survival was 69% (62–74). In multivariate analyses, patients who were high risk according to the International Prognostic Scoring System for Waldenström Macroglobulinemia had significantly worse progression-free survival and overall survival than did those who were low risk. Additionally, progression-free survival was shortened in patients treated with monotherapy compared with those treated with chemoimmunotherapy or other combination therapies and in those treated at an academic institution compared with those treated in the community. Constitutional symptoms (excluding fatigue) were associated with worsened overall survival. Interpretation: This large observational dataset should inform and help set guidelines, and improve understanding of treatment practices and outcomes, for European patients with Waldenström's macroglobulinaemia. Funding: Pharmacyclics LLC (an AbbVie company). © 2018 Elsevier Lt

To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients

In chronic lymphocytic leukaemia (CLL), the clinical course of patients is heterogeneous. Some present an aggressive disease onset and require immediate therapy, while others remain without treatment for years. Current disease staging systems developed by Rai and Binet may be useful in forecasting patient survival time, but do not discriminate between stable and progressive forms of the disease in the early stages. Recently ample attention has been directed towards identifying new disease prognostic markers capable of predicting clinical aggressiveness at diagnosis. In the present study serum samples from stable (n = 51) and progressive (n = 42) CLL patients and controls (n = 45) were used with aim to discover metabolic indicators of disease status. First an LC-MS based metabolic fingerprinting method was used to analyse selected samples in order to find a potential markers discriminating aggressive from indolent patients. Ten of these discovered markers were validated on the whole set of samples with an independent analytical technique. Linoleamide (p = 0.002) in addition to various acylcarnitines (p = 0.001–0.000001) showed to be significant markers of CLL in its aggressive form. Acetylcarnitine (p = 0.05) and hexannoylcarnitine (p = 0.005) were also distinguishable markers of indolent subjects. Forming a panel of selected acylcarnitines and fatty acid amides, it was possible to reach a potentially highly specific and sensitive diagnostic approach (AUC = 0.766)