Heparin resistance can be defined as high doses of unfractionated heparin (UFH), greater than 35,000 IU/day, required to raise the activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) to within therapeutically desired ranges or the impossibility of doing so. The most common pathology responsible is the deficiency of anti-thrombin III (ATIII) deficiency. Other clinically relevant conditions that can present with heparin resistance are congenital deficiencies; use of high doses of heparin during extracorporeal circulation, use of asparaginase therapy and disseminated intravascular coagulation (DIC). Most of these conditions effect the ATIII levels. Patients are typically identified in an acute phase, when determination of the cause of resistance is challenging. We present a case where a patient presented with suspected heparin resistance in an acute phase of sickness, where timely intervention was able to prevent a potentially fatal situation. Abbreviations: Neuroendocrine tumors (NETs), World health Organization (WHO), Radiation therapy (RT).

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard Asparaginase-based therapy for childhood acute lymphoblastic leukaemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids or Asparaginase indicated that loss of intracellular ATP generation is a significant factor. In isolated mouse pancreatic acinar cells or cell clusters, we now report that removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or Asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data we suggest that galactose feeding may be used to protect against AP.

Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia-type chemotherapy combined with L-Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.

A method for monitoring l-asparagine (ASN) depletion in patients' serum using reversed-phase high-performance liquid chromatography with precolumn o-phthalaldehyde and ethanethiol (ET) derivatization is described. In order to improve the signal and stability of analytes, several important factors including precipitant reagent, derivatization conditions and detection wavelengths were optimized. The recovery of the analytes in biological matrix was the highest when 4% sulfosalicylic acid (1:1, v/v) was used as a precipitant reagent. Optimal fluorescence detection parameters were determined as λex = 340 nm and λem = 444 nm for maximal signal. The signal of analytes was the highest when the reagent ET and borate buffer of pH 9.9 were used in the derivatization solution. And the corresponding derivative products were stable up to 19 h. The validated method had been successfully applied to monitor ASN depletion and l-aspartic acid, l-glutamine, l-glutamic acid levels in pediatric patients during l-asparaginase therapy.

Prior to the 2000, patients with extranodal NK/T-cell lymphoma, nasal type (ENKL) were typically treated with anthracycline-containing chemotherapy, such as CHOP therapy, and the therapeutic outcomes were unsatisfactory. Since the early 2000s, next-generation therapies without anthracyclines have been developed and tested in clinical trials, markedly changing ENKL treatment. A retrospective, Next-Generation Therapy for NK/T-Cell Lymphoma in East Asia (NKEA) Part A, study in Japan investigated the current state of ENKL management. The results revealed that radiotherapy and dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) concurrent chemoradiotherapy was selected as the first-line therapy in 66% patients with localized ENKL, diagnosed between 2010 and 2013 in 31 institutes in Japan. The 5-year overall survival and progression-free survival rates in 150 patients treated with RT-DeVIC in clinical practice were 72% and 61%, respectively, confirming the results of an RT-DeVIC clinical trial. Furthermore, the NKEA study highlighted several limitations of current ENKL management strategies. Now is the time to explore effective therapies for ENKL beyond the current next-generation therapies. International cooperation, utilizing the strengths of each country's treatment protocols, will contribute to advancement in ENKL treatment.

l-Asparaginase (l-ASNase) is a vital enzyme for medical treatment and food industry. Here, we assessed the use of Fe3O4@Mobil Composition of Matter No. 41 (MCM-41) magnetic nanoparticles as carrier matrix for l-ASNase immobilization. In addition, surface of Fe3O4@MCM-41 magnetic nanoparticles was functionalized with 3-mercaptopropyltrimethoxysilane (MPTMS) to enhance stability of l-ASNase. The chemical structure, thermal properties, magnetic profile and morphology of the thiol-functionalized Fe3O4@MCM-41 magnetic nanoparticles were characterized with Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC), vibrating sample magnetometer (VSM), scanning electron microscope (SEM), energy dispersive X-ray (EDX) spectroscopy and zeta-potential measurement. l-ASNase was covalently immobilized onto the thiol-functionalized Fe3O4@MCM-41 magnetic nanoparticles. The properties of the immobilized enzyme, including optimum pH, temperature, kinetic parameters, thermal stability, reusability and storage stability were investigated and compared to free one. Immobilized enzyme was found to be stable over a wide range of pH and temperature range than free enzyme. The immobilized l-ASNase also showed higher thermal stability after 180 min incubation at 50 °C. The immobilized enzyme still retained 63% of its original activity after 16 times of reuse. The Km value for the immobilized enzyme was 1.15-fold lower than the free enzyme, which indicates increased affinity for the substrate. Additionally, the immobilized enzyme was active over 65% and 53% after 30 days of storage at 4 °C and room temperature (∼25 °C), respectively. Thereby, the results confirmed that thiol-functionalized Fe3O4@MCM-41 magnetic nanoparticles had high efficiency for l-ASNase immobilization and improved stability of L-ASNase.

This note highlights our understanding and thinking about the feasibility of l-asparaginase as therapeutics for multiple diseases. l-asparaginase enzyme (l-asparagine amidohydrolase, EC 3.5.1.1) is prominently known for its chemotherapeutic application. It is primarily used in the treatment of acute lymphoblastic leukemia in children. It is also used in the treatment of other forms of cancer Hodgkin disease, lymphosarcoma, acute myelomonocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma (Lopes et al. Crit Rev Biotechnol 23:1-18, 2015). It deaminates l-asparagine present in the plasma pool causing the demise of tumor cell due to nutritional starvation. The anti-tumorigenic property of this enzyme has been exploited for over four decades and evidenced as a boon for the cancer patients. Presently, the medical application of l-asparaginase is limited only in curing various forms of cancer.

Flor yeast strains represent a specialized group of Saccharomyces cerevisiae yeasts used for biological wine aging. We have sequenced the genomes of three flor strains originated from different geographic regions and used for production of sherry-like wines in Russia. According to the obtained phylogeny of 118 yeast strains, flor strains form very tight cluster adjacent to the main wine clade. SNP analysis versus available genomes of wine and flor strains revealed 2,270 genetic variants in 1,337 loci specific to flor strains. Gene ontology analysis in combination with gene content evaluation revealed a complex landscape of possibly adaptive genetic changes in flor yeast, related to genes associated with cell morphology, mitotic cell cycle, ion homeostasis, DNA repair, carbohydrate metabolism, lipid metabolism, and cell wall biogenesis. Pangenomic analysis discovered the presence of several well-known "non-reference" loci of potential industrial importance. Events of gene loss included deletions of asparaginase genes, maltose utilization locus, and FRE-FIT locus involved in iron transport. The latter in combination with a flor-yeast-specific mutation in the Aft1 transcription factor gene is likely to be responsible for the discovered phenotype of increased iron sensitivity and improved iron uptake of analyzed strains. Expansion of the coding region of the FLO11 flocullin gene and alteration of the balance between members of the FLO gene family are likely to positively affect the well-known propensity of flor strains for velum formation. Our study provides new insights in the nature of genetic variation in flor yeast strains and demonstrates that different adaptive properties of flor yeast strains could have evolved through different mechanisms of genetic variation.

The lectin pathway of the complement system can activate the coagulation system in vitro, but the role of the lectin pathway in haemostatic activation and thrombosis in vivo is not clear. We performed a systematic review of the existing literature on associations between the lectin pathway and arterial and venous thrombosis, in accordance with the Assessing the Methodological Quality of Systematic Reviews guidelines. PubMed and Embase were searched from January 1990 to March 2017. We included original studies on human study populations investigating associations between the lectin pathway (protein serum levels, genotype or gene expression) and thrombotic conditions or laboratory coagulation markers. Exclusion criteria were case studies including fewer than five cases, conference abstracts or any other language than English. In total, 43 studies were included which investigated associations between the lectin pathway and cardiovascular thrombotic events (CVEs) (n = 22), ischaemic stroke (n = 9), CVE and stroke (n = 1) and other conditions (systemic lupus erythematosus [n = 6], sepsis-related coagulopathy [n = 3], pulmonary embolism [n = 1], asparaginase treatment [n = 1]). Studies on the lectin pathway and CVE risk reported discrepant results, as both high and low mannose-binding lectin (MBL) serum levels were found to correlate with increased CVE risk. In ischaemic stroke patients, occurrence of stroke as well as increased stroke severity and poor outcome were consistently associated with high serum MBL. For other thromboembolic conditions, only few studies were identified. In conclusion, lectin pathway activation may negatively influence outcome after ischaemic stroke and possibly contribute to CVE risk. Further research is warranted to elucidate the role of the lectin pathway in other thrombotic conditions.

B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasone/vincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 [http://www.umin.ac.jp/ctr/].