Targeting E-selectin to tackle cancer using uproleselan

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis-extravasation and adhesion-thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment

THE VARIABILITY OF MULTI-DRUG RESISTANCE ABCB1 GENE IN THE ROMA POPULATION FROM CROATIA

When overexpressed, a large transmembrane P-glycoprotein, the product of the ABCB1 gene, is a notable impediment to brain-targeted therapies (like antiepileptics) and chemotherapies. Some of the genetic biomarkers with evidence of multi-drug resistance in ABCB1 ― rs1045642, rs1128503, and rs3213619 ― were analyzed in 440 subjects, members of three socio-culturally different Roma (Gypsy) groups of Croatia. Minor allele frequencies (MAFs) of rs1045642 and rs1128503 were the highest in the Balkan Roma (63.6% and 69.4%, respectively) when compared to the Baranja (52.3% and 62.5%) and the Međimurje Roma (48.8% and 54.5%) (p=0.0005 and p=0.0011, respectively). rs3213619 was monomorphic in the Međimurje group, while its MAFs in other two Roma groups were very low (<1.9%). The distribution of five detected haplotypes (four in the Međimurje group) significantly differed between the Roma subpopulations (p<0.0001), just like the frequencies of diplotypes (p=0.0008). At a global scale, the positive relationship between genetic and geographic distances between the 21 investigated populations indicates isolation by spatial distance. However, this is not true for the relationship between Roma and other populations due to their population history. The analyzed ABCB1 loci indicate genetic distinctiveness of the Roma population

Targeting CD47 as a novel immunotherapy for multiple myeloma

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the don\u27t eat me signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the don\u27t eat me signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 don\u27t eat me signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Targeting E-selectin to Tackle Cancer Using Uproleselan

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis&mdash;extravasation and adhesion&mdash;thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment

Identification of Synthetic Organic Pigments (SOPs) Used in Modern Artist’s Paints with Secondary Ion Mass Spectrometry with MeV Ions

This work reports on the first systematic study using secondary ion mass spectrometry with MeV ions (MeV-SIMS) for analysis of synthetic organic pigments (SOPs) that can be usually found in modern and contemporary art paints. In order to prove the applicability of the method to different chemical classes of SOPs, 17 pigments were selected for the analyses. The focus was on blue and green phthalocyanines, yellow and red (naphthol AS) azo pigments, red quinacridone, anthraquinone, and diketopyrrolo-pyrrole pigments. Since there are no reference spectra available for this technique, pure pigment powders were measured first to create a database. Simple two-component paint systems were also prepared for testing purposes by mixing synthetic organic pigments with alkyd and acrylic binders. Commercial paints that contain the SOPs with identical C.I. numbers as in the prepared two-component samples were analyzed. All pigments were successfully identified in commercial products in the MeV-SIMS mass spectra through molecular and larger specific fragment ion peaks in the positive-ion mode. The main advantages of MeV-SIMS over other techniques used in SOPs identification, like pyrolysis gas chromatography mass spectrometry (Py-GC/MS), direct-temperature resolved mass spectrometry (DTMS), and laser desorption ionization mass spectrometry (LDIMS), can be summarized as follows: (i) pigments and binders can be detected simultaneously in the same mass spectrum acquired over a short measurement time (up to 500 s), (ii) only small sample flakes are required for the measurements, which are analyzed without any chemical treatment prior to the analyses, (iii) samples are not consumed during the analyses and can be reused for other measurements, e.g., multielemental analysis by other ion beam analysis (IBA) techniques, such as particle-induced X-ray emission (PIXE). Compared to, e.g., Raman spectroscopy, the significant benefit of MeV-SIMS is the exact identification of the SOPs in the paints even if pigments of similar structures are measured

Targeting CD47 as a Novel Immunotherapy for Multiple Myeloma

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the &ldquo;don&rsquo;t eat me&rdquo; signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the &ldquo;don&rsquo;t eat me&rdquo; signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 &ldquo;don&rsquo;t eat me&rdquo; signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients

Intraoperative transfusion practices in Europe

© 2016 The Author. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.Background: Transfusion of allogeneic blood influences outcome after surgery. Despite widespread availability of transfusion guidelines, transfusion practices might vary among physicians, departments, hospitals and countries. Our aim was to determine the amount of packed red blood cells (pRBC) and blood products transfused intraoperatively, and to describe factors determining transfusion throughout Europe. Methods: We did a prospective observational cohort study enrolling 5803 patients in 126 European centres that received at least one pRBC unit intraoperatively, during a continuous three month period in 2013. Results: The overall intraoperative transfusion rate was 1.8%; 59% of transfusions were at least partially initiated as a result of a physiological transfusion trigger- mostly because of hypotension (55.4%) and/or tachycardia (30.7%). Haemoglobin (Hb)- based transfusion trigger alone initiated only 8.5% of transfusions. The Hb concentration [mean (sd)] just before transfusion was 8.1 (1.7) g dl-1 and increased to 9.8 (1.8) g dl-1 after transfusion. The mean number of intraoperatively transfused pRBC units was 2.5 (2.7) units (median 2). Conclusions: Although European Society of Anaesthesiology transfusion guidelines are moderately implemented in Europe with respect to Hb threshold for transfusion (7-9 g dl-1), there is still an urgent need for further educational efforts that focus on the number of pRBC units to be transfused at this threshold

Intraoperative transfusion practices and perioperative outcome in the European elderly: A secondary analysis of the observational ETPOS study

The demographic development suggests a dramatic growth in the number of elderly patients undergoing surgery in Europe. Most red blood cell transfusions (RBCT) are administered to older people, but little is known about perioperative transfusion practices in this population. In this secondary analysis of the prospective observational multicentre European Transfusion Practice and Outcome Study (ETPOS), we specifically evaluated intraoperative transfusion practices and the related outcomes of 3149 patients aged 65 years and older. Enrolled patients underwent elective surgery in 123 European hospitals, received at least one RBCT intraoperatively and were followed up for 30 days maximum. The mean haemoglobin value at the beginning of surgery was 108 (21) g/l, 84 (15) g/l before transfusion and 101 (16) g/l at the end of surgery. A median of 2 [1–2] units of RBCT were administered. Mostly, more than one transfusion trigger was present, with physiological triggers being preeminent. We revealed a descriptive association between each intraoperatively administered RBCT and mortality and discharge respectively, within the first 10 postoperative days but not thereafter. In our unadjusted model the hazard ratio (HR) for mortality was 1.11 (95% CI: 1.08–1.15) and the HR for discharge was 0.78 (95% CI: 0.74–0.83). After adjustment for several variables, such as age, preoperative haemoglobin and blood loss, the HR for mortality was 1.10 (95% CI: 1.05–1.15) and HR for discharge was 0.82 (95% CI: 0.78–0.87). Preoperative anaemia in European elderly surgical patients is undertreated. Various triggers seem to support the decision for RBCT. A closer monitoring of elderly patients receiving intraoperative RBCT for the first 10 postoperative days might be justifiable. Further research on the causal relationship between RBCT and outcomes and on optimal transfusion strategies in the elderly population is warranted. A thorough analysis of different time periods within the first 30 postoperative days is recommended