Ca2+ monitoring in Plasmodium falciparum using the yellow cameleon-Nano biosensor

Calcium (Ca2+)-mediated signaling is a conserved mechanism in eukaryotes, including the human malaria parasite, Plasmodium falciparum. Due to its small size (300?nM). We determined that the mammalian SERCA inhibitor thapsigargin and antimalarial dihydroartemisinin did not perturb SERCA activity. The change of the cytosolic Ca2+ level in P. falciparum was additionally detectable by flow cytometry. Thus, we propose that the developed YC-Nano-based system is useful to study Ca2+ signaling in P. falciparum and is applicable for drug screening.We are grateful to Japanese Red Cross Blood Society for providing human RBC and plasma. We also thank Tanaka R, Ogoshi (Sakura) M and Matsumoto N for technical assistance and Templeton TJ for critical reading. This study was conducted at the Joint Usage / Research Center on Tropical Disease, Institute of Tropical Medicine, Nagasaki University, Japan. KP was a Tokyo Biochemical Research Foundation (TBRF, http://www.tokyobrf.or.jp) post-doctoral fellow and PEF was a Japanese Society of Promotion Sciences (JSPS) post-doctoral fellow. This work was supported in part by the TBRF (K.P.), JSPS (P.E.F.), Takeda Science Foundation (K.Y.), Grants-in-Aids for Scientific Research 24590509 (K.Y.), 22390079 (O.K.), and for Scientific Research on Innovative Areas 23117008 (O.K.), MEXT, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Photochemical Air-pollutants—a Threat to Mediterranean Coniferous Forests and Upland Ecosystems

Photochemical smog in the densely-populated coastal region of Israel often results in temporary atmospheric ozone concentrations in excess of 0.1 ppm. In view of the rapid growth in urban—industrial development, energy consumption, and motorized traffic, these concentrations are increasing from year to year and the same is presumably true for other Mediterranean countries suffering similar conditions.Moreover, as in California, these photochemical air pollutants can be transported inland under suitable meteorological conditions and may lead to ozone concentrations well above 0.05 ppm even in remote mountain regions with forested slopes. This is the case in the Shaar Hagai canyon leading to Jerusalem, where more than 0.2 ppm oxidant concentrations have been measured and where widespread decline and mortality of Pinus hale-pensis is occuring, accompanied by severe infestation by Matsucoccus josephi scales and Scolytidae beetles. Earlier stages of this decline can also be observed in other planted pine forests in Israel.</jats:p

Protection against malaria in Aotus monkeys immunized with a recombinant blood-stage antigen fused to a universal T-cell epitope: correlation of serum gamma interferon levels with protection

The major surface antigen p190 of the human malaria parasite Plasmodium falciparum contains nonpolymorphic, immunogenic stretches of amino acids which are attractive components for a subunit vaccine against malaria. One such polypeptide, termed 190L, is contained in the 80-kDa processing product of p190, which constitutes the major coat component of mature merozoites. We report here that immunization of Aotus monkeys with 190L gives only poor protection against P. falciparum challenge. However, addition by genetic engineering of a universal T-cell epitope (CS.T3) to 190L improved immunity, and as a result three of four monkeys were protected following challenge infection with blood-stage parasites. Neither antibody against the immunizing antigens or against blood-stage parasites nor the capacity of the monkeys' sera to inhibit in vitro parasite invasion correlated with protection. However, in contrast to sera from nonprotected monkeys, sera from protected animals contained elevated levels of gamma interferon. These results suggest that gamma interferon is directly or indirectly involved in the process of asexual parasite control in vivo.</jats:p

Analysis of Quality-of-Life (QoL) in Patients Receiving NEPA for Prevention of Chemotherapy-Induced Nausea (CINV) and Vomiting

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is a common and distressing side effect that has a detrimental impact on QoL. For pts receiving highly emetogenic chemotherapy (HEC), which includes those on anthracycline-cyclophosphamide (AC)-based regimens, a triple combination of a neurokinin-1 receptor antagonist (NK1 RA), a 5-hydroxytryptamine-3 (5-HT3) RA and dexamethasone is recommended by the NCCN and MASCC/ESMO. The complexity of the NK1 RA-based schedules may be a reason for the low adherence to antiemetic guidelines and a not sufficient control of CINV in pts receiving HEC and MEC. NEPA is the only available fixed-combination antiemetic. It is composed of an NK1 RA, netupitant (300 mg) and a 5-HT3 RA, palonosetron (0.50 mg); thus, it acts by blocking two main emetic pathways in a single dose and eases compliance to guidelines. Methods: Prospective, non-interventional study at 162 sites in Germany from 09/2015 to 03/2018. The aim was to determine QoL of adult cancer pts receiving NEPA for the prevention of nausea and vomiting associated with 1 or 2 day HEC or MEC in daily clinical practice. The primary outcome was measured via the Functional Living Index-Emesis (FLIE) questionnaire. FLIE questionnaires were analyzed according to the FLIE scoring and administration manual v12; higher scores correlated to better performance on daily life activities due to the lower occurrence of nausea and vomiting. 'No impact on daily life (NIDL) activities' for individual nausea and vomiting domains was defined as a FLIE score higher than 53.8; NIDL for the combined domains of nausea and vomiting was defined as a FLIE score higher than 108. Secondary objectives included evaluating effectiveness, as determined by measuring the rate of complete response (CR) and rescue medication, as well as safety outcomes. Efficacy was documented by the treating physicians and via patient diaries for 3 Ctx cycles within 24 hrs and on 4 additional d after Ctx. Safety, additional medication and physicians' overall satisfaction was reported via eCRF. Results: A total of 2429 pts were enrolled, 2405 of whom were assessed for eligibility; of these, 2173 were included in the final analysis and constitute the full analysis set population (FAS). Evaluable FLIE questionnaires were collected from 1886 (88%) pts in cycle 1, 1795 (88%) pts in cycle 2 and 1698 (86%) pts in cycle 3. A total of 1389 pts received HEC and 764 MEC in cycle 1. The majority of pts (91%) were scheduled to receive 1-day ctx at study entry. More than half of the pts (1230, 56%) received anthracycline/cyclophosphamide-(AC), 19% carboplatin-, 8% cisplatin-, 7% oxaliplatin- and 9% other CTs. NIDL due to vomiting during cycle 1 was reported by 84% of pts in the HEC group and 82% in the MEC group. These frequencies were maintained in cycles 2 and 3. NIDL due to nausea increased from 54% in cycle 1 to 58% in cycle 3 for pts receiving HEC, and from 59% in cycle 1 to 66% in cycle 3 for pts in the MEC group. The rates for the combined domain of NIDL due to nausea and vomiting were consistent across cycle 1 (64%) and in cycles 2 and 3 (66% in each cycle) for pts in the HEC group, while the rates increased from 67% in cycle 1 to 73 and 74% in cycles 2 and 3, respectively, for pts receiving MEC. The CR rate (no emesis and no use of rescue medication) was 89% in the acute phase (0-24 h), 87% in the delayed phase (25-120 h) and 83% in the overall period (0-120 h) in cycle 1. The no significant nausea (NSN) rate was 79 % in the acute, 75 % in the delayed and 67 % in the overall phase in cycle. The majority of physicians (≥89%) and pts (≥86%) rated the effectiveness of NEPA prophylaxis as 'very good' or 'good' during all three ctx cycles. The most common NEPA-related AEs, which occurred in &amp;gt;1% of pts in the overall study period, were fatigue (3%), constipation (3%), nausea (2%) and insomnia (2%). There were no reports of NEPA-related deaths. Conclusions: Real-life data show that NEPA was effective in the prevention of chemotherapy-induced nausea and vomiting in cancer patients. NEPA had beneficial effects on the quality of life and was highly effective in the acute and delayed phase of HEC and MEC. NEPA antiemetic effectiveness was rated highly both by patients and physicians. Disclosures Karthaus: RIEMSER: Consultancy, Honoraria. Schilling:Riemser: Honoraria. </jats:sec