Human CD22-Transgenic,Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments

Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22⁺ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22⁺ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22⁺ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.     

Role of Orai3 in the Pathophysiology of Cancer

The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca²⁺ currents, the store-operated current, I_crac, involving functional interactions between the stromal interaction molecules (STIM), STIM1/STIM2, and Orai1/Orai2/Orai3, as well as the store-independent arachidonic acid (AA) (or leukotriene C4)-regulated current I_arc, which involves Orai1, Orai3 and STIM1. Overexpression of functional Orai3 has been described in different neoplastic cells and cancer tissue samples as compared to non-tumor cells or normal adjacent tissue. In these cells, Orai3 exhibits a cell-specific relevance in Ca²⁺ influx. In estrogen receptor-positive breast cancer cells and non-small cell lung cancer (NSCLC) cells store-operated Ca²⁺ entry (SOCE) is strongly dependent on Orai3 expression while in colorectal cancer and pancreatic adenocarcinoma cells Orai3 predominantly modulates SOCE. On the other hand, in prostate cancer cells Orai3 expression has been associated with the formation of Orai1/Orai3 heteromeric channels regulated by AA and reduction in SOCE, thus leading to enhanced proliferation. Orai3 overexpression is associated with supporting several cancer hallmarks, including cell cycle progression, proliferation, migration, and apoptosis resistance. This review summarizes the current knowledge concerning the functional role of Orai3 in the pathogenesis of cancer.     

Isolation of Fucoxanthin from Brown Algae and Its Antioxidant Activity: In Vitro and 5% Fish Oil‐In‐Water Emulsion

Fucoxanthin, a nonprovitamin A carotenoid, is a yellowish‐brown pigment found abundantly in brown algae. Along with chlorophyll a, it is bound to proteins and acts as a light‐harvesting and a light‐transferring pigment. The occurrence of carotenoids and chlorophylls in photosynthetic tissues complicates the isolation of pure fucoxanthin. The present study deals with a method for the isolation of fucoxanthin by low‐temperature crystallization and testing its antioxidant activity both in in vitro assays and in 5% oil‐in‐water emulsion. The yield of fucoxanthin obtained with this method ranged from 0.1% to 0.5% of dried algae depending on the species. Fucoxanthin showed good α,α‐diphenyl‐β‐picrylhydrazyl radical‐scavenging and iron‐chelating properties. However, it showed low reducing power and was poor in the inhibition of lipid oxidation in a liposome model system. When tested in 5% fish oil‐in‐water emulsion with iron as an oxidation inducer, fucoxanthin showed antioxidant activity by resulting in low levels of volatile oxidation products and low tocopherol loss compared to control and butylated hydroxytoluene.     

Flavour development in pork. Influence of flavour precursor concentrations in longissimus dorsi from pigs with different raw meat qualities

Flavour development and overall eating quality of pan-fried pork chops of longissimus dorsi from eight different raw meat qualities aged for 4 and 15 days were assessed by a trained sensory panel. The raw meat qualities were obtained through combinations of strategic feeding/fasting (control vs. low glycogen concentration), slaughter live-weight (84kg vs. 110kg), and gender (female vs. castrate). The flavour development was investigated for possible correlation with the concentrations of selected individual flavour precursors present in the raw meat: monosaccharides, IMP and degradation products, fatty acids, lactate and thiamine. Differences in precursor concentrations between the raw meat qualities were observed with feeding/fasting and ageing as the main factors with the largest influence of all experimental factors. However, the concentrations of the precursors could not explain the differences in sensory perception of the pan-fried pork chops. Overall, the differences were small.     

Alpha-tocopherol concentration and stereoisomer composition in plasma and milk from dairy cows fed natural or synthetic vitamin E around calving

The aim of this study was to compare the effects of supplementing dairy cows with 1000 IU/day of all-rac-alpha-tocopheryl acetate (SynAc), RRR-alpha-tocopheryl acetate (NatAc), or RRR-alpha-tocopherol (NatAlc), from approximately 3 weeks before estimated calving until 2 weeks after calving, on the concentration of alpha-tocopherol and its stereoisomers (RRR-, RSS-, RRS-, RSR- and the four 2S-forms of alpha-tocopherol) in blood and milk. An unsupplemented group was included as control. Blood samples were collected at 3, 2 and 1 weeks before estimated calving, at calving, and 3, 7 and 14 days after calving, while milk samples were taken twice within 24 h after calving and at 7 and 14 days in milk. Overall, time and treatment had significant effects on plasma alpha-tocopherol with higher concentrations in NatAc than in the other groups. In addition, SynAc had higher concentrations than Control, and NatAlc tended to be higher than Control. The lowest plasma concentrations were observed at calving and 3 days after calving. Independent of treatment, the concentration was higher in colostrum than in milk day 7 and 14 after calving. Analyses of the stereoisomer distribution in plasma and milk showed that, irrespective of dietary treatment, RRR-alpha-tocopherol was the most predominant form, constituting more than 86%, whereas the remaining part of alpha-tocopherol was made up by the three synthetic 2R isomers, while the 2S isomers only contributed less than 1% of the total alpha-tocopherol. In control cows and cows supplemented with natural vitamin E, the proportion of RRR-alpha-tocopherol in plasma and milk constituted more than 98% of the total alpha-tocopherol. In conclusion, the results indicate that daily oral supplementation of dairy cows with RRR-alpha-tocopheryl acetate gives the highest blood concentrations of alpha-tocopherol in the periparturient period. Analyses of the distribution of the individual stereoisomers of alpha-tocopherol further indicate that the bioavailability of RRR-alpha-tocopherol relative to synthetic stereoisomers in cattle is considerably higher than officially accepted until now.     

Increasing frame rate in ultrasound imaging by temporal morphing using tissue Doppler

The diagnostic value of echocardiographic images seems to diminish when the frame rate is low. In this work, morphing based on velocity information was used to improve the perceived smoothness of B-mode cine-loops with low frame rate. Based on an estimate of the velocity field calculated from B-mode speckle tracking and tissue Doppler measurements, morphed cine-loops with arbitrarily high frame rate were created. Morphing was applied to cardiac ultrasound cine-loops with apical insonation. The quality of the morphed data was evaluated by removing frames from duplex B-mode and tissue Doppler recordings, then replacing the removed B-mode frames with morphed ones. The decimated and morphed sequences were compared to the original ones. Wall motion scoring, a subjective evaluation technique for regional viability of the myocardium, was applied to data from 20 patients with varying pathology. Sixty cine-loops were scored twice, first with original data and later with morphed data. The results were compared for each recording, and the scorings were identical in the two cases for 94% of the segments. We conclude that much of the diagnostic value is retained in recordings with 15 frames per second when temporal morphing is applied.     

Characterization of complex polysorbate formulations by means of shape-selective mass spectrometry

Complex synthetic formulations based on polysorbates can be challenging to characterize. They may be composed of many similar products including those of the same molecular weight, which cannot be readily separated by separation science approaches. Carbon number variation and ethylene oxide distribution add to the complexity. The properties of these formulations will be dependent on the chemical structure and relative concentration of formulation components. Here we describe the use of two experimental approaches based on mass spectrometry to provide enhanced characterization of these formulations. The first utilizes an atmospheric pressure solids analysis probe to rapidly determine the percentage content of individual esters in a formulation. These are shown to be in good agreement with product specification sheets. In a second approach, mobility separation has been integrated into a MALDI-MS/MS experiment to categorize major, minor, and trace ingredients. Components of identical molecular mass in the polysorbate formulations have been separated by ion mobility and then fragmented for additional characterization. The rapidity and level of structural detail provided by these experiments offers a significant opportunity to develop practical screening methods for complex formulations.     

High temperature water-gas shift step in the production of clean hydrogen rich synthesis gas from gasified biomass

The possibility of using the water-gas shift (WGS) step for tuning the H₂/CO-ratio in synthesis gas produced from gasified biomass has been investigated in the CHRISGAS (Clean Hydrogen Rich Synthesis Gas) project. The synthesis gas produced will contain contaminants such as H₂S, NH₃ and chloride components. As the most promising candidate FeCr catalyst, prepared in the laboratory, was tested. One part of the work was conducted in a laboratory set up with simulated gases and another part in real gases in the 100 kW Circulating Fluidized Bed (CFB) gasifier at Delft University of Technology. Used catalysts from both tests have been characterized by XRD and N₂ adsoption/desorption at ?196 °C.In the first part of the laboratory investigation a laboratory set up was built. The main gas mixture consisted of CO, CO₂, H₂, H₂O and N₂ with the possibility to add gas or water-soluble contaminants, like H₂S, NH₃ and HCl, in low concentration (0–3 dm³ m^?3). The set up can be operated up to 2 MPa pressure at 200–600 °C and run un-attendant for 100 h or more. For the second part of the work a catalytic probe was developed that allowed exposure of the catalyst by inserting the probe into the flowing gas from gasified biomass.The catalyst deactivates by two different causes. The initial deactivation is caused by the growth of the crystals in the active phase (magnetite) and the higher crystallinity the lower specific surface area. The second deactivation is caused by the presence of catalytic poisons in the gas, such as H₂S, NH₃ and chloride that block the active surface.The catalyst subjected to sulphur poisoning shows decreased but stable activity. The activity shows strong decrease for the ammonia and HCl poisoned catalysts. It seems important to investigate the levels of these compounds before putting a FeCr based shift step in industrial operation. The activity also decreased after the catalysts had been exposed to gas from gasified biomass. The exposed catalysts are not re-activated by time on stream in the laboratory set up, which indicates that the decrease in CO₂-ratio must be attributed to irreversible poisoning from compounds present in the gas from the gasifier.It is most likely that the FeCr catalyst is suitable to be used in a high temperature shift step, for industrial production of synthesis gas from gasified biomass if sulphur is the only poison needed to be taken into account. The ammonia should be decomposed in the previous catalytic reformer step but the levels of volatile chloride in the gas at the shift step position are not known.     

Systematic literature review shows that appetite rating does not predict energy intake

Ratings of appetite are commonly used to assess appetite modification following an intervention. Subjectively rated appetite is a widely employed proxy measure for energy intake (EI), measurement of which requires greater time and resources. However, the validity of appetite as a reliable predictor of EI has not yet been reviewed systematically. This literature search identified studies that quantified both appetite ratings and EI. Outcomes were predefined as: (1) agreement between self-reported appetite scores and EI; (2) no agreement between self-reported appetitescores and EI. The presence of direct statistical comparison between the endpoints, intervention type and study population were also recorded. 462 papers were included in this review. Appetite scores failed to correspond with EI in 51.3% of the total studies. Only 6% of all studies evaluated here reported a direct statistical comparison between appetite scores and EI. χ² analysis demonstrated that any relationship between EI and appetite was independent of study type stratification by age, gender or sample size. The very substantive corpus reviewed allows us to conclude that self-reported appetite ratings of appetite do not reliably predict EI. Caution should be exercised when drawing conclusions based from self-reported appetite scores in relation to prospective EI.