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Valeria Magarotto,1 Julien Thevenon,2 Kate Morgan,3 Silene ten Seldam,3 Wafae Iraqi,4 Xavier Guillaume,5 Marjorie Leclerc,5 Claire Graziani-Taugeron,5 Bleuenn Rault,5 Dahbia Horchi5 1MD, Janssen-Cilag, Cologno Monzese, MI, Italy; 2Medical Affairs, Janssen Pharmaceuticals, Issy-les-Moulineaux, France; 3Myeloma Patients Europe, Brussels, Belgium; 4Patient Engagement, Janssen Pharmaceuticals, Issy-les-Moulineaux, France; 5RWE Data & Analytics, Oracle Life Sciences, Paris, FranceCorrespondence: Xavier Guillaume; Claire Graziani-Taugeron, Oracle France, 198 Avenue de France, Paris, 75013, France, Email xavier.guillaume@oracle.com; claire.graziani-taugeron@oracle.comPurpose: To provide real-world data on patient perceptions and experiences with subcutaneous (SC) versus intravenous (IV) daratumumab.Patients and Methods: This was a cross-sectional, mixed-method (qualitative/quantitative) survey conducted in France, Germany, Spain and the United Kingdom involving multiple myeloma (MM) patients who switched from IV to SC daratumumab in the last 12 months (qualitative phase) or 24 months (quantitative phase [26 months in the UK]) prior to enrollment in the study.Results: Nine patients (mean age 65 years) participated in the qualitative phase and 113 patients (mean age 65.1 years) in the quantitative phase. Qualitative study results provided insights for the quantitative study and highlighted the benefits of switching from daratumumab IV to daratumumab SC as an improvement and a satisfactory change in patients’ treatment journey. Quantitative survey showed that patients were significantly less anxious, stressed and nervous before SC injections than IV infusions (mean score: 1.3, 1.1, 1.4 versus 2.1, 2.0, 2.0 respectively, p< 0.001), and significantly more reassured, ready/well-prepared, usual self and relieved (mean score: 3.8, 4.3, 3.7, 3.6 versus 3.0, 3.6, 3.1, 3.0 respectively, p< 0.001). Immediately after SC first injection, 96.5% patients were feeling well or very well versus 77.9% immediately after IV first infusion (p< 0.001). 97.3% patients were satisfied with their SC treatment versus 89.4% for the IV injection (p< 0.001). Patients spent significantly less time in hospital for an SC injection of daratumumab than for an IV infusion, 1.5 hours and 5.0 hours respectively (p< 0.001). In the UK, the differences between the two administration forms were less visible, likely because of confounding factors including a longer time passed since the switch from the IV to the SC form and administration of the survey.Conclusion: In line with results from other studies, the SC form of daratumumab had less impact on patients’ emotional burden than the IV form.Keywords: multiple myeloma, daratumumab, mode of administration, patients’ emotional burden, mixed method

The aim of this survey is to identify and characterize new products in plant biotechnology since 2015, especially in relation to the advent of New Breeding Techniques (NBTs) such as gene editing based on the CRISPR-Cas system. Transgenic (gene transfer or gene silencing) and gene edited traits which are approved or marketed in at least one country, or which have a non-regulated status in the USA, are collected, as well as related patents worldwide. In addition, to shed light on potential innovation for Africa, field trials on the continent are examined. The compiled data are classified in application categories, including agronomic improvements, industrial use and medical use, namely production of recombinant therapeutic molecules or vaccines (including against Covid-19). The data indicate that gene editing appears to be an effective complement to 'classical' transgenesis, the use of which is not declining, rather than a replacement, a trend also observed in the patenting landscape. Nevertheless, increased use of gene editing is apparent. Compared to transgenesis, gene editing has increased the proportion of some crop species and decreased others amongst approved, non-regulated or marketed products. A similar differential trend is observed for breeding traits. Gene editing has also favored the emergence of new private companies. China, and prevalently its public sector, overwhelmingly dominates the patenting landscape, but not the approved/marketed one, which is dominated by the USA. The data point in the direction that regulatory environments will favor or discourage innovation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Three dimensional (3-D) cultures of pineal cell aggregates were obtained by constant gyratory shaking the heterogenous cell populations, obtained from the rat pineals, in the DMEM (Dulbecco's modified Eagle's medium). Within 4 days, the pineal cells became organized into a tissue like configuration appearing as a compact ball, evidenced by the scanning electron microscopy. The 3-D aggregates seemed to be mainly composed of pinealocytes (round-oval cells), glial (elongated cells) and other unknown cells. The heterogenous cells were separated by intercellular spaces. The ultrastructural characteristics revealed by transmission electron microscopy exhibited the presence of granular lysosomes, typical of pinealocytes actively involved in the secretion. These pineal cell aggregates secreted melatonin and other indole amines i.e. 5-methoxytryptamine (5-MT), indole acetic acid (IAA), 5-methoxy-3-indole acetic acid (5-MIAA), tryptophol (TOL) and 5-methoxytryptophol (5-MTL) in the culture medium, indicating the functional aspect of pinealocytes. The 3-D aggregates cultures had advantages over the pineal monolayer cultures as, after 4 days of culture, the amounts of indole amines secreted by 3-D aggregates were higher than those secreted by monolayer cultures. Besides, the 3-D aggregates remained functional till 24 days in the gyratory culture conditions. In the continuous perifusion system, the 3-D aggregates secreted melatonin while challanged with isoproterenol. This 3-D model of pineal cell aggregates might be useful, in future, to perform other kinetic studies of the release of indole amines in perifusion experiments as this system allows the maintenance of pineal cells for a long period of time.

Perhexiline maleate (PM) is an anti-anginal agent of amphiphilic character involved in lipidosis disorders. Experiments were carried out to study PM action on LH release from rat anterior pituitary cell aggregates. PM caused significant and dose-dependent increases of basal LH release when the aggregates had been previously treated with PM for 20 min, then incubated for 30 min with the same concentration of drug after renewal of the culture medium. The increases of basal LH secretion induced by PM were 69% (p < 0.001) at a concentration of 10(-7)M, 130% (p < 0.001) at a concentration of 10(-5)M and 250% (p < 0.001) at a concentration of 10(-4)M. PM also increased the LHRH-stimulated LH release by 25.5% (p < 0.05) at a concentration of 10(-5)M and by 74.5% (p < 0.01) at the concentration of 10(-4)M. The results showed that PM was more potent on basal LH release than on LH stimulated by LHRH. The mechanism of this action remains unclear. It may be due to the lipidosis property of the drug.

Contractile responses to norepinephrine (noradrenaline, NE 10(-5) M) in the canine saphenous vein (SV) are significantly, although slightly, reduced (14%) when induced in a physiological medium depleted of calcium for 1 hour (+ EGTA). In contrast, they are inhibited by about 75% after 24 hr in calcium free physiological saline solution (P.S.S.). ED50 of norepinephrine in 1-hr calcium-free medium and in normal Ca++ P.S.S. are 6 x 10(-7)M and 4.2 x 10(-7)M, respectively. Two blockers of extracellular calcium entry have also been cited as inhibitors of intracellular calcium pool refilling. At concentrations of 10(-6)M, 10(-5)M and 10(-4)M, diltiazem and nicardipine inhibit the norepinephrine-induced contractions (NIC) in a concentration-dependent manner. At 10(-4)M, the two calcium blockers inhibit the NIC by 70% and by 72% respectively in Ca++ free (+ EGTA) P.S.S. Nifedipine and verapamil only begin to significantly inhibit NIC in Ca++ free (+ EGTA) P.S.S. at concentrations equal to or greater than 10(-5)M. At 10(-4)M concentration, control inhibition in Ca++ free P.S.S. was observed as 60% and 49%, respectively. Contrary to the other 3 calcium antagonists tested, diltiazem antagonises NIC significantly less in calcium-containing medium (45%) than in calcium-free medium (72%). Procaine at a concentration of 10(-3)M, described as sufficient to totally inhibit calcium release from its intracellular storage sites, only inhibits NIC by 52% in calcium free (+ EGTA) P.S.S. These results are consistent with the following conclusion: i) in the canine saphenous vein (SV), NIC is mainly mediated by calcium mobilization from its intracellular storage sites; ii) the calcium antagonists tested here and procaine are unable to totally inhibit, even at high concentrations, the contractions induced via intracellular calcium release; this characteristic is nonsignificant for nifedipine and verapamil at low concentrations (10(-6)M). iii) verapamil and nifedipine, like diltiazem and nicardipine at high concentrations, may not only possess the characteristics of extracellular calcium entry blockers, but also that of partial antagonist of NIC via non specific mechanisms; iv) diltiazem may relax the vascular smooth muscle of SV, not only by the above two properties, but also through another mechanism yet unknown; v) partial persistence of NIC on the SV under conditions of short or long extracellular calcium depletion may be due to a mechanism of intracellular Ca++ recycling, the smooth muscle cell partially retaining its intracellular Ca++.

P2 purinergic receptors and pyrimidinoceptors were studied by comparing the contractile responses to UTP with those to ATP, in the dog internal maxillary vein (IMV) after endothelium removal. The contraction curves were very different: rapid subsidence with ATP and sustained contraction with UTP. alpha beta methylene ATP induced desensitization to ATP, whereas it did not antagonize the UTP-induced contractions. Reactive blue 2 (RB2) was incapable of antagonizing contractions to ATP and UTP in this vessel. We showed that Nicardipine, a calcium antagonist, was more potent on the UTP-induced than on the ATP-induced contractions. The fact that RB2 did not potentialize the UTP-induced contractions, unlike what has been observed in the dog saphenous vein, suggests that a new category of pyrimidinoceptors have been evidenced on the IMV. Our results also indicate that ATP induces contraction via P2x rather than P2y purinoceptors. The receptors described here are localized on the vascular smooth muscle.

The effect of naloxone and beta-casomorphin on luteinizing hormone (LH) release from pituitary cell aggregates, obtained by three-dimensional culture, with or without mediobasal hypothalamic fragments was studied in vitro. Short-term naloxone perifusion at a concentration of 10(-5)M did not modify either basal or LHRH-stimulated LH release from the pituitary cell aggregates. In contrast, a 12-min naloxone perifusion at the same concentration caused an increase in LH release in the mediobasal hypothalamic-pituitary cell aggregate axis. This increase was rapid (12-16 min after time pulse), marked [up to 10 times (p less than 0.004) the initial base line], short (return to the base line secretion 32-40 min after the beginning of the time pulse) and dose-dependent, with a rise greater than 1000% at a concentration of 10(-4) (p less than 0.006). The same effect was observed when a second pulse was applied 48 min after the first one. LH release induced by naloxone was antagonized 56 +/- 2% (p less than 0.03) by beta-casomorphin (an exogenous opiate) at a concentration of 10(-5) M. beta-casomorphin alone did not modify LH basal secretion, but inhibited 25.1 +/- 2.4% (p less than 0.008) LH release enhanced by LHRH. These results indicate that naloxone, an opiate antagonist, markedly increases LH release via a mu-type opioid receptor mechanism at the hypothalamic level only, during short-term exposure.

Female rats were immunized with mixed 17 beta-estradiol-6-carboxymethyloxime-bovine serum albumin and testosterone-3-carboxymethyloxime-bovine serum albumin. All the animals produced antibodies against the 2 haptens and were better immunized against 17 beta-estradiol than against testosterone. Nevertheless the disappearance of cyclic ovarian function was only obtained in animals highly immunized against the two antigens. The 17 beta-estradiol serum concentration increased with the level of immunization whereas the progesterone concentration fell. Persistent vaginal cornification was observed and ovarian lesions (large fluid filled cysts, hemorrhagic follicles and absence of corpora lutea) coincided with increased serum levels of luteinizing hormone and prolactin.

Adenosine triphosphate (ATP) and uridine triphosphate (UTP) receptors were studied by comparing the contractile responses to UTP with those to ATP in the rat tail and femoral arteries and dog saphenous vein, after endothelium removal confirmed by histology, and near abolition of relaxation to acetylcholine. Contractions induced by ATP and UTP were dose dependent, as assessed from preparations at resting tension. Contraction curves were very different: rapid subsidence with ATP and sustained contraction with UTP. In the rat tail artery and the dog saphenous vein, quinidine, nordihydroguaiaretic acid (NDGA) and phentolamine inhibited the contractions induced by ATP, whereas those induced by UTP were only slightly reduced in the presence of NDGA and were not antagonized by quinidine and phentolamine. In all three vessels, alpha-beta methylene ATP induced desensitization to ATP, whereas it did not antagonize the UTP-induced contractions. Reactive blue 2 was incapable of antagonizing contractions to ATP and UTP in these preparations. In addition, UTP-induced contractions were hardly inhibited in a calcium-free Krebs solution, whereas ATP was totally inhibited. We showed that a calcium antagonist, nicardipine, was more potent on the UTP-induced than on the ATP-induced contractions. These results showed the UTP-induced contraction to be mediated by a new class of receptors, qualified here as 'pyrimidinoceptors', for which no antagonist is known. These results were obtained in the tail and femoral arteries of the rat and from the dog saphenous vein. ATP induced contraction in these three vessels via P2x purinoceptors. P2x purinoceptors and 'pyrimidinoceptors' are localized on the vascular smooth muscle.

Following active immunization of female rats against estradiol-17 beta, the amount of specific binding sites for estrogen decreased in uterine cytosol as a function of antiserum titres. They were undetected when antibodies titres were higher than 1/2000. Moreover, a binding protein specific for estradiol-17 beta appeared. Estradiol binding was not displaced with an excess of unlabeled DES nor precipitated with protamine sulfate. The sedimentation coefficient of the hormone-protein complex (7-8 S) was not modified in medium of high ionic strength (0.4 M KCl). That protein represented antibodies to Estradiol-17 beta which could be precipitated with antiserum to rat IgG.

A continuous flow incubation (perifusion) was used to examine the effect of 5 alpha-androstane-3 beta, 17 beta diol 3 beta diol) on the release of FSH induced by LH-RH. Over a 3 h-period the 3 beta diol exerts inhibitory effects on male and female pituitaries at high dose (1 microgram/ml) and only on male pituitaries at low dose (100 ng/ml).

In vitro (perifusion of rat pituitaries) the 5 alpha-androstane-3 beta, 17 beta diol (3 beta diol) exerts inhibitory effects on Gn-RH stimulated LH secretion. The 3 beta diol is more potent at high dose (1 micrograms/ml) than low dose (100 ng/ml) and in the male rat than in the female rat.

Female rats were immunized with 17 beta-estradiol-6-carboxymethyloxime-bovine serum albumin. They developed antibodies to estradiol and, to a very low extent, antibodies to BSA. Anti-estradiol antibodies possessed tight specificity to estradiol-17 beta, without cross-reactivities with other estrogens. It was demonstrated that the specific estradiol binding in uterine and pituitary cytosols gradually decreased when antiserum titres increased. In uterine cytosols, the presence of progesterone receptor was studied using promegestone (R50 20) as ligand. No significant variations in promegestone binding were observed. Competition experiments however, questioned the permanence in immunized rats of the actual progesterone receptor or of a promegestone binding protein.

Colonies of Thelohania apodemi in fresh preparations of the brain of the field mouse show an intense fluorescence with ultra violet radiation. This phenomenon is undoubtedly due to the presence of chitin in the spore envelope. It is to our knowledge the first time that such a phenomenon of fluorescence has been described in the Microsporida.

Active simultaneous immunization of female rats against 17 beta-estradiol and testosterone induced formation of ovarian haemorrhagic and cystic follicles. A 2-fold increase in serum luteinizing hormone but any differences in prolactin levels were noted.

Phentolamine (10(-5) M) and an inhibitor of the lipoxygenase pathway, nordihydroguaiaretic acid (N. D. G. A.; 8 10(-6) M) antagonized the ATP induced contraction but not antagonized the UTP induced contraction on both rat tail artery and dog saphenous vein. We conclude that the receptors to ATP are distinct from receptors to UTP and that the P2 purinoceptors are an heterogeneous group.