Adcitmer® , a new CD56-targeting monomethyl auristatin E-conjugated antibody, is a potential therapeutic approach in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. OBJECTIVES: To produce and evaluate the therapeutic performance of a new antibody-drug conjugate (Adcitmer® ) targeting CD56 in preclinical models of MCC. METHODS: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56-targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56-targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. RESULTS: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56-targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56-mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. CONCLUSIONS: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors.

Unusual kinematics of the Papatea fault (2016 Kaikoura earthquake) suggest anelastic rupture.

A key paradigm in seismology is that earthquakes release elastic strain energy accumulated during an interseismic period on approximately planar faults. Earthquake slip models may be further informed by empirical relations such as slip to length. Here, we use differential lidar to demonstrate that the Papatea fault-a key element within the 2016 Mw 7.8 Kaikoura earthquake rupture-has a distinctly nonplanar geometry, far exceeded typical coseismic slip-to-length ratios, and defied Andersonian mechanics by slipping vertically at steep angles. Additionally, its surface deformation is poorly reproduced by elastic dislocation models, suggesting the Papatea fault did not release stored strain energy as typically assumed, perhaps explaining its seismic quiescence in back-projections. Instead, it slipped in response to neighboring fault movements, creating a localized space problem, accounting for its anelastic deformation field. Thus, modeling complex, multiple-fault earthquakes as slip on planar faults embedded in an elastic medium may not always be appropriate.

Prevention and control of health care-associated waterborne infections in health care facilities.

The current article is a review of the public health risks attributable to waterborne pathogens in health care. The consequences of health care-associated infections (HAIs) are discussed. Not only are Legionella spp involved in HAIs, but also Pseudomonas aeruginosa, other gram-negative microorganisms, fungi, and amoeba-associated bacteria. This is particularly noteworthy among immunocompromised patients. New prevention strategies and control measures brought about through advanced planning, facility remodelling and reconstruction, disinfection, and filtration have resulted in a significant reduction of the incidence of waterborne HAIs. The positive consequences of a comprehensive multibarrier approach including prevention and control programs in health care facilities are discussed. Environmental cultures are now integrated within the infection control program of some European countries. In high-risk areas, the application of disposable sterile point-of-use filters for faucets and shower heads appears to be the practice of choice to efficiently control waterborne pathogens and to prevent infections.

Histogenesis of the striopallidal system in the rat. Neurogenesis of its neurons.

This study discusses the histogenesis of the structures of the extrapyramidal system. The first part based on [3H]thymidine autoradiography provides data on the time of origin of the various neuronal populations that characterize different structures of the extrapyramidal system. Such data are essential to any further study dealing with the localization of the different sites of origin of the neurons along the ependymal matrix and with their migration during the histogenetic sequences leading to their definitive pattern of adult distribution. The neurons of globus pallidus and of the entopeduncular nucleus are generated on days 12-15 and days 11-14, respectively. A peak of neurogenesis occurs on day 12 for the entopeduncular nucleus and on day 14 for the globus pallidus. In the pallidum, the first neurons to form on day 12 settle caudally, while neurons generated on day 15 settle in the rostral extremity. The genesis of the medium-sized neurons of the neostriatum extends from day 12 to at least postnatal day 2. A peak is obvious on day 15. Although the neurogenesis of these neurons follows a mild caudorostral gradient, a more careful examination reveals four different patterns of settlement according to the area involved and the period of gestation. At the level of the caudal neostriatum, the neurons display a clear mediolateral spatiotemporal gradient. More rostrally, the neurons generated on days 13, 14 and 15 show two patterns of settlement. On the one hand, many neurons settle rather densely along the external capsule on day 13, occupying more rostral levels on days 14 and 15. On the other hand, in the body of the neostriatum, clusters of isochronically generated neurons are obvious. Later, newly generated neurons display a rather homogeneous distribution in the structure. A parallel is drawn between these patterns of development and the patterns of distribution of afferent terminals or neurotransmitters. The large chromophilic neurons of the neostriatum appear exclusively during the early period. Two peaks of neurogenesis are apparent. The one on day 13 comprises neurons that settle caudally. It is contemporaneous to the neurogenesis of the adjacent basal nucleus. The second peak occurs on day 15 and corresponds to that of the medium-sized neurons.

Histogenesis at the level of the basal forebrain: the entopeduncular nucleus.

This study shows that the neurons of the entopeduncular nucleus are derived from a longitudinal slab of isochronically generated neurons on day 11 and 15 h of gestation. Many neurons of this longitudinal slab which we have named the basal forebrain cell column, originate from an ependymal matrix closely associated with the ventral diencephalic sulcus and later become associated with the basal forebrain bundle. Other neurons also originate from the ependymal matrix at the site of emergence of the optic recess and keep close relationships with the optic chiasma through the following stages of development to form the retrochiasmatic nucleus. During the second half of day 12 of gestation, the mantle layer of the forebrain shows an early zone of differentiation along its ventrolateral aspect. At this stage, the basal forebrain cell column extends unbroken from the tuberculum posterius to the chiasmatic plate primordium (site of generation of the retrochiasmatic nucleus). At the level of the caudal aspect of the optic stalk however, the basal forebrain cell column divides in two limbs associated to the ventral and dorsal edges of the optic stalk as it emerges from the forebrain. On day 14 of gestation, the neurons of the dorsal limb of the basal forebrain cell column occupy the mantle layer of the neural tube at least as far rostrally as the ventricular elevation in front of the optic stalk in the floor of the foramen of Monro. The neurons derived from the basal forebrain cell column begin breaking up into a series of more definite nuclei at later stages of development. The main finding of this study is the disclosure of the fact that the entopeduncular nucleus as well as other cell groups as dissimilar as the lateral preoptic area, the central, medial and anterior cortical amygdaloid complex and neurons of the dorsal hypothalamic area appear to be embryologically related, as they are all derived from a common longitudinal slab of the matrix of the forebrain.