AL101, a gamma-secretase inhibitor,has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling

Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.Subject terms: Head and neck cancer, Targeted therapies     

Parametric evaluation of forced expiration using a numerical model

Numerical calculations were performed to study the influence of several physiologic parameters on a forced expiration. It was found that the axial distribution of airway compliance produced profound changes in the detailed flow pattern, as characterized by the axial distributions of speed index and area ratio, but had little effect on the flow-volume curve. Similar results were obtained when the expression for frictional losses was changed to reflect new experimental results. In contrast, changes in airway size and geometry altered both the detailed flow pattern and the mean expiratory flow rate. The shape of the flow-volume curve remained unchanged.     

The use of thermals by soaring migrants

The use of thermals during the spring and autumn migration across Israel by four species of soaring birds (White Pelican Pelecanus onocrotalus, White Stork Ciconia ciconia, Lesser Spotted Eagle Aquila pomarina and Honey Buzzard Pernis apivorus) was studied by monitoring them with a motorized glider, light aircraft and radar. This is the first study in which soaring migrants have been followed in flight for any length of time and their flight performance has been recorded directly. The birds flew in an average height band between 344 and 1123 m above ground level. Altitude increased from the morning towards noon and decreased again in the afternoon. Average velocities were 29.2 km/h, 38.7 km/h, 50.9 km/h and 45.2 km/h for White Pelicans, White Storks, Lesser Spotted Eagles and Honey Buzzards, respectively. Atmospheric conditions had a major effect on flight velocity. White Storks showed a positive correlation between the flight velocity and the height between the base and top of the thermals. In White Pelicans, there was a correlation between velocity and mean height. Wing load (body mass/wing area) was positively related to the climbing time in thermals and negatively related to the mean height used by a species. There was also a positive, but not significant, relationship between wing load and velocity. Soaring birds appreciably extend the distance covered in migration in relation to the straight line from their breeding to wintering grounds (by 48–91%). The increased distance, caused through circumventing sea areas, ranged between 22–34%, while the increase resulting from soaring accounted for an additional 22–57% of the route.     

Adaptive microgeographic differentiation of allozyme polymorphism in landsnails

To elucidate the forees maintaining protein polymorphisms, microgeographic differentiation in proteins, encoded by 30 loci, was tested in 285 individuals comprising 3 species of landsnails in Israel. Each test consisted of 2 close subpopulations: one from the drier and warmer south-facing slope and the other from the opposite wetter and cooler north-facing slope. The 5 tests involved 2 of Buliminus labrosus in Mediterranean Count Carmel; 1 of Sphincterochila zonata in the northern, and 2 of S. prophetarum in the central Negev desert. The results indicate significant allele differences between the two slopes in several loci in each of the 5 local tests, involving primarily esterases (Est), aspartate aminotransferase (Aat) and leucine amino peptidases (Lap). The differential slope patterns appear to be adaptive, and are presumably maintained by microclimatic diversifying selection.     

Reactivity and selectivity in light-induced free radical reactions of 2-propanol with purine and pyrimidine mononucleotides and dinucleoside monophosphates.

Photoalkylation reactions with 2-propanol, initiated with di-tert-butyl peroxide, of a variety of purine and pyrimidine mononucleotides and dinucleoside monophosphates lead to the substitution of an alpha-hydroxyisopropyl group for the H-8 atom of adenosine and the addition of the alcohol across the 5,6-double bond of the pyrimidines. Adenosine moieties blocked at their 3'-hydroxyl group are alkylated faster than those blocked at their 5'-hydroxyl. The reactivity of the uridine moieties of 3'-UMP, 5'-UMP, and uridylyl-(3',5')-uridine is not affected by the location of the phosphate group. However, the uridine moiety of uridylyl-(3',5')-adenosine is modified faster than that of adenylyl-(3',5')-uridine. It is suggested that steric hindrance imposed by the phosphate group determines the reactivity of adenosine moieties, while base stacking involving adenosine determines the reactivity of uridine moieties. These two effects play a major role in controlling the nature and degree of the selectivity of these photoalkylation reactions for either adenosine or uridine. Cytidine has been found to be inert in these reactions.     

Is there a connection between weather at departure sites,onset of migration and timing of soaring‐bird autumn migration in Israel?

Aims Different aspects of soaring‐bird migration are influenced by weather. However, the relationship between weather and the onset of soaring‐bird migration, particularly in autumn, is not clear. Although long‐term migration counts are often unavailable near the breeding areas of many soaring birds in the western Palaearctic, soaring‐bird migration has been systematically monitored in Israel, a region where populations from large geographical areas converge. This study tests several fundamental hypotheses regarding the onset of migration and explores the connection between weather, migration onset and arrival at a distant site. Location Globally gridded meteorological data from the breeding areas in north‐eastern Europe were used as predictive variables in relation to the arrival of soaring migrants in Israel. Methods Inverse modelling was used to study the temporal and spatial influence of weather on initiation of migration based on autumn soaring‐bird migration counts in Israel. Numerous combinations of migration duration and temporal influence of meteorological variables (temperature, sea‐level pressure and precipitable water) were tested with different models for meteorological sensitivity. Results The day of arrival in Israel of white storks, honey buzzards, Levant sparrowhawks and lesser spotted eagles was significantly and strongly related to meteorological conditions in the breeding area days or even weeks before arrival in Israel. The cumulative number of days or cumulative value above or below a meteorological threshold performed significantly better than other models tested. Models provided reliable estimates of migration duration for each species. Main conclusions The meteorological triggers of migration at the breeding grounds differed between species and were related to deteriorating living conditions and deteriorating migratory flight conditions. Soaring birds are sensitive to meteorological triggers at the same period every year and their temporal response to weather appears to be constrained by their annual routine.     

What determines conformity to Bergmann's rule?

Aim  Bergmann's rule, the tendency of body size within species in bird and mammal populations to be positively correlated with latitude, is among the best known biogeographical generalizations. The factors behind such clines, however, are not well understood. Here we use a large data base of 79 mammalian carnivore species to examine the factors affecting latitudinal size clines.
Location  Worldwide.
Methods  We measured the skulls and teeth of carnivores in natural history museums, and calculated the amount of variation in size explained by latitude, supplementing our measurements with published data. We examined the effects of a number of variables on the tendency to show latitudinal clines.
Results  We found that geographical range and latitudinal extent are strongly related to size clines. Minimum temperatures across the range, net primary productivity and habitat diversity also have some, albeit much less, influence.
Main conclusions  We suggest that species with large geographical ranges are likely to encounter significant heterogeneity in those factors that influence body size, and are thus likely to exhibit size clines. However, the key factors that determine body size may not always operate along a latitudinal (or other geographical) cline, but be spatially linked to patches in the species range. One such important factor is likely to be food availability, which we show is a strong predictor of size in the brown bear ( Ursus arctos ) but is not associated with a latitudinal cline. We argue that the spatial distribution of key resources within the species range constitutes a significant predictor of carnivore body size.     

A Map of Protein-Metabolite Interactions Reveals Principles of Chemical Communication

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