Localized bank collapse or regional event?

This study presents a detailed synopsis of the sedimentological and structural features displayed within an underdescribed enigmatic facies observed in the basal Lower Jurassic Kayenta Formation of the Colorado Plateau. The facies comprises pebble to cobble-sized clasts of fine to medium-grained crossbedded sandstone with mud-draped and deformed foresets, as well as clasts of parallel-laminated but highly contorted siltstone and mudstone, supported in a silty to sandy matrix. The deposits are internally deformed and show both ductile and brittle structures in close spatial proximity, with a consistent and pervasive westdirected sense of shear. The facies occurs consistently within the same approximate stratigraphic interval, at or near the base of the Kayenta Formation. It is, however, observed only at four localities, distributed in a crudely linear arrangement parallel to the Utah-Idaho trough, despite extensive studies of outcrops of the same stratigraphic interval widely distributed across both Utah and Arizona. This study interprets the depositional processes as that of a partially subaerial debris flow with depositional events perhaps taking place during the waning period after ephemeral stream activity. The clast morphology and composition suggests a local source for the sediment entrained within the flow, and a limited transport distance. All of these observations are difficult to reconcile with the consistency of the stratigraphic interval in which the facies occur, or with the regional distribution of preserved examples. Consequently, this study discusses the potential for a common and time-equivalent triggering mechanism across all examples, which may have regional significance in the Jurassic evolution of the region

‘Block and basin’ style rift basins: sedimentological insights from the Mississippian Fell Sandstone Formation

The block and basin tectonostratigraphic framework for the northern Pennine (rift) Basin, within which buoyant granite intrusions core intra-basin fault-bounded blocks, has long held traction. However, many of the elements of this framework are rooted in primitive tectonic models and, perhaps unsurprisingly, corresponding depositional models often reflect this. Using sedimentological and sedimentary provenance approaches, the synrift (Mississippian) fluvio-deltaic Fell Sandstone Formation and age-equivalent strata within the northern Pennine Basin are examined. Highlighted divergences from classically depicted models relate to occurrences of pre-Carboniferous basement domes or monoclines, which are unbounded by major vertically displacing (>100 m) fault systems. Such structures in the northern Pennine Basin are all granite-cored and their origins are associated with their buoyancy and flexural isostatic processes. One such basement dome, the Cheviot Block, confined and deflected the Fell Sandstone fluvio-deltaic system from the west, causing locally elevated net sand content and variations in the dominant palaeodrainage direction. Central parts of the Alston Block, which forms a regional monocline along an east–west axis, were comparatively uplifted because of flexural isostatic responses to granite intrusions. The findings presented are at variance not only with classically depicted depositional models for the region, but also with more general depictions of dominantly normal fault-driven rift basin systems

Arginase therapy combines effectively with checkpoint blockade or agonist anti-OX40 immunotherapy to control tumor growth.

Metabolic dysregulation is a hallmark of cancer; for instance, many tumors exhibit auxotrophy for various amino acids, such as arginine, as they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase 1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase 1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct anti-tumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments anti-tumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Indeed, tumor-bearing mice (CT26; MC38; MCA-205) receiving pegzilarginase in combination with aPD-L1 or agonist aOX40 mAb experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust anti-tumor immunity characterized by increased intratumoral effector CD8+ T cells and M1-polarization of tumor-associated macrophages. Our data suggests potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both APCs and tumor cells, and increased presence of M1-like anti-tumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer

Combined Replenishment of miR-34a and let-7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models

Neuroblastoma (NB) tumor substantially contributes to childhood cancer mortality. The design of novel drugs targeted to specific molecular alterations becomes mandatory, especially for high-risk patients burdened by chemoresistant relapse. The dysregulated expression of MYCN, ALK, and LIN28B and the diminished levels of miR-34a and let-7b are oncogenic in NB. Due to the ability of miRNA-mimics to recover the tumor suppression functions of miRNAs underexpressed into cancer cells, safe and efficient nanocarriers selectively targeted to NB cells and tested in clinically relevant mouse models are developed. The technology exploits the nucleic acids negative charges to build coated-cationic liposomes, then functionalized with antibodies against GD2 receptor. The replenishment of miR-34a and let-7b by NB-targeted nanoparticles, individually and more powerfully in combination, significantly reduces cell division, proliferation, neoangiogenesis, tumor growth and burden, and induces apoptosis in orthotopic xenografts and improves mice survival in pseudometastatic models. These functional effects highlight a cooperative down-modulation of MYCN and its down-stream targets, ALK and LIN28B, exerted by miR-34a and let-7b that reactivate regulatory networks leading to a favorable therapeutic response. These findings demonstrate a promising therapeutic efficacy of miR-34a and let-7b combined replacement and support its clinical application as adjuvant therapy for high-risk NB patients