Overall evaluation of Skylab imagery for mapping of Latin America

The author has identified the following significant results. Skylab imagery is both desired and needed by the Latin American catographic agencies. The imagery is cost beneficial for the production of new mapping and maintenance of existing maps at national topographic series scales. If this information was available on a near time routine coverage basis, it would provide an excellent additional data base to the Latin American cartographic community, specifically Argentina, Bolivia, Chile, Colombia, Dominican Republic, Guatemala, Paraguay, and Venezuela

Ligand binding and homology modelling of insect odorant-binding proteins

This review describes the main characteristics of odorant-binding proteins (OBPs) for homology modelling and presents a summary of structure prediction studies on insect OBPs, along with the steps involved and some limitations and improvements. The technique involves a computing approach to model protein structures and is based on a comparison between a target (unknown structure) and one or more templates (experimentally determined structures). As targets for structure prediction, OBPs are considered to play a functional role for recognition, desorption, scavenging, protection and transportation of hydrophobic molecules (odourants) across an aqueous environment (lymph) to olfactory receptor neurones (ORNs) located in sensilla, the main olfactory units of insect antennae. Lepidopteran pheromone-binding proteins, a subgroup of OBPs, are characterized by remarkable structural features, in which high sequence identities (approximately 30%) among these OBPs and a large number of available templates can facilitate the prediction of precise homology models. Approximately 30 studies have been performed on insect OBPs using homology modelling as a tool to predict their structures. Although some of the studies have assessed ligand-binding affinity using structural information and biochemical measurements, few have performed docking and molecular dynamic (MD) simulations as a virtual method to predict best ligands. Docking and MD simulations are discussed in the context of discovery of novel semiochemicals (super-ligands) using homology modelling to conceive further strategies in insect management

Antifeedant activity of red clover root isoflavonoids on Hylastinus obscurus.

In the last decade, there has been increasing interest in investigating the impact of flavonoids on insects, specifically for pest control. In this study, we investigated the impact of isoflavonoids upon the feeding behavior of the clover root borer, Hylastinus obscurus Marsham (Coleoptera: Curculionidae), which is one of the most serious global pests associated with red clover, Trifolium pratense L. Four aglycones isoflavonoids: genistein (1), formononetin (2), daidzein (3) and biochanin A (4) were isolated and identified by HPLC, from roots of two Chilean red clover cultivars. The first two compounds, formononetin (2) and genistein (1), showed high feeding deterrent activity when they were evaluated in artificial diets. This antifeedant effect of isoflavones on feeding behavior of H. obscurus suggests that they are responsible for a decreasedin insect weight gain as compared with the control. This information could be useful respectively, to farmers and researcher to produce and create plants resistant to curculioni

Macrofauna from the sandy shore of the Johnny Cay Regional Natural Park, San Andrés and Providencia, biosphere reserve, Colombian Caribbean region

Despite their great importance, the sandy shores have not received the attention deserved. In Colombia they have been approached mainly from physical and geological standpoints, with few studies on the associated biodiversity, as is the case of the Johnny Cay Regional Natural Park in the Colombian Caribbean Region. To have a future frame of reference to evaluate and monitor the environmental impact on the sandy coast of Johnny Cay, the macrofaunal community of this ecosystem was characterized. Two stations were established, where three sediment samples were taken per beach zone (infralittoral, mesolittoral, and supralittoral), using a 16 cm diameter core, for a total of nine samples per station. The samples were sieved through a 500 µm mesh and processed in a laboratory. The macrofaunal community of Johnny Cay was represented by 1628 organisms, belonging to 20 families of the phyla Annelida, Nematoda, Mollusca, and Arthropoda (subphylum Crustacea). Annelids were the dominant group, representing 98% of total abundance, with two new family reports (Naididae and Enchytraeidae) for the Colombian Caribbean sandy beaches. The station EST_549 presented 67% of the macrofauna; this station is characterized by its hydro-dynamism, with a change of material due to the division in the opposite direction of the waves. Substrate samples were also taken in each beach zone for sedimentological analysis of grain size, carbonate content, organic matter content, and mineralogy; these variables were correlated with the community structure, obtaining a better correlation between the medium and coarse sands, and the width of the beach zone with the biological component. This work presents the baseline for the macrofaunal community of Johnny Cay sandy shore and sets the initial steps for its preservation and conservation

Lymphoma-on-chip model reveals that lymph node stromal cells promote diffuse large B-cell lymphoma survival and migration

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma, often developing resistance to current treatments. Development and testing of new therapies is hampered by lack of good in vivo and in vitro models mimicking human disease. Here, we developed a lymphoma-on-chip model to investigate the tumor-supportive roles of lymph node stromal cells (LNSCs) – fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) – in the DLBCL microenvironment. The model includes a tubular vessel lined with LECs surrounded by a hydrogel with DLBCL cells and FRCs. Our findings reveal that FRCs promote DLBCL survival and facilitate tumor cell migration towards lymphatic vessels. Moreover, we demonstrate that DLBCL cells increase permeability of lymphatic vessels, which is further enhanced in presence of FRCs. This lymphoma-on-chip model reveals the important role of LNSCs in DLBCL progression, and offers an innovative tool to study the DLBCL microenvironment and test potential therapeutic targets to improve patient outcomes.</p

Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma.

Cell surface expression levels of GPRC5D, an orphan G protein-coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM

Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255

Distinct peripheral T-cell and NK-cell profiles in HGBL-MYC/BCL2 vs patients with DLBCL NOS

Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBL-MYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T cells but decreased CD4+ T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR+/ CD38+) T cells, PD-1+CD4+ T cells, and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T cells were increased only in HGBL-MYC/BCL2. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T cells of patients with HGBL-MYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+– and DNAM-1+–expressing NK cells. Although NK cells of patients with HGBL-MYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBL-MYC/BCL2. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC-rearranged lymphomas.</p

The bone marrow NK-cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy

Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry, and functional assays to investigate the bone marrow NK-cell compartment of patients with MM at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK-cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving measurable (or minimal) residual disease (MRD) negativity after consolidation in patients treated with daratumumab, bortezomib, thalidomide, and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial. In contrast, NK-cell distribution did not predict MRD negativity in patients treated in the control arm without daratumumab. These findings highlight the impact of the bone marrow NK-cell compartment on therapeutic outcomes in patients with MM receiving immunotherapy with CD38-targeting antibodies.</p