Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibits anticancer immunity via CCL2.

The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.

Programmable multispecific DNA-origami-based T-cell engagers.

Multispecific antibodies have emerged as versatile therapeutic agents, and therefore, approaches to optimize and streamline their design and assembly are needed. Here we report on the modular and programmable assembly of IgG antibodies, F(ab) and scFv fragments on DNA origami nanocarriers. We screened 105 distinct quadruplet antibody variants in vitro for the ability to activate T cells in the presence of target cells. T-cell engagers were identified, which in vitro showed the specific and efficient T-cell-mediated lysis of five distinct target cell lines. We used these T-cell engagers to target and lyse tumour cells in vivo in a xenograft mouse tumour model. Our approach enables the rapid generation, screening and testing of bi- and multispecific antibodies to facilitate preclinical pharmaceutical development from in vitro discovery to in vivo proof of concept.

Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia.

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development.

NAVIGATOR: an Italian regional imaging biobank to promote precision medicine for oncologic patients.

NAVIGATOR is an Italian regional project boosting precision medicine in oncology with the aim of making it more predictive, preventive, and personalised by advancing translational research based on quantitative imaging and integrative omics analyses. The project's goal is to develop an open imaging biobank for the collection and preservation of a large amount of standardised imaging multimodal datasets, including computed tomography, magnetic resonance imaging, and positron emission tomography data, together with the corresponding patient-related and omics-related relevant information extracted from regional healthcare services using an adapted privacy-preserving model. The project is based on an open-source imaging biobank and an open-science oriented virtual research environment (VRE). Available integrative omics and multi-imaging data of three use cases (prostate cancer, rectal cancer, and gastric cancer) will be collected. All data confined in NAVIGATOR (i.e., standard and novel imaging biomarkers, non-imaging data, health agency data) will be used to create a digital patient model, to support the reliable prediction of the disease phenotype and risk stratification. The VRE that relies on a well-established infrastructure, called D4Science.org, will further provide a multiset infrastructure for processing the integrative omics data, extracting specific radiomic signatures, and for identification and testing of novel imaging biomarkers through big data analytics and artificial intelligence.

Calcitonin Gene-Related Peptide Protects Against Cardiovascular Dysfunction Independently of Nitric Oxide In Vivo.

[Figure: see text].

Monitoring compliance with standards of care for chronic diseases using healthcare administrative databases in Italy: Strengths and limitations.

BACKGROUND: A recent comprehensive report on healthcare quality in Italy published by the Organization of Economic Co-operation and Development (OECD) recommended that regular monitoring of quality of primary care by means of compliance with standards of care for chronic diseases is performed. A previous ecological study demonstrated that compliance with standards of care could be reliably estimated on regional level using administrative databases. This study compares estimates based on administrative data with estimates based on GP records for the same persons, to understand whether ecological fallacy played a role in the results of the previous study. METHODS: We compared estimates of compliance with diagnostic and therapeutic standards of care for type 2 diabetes (T2DM), hypertension and ischaemic heart disease (IHD) from administrative data (IAD) with estimates from medical records (MR) for the same persons registered with 24 GP's in 2012. Data were linked at an individual level. RESULTS: 32,688 persons entered the study, 12,673 having at least one of the three diseases according to at least one data source. Patients not detected by IAD were many, for all three conditions: adding MR increased the number of cases of T2DM, hypertension, and IHD by +40%, +42%, and +104%, respectively. IAD had imperfect sensitivity in detecting population compliance with therapies (adding MR increased the estimate, from +11.5% for statins to +14.7% for antithrombotics), and, more substantially, with diagnostic recommendations (adding MR increased the estimate, from +23.7% in glycated hemoglobin tests, to +50.5% in electrocardiogram). Patients not detected by IAD were less compliant with respect to those that IAD correctly identified (from -4.8 percentage points in proportion of IHD patients compliant with a yearly glycated hemoglobin test, to -40.1 points in the proportion of T2DM patients compliant with the same recommendation). IAD overestimated indicators of compliance with therapeutic standards (significant differences ranged from 3.3. to 3.6 percentage points) and underestimated indicators of compliance with diagnostic standards (significant differences ranged from -2.3 to -14.1 percentage points). CONCLUSION: IAD overestimated the percentage of patients compliant with therapeutic standards by less than 6 percentage points, and underestimated the percentage of patients compliant with diagnostic standards by a maximum of 14 percentage points. Therefore, both discussions at local level between GP's and local health unit managers and discussions at central level between national and regional policy makers can be informed by indicators of compliance estimated by IAD, which, based on those results, have the ability of signalling critical or excellent clusters. However, this study found that estimates are partly flawed, because a high number of patients with chronic diseases are not detected by IAD, patients detected are not representative of the whole population of patients, and some categories of diagnostic tests are markedly underrecorded in IAD (up to 50% in the case of electrocardiograms). Those results call to caution when interpreting IAD estimates. Audits based on medical records, on the local level, and an interpretation taking into account information external to IAD, on the central level, are needed to assess a more comprehensive compliance with standards.