Multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.

A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper-free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as β-glucocerebrosidase inhibitors.

Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy.

Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs.

Unlabelled: Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication.

Experimental validation of absorbed dose-to-medium calculation algorithms in heterogeneous media.

The aim of this work was to determine heterogeneous correction factorshQclin,Qreffclin,frefdetm,wto validate absorbed dose-to-mediumDm,Qclinm,fclincalculation algorithms from detector readings. The impact of detector orientation perpendicular and parallel to the beam central axis on the correction factors was also investigated.ThehQclin,Qreffclin,frefdetm,wfactors were calculated for four types of detectors (PTW PinPoint T31016, PTW microDiamond T60019, PTW microSilicon T60023 and EBT3 film) placed in different media (cortical bone, lung, adipose tissue, Teflon and RW3) for the 6 MV energy beam with a 10 × 10 cmfield size.

Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation.

The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells.

Sphingolipid paracrine signaling impairs keratinocyte adhesion to promote melanoma invasion.

Melanoma is the deadliest form of skin cancer due to its propensity to metastasize. It arises from melanocytes, which are attached to keratinocytes within the basal epidermis. Here, we hypothesize that, in addition to melanocyte-intrinsic modifications, dysregulation of keratinocyte functions could initiate early-stage melanoma cell invasion.

Cell cross talk within the lymphoma tumor microenvironment: follicular lymphoma as a paradigm.

Follicular lymphoma (FL) is an indolent yet incurable germinal center B-cell lymphoma retaining a characteristic follicular architecture. FL tumor B cells are highly dependent on direct and indirect interactions with a specific and complex tumor microenvironment (TME). Recently, great progress has been made in describing the heterogeneity and dynamics of the FL TME and in depicting how tumor clonal and functional heterogeneity rely on the integration of TME-related signals.

Immune changes in hilar tumor draining lymph nodes following node sparing neoadjuvant chemoradiotherapy of localized cN0 non-small cell lung cancer.

Background: While much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level. The objective of this retrospective study was to assess the immune and biological changes arising in non-involved TDLNs upon node sparing concurrent chemoradiotherapy (CRT) of non-small cell lung cancer (NSCLC) tumors.

Methods: Patients with proven localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT) or without (CRT) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the non-involved TDLN station (stations XI), were identified.

Venous thromboembolism prophylaxis and multiple myeloma patients in real-life: Results of a large survey and clinical guidance recommendations from the IFM group.

Venous thromboembolism (VTE) remains a critical issue in the management of patients with multiple myeloma (MM), particularly when immunomodulatory drugs (IMiDs) combined with dexamethasone therapy are being prescribed as first-line and relapse therapy. One possible explanation for the persistent high rates of VTE, is the use of inappropriate thromboprophylaxis strategies for patients starting antimyeloma treatment. To tackle the issue, the Intergroupe francophone du myélome (IFM) offered convenient guidance for VTE thromboprophylaxis in MM patients initiating systemic therapy.

Stem cell-like reprogramming is required for leukemia-initiating activity in B-ALL.

B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs).

The STEMRI trial: Magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma stem-like cells.

Despite maximally safe resection of the magnetic resonance imaging (MRI)-defined contrast-enhanced (CE) central tumor area and chemoradiotherapy, most patients with glioblastoma (GBM) relapse within a year in peritumoral FLAIR regions. Magnetic resonance spectroscopy imaging (MRSI) can discriminate metabolic tumor areas with higher recurrence potential as CNI+ regions (choline/-acetyl-aspartate index >2) can predict relapse sites. As relapses are mainly imputed to glioblastoma stem-like cells (GSCs), CNI+ areas might be GSC enriched.

AMPK activation induces immunogenic cell death in AML.

Survival of patients with acute myeloid leukemia (AML) can be improved by allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of the antileukemic activity of T and natural killer cells from the donor. However, the use of allo-HSCT is limited by donor availability, recipient age, and potential severe side effects. Similarly, the efficacy of immunotherapies directing autologous T cells against tumor cells, including T-cell recruiting antibodies, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors are limited in AML because of multiple mechanisms of leukemia immune escape.

Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine.

Background: Follicular lymphoma (FL), the most common indolent non-Hodgkin's Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses.

Methods: To capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability.

3D chromatin interactions involving Drosophila insulators are infrequent but preferential and arise before TADs and transcription.

In mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. In Drosophila the role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging.

Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.

Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions.

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients.

Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in and/or genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins.