Optimization and first electronic implementation of the Constant-Fraction Time-Over-Threshold pulse shape discrimination method

In this contribution we report on further investigations of the recently-evaluated Constant-Fraction Time-over-Threshold (CF-ToT) method for neutron/gamma-ray pulse shape discrimination (PSD). The superiority of the CF-ToT PSD method over the constant-threshold (CT-ToT) method was previously demonstrated, down to low neutron energy thresholds of 100 keVee. Here, we report on a quantitative comparison between the traditionally used Charge Comparison (CC) method and the CF-ToT method using a stilbene scintillator coupled to a silicon photomultiplier, implementing an offline analysis of recorded fast-neutron and gamma-ray waveforms. An optimization of the constant fraction value indicates that a 20%-fraction yields the optimum figure-of-merit (FOM) and gamma-ray peak-to-valley (P/V) ratio. The results obtained for a particle energy threshold of 100 keVee show that the FOM and P/V values achieved with the CF-ToT method are superior to those obtained using the standard CC method. In addition, a first electronic implementation of the CF-ToT method was performed using simple circuitry suitable for multichannel architecture. Initial results obtained with this circuit prototype are presented.Comment: 10 pages, 8 figures. To be submitted to JINS

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients

The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response

Comment in: DePICting T cell-APC crosstalk in cancer. Zhang T, Dong C. Nat Cancer. 2022 Mar;3(3):265-267. doi: 10.1038/s43018-022-00345-6. PMID: 35352059 No abstract available.International audienceDespite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4+PD-1+CXCL13+ T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific αβ TCR CD4+ T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht-dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy

The transcriptional and regulatory identity of erythropoietin producing cells

Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies