Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo–derived senescence signature (SenSig) using a foreign body response–driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type–specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34–CSF1R–TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.</p

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin

Décanalisation de particules α par les dislocations dans l'aluminium

The origin of particle dechanneling due to dislocations is briefly recalled. An experiment is then described in which one measures (by electron microscopy) the dislocation density for a slightly cold-worked aluminium sample and the fraction of α particles dechanneled by these dislocations. In the case of 5 MeV α particles channeled along dense {111} planes, the mean dechanneling width of dislocations is found to be (140 + 40) Å. This value is in correct agreement with a theorical evaluation of 175 Å.On rappelle d'abord l'origine de la décanalisation des particules par les dislocations. On décrit alors une expérience où l'on mesure la densité en dislocations d'un échantillon d'aluminium (par microscopie électronique) et la fraction de particules α décanalisées par ces dislocations. Pour des particules α de 5 MeV canalisées le long des plans {111} la largeur décanalisante moyenne autour d'une dislocation est trouvée égale à (140 + 40) Å. Cette valeur est en accord raisonnable avec une évaluation théorique de 175 Å

Disorder in the quasi-one-dimensional conductor monoclinic tantalum trisulfide TaS3

Single crystals of monoclinic tantalum trisulfide TaS3 have been irradiated with fast electrons and neutrons. Resistivity versus temperature curves have been recorded, before and after irradiation from 30 to 300 K and electron diffraction patterns have been followed, in situ, during irradiation at 7 K in a high voltage electron microscope. Irradiation defects even in low concentrations of about 10-3 have been shown to pin the charge density waves, to prevent their low temperature ordering and to smear out the phase transitions from the resistivity versus temperature curves. In spite of that, the insulating low temperature properties do not disappear. In fact, the monoclinic TaS 3 is shown to be the first low dimensional conductor in which the pinning of the charge density waves produces no change in the low temperature resistivity.Nous avons irradié aux neutrons et aux électrons, des monocristaux de trisulfure de tantale TaS3, mesuré leur résistance en fonction de la température avant et après irradiation, et suivi à 7 K dans un microscope électronique à haute tension l'évolution sous irradiation des diagrammes de microdiffraction électronique. Même à des concentrations de l'ordre de 10-3 at., les défauts d'irradiation sont capables d'épingler les ondes de densité de charge, d'empêcher leur mise en ordre à basse température et de gommer les transitions de phase des courbes résistance-température. En dépit de tout ceci les propriétés de la phase isolante ne sont guère affectées par l'irradiation et TaS3 apparait comme le premier conducteur unidimensionnel dans lequel l'épinglage des ondes de densité de charge ne produit aucun changement dans la résistivité à basse température

Long-term survival after pancreatic resection for renal cell carcinoma metastasis

BACKGROUND: Surgical resection of pancreatic metastasis (PM) is the only reported curative treatment for renal cell carcinoma. However, there is currently little information regarding very long-term survival. The primary objective of this study was to determine the 10-year survival of this condition using the largest surgical series reported to date. METHODS: Between May 1987 and June 2003, we conducted a retrospective study of 62 patients surgically treated for PM from renal cell carcinoma at 12 Franco-Belgian surgical centers. Follow-up ended on May 31, 2012. RESULTS: There were 27 male (44 %) and 35 female (56 %) patients with a median age of 54 years [31-75]. Mean disease-free interval from resection of primary tumor to reoperation for pancreatic recurrence was 9.8 years (median 10 years [0-25]). During a median follow-up of 91 months [12-250], 37 recurrences (60 %) were observed. After surgical resection of repeated recurrences, overall median survival time was 52.6 months versus 11.2 months after nonoperative management (p = 0.019). Cumulative 3-, 5-, and 10-year overall survival (OS) rates were 72, 63, and 32 %, respectively. The corresponding disease-free survival rates were 54, 35, and 27 %, respectively. Lymph node involvement and existence of extrapancreatic metastases before PM were associated with poor overall survival. CONCLUSIONS: Aggressive surgical management of single or multiple PM, even in cases of extrapancreatic disease, should be considered in selected patients to allow a chance of long-term survival