Fundación Instituto Leloir

About: Fundación Instituto Leloir is a facility organization based out in Buenos Aires, Argentina. It is known for research contribution in the topics: Dentate gyrus & Neurogenesis. The organization has 702 authors who have published 1052 publications receiving 39299 citations.

Changes in the TCRβ Repertoire and Tumor Immune Signature From a Cutaneous Melanoma Patient Immunized With the CSF-470 Vaccine: A Case Report.

Abstract: The allogeneic therapeutic vaccine CSF-470 has demonstrated a significant benefit over medium-dose IFNα2b in the distant metastasis-free survival for stages IIB-IIC-III cutaneous melanoma patients in a randomized phase II/III clinical trial (CASVAC-0401, NCT01729663). At the end of the 2-year CSF-470 immunization protocol, patient #006 developed several lung and one subcutaneous melanoma metastases; this later was excised. In this report, we analyzed the changes throughout vaccination of immune populations in blood and in the tumor tissue, with special focus on the T-cell repertoire. Immunohistochemistry revealed a marked increase in CD8+, CD4+, and CD20+ lymphocytes infiltrating the metastasis relative to the primary tumor. Lymphocytes were firmly attached to dying-tumor cells containing Granzyme-B granules. Whole-exon sequencing assessment indicated a moderate-to-high tumor mutational burden, with BRAFV600E as the main oncogenic driver. Mutational signature presented large numbers of mutations at dipyrimidines, typical of melanoma. Relevant tumor and immune-related genes from the subcutaneous metastasis were addressed by RNA-Seq analysis, revealing expression of typical melanoma antigens and proliferative tumor-related genes. Stimulatory and inhibitory immune transcripts were detected as well as evidence of active T-cell effector function. Peripheral blood monitoring revealed an increase in CD4+ and CD8+ cells by the end of the immunization protocol. By CDR3-T-cell receptor β (TCRβ) sequencing, generation of new clones and an increase in oligoclonality was observed in the peripheral T-cells immune repertoire throughout immunization. A shift, with the expansion of selected preexisting and newly arising clones with reduction of others, was detected in blood. In tumor-infiltrating lymphocytes, prevalent clones (50%) were both new and preexisting that were expanded in blood following CSF-470 immunization. These clones persisted in time, since 2 years after completing the immunization, 51% of the clones present in the metastasis were still detected in blood. This is the first report of the modulation of the TCRβ repertoire from a melanoma patient immunized with the CSF-470 vaccine. After immunization, the changes observed in peripheral immune populations as well as in the tumor compartment suggest that the vaccine can induce an antitumor adaptive immune repertoire that can reach tumor lesions and persists in blood for at least 2 years.

Functional conservation of clock output signaling between flies and intertidal crabs.

Abstract: Intertidal species have both circadian and circatidal clocks. Although the behavioral evidence for these oscillators is more than 5 decades old, virtually nothing is known about their molecular clockwork. Pigment-dispersing hormones (PDHs) were originally described in crustaceans. Their insect homologs, pigment-dispersing factors (PDFs), have a prominent role as clock output and synchronizing signals released from clock neurons. We show that gene duplication in crabs has led to two PDH genes (β-pdh-I and β-pdh-II). Phylogenetically, β-pdh-I is more closely related to insect pdf than to β-pdh-II, and we hypothesized that β-PDH-I may represent a canonical clock output signal. Accordingly, β-PDH-I expression in the brain of the intertidal crab Cancer productus is similar to that of PDF in Drosophila melanogaster, and neurons that express PDH-I also show CYCLE-like immunoreactivity. Using D. melanogaster pdf-null mutants (pdf01) as a heterologous system, we show that β-pdh-I is indistinguishable from pdf in i...

Phytochrome B and PCH1 protein dynamics store night temperature information.

Abstract: Plants experience temperature fluctuations during the course of the daily cycle, and although stem growth responds rapidly to these changes we largely ignore whether there is a short-term memory of previous conditions. Here we show that nighttime temperatures affect the growth of the hypocotyl of Arabidopsis thaliana seedlings not only during the night but also during the subsequent photoperiod. Active phytochrome B (phyB) represses nighttime growth and warm temperatures reduce active phyB via thermal reversion. The function of PHOTOPERIODIC CONTROL OF HYPOCOTYL1 (PCH1) is to stabilise active phyB in nuclear bodies but, surprisingly, warmth reduces PCH1 gene expression and PCH1 stability. When phyB was active at the beginning of the night, warm night temperatures enhanced the levels of nuclear phyB and reduced hypocotyl growth rate during the following day. However, when end-of-day far-red light minimised phyB activity, warm night temperatures reduced the levels of nuclear phyB and enhanced the hypocotyl growth rate during the following day. This complex growth pattern was absent in the phyB mutant. We propose that temperature-induced changes in the levels of PCH1 and in the size of the physiologically relevant nuclear pool of phyB amplify the impact of phyB-mediated temperature sensing.