Publications by authors named "Francisca Reyes-Turcu"

Article Synopsis
  • The FDA approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who have certain genetic alterations and have previously undergone endocrine therapy.
  • The approval came from the CAPItello-291 trial, which involved 708 patients, showing that capivasertib significantly improved progression-free survival, particularly in patients with specific tumor alterations.
  • While capivasertib showed benefits, it also led to higher rates of severe side effects like hyperglycemia, skin issues, and diarrhea in some patients.
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Article Synopsis
  • * The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), under the U.S. Department of Health and Human Services, coordinates efforts among agencies like NIAID, BARDA, and FDA to enhance preparedness.
  • * Advances in radiation biodosimetry incorporate various scientific fields and technologies, improving the ability to assess exposure and strengthen biodefense capabilities through automated methods and laboratory networks.
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On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic fusion-positive non-small cell lung cancer (NSCLC), (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic -mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54-73] in prior platinum-treated fusion-positive NSCLC to 100% (95% CI, 63-100) in systemic therapy-naïve fusion-positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months.

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On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.

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On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer.

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The regulation of protein-coding and noncoding RNAs is linked to nuclear processes, including chromatin modifications and gene silencing. However, the mechanisms that distinguish RNAs and mediate their functions are poorly understood. We describe a nuclear RNA-processing network in fission yeast with a core module comprising the Mtr4-like protein, Mtl1, and the zinc-finger protein, Red1.

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Article Synopsis
  • * In the fission yeast Schizosaccharomyces pombe, RNAi works alongside heterochromatin factors to silence various genes, including those involved in sexual differentiation and retrotransposons, with the exosome RNA degradation machinery also playing a key role.
  • * The creation of siRNAs and heterochromatin formation is triggered by the poly(A) polymerase Pla1 and is influenced by environmental conditions and developmental signals, revealing a connection between RNAi and developmental gene
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The assembly of heterochromatin in eukaryotic genomes is critical for diverse chromosomal events including regulation of gene expression, silencing of repetitive DNA elements, proper segregation of chromosomes and maintenance of genomic integrity. Previous studies have shown that noncoding RNAs and the RNA interference (RNAi) machinery promote the assembly of heterochromatin that serves as a multipurpose platform for targeting effectors involved in various chromosomal processes. Recent work has revealed that RNAi-independent mechanisms, involving RNA processing activities that utilize both noncoding and coding RNAs, operate in the assembly of heterochromatin.

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Facultative heterochromatin that changes during cellular differentiation coordinates regulated gene expression, but its assembly is poorly understood. Here, we describe facultative heterochromatin islands in fission yeast and show that their formation at meiotic genes requires factors that eliminate meiotic messenger RNAs (mRNAs) during vegetative growth. Blocking production of meiotic mRNA or loss of RNA elimination factors, including Mmi1 and Red1 proteins, abolishes heterochromatin islands.

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Heterochromatin assembly at Schizosaccharomyces pombe centromeres involves a self-reinforcing loop mechanism wherein chromatin-bound RNAi factors facilitate targeting of Clr4-Rik1 methyltransferase. However, the initial nucleation of heterochromatin has remained elusive. We show that cells lacking Mlo3, a protein involved in mRNP biogenesis and RNA quality control, assemble functional heterochromatin in RNAi-deficient cells.

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Modification of proteins by ubiquitin (Ub) and Ub-like (Ubl) modifiers regulates a variety of cellular functions. The ability of Ub to form chains of eight structurally and functionally distinct types adds further complexity to the system. Ub-specific proteases (USPs) hydrolyse polyUb chains, and some have been suggested to be cross-reactive with Ubl modifiers, such as neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and interferon-stimulated gene 15 (ISG15).

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Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin(-like) protein, and remodel polyubiquitin(-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Most DUB activity is cryptic, and conformational rearrangements often occur during the binding of ubiquitin and/or scaffold proteins.

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At least eight types of ubiquitin chain exist, and individual linkages affect distinct cellular processes. The only distinguishing feature of differently linked ubiquitin chains is their structure, as polymers of the same unit are chemically identical. Here, we have crystallized Lys 63-linked and linear ubiquitin dimers, revealing that both adopt equivalent open conformations, forming no contacts between ubiquitin molecules and thereby differing significantly from Lys 48-linked ubiquitin chains.

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DUBs (deubiquitinating enzymes) are a family of proteases responsible for the specific removal of ubiquitin attached to target proteins and thus control the free cellular pools of this molecule. DUB activity is usually assayed using full-length ubiquitin, and these enzymes generally show low activity towards small substrates that constitute the P4-P1 LRGG (Lys-Arg-Gly-Gly) C-terminal motif of ubiquitin. To gain insight into the C-terminal recognition region of ubiquitin by DUBs, we synthesized positional scanning libraries of fluorigenic tetrapeptides and tested them on three examples of human DUBs [OTU-1 (ovarian tumour 1), Iso-T (isopeptidase T) and UCH-L3 (ubiquitin C-terminal hydrolase L3)] and one viral ubiquitin-specific protease, namely PLpro (papain-like protease) from SARS (severe acute respiratory syndrome) virus.

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Article Synopsis
  • Polyubiquitin conjugation to target proteins is a key signal that influences their stability, location, and function, yet limited knowledge exists on how ubiquitin binding domains interact with polyubiquitin in full proteins.
  • Isopeptidase T (IsoT) plays a crucial role in breaking down unanchored polyubiquitin and features four distinct ubiquitin binding domains, including a zinc finger and two UBA domains, whose functions were previously unclear.
  • Research indicates that the UBA domains are involved in binding different polyubiquitin forms and that IsoT has multiple binding sites, with interactions being driven by enthalpy and requiring conformational changes in both IsoT and the polyubiquitin.
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Article Synopsis
  • * The study focuses on the yeast protein Otu1, which binds more effectively to polyubiquitin chains than to monoubiquitin and specifically hydrolyzes longer chains linked by Lys(48).
  • * Researchers determined the x-ray crystal structure of Otu1's OTU domain complexed with ubiquitin, uncovering a new method of ubiquitin recognition and variations in the papain protease catalytic site, shedding light on OTU proteins' function in ubiquitin processing.
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Ubiquitin binding proteins regulate the stability, function, and/or localization of ubiquitinated proteins. Here we report the crystal structures of the zinc-finger ubiquitin binding domain (ZnF UBP) from the deubiquitinating enzyme isopeptidase T (IsoT, or USP5) alone and in complex with ubiquitin. Unlike other ubiquitin binding domains, this domain contains a deep binding pocket where the C-terminal diglycine motif of ubiquitin is inserted, thus explaining the specificity of IsoT for an unmodified C terminus on the proximal subunit of polyubiquitin.

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