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BACKGROUND: Real-world data for advanced/metastatic non-small-cell lung cancer (NSCLC) with mutations in human epidermal growth factor 2 (HER2) are scarce. We aimed to assess treatment patterns and outcomes among patients with HER2-mutant advanced/metastatic NSCLC. PATIENTS AND METHODS: This retrospective nationwide electronic health record study evaluated patient characteristics, treatment patterns, treatment duration, and overall survival for adults with HER2-mutant advanced/metastatic NSCLC without epidermal growth factor receptor mutation. RESULTS: Of 55 included patients, median (quartile 1 [Q1]-quartile 3 [Q3]) age was 63.0 (58.0-72.0) years, 42 (76%) were women, and 39 (71%) were current/former smokers. In first-line therapy, 14 regimens were used for median (Q1-Q3) duration of 3.1 (2.4-6.2) months, with most patients (n = 39, 71%) receiving platinum-based chemotherapy alone or in combination with other agents. Median (95% CI) overall survival from first-line treatment initiation was 19.0 (12.2-not estimable) months, with no significant association with age, sex, or smoking status. Thirty-five (64%) patients received second-line therapy for median (Q1-Q3) duration of 3.3 (2.0-5.2) months. Fourteen second-line regimens were used; most commonly immunotherapy alone or in combination with other agents (n = 16, 46%). Sixteen (46%) patients received third-line therapy for median (Q1-Q3) duration of 1.9 (1.3-2.7) months. Nine third-line regimens were used, with 7 (44%) patients receiving HER2-directed agents. CONCLUSION: First- and second-line treatments for HER2-mutant NSCLC varied widely and treatment duration was short. The approval of trastuzumab deruxtecan for NSCLC supports wider HER2 testing to identify eligible patients for HER2-directed therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Registros Electrónicos de Salud , Neoplasias Pulmonares , Mutación , Receptor ErbB-2 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Anciano , Estudios Retrospectivos , Estados Unidos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Resultado del Tratamiento , Bases de Datos Factuales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metástasis de la Neoplasia , Tasa de SupervivenciaRESUMEN
CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) has become a breeding tool of choice for eliciting targeted genetic alterations in crop species as a means of improving a wide range of agronomic traits, including disease resistance, in recent years. With the recent development of CRISPR/Cas9 technology in Medicago sativa (alfalfa), which is an important perennial forage legume grown worldwide, its use for the enhancement of pathogen resistance is almost certainly on the horizon. In this chapter, we present detailed procedures for the generation of a single nonhomologous end-joining-derived indel at a precise genomic locus of alfalfa via CRISPR/Cas9. This method encompasses crucial steps in this process, including guide RNA design, binary CRISPR vector construction, Agrobacterium-mediated transformation of alfalfa explants, and molecular assessments of transformed genotypes for transgene and edit identification.
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Sistemas CRISPR-Cas , Edición Génica , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Medicago sativa/genética , Resistencia a la Enfermedad/genética , Fitomejoramiento , Mutación INDELRESUMEN
The laboratory axolotl (Ambystoma mexicanum) is widely used in biological research. Recent advancements in genetic and molecular toolkits are greatly accelerating the work using axolotl, especially in the area of tissue regeneration. At this juncture, there is a critical need to establish gene and transgenic nomenclature to ensure uniformity in axolotl research. Here, we propose guidelines for genetic nomenclature when working with the axolotl.
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Ambystoma mexicanum , Cicatrización de Heridas , Ambystoma mexicanum/genética , Animales , Animales Modificados GenéticamenteRESUMEN
While first line targeted therapies are the current standard of care treatment for non-small cell lung cancer (NSCLC) with actionable mutations, the cancer cells inevitably acquire resistance to these agents over time. Immune check-point inhibitors (ICIs) have improved the outcomes of metastatic NSCLC, however, its efficacy in those with targetable drivers is largely unknown. In this manuscript, we reviewed the published data on ICI therapies in NSCLC with ALK, ROS1, BRAF, c-MET, RET, NTRK, KRAS, and HER2 (ERBB2) alterations. We found that the objective response rates (ORRs) associated with ICI treatments in lung cancers harboring the BRAF (0-54%), c-MET (12-49%), and KRAS (18.7-66.7%) alterations were comparable to non-mutant NSCLC, whereas the ORRs in RET fusion NSCLC (less than10% in all studies but one) and ALK fusion NSCLC (0%) were relatively low. The ORRs reported in small numbers of patients and studies of ROS1 fusion, NTRK fusion, and HER 2 mutant NSCLC were 0-17%, 50% and 7-23%, respectively, making the efficacy of ICIs in these groups of patients less clear. In most studies, no significant correlation between treatment outcome and PD-L1 expression or tumor mutation burden (TMB) was identified, and how to select patients with NSCLC harboring actionable mutations who will likely benefit from ICI treatment remains unknown.
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The advent of genome editing has opened new avenues for targeted trait enhancement in fruit, ornamental, industrial, and all specialty crops. In particular, CRISPR-based editing systems, derived from bacterial immune systems, have quickly become routinely used tools for research groups across the world seeking to edit plant genomes with a greater level of precision, higher efficiency, reduced off-target effects, and overall ease-of-use compared to ZFNs and TALENs. CRISPR systems have been applied successfully to a number of horticultural and industrial crops to enhance fruit ripening, increase stress tolerance, modify plant architecture, control the timing of flower development, and enhance the accumulation of desired metabolites, among other commercially-important traits. As editing technologies continue to advance, so too does the ability to generate improved crop varieties with non-transgenic modifications; in some crops, direct transgene-free edits have already been achieved, while in others, T-DNAs have successfully been segregated out through crossing. In addition to the potential to produce non-transgenic edited crops, and thereby circumvent regulatory impediments to the release of new, improved crop varieties, targeted gene editing can speed up trait improvement in crops with long juvenile phases, reducing inputs resulting in faster market introduction to the market. While many challenges remain regarding optimization of genome editing in ornamental, fruit, and industrial crops, the ongoing discovery of novel nucleases with niche specialties for engineering applications may form the basis for additional and potentially crop-specific editing strategies.
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Sistemas CRISPR-Cas , Productos Agrícolas/genética , Frutas/genética , Edición Génica , Genoma de Planta , Fitomejoramiento/métodos , Plantas Modificadas Genéticamente/genética , Marcación de GenRESUMEN
The high selection pressure applied in rice breeding since its domestication thousands of years ago has caused a narrowing in its genetic variability. Obtaining new rice cultivars therefore becomes a major challenge for breeders and developing strategies to increase the genetic variability has demanded the attention of several research groups. Understanding mutations and their applications have paved the way for advances in the elucidation of a genetic, physiological, and biochemical basis of rice traits. Creating variability through mutations has therefore grown to be among the most important tools to improve rice. The small genome size of rice has enabled a faster release of higher quality sequence drafts as compared to other crops. The move from structural to functional genomics is possible due to an array of mutant databases, highlighting mutagenesis as an important player in this progress. Furthermore, due to the synteny among the Poaceae, other grasses can also benefit from these findings. Successful gene modifications have been obtained by random and targeted mutations. Furthermore, following mutation induction pathways, techniques have been applied to identify mutations and the molecular control of DNA damage repair mechanisms in the rice genome. This review highlights findings in generating rice genome resources showing strategies applied for variability increasing, detection and genetic mechanisms of DNA damage repair.
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The ability to create targeted mutations in specific genes, and therefore a loss-of-function condition, provides essential information about their endogenous functions during development and homeostasis. The discovery that CRISPR-Cas9 can target specific sequences according to base-pair complementarity and readily create knockouts in a desired gene has elevated the implementation of genetic analysis in numerous organisms. As CRISPR-Cas9 has become a powerful tool in a number of species, multiple methods for designing, creating, and screening editing efficiencies have been published, each of which has unique benefits. This chapter presents a cost-efficient, accessible protocol for creating knockout mutants in zebrafish using insertions/deletions (INDELS), from target site selection to mutant propagation, using basic laboratory supplies. The presented approach can be adapted to other systems, including any vertebrate species.