Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of ...348 estrogen receptor-positive (ER+) breast cancers treated with CDK4/6i and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, the suppression of which restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.
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•FAT1 or RB1 loss is associated with clinical resistance to CDK4/6 inhibitors•Knockout of FAT1 causes Hippo pathway suppression in ER+ cancers•YAP/TAZ nuclear localization induces CDK6 overexpression•Genomic alterations causing YAP activation lead to CDK6-mediated resistance
Li et al. identify inactivation of RB1 and FAT1 to be associated with resistance of ER+ breast cancer to CDK4/6 inhibitors (CDK4/6i). FAT1 loss increases CDK6 expression via the Hippo pathway. Inactivation of the Hippo pathway component NF2 also increases CDK6 expression and reduces sensitivity to CDK4/6i.
Large predators are overabundant in mid-Cretaceous continental dinosaur assemblages of North Africa. Such unbalanced ecosystem structure involves, among predatory dinosaurs, typical abelisaurid or ...carcharodontosaurid theropods co-occurring with long-snouted spinosaurids of debated ecology. Here, we report calcium (Ca) isotope values from tooth enamel (expressed as δ44/42Ca) to investigate resource partitioning in mid-Cretaceous assemblages from Niger (Gadoufaoua) and Morocco (Kem Kem Beds). In both assemblages, spinosaurids display a distinct isotopic signature, the most negative in our dataset. This distinct taxonomic clustering in Ca isotope values observed between spinosaurids and other predators provides unambiguous evidence for niche partitioning at the top of the trophic chains: spinosaurids foraged on aquatic environments while abelisaurid and carcharodontosaurid theropods relied almost exclusively on terrestrial resources.
Inactive state-selective KRAS(G12C) inhibitors
demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer
. The genetic basis ...for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.
The Wide-Field Imager for Solar Probe Plus (WISPR) Vourlidas, Angelos; Howard, Russell A.; Plunkett, Simon P. ...
Space science reviews,
12/2016, Letnik:
204, Številka:
1-4
Journal Article, Web Resource
Recenzirano
Odprti dostop
The Wide-field Imager for Solar PRobe Plus (WISPR) is the sole imager aboard the Solar Probe Plus (SPP) mission scheduled for launch in 2018. SPP will be a unique mission designed to orbit as close ...as 7 million km (9.86 solar radii) from Sun center. WISPR employs a 95
∘
radial by 58
∘
transverse field of view to image the fine-scale structure of the solar corona, derive the 3D structure of the large-scale corona, and determine whether a dust-free zone exists near the Sun. WISPR is the smallest heliospheric imager to date yet it comprises two nested wide-field telescopes with large-format (2 K × 2 K) APS CMOS detectors to optimize the performance for their respective fields of view and to minimize the risk of dust damage, which may be considerable close to the Sun. The WISPR electronics are very flexible allowing the collection of individual images at cadences up to 1 second at perihelion or the summing of multiple images to increase the signal-to-noise when the spacecraft is further from the Sun. The dependency of the Thomson scattering emission of the corona on the imaging geometry dictates that WISPR will be very sensitive to the emission from plasma close to the spacecraft in contrast to the situation for imaging from Earth orbit. WISPR will be the first ‘local’ imager providing a crucial link between the large-scale corona and the
in-situ
measurements.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of ...cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the
effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.
Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion located in the 3′ UTR of the DMPK gene. Expanded DMPK transcripts aggregate into nuclear foci and alter the function of RNA-binding ...proteins, leading to defects in the alternative splicing of numerous pre-mRNAs. To date, there is no curative treatment for DM1. Here we investigated a gene-editing strategy using the CRISPR-Cas9 system from Staphylococcus aureus (Sa) to delete the CTG repeats in the human DMPK locus. Co-expression of SaCas9 and selected pairs of single-guide RNAs (sgRNAs) in cultured DM1 patient-derived muscle line cells carrying 2,600 CTG repeats resulted in targeted DNA deletion, ribonucleoprotein foci disappearance, and correction of splicing abnormalities in various transcripts. Furthermore, a single intramuscular injection of recombinant AAV vectors expressing CRISPR-SaCas9 components in the tibialis anterior muscle of DMSXL (myotonic dystrophy mouse line carrying the human DMPK gene with >1,000 CTG repeats) mice decreased the number of pathological RNA foci in myonuclei. These results establish the proof of concept that genome editing of a large trinucleotide expansion is feasible in muscle and may represent a useful strategy to be further developed for the treatment of myotonic dystrophy.
Lo Scrudato and colleagues have used the CRISPR-Cas9 system to excise large CTG repeat expansions in the DMPK gene causing myotonic dystrophy type 1 (DM1), and they demonstrate that genome editing in patient-derived muscle cells and skeletal muscle of a mouse model reduces pathological signs of the disease.
There are limited data supporting the commonly suggested 5 mm margin cutoff as the optimum value in defining clear margins in oral cancer. A database search of Pubmed/Medline, Web of Science, and ...EBSCOhost was performed from inception to June 2022. A random‐effects model was chosen for this meta‐analysis. The Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines were followed throughout this study. Seven studies met study criteria (2215 patients). The risk ratio was significantly higher for margins <5 mm when compared to those ≥5 mm (2.09 (95%CI: 1.53–2.86, I2 = 0.47)). Subgroup analysis (I2 = 0.15) of margin distances of 0.0–0.9, 1.0–1.9, 2.0–2.9, 3.0–3.9, and 4.0–4.9 mm calculated risk ratios for local recurrence of 2.96, 2.01, 2.17, 1.8, and 0.98, respectively. Margins between 4.0 and 4.9 mm had similar risk ratios for local recurrence compared to ≥5 mm, while margins <4.0 were significantly higher.
Abstract
CRISPR/Cas9 is an attractive platform to potentially correct dominant genetic diseases by gene editing with unprecedented precision. In the current proof-of-principle study, we explored the ...use of CRISPR/Cas9 for gene-editing in myotonic dystrophy type-1 (DM1), an autosomal-dominant muscle disorder, by excising the CTG-repeat expansion in the 3′-untranslated-region (UTR) of the human myotonic dystrophy protein kinase (DMPK) gene in DM1 patient-specific induced pluripotent stem cells (DM1-iPSC), DM1-iPSC-derived myogenic cells and DM1 patient-specific myoblasts. To eliminate the pathogenic gain-of-function mutant DMPK transcript, we designed a dual guide RNA based strategy that excises the CTG-repeat expansion with high efficiency, as confirmed by Southern blot and single molecule real-time (SMRT) sequencing. Correction efficiencies up to 90% could be attained in DM1-iPSC as confirmed at the clonal level, following ribonucleoprotein (RNP) transfection of CRISPR/Cas9 components without the need for selective enrichment. Expanded CTG repeat excision resulted in the disappearance of ribonuclear foci, a quintessential cellular phenotype of DM1, in the corrected DM1-iPSC, DM1-iPSC-derived myogenic cells and DM1 myoblasts. Consequently, the normal intracellular localization of the muscleblind-like splicing regulator 1 (MBNL1) was restored, resulting in the normalization of splicing pattern of SERCA1. This study validates the use of CRISPR/Cas9 for gene editing of repeat expansions.
Purpose of review
To review the recent literature on indications for and functional outcomes following laryngectomy for severe laryngeal dysfunction.
Recent findings
The use of functional ...laryngectomy as a definitive treatment for severe laryngeal dysfunction is increasing as more patients with head and neck cancer are treated with definitive chemoradiotherapy. Data are emerging on the efficacy of this technique as measured by aspiration, recurrent pneumonias, enteral tube feeding dependence, and surgical complication rates. Though most patients have marked improvement in aspiration and oral intake, difficulties in swallowing and voicing functions may persist.
Summary
Functional laryngectomy is an effective treatment for end-stage laryngeal dysfunction. There is a clear benefit with regard to prevention of aspiration and alleviation of nothing by mouth status. However, qualitative speech and swallowing outcomes are less well studied, though available data suggest that many patients still suffer some degree of continued chronic impairment. More research is needed on these outcomes in order to appropriately counsel patients regarding long-term functional outcomes.
Free flap surgery has revolutionized our ability to perform composite reconstructions following ablative surgery. Although flap failure is rare (∼5%), it results in high patient morbidity if not ...recognized and corrected early. There are numerous means to assess flap viability. We review the recent literature on flap monitoring, and discuss the difference between techniques in regard to overall flap survival, cost, and ease of use.
The current literature on implantable Doppler, microdialysis, video-based application (Eulerian), fluorescence angiography, spectroscopy, contrast-enhanced duplex, and activated clotting time is reviewed. Of these methods, implantable Doppler and spectroscopy have the most recent and largest series of data describing efficacy with implantable Doppler, demonstrating comparable flap survival rates to clinical monitoring. Arterial implantable Doppler has the additional benefit of less false-positives than venous Doppler. Spectroscopy demonstrates promise with commensurate flap survival rates and improved salvage rates over clinical monitoring.
Clinical monitoring alone has proven to be so effective that it is difficult to demonstrate better outcomes with alternative methods. That said, a minimally invasive, reliable method that does not require physician assessment on a frequent basis would prove ideal in many small centers and academic centers limited by resident hours. Venous and, more recently, arterial monitoring have been successfully implemented at many programs. Spectroscopy appears promising, but the data are still limited.
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