Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who ...have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).
At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.
Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).
We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in ...the first subjects tested.
We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings).
Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis.
This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.
In these studies, the role of ceramide-1-phosphate (C1P) in the wound-healing process was investigated. Specifically, fibroblasts isolated from mice with the known anabolic enzyme for C1P, ceramide ...kinase (CERK), ablated (CERK−/− mice) and their wild-type littermates (CERK+/+) were subjected to in vitro wound-healing assays. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrated steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK−/− fibroblasts. This observed difference was reflected in scratch-induced eicosanoid levels. Similar, but somewhat less intense, changes were observed in a more complex system utilizing skin biopsies obtained from CERK-null mice. Importantly, C1P levels increased during the early stages of human wound healing correlating with the transition from the inflammatory stage to the peak of the fibroplasia stage (e.g., proliferation and migration of fibroblasts). Finally, the loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK−/−. As the proper migration of fibroblasts is one of the necessary steps of wound healing, these studies demonstrate a novel requirement for the CERK-derived C1P in the proper healing response of wounds.
How Local Is the Local Field Potential? Kajikawa, Yoshinao; Schroeder, Charles E.
Neuron (Cambridge, Mass.),
12/2011, Letnik:
72, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Local field potentials (LFPs) are of growing importance in neurophysiological investigations. LFPs supplement action potential recordings by indexing activity relevant to EEG, ...magnetoencephalographic, and hemodynamic (fMRI) signals. Recent reports suggest that LFPs reflect activity within very small domains of several hundred micrometers. We examined this conclusion by comparing LFP, current source density (CSD), and multiunit activity (MUA) signals in macaque auditory cortex. Estimated by frequency tuning bandwidths, these signals' “listening areas” differ systematically with an order of MUA < CSD < LFP. Computational analyses confirm that observed LFPs receive local contributions. Direct measurements indicate passive spread of LFPs to sites more than a centimeter from their origins. These findings appear to be independent of the frequency content of the LFP. Our results challenge the idea that LFP recordings
typically integrate over extremely circumscribed local domains. Rather, LFPs appear as a mixture of local potentials with “volume conducted” potentials from distant sites.
► We studied the scale of neural domain indexed by the local field potential (LFP) ► We found that LFPs can index neural domains on a centimeter or greater scale ► First and second spatial derivatives of the LFP can reduce this scale to tens of micrometers ► The analytic value of the LFP can be enhanced by thus varying its spatial scale
Oppositely charged polymers can undergo the process of complex coacervation, which refers to a liquid–liquid phase separation driven by electrostatic attraction. These materials have demonstrated ...considerable promise as the basis for complex, self-assembled materials. In this review, we provide a broad overview of the theoretical tools used to understand the physical properties of polymeric coacervates. In particular, we discuss historic theories (Voorn–Overbeek, Random Phase Approximation), and then describe recent developments in the field (Field Theoretic, Counterion Release, Molecular Simulation, and Polymer Reference Interaction Site Model methods). We provide context for these methods, and map out the patchwork of theoretical models that are used to describe a diverse array of coacervate systems. We use this review of the literature to clarify a number of important theoretical challenges remaining in our physical understanding of complex coacervation.
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•Polymeric complex coacervates are an important class of electrostatically-driven polymer materials.•Historic theories are often invoked to describe polymer coacervates, however do not capture important physical behaviors•A broad palette of new theoretical methods capture many relevant physical effects in coacervates, albeit with limitations•New methods are needed to describe or predict all the physical effects in emerging coacervate-driven self-assembly
Herbert “Herb” Tabor, who celebrated his 100th birthday this past year, served the Journal of Biological Chemistry as a member of the Editorial Board beginning in 1961, as an Associate Editor, and as ...Editor-in-Chief for 40 years, from 1971 until 2010. Among the many discoveries in biological chemistry during this period was the identification of RNA modification by C6 deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA. This posttranscriptional RNA modification by adenosine deamination, known as A-to-I RNA editing, diversifies the transcriptome and modulates the innate immune interferon response. A-to-I editing is catalyzed by a family of enzymes, adenosine deaminases acting on dsRNA (ADARs). The roles of A-to-I editing are varied and include effects on mRNA translation, pre-mRNA splicing, and micro-RNA silencing. Suppression of dsRNA-triggered induction and action of interferon, the cornerstone of innate immunity, has emerged as a key function of ADAR1 editing of self (cellular) and nonself (viral) dsRNAs. A-to-I modification of RNA is essential for the normal regulation of cellular processes. Dysregulation of A-to-I editing by ADAR1 can have profound consequences, ranging from effects on cell growth and development to autoimmune disorders.
Applied evolution: Regions of the M. jannaschii tyrosyl tRNACUA thought to interact with elongation factor Tu were randomized, and the resulting tRNA libraries were subjected to in vitro evolution. ...The tRNAs identified resulted in significantly improved yields of proteins containing nonnatural amino acids. In some cases, the degree of improvement varied in an amino acid dependent manner.
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