Summary Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women ...with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov ( NCT00045032 ). Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. Funding F Hoffmann-La Roche (Roche).
Abstract
Photosynthetic microbes are of emerging interest as production organisms in biotechnology because they can grow autotrophically using sunlight, an abundant energy source and CO
2
, a ...greenhouse gas. Important traits for such microbes are fast growth and amenability to genetic manipulation. Here we describe
Synechococcus
elongatus
UTEX 2973, a unicellular cyanobacterium capable of rapid autotrophic growth, comparable to heterotrophic industrial hosts such as yeast.
Synechococcus
UTEX 2973 can be readily transformed for facile generation of desired knockout and knock-in mutations. Genome sequencing coupled with global proteomics studies revealed that
Synechococcus
UTEX 2973 is a close relative of the widely studied cyanobacterium
Synechococcus
elongatus
PCC 7942, an organism that grows more than two times slower. A small number of nucleotide changes are the only significant differences between the genomes of these two cyanobacterial strains. Thus, our study has unraveled genetic determinants necessary for rapid growth of cyanobacterial strains of significant industrial potential.
The study of emotional states has recently received considerable attention within the cognitive and neural sciences. However, limited work has been done to synthesize this growing body of literature ...within a coherent hierarchical, neuro-cognitive framework. In this article, we review evidence pertaining to three interacting hierarchical neural systems associated with the generation, perception and regulation of one's own emotional state. In the framework we propose, emotion generation proceeds through a series of appraisal mechanisms - some of which appear to require more cognitively sophisticated computational processing (and hence more time) than others - that ultimately trigger iterative adjustments to one's bodily state (as well as to the modes of processing in other cognitive systems). Perceiving one's own emotions then involves a multi-stage interoceptive/somatosensory process by which these body state patterns are detected and assigned conceptual emotional meaning. Finally, emotion regulation can be understood as a hierarchical control system that, at various levels, modulates autonomic reactions, appraisal mechanisms, attention, the contents of working memory, and goal-directed action selection. We highlight implications this integrative model may have for competing theories of emotion and emotional consciousness and for guiding future research.
Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with ...frailty. This study aimed to examine this association using nationally representative electronic health record data.
This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio aHR 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out.
Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.
DNA mismatch repair (MMR) increases replication fidelity by eliminating mispaired bases resulting from replication errors. In Saccharomyces cerevisiae, mispairs are primarily detected by the ...Msh2-Msh6 complex and corrected following recruitment of the Mlh1-Pms1 complex. Here, we visualized functional fluorescent versions of Msh2-Msh6 and Mlh1-Pms1 in living cells. We found that the Msh2-Msh6 complex is an S phase component of replication centers independent of mispaired bases; this localized pool accounted for 10%–15% of MMR in wild-type cells but was essential for MMR in the absence of Exo1. Unexpectedly, Mlh1-Pms1 formed nuclear foci that, although dependent on Msh2-Msh6 for formation, rarely colocalized with Msh2-Msh6 replication-associated foci. Mlh1-Pms1 foci increased when the number of mispaired bases was increased; in contrast, Msh2-Msh6 foci were unaffected. These findings suggest the presence of replication machinery-coupled and -independent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric Mlh1-Pms1 foci that represent sites of active MMR.
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► S. cerevisiae Msh2-Msh6 is present in DNA replication factory foci ► Lagging-strand DNA mismatch repair (MMR) preferentially requires Exo1 ► Msh2-Msh6 foci-independent MMR is preferentially dependent on Exo1 ► Pms1 foci are active in MMR and contain substoichiometric amounts of Msh2-Msh6
In vivo imaging reveals that two mismatch repair protein complexes involved in mismatch repair have distinct functions, as one recognizes mispaired bases and one mediates active repair. The recognition complex is coupled to the DNA replication machinery, facilitating the detection of mismatches occurring during DNA synthesis.
This article discusses from a personal and present-day perspective the first studies of large highly charged individual molecular ions that were conducted using electrospray ionization with Fourier ...transform ion cyclotron resonance MS in the mid-1990s. These studies are distinguished from Current Charge Detection Mass Spectrometry (CDMS) primarily by their use of individual ion charge state changes due to reactions for accurate charge determination. This work describes the key differences in technologies and methods with present CDMS and the likely implications of these differences. I comment on surprising individual ion behavior observed in some measurements involving increases in charge state, as well as their possible basis, and also briefly discuss the potential utility of the reaction-based mass measurement approach used in the context of what might more globally be referred to as “Charge Determination Mass Spectrometry”.
The hierarchical basis of neurovisceral integration Smith, Ryan; Thayer, Julian F.; Khalsa, Sahib S. ...
Neuroscience and biobehavioral reviews,
April 2017, 2017-Apr, 2017-04-00, 20170401, Volume:
75
Journal Article
Peer reviewed
•Neurovisceral integration (NVI) theory has received considerable empirical support.•A detailed model of the functional neuroanatomy underlying NVI findings is lacking.•We describe an eight-level ...neural hierarchy underlying NVI and cardiac vagal control.•The interactions within this hierarchy may implement predictive coding computations.•Implications for understanding physiology, emotion, and cognition are discussed.
The neurovisceral integration (NVI) model was originally proposed to account for observed relationships between peripheral physiology, cognitive performance, and emotional/physical health. This model has also garnered a considerable amount of empirical support, largely from studies examining cardiac vagal control. However, recent advances in functional neuroanatomy, and in computational neuroscience, have yet to be incorporated into the NVI model. Here we present an updated/expanded version of the NVI model that incorporates these advances. Based on a review of studies of structural/functional anatomy, we first describe an eight-level hierarchy of nervous system structures, and the contribution that each level plausibly makes to vagal control. Second, we review recent work on a class of computational models of brain function known as “predictive coding” models. We illustrate how the computational dynamics of these models, when implemented within our proposed vagal control hierarchy, can increase understanding of the relationship between vagal control and both cognitive performance and emotional/physical health. We conclude by discussing novel implications of this updated NVI model for future research.
To examine the association between antihypertensive treatment and specific adverse events.
Systematic review and meta-analysis.
Randomised controlled trials of adults receiving antihypertensives ...compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up.
Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020.
The primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ
).
Of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ
=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ
=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ
=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ
=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ
=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction.
This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function.
PROSPERO CRD42018116860.
Shotgun proteomic data are affected by a variety of known and unknown systematic biases as well as high proportions of missing values. Typically, normalization is performed in an attempt to remove ...systematic biases from the data before statistical inference, sometimes followed by missing value imputation to obtain a complete matrix of intensities. Here we discuss several approaches to normalization and dealing with missing values, some initially developed for microarray data and some developed specifically for mass spectrometry-based data.
Nanoscale or single-cell technologies are critical for biomedical applications. However, current mass spectrometry (MS)-based proteomic approaches require samples comprising a minimum of thousands of ...cells to provide in-depth profiling. Here, we report the development of a nanoPOTS (nanodroplet processing in one pot for trace samples) platform for small cell population proteomics analysis. NanoPOTS enhances the efficiency and recovery of sample processing by downscaling processing volumes to <200 nL to minimize surface losses. When combined with ultrasensitive liquid chromatography-MS, nanoPOTS allows identification of ~1500 to ~3000 proteins from ~10 to ~140 cells, respectively. By incorporating the Match Between Runs algorithm of MaxQuant, >3000 proteins are consistently identified from as few as 10 cells. Furthermore, we demonstrate quantification of ~2400 proteins from single human pancreatic islet thin sections from type 1 diabetic and control donors, illustrating the application of nanoPOTS for spatially resolved proteome measurements from clinical tissues.
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