There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

/pdf/ampk-and-mtor-regulate-autophagy-through-direct-14wqsz16ke.pdf

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

In 2004, the first American Heart Association scientific statement on “Air Pollution and Cardiovascular Disease” concluded that exposure to particulate matter (PM) air pollution contributes to card...

https://cdr.lib.unc.edu/downloads/p2676x621

Particulate Matter Air Pollution and Cardiovascular Disease An Update to the Scientific Statement From the American Heart Association

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

CA : A Cancer Journal for Clinicians

EP08.02-153 The Efficacy and Safety of EGFR-TKIs plus Anlotinib in Maintenance Therapy for Oligoprogressive Advanced or Metastatic EGFR Mutant NSCLC

Abstract Investigating the causal relationship between exposure and time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using hazard ratio (HR) as the marginal causal effect measure due to noncollapsibility. In this article, we advocate using restricted mean survival time (RMST) difference as a marginal causal effect measure, which is collapsible and has a simple interpretation as the difference of area under survival curves over a certain time horizon. To address both measured and unmeasured confounding, a matched design with sensitivity analysis is proposed. Matching is used to pair similar treated and untreated subjects together, which is generally more robust than outcome modeling due to potential misspecifications. Our propensity score matched RMST difference estimator is shown to be asymptotically unbiased, and the corresponding variance estimator is calculated by accounting for the correlation due to matching. Simulation studies also demonstrate that our method has adequate empirical performance and outperforms several competing methods used in practice. To assess the impact of unmeasured confounding, we develop a sensitivity analysis strategy by adapting the E-value approach to matched data. We apply the proposed method to the Atherosclerosis Risk in Communities Study (ARIC) to examine the causal effect of smoking on stroke-free survival.

Matched design for marginal causal effect on restricted mean survival time in observational studies

Methods to account for classification error in county assignment for a periodic dual-frame telephone survey

PURPOSE
As a challenging but important optimization problem, the inverse planning for volumetric modulated arc therapy (VMAT) has attracted much research attention. The column generation (CG) type method is so far one of the most effective solution schemes. However, it often relies on simplifications leading to significant gaps between the output and the actual feasible plan. This paper presents a novel column generation (NCG) approach to push the planning results substantially closer to practice.


METHODS
The proposed NCG algorithm is equipped with multiple new quality-enhancing and computation-facilitating modules as below (A) Flexible constraints are enabled on both dose rates and treatment time to adapt to machine capabilities as well as planner's preferences, respectively; (B) A cross-control-point intermediate aperture simulation is incorporated to better conform to the underlying physics; (C) New pricing and pruning subroutines are adopted to achieve better optimization outputs. To evaluate the effectiveness of this NCG, five VMAT plans, i.e., three prostate cases and two head-and-neck cases, were computed using proposed NCG. The planning results were compared with those yielded by a historical benchmark planning scheme.


RESULTS
The NCG generated plans of significantly better quality than the benchmark planning algorithm. For prostate cases, NCG plans satisfied all PTV criteria whereas CG plans failed on D10% criteria of PTVs for over 9 Gy or more on all cases. For head-and-neck cases, again, NCG plans satisfied all PTVs criteria while CG plans failed on D10% criteria of PTVs for over 3 Gy or more on all cases as well as the max dose criteria of both cord and brain stem for over 13 Gy on one case. Moreover, the pruning scheme was found to be effective in enhancing the optimization quality.


CONCLUSIONS
The proposed NCG inherits the computational advantages of the traditional CG, while capturing a more realistic characterization of the machine capability and underlying physics. The output solutions of the NCG are substantially closer to practical implementation. This article is protected by copyright. All rights reserved.

A practical algorithm for VMAT optimization using column generation techniques.

Background: Platelet derived growth factor (PDGF) and PDGFR- are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR- expression and prognostic value in small cell lung cancer (SCLC) was investigated. Methods and Materials: Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR- specific antibody. Patients were divided into low and high staining groups based on intensity. Results: There was high intensity PDGFR- staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR- staining, with only 4 patients showing no PDGFR- staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR- staining vs. those with high level staining SCLC tumors (p 0.538). Conclusions: The present study found that the majority of SCLC patients express, at least, a low level of PDGF-. However, the level of PDGFR- expression was not a statistically significant predictor of 5 year overall survival in SCLC. © 2007 Elsevier Inc. Platelet derived endothelial growth factor, Lung cancer, Tissue array, STI571, Biomarker, Prognosis.

Bo Lu

Papers

EP08.02-153 The Efficacy and Safety of EGFR-TKIs plus Anlotinib in Maintenance Therapy for Oligoprogressive Advanced or Metastatic EGFR Mutant NSCLC

Matched design for marginal causal effect on restricted mean survival time in observational studies

Methods to account for classification error in county assignment for a periodic dual-frame telephone survey

A practical algorithm for VMAT optimization using column generation techniques.

Pdgfr- expression in small cell lung cancer patients