## Τετάρτη, 31 Μαΐου 2017

### Transient ischemic attacks on turning the head to one side, with immediate remission of symptoms when the head returned to the neutral position.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

### Objective and design

An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action.

### Material

Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(−) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn).

### Treatment

Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration.

### Methods

Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test.

### Results

Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.001).

### Conclusions

Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.

http://ift.tt/2qIzCMz

### Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels. Some research has confirmed the hedgehog (Hh) signaling pathway plays an important role in RA pathogenesis; furthermore, patched 1 (PTCH1) is a negative fraction of Hh signaling pathway. We used 5-aza-2′-deoxycytidine (5-azadc) as DNA methylation inhibitor. In our research, we found MeCP2 reduced PTCH1 expression in AA FLSs; 5-azadc obstructed the loss of PTCH1 expression. 5-Azadc, treatment of AA FLSs, also blocks the release of inflammatory cytokines. In order to probe the potential molecular mechanism, we assumed the epigenetic participation in the regulation of PTCH1. Results demonstrated that PTCH1 hypermethylation is related to the persistent FLS activation and inflammation in AA rats. Knockdown of MeCP2 using small-interfering RNA technique added PTCH1 expression in AA FLSs. Our results indicate that DNA methylation may offer molecule mechanisms, and the reduced PTCH1 methylation level could regulate inflammation through knockdown of MeCP2.

Graphical Abstract

PTCH1 is an inhibitory protein of the Hedgehog signaling pathway. Increased expression of PTCH1 can inhibit the expression of Gli1 and Shh, thereby inhibiting the activation of Hedgehog signaling pathway. Inactivated Hedgehog signaling pathway inhibits the secretion of IL-6 and TNF-α. MeCP2 mediates hypermethylation of PTCH1 gene and decreases the expression of PTCH1 protein, thus activating Hedgehog signaling pathway and increasing secretion of IL-6 and TNF-α

http://ift.tt/2sgwklH

### Abstract

The objective of the study was to clarify whether controlling nutritional status (CONUT) is useful for predicting the long-term prognosis of patients hospitalized with heart failure (HF). A total of 482 (57.5%) HF patients from the Ibaraki Cardiovascular Assessment Study-HF (N = 838) were enrolled (298 men, 71.7 ± 13.6 years). At admission, blood samples were collected and nutritional status assessed using CONUT. CONUT scores were defined as follows: 0–1, normal; 2–4, light; 5–8, moderate; and 9–12, severe undernutrition. Accordingly, 352 (73%) patients had light-to-severe nutritional disturbances. In the follow-up period [median 541.5 (range 354–786) days], 109 deaths were observed. A Kaplan–Meier analysis revealed that all-cause deaths occurred more frequently in HF patients with nutritional disturbances [n = 93 (26.4%)] than in those with normal nutrition [n = 16 (12.3%); log-rank p < 0.001]. The Cox proportional hazard analyses revealed that a per point increase in the CONUT score was associated with an increased risk of all-cause death (hazard ratio 1.142; 95% confidence interval, 1.044–1.249) after controlling simultaneously for age, sex, previous history of HF hospitalization, log brain natriuretic peptide, and use of therapeutic agents at admission (tolvaptan and aldosterone antagonists). This study suggests that nutritional screening using CONUT scores is helpful in predicting the long-term prognosis of patients hospitalized with HF in a multicenter registry setting.

http://ift.tt/2spIgAI

### Abstract

RNA degradation is a major problem in tissue banking. We explored the effect of thawing flash-frozen biospecimens on the quality and integrity of RNA for genetic testing as well as for other cancer research studies. The histological quality of the frozen tumor sections was evaluated by using hematoxylin and eosin staining. RNA extraction from 60 lung cancer tissue samples subjected to various freeze/thaw cycles was performed using the RNeasy Plus isolation kit. RNA integrity was assessed by using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Furthermore, RNA from different groups was used for fluorescence Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene mutation to verify whether it can be used for research or clinical testing. Highly variable RIN values were observed among the samples, which showed no correlation with the number of freeze/thaw cycles conducted. However, after 3 freeze/thaw cycles (each thaw event lasted for 10 min), an increasing number of changes in peak intensity in RINs were observed. After 5 freeze/thaw cycles, RNA integrity decreased to approximately 35%. After 3 freeze/thaw cycles, the RNA could still be used for RT-PCR analysis of EML4-ALK fusion gene mutations; whereas those subjected to 5 freeze/thaw cycles could not. Limited (<3) freeze/thaw cycles did not adversely affect the quality of RNA extracted from tumor tissues and subsequent RT-PCR analysis. Our data could be utilized in the establishment of a standardized procedure for tissue biospecimen collection and storage.

http://ift.tt/2rGRSuF

### Abstract

The review discusses the role of omnipresent transcription factors of the NF1 family in the development, establishment and regulation of tissue-specific gene expression in multicellular organisms with a different degree of complexity. The molecular mechanisms underlying the effect of these transcription factors on the development of tissues in the evolutionary lineage of multicellular animals are analyzed.

http://ift.tt/2rdMaPz

### Movement-Dependent Spatial Expansion of Visual Receptive Fields of Neurons of the Extrastriate Cortex

The spatial structure of the receptive field (RF) of a visually sensitive neuron, as defined by presentation of stationary visual stimuli, predetermines in most cases central processing of visual information concerning moving visual images. In our study, properties of a group of neurons in the extrastriate cortical area 21a (≈18% of the examined sampling) with extremely small RF sizes (≈1.5 deg2) determined by stationary visual stimuli were investigated. It was found that spatial dimensions of each neuronal RFs may undergo manifold expansions; the neuronal response profiles depended strongly on the size, shape, and contrast of the applied moving stimuli. As a result, a high degree of diversification of neuronal response patterns depending of the shapes and contrasts of applied moving stimuli was observed. These data confirm the suggestion that the RFs of neurons in the extrastriate area 21a undergo temporary dynamic changes due to activation of surrounding neuronal groups/networks by moving visual stimuli. Thus, it is evident that processing of visual information in the course of visual image recognition is realized by integrated activity of a complex of the corresponding cortical networks of visually sensitive neurons.

http://ift.tt/2qDArqP

### Effect of Night Shift-Related Tiredness on Eye Saccades

Parameters of saccades (latency, amplitude, duration, and velocity) were measured using a saccadometer in 32 nurses (30 women and 2 men) before and after a night shift. The mean latency of saccades was found to significantly increase after this period (209.6 ± 6.84 vs. 188.6 ± 6.08 msec, P = 0.002); the same was found with respect to the saccade duration (55.0 ± 0.97 vs. 54.2 ± 1.23 msec, P < 0.05). Thus, stress and sleep deprivation noticeably influence the parameters of saccades; the latter, nonetheless, remain within a physiological range. Considering that a number of brain structures are involved in the control of saccade parameters, the above-described modulations of saccades can be potentially used as generalized indices characterizing the level of brain tiredness.

http://ift.tt/2rWoSia

### Short- and Long-Term Effects of Methylphenidate on Cost-Benefit Decision Making in Adult Rats

Decision making is one of the most complicated and controversial topics in neuroscience. Today, there are important classes of chemicals that increase cognitive performance; in particular these are psychostimulants (e.g., methylphenidate, MPH). However, the long-term effects of MPH on cost-benefit decision making in healthy animals remain unknown. Therefore, we aimed to compare the short- and long-term effects of MPH in adult healthy male rats on the decision making in two distinct T-maze tasks and the ability of the animals to adjust the height of the obstacle in a T-maze or to process information on the reward amount. We found that short-term effects of MPH (2 weeks) played a significant role in making the correct decision in T-maze tasks, while the respective effects of long-term administration (12 weeks) were much weaker. These data suggest that chronic application of MPH has short- but not long-term effects on cost-benefit decision making in healthy adult animals.

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### Effects of Stereotactic Introduction of Baclofen in the Medullary Cardiovascular Nuclei of Rats

In rats anesthetized with urethane (1.7 g/kg, i. p.), we investigated the effects of stereotaxic microinjections of baclofen into the medullary nuclei involved in the neural control of cardiovascular activity (nuclei paramedianus, ambiguus, and reticularis lateralis). Changes in the hemodynamic parameters (systolic and diastolic blood pressure and heart rate) were measured. Injections of the above GABAB receptor agonist (10–7, 10–6, or 10–5 M, 0.1 μl) into the medullary cardiovascular nuclei was accompanied by changes in the blood pressure, the magnitude and direction of which depended not only on the baclofen concentration but also on the site of injection (into one nucleus or another). Injections of the agent into the nucl. ambiguus at a 10–7 M concentration resulted in an increase in the blood pressure, but a 10–5 M concentration provided significant reduction of the systolic and diastolic blood pressure. If baclofen was injected into the nucl. reticularis lat., the blood pressure also increased or decreased but the concentration dependence was opposite to the above described. Injections of the agent into the nucl. paramedianus were always accompanied by significant increases in the blood pressure. Changes in the heart rate following baclofen injections into the nuclei under study were insignificant. The specificities of the baclofen-induced effects are probably related to peculiarities of the functioning of GABAB receptors, the activation of which may mediate the effects of multiple neuronal mechanisms.

http://ift.tt/2rWfPxM

### Abstract

One of the causes of autoimmune diseases is the production of antibodies to extracellular loops of hormonal receptors coupled with heterotrimeric G-proteins (GPCR) and to ectodomains of receptors with tyrosine kinase activity. In recent years, the range of these diseases has considerably extended, raising interest to the mechanisms of their genesis and actualizing the search for effective ways of their prevention and treatment. The antibodies against extracellular regions of α1-, β1- and β2-adrenergic receptors and m2-muscarinic acetylcholine receptors (m2-MAChR) were found in patients with various forms of cardiomyopathy and other pathologies of the cardiovascular system; the antibodies against m3-MAChR were detected in Sjögren's syndrome and biliary cirrhosis; the antibodies against angiotensin receptors type 2 were found in pregnant women with pre-eclampsia and in different forms of hypertension; the antibodies to thyroid-stimulating hormone receptor were detected in Graves' disease and other autoimmune thyroid pathologies. The role of antibodies specific to the ectodomain of muscle specific receptor tyrosine kinase in the development of generalized myasthenia and those against the extracellular domain of platelet-derived growth factor receptor in the development of systemic sclerosis and other fibroses was shown. In the present review, we systematize and analyze the data on the molecular mechanisms that underlie the production of antibodies to GPCR and receptor tyrosine kinases and determine the development of autoimmune diseases they induce. Possible approaches toward their prevention and correction are also discussed.

http://ift.tt/2rdN7HG

### Abstract

This study addresses the influence of combinations of two encoded amino acids with opposite, memory-inhibiting and memory-enhancing, effects on short-term and long-term memory formation in the honeybee. Experimentation was based on the classical proboscis extension response conditioning by a single-trial exposure to clove odor with a sucrose solution reward. The presence of the acquired conditioned response was tested 1 min (short-term memory) and 180 min (long-term memory) after the learning trial. The data obtained suggest a stimulatory (memory-enhancing) effect of the combination of two amino acids, individual effects of which are opposite. The stimulatory amino acid was present in the mixture in all the trials (8 combinations) at a subthreshold concentration, i.e. it did not influence memory formation. In some trials, the stimulatory effect of an amino acid mixture (for example, stimulatory aspartic acid combined with inhibitory lysine or serine) significantly exceeded that of a single stimulatory amino acid applied at a threshold concentration. Interestingly, the effect of amino acid combinations on memory formation in honeybees resembles their effect on cell proliferation in rat tissue explants of various origin.

http://ift.tt/2qIMIcC

### Abstract

In psychrophilic and thermophilic fish, significant differences were revealed under an optimal body temperature in the heart rate, initial atrial activity duration and descending slope of the P II wave. Differences were also detected in atrial electric activity during the initial and final periods of depolarization, reflecting different localization of the initial excitation area and the movement of the depolarization front toward the atrioventricular border.

http://ift.tt/2qIAMrc

### Abstract

A comparative analysis of enzymological characteristics of cholinesterase (ChE) and monoamine oxydase (MAO) from the optic ganglia was performed in the Pacific squid Todarodes pacificus and Commander squid Berryteuthis magister caught in their four habitats across the Pacific Northwest. A substrate–inhibitor analysis revealed a homogeneity of T. pacificus and B. magister ChE preparations as well as homogeneity of T. pacificus vs. heterogeneity of B. magister MAO preparations. In case of thiocholine derivatives, the rate of hydrolysis induced by T. pacificus ChE was practically independent of the structure of the acyl group, whereas in case of B. magister ChE it was found to decrease in this substrate series. It is only T. pacificus MAO that was found to be able to deaminate also a diaminooxydase substrate histamine. ChE activity was higher in T. pacificus than in B. magister for the whole substrate series, while for MAO the same activity pattern was observed for tyramine, tryptamine and serotonin. In both squids, the sensitivity of ChE to organophosphorus inhibitors containing the dimethylbutyl group was by several orders of magnitude higher than that in mammals. The sensitivity of ChE to the siloxane reversible inhibitors was lower in T. pacificus ChE and much lower in B. magister than in mammals.

http://ift.tt/2rdxhMU

### Abstract

The effect of serotonin solutions on the locomotor activity of cercariae with different swimming patterns, Cryptocotyle lingua and Himasthla elongate, was investigated during their lifespan using motion track analysis and a frame-by-frame count of behavioral elements. Serotonin caused a noticeable alteration of several locomotion parameters in both species studied, while the activity per se decreased significantly with age. In intermittently swimming C. lingua cercariae, serotonin induced an increase in the frequency of active swimming phases (spurts) without significant changes in the duration and velocity of the spurts themselves. In continuously swimming H. elongata cercariae, serotonin increased the number of stops during the first hour after the emission from the host mollusk under a constant average swimming velocity. Immunocytochemical visualization of serotonin revealed a decline in its level with age (time after emission) and different dynamics of this process in neurons located in the tail and body of C. lingua cercariae. The data are interpreted in the light of the modulatory role of serotonin known for other animals.

http://ift.tt/2qIiHK4

### Abstract

The tasks, methods and principles of the evolution of functions are overviewed at various levels of organization of physiological systems with the focus on the central problem of physiological evolution—the origin of life and formation of protocellular functions. This stage of evolution is associated with the emergence of the plasma membrane and ion asymmetry of the cell relative to the extracellular environment. For a long time, evolution proceeded in the sea, where extracellular sodium ions in tandem with the intracellular potassium dominance created conditions for the emergence of electrogenesis, polar cells and epithelia, as well as for the formation of the extracellular body fluid system, making up the internal environment of multicellular organisms. The features of the evolution of organs and functional systems are analyzed. During evolution, hormones, autakoids and incretins began to be involved in the regulation of functions alongside with the nervous system. Sodium-dependent processes in the plasma membrane stimulated the development of absorptive, digestive, excretory, respiratory and homeostatic functions. The substance and patterns of functional evolution are discussed.

http://ift.tt/2rdPo5n

### Abstract

Immunoreactivity for calcium-binding proteins parvalbumin (PV) and calbindin (CB) was studied in the pigeon (Columba livia) telencephalic auditory center. All its regions displayed overlapping distribution patterns of PV and CB immunoreactivity, although in the central (L2) vs. peripheral (L1, L3, CMM) layers they were dissimilar. L2 and the inner L1 sublayer (L1i) were distinguished by a higher immunoreactivity of neuropil for both proteins and the presence (in L2) of numerous small densely packed granular-type cells: heavily stained PV-ir and, as a rule, poorly stained CB-ir neurons. In Lli, the number of neurons and the density of neuropil immunoreactive to both proteins decreased. The outer L1 sublayer (L1e) as well as L3 and CMM were characterized by a generally lesser density and irregular distribution of immunoreactive neuropil and a heterogenous repertoire of PV-ir and CB-ir neurons referring to diverse morphological types, with an increased number of large multipolar cells. The differences in PV and CB immunoreactivity among different regions of the pigeon telencephalic auditory center revealed the similarity of the latter to the laminar auditory cortex in mammals.

http://ift.tt/2qIxLHl

### Serotonin-induced sensitization of nicotinic acetylcholine receptors in the soil nematode Caenorhabditis elegans

http://ift.tt/2rdKHsv

### Purpose of Review

We review the genetics of the autosomal dominant, multi-system disorder Alagille syndrome, and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion.

### Recent Findings

Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human-induced pluripotent stem cells provide new opportunities in which to study disease mechanisms and manifestations.

### Summary

We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients.

http://ift.tt/2rrIlGJ

### Malignant Duodenal GIST in a Patient with Situs Inversus Totalis—a Rare Association and Brief Review of Literature

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### Plica neuropathica (matting hair) in an autistic patient

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### Effects of sesamin on chondroitin sulfate proteoglycan synthesis induced by interleukin-1beta in human chondrocytes

Numerous studies have reported on the health benefits of sesamin, a major lignin found in sesame (S. indicum) seeds. Recently, sesamin was shown to have the ability to promote chondroitin sulfate proteoglycan syn...

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### Simple test could save lives - Shepparton News

 Shepparton News Simple test could save lives Shepparton News As well as the start of winter, today is also the start of Bowel Cancer Awareness Month, an initiative of Bowel Cancer Australia to put the uncomfortable topic on the tip of everyone's tongue. Although nearly everyone is already ''aware'' of bowel ... and more »

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### Protective Strategies Against Dysphonia in Teachers: Preliminary Results Comparing Voice Amplification and 0.9% NaCl Nebulization

This study aimed to compare the effects of two protective strategies, voice amplification (VA) and 0.9% NaCl nebulization (NEB), on teachers' voice in the work setting.

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### Comparison of Effects Produced by Physiological Versus Traditional Vocal Warm-up in Contemporary Commercial Music Singers

The present study aimed to observe whether physiological warm-up and traditional singing warm-up differently affect aerodynamic, electroglottographic, acoustic, and self-perceived parameters of voice in Contemporary Commercial Music singers.

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### 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Marie Hoshino, Kotaro Kaneko, Yoichi Miyamoto, Kentaro Yoshimura, Dai Suzuki, Takaaki Akaike, Tomohiro Sawa, Tomoaki Ida, Shigemoto Fujii, Hideshi Ihara, Junichi Tanaka, Risa Tsukuura, Daichi Chikazu, Kenji Mishima, Kazuyoshi Baba, Ryutaro Kamijo
In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C-type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8-nitro-cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8-nitro-cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8-nitro-cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8-Nitro-cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8-bromo-cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8-nitro-cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO.

### Graphical abstract

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### Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma

Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multimodality approach to evaluate the phenotypic effects and metabolic changes that occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate production in vitro, followed by cell growth inhibition. In vivo, we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas. Cancer Res; 77(11); 3113–20. ©2017 AACR.

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### TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775–8. ©2017 AACR.

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### Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. Cancer Res; 77(11); 3013–26. ©2017 AACR.

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### Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 2779–83. ©2017 AACR.

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### A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.

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### Widespread Use of Misidentified Cell Line KB (HeLa): Incorrect Attribution and Its Impact Revealed through Mining the Scientific Literature

Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 correct and 171 incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between correct and incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication. Cancer Res; 77(11); 2784–8. ©2017 AACR.

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### Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC—oncogenic alterations commonly found in non–small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070–81. ©2017 AACR.

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### BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

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### Correction: Chromosome Instability Modulated by BMI1-AURKA Signaling Drives Progression in Head and Neck Cancer

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### Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk

Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor–positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis. Cancer Res; 77(11); 2800–9. ©2017 AACR.

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### SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer

Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990–3000. ©2017 AACR.

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### Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase–substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810–21. ©2017 AACR.

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### ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040–56. ©2017 AACR.

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### Variability in Chromatin Architecture and Associated DNA Repair at Genomic Positions Containing Somatic Mutations

Dynamic chromatin structures result in differential chemical reactivity to mutational processes throughout the genome. To identify chromatin features responsible for mutagenesis, we compared chromatin architecture around single-nucleotide variants (SNV), insertion/deletions (indels), and their context-matched, nonmutated positions. We found epigenetic differences between genomic regions containing missense SNVs and those containing frameshift indels across multiple cancer types. Levels of active histone marks were higher around frameshift indels than around missense SNV, whereas repressive histone marks exhibited the reverse trend. Accumulation of repressive histone marks and nucleosomes distinguished mutated positions (both SNV and indels) from the context-matched, nonmutated positions, whereas active marks were associated with substitution- and cancer type–specific mutagenesis. We also explained mutagenesis based on genome maintenance mechanisms, including nucleotide excision repair (NER), mismatch repair (MMR), and DNA polymerase epsilon (POLE). Regional NER variation correlated strongly with chromatin features; NER machineries exhibited shifted or depleted binding around SNV, resulting in decreased NER at mutation positions, especially at sites of recurrent mutations. MMR-deficient tumors selectively acquired SNV in regions with high active histone marks, especially H3K36me3, whereas POLE-deficient tumors selectively acquired indels and SNV in regions with low active histone marks. These findings demonstrate the importance of fine-scaled chromatin structures and associated DNA repair mechanisms in mutagenesis. Cancer Res; 77(11); 2822–33. ©2017 AACR.

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### The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092–100. ©2017 AACR.

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### SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells

Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.

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### Water Concentration Analysis of the Surgical Margin—Response

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### Abstract

Technical dichlorodiphenyltrichloroethane (DDT) has been used worldwide as a pesticide since the beginning of the 1940s. Due to its persistence, DDT residues are still ubiquitously distributed in the environment. Photochemical UV degradation has been shown to be a potent degradation path for DDT and most of the resulting photoproducts have been identified up to now. Nevertheless, in 2012, a new DDT metabolite, most likely formed photochemically from DDE, was detected in ray liver samples from Brazil, an area which is highly contaminated with DDT. This study includes photochemical generation, chemical synthesis and isolation of this compound which was verified to consist of both cis- and trans-2,4-dichloro-1-[2-chloro-1-(4-chlorophenyl)ethenyl]benzene. Both stereoisomers were resolved by gas chromatography on a polar capillary column and detected in more than 60 biotic (e.g. marine mammals, birds, human milk) and abiotic samples (fat deposits in kitchen hoods) from different areas all over the world. The stereoisomer distribution and concentrations (0.3–3.9% relative to corresponding 1,1-dichloro-2,2-bis(p-chlorophenyl) ethane (p,p-DDE) levels) were determined by means of the synthesized analytical standard, indicating the widespread occurrence of this compound as an additional minor metabolite of DDT.

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### Abstract

RNA degradation is a major problem in tissue banking. We explored the effect of thawing flash-frozen biospecimens on the quality and integrity of RNA for genetic testing as well as for other cancer research studies. The histological quality of the frozen tumor sections was evaluated by using hematoxylin and eosin staining. RNA extraction from 60 lung cancer tissue samples subjected to various freeze/thaw cycles was performed using the RNeasy Plus isolation kit. RNA integrity was assessed by using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Furthermore, RNA from different groups was used for fluorescence Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene mutation to verify whether it can be used for research or clinical testing. Highly variable RIN values were observed among the samples, which showed no correlation with the number of freeze/thaw cycles conducted. However, after 3 freeze/thaw cycles (each thaw event lasted for 10 min), an increasing number of changes in peak intensity in RINs were observed. After 5 freeze/thaw cycles, RNA integrity decreased to approximately 35%. After 3 freeze/thaw cycles, the RNA could still be used for RT-PCR analysis of EML4-ALK fusion gene mutations; whereas those subjected to 5 freeze/thaw cycles could not. Limited (<3) freeze/thaw cycles did not adversely affect the quality of RNA extracted from tumor tissues and subsequent RT-PCR analysis. Our data could be utilized in the establishment of a standardized procedure for tissue biospecimen collection and storage.

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### College finds possible correlation between TMI partial meltdown ... - The Sentinel

 The Sentinel College finds possible correlation between TMI partial meltdown ... The Sentinel Penn State College of Medicine Wednesday reported that its researchers are showing, for the first time, a possible correlation between the partial meltdown at ... Researchers study correlation between TMI, thyroid cancerWGAL Lancaster all 8 news articles »

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### HIV status may affect the progression of HPV infection to cervical pre-cancer

A study of Senegalese women showed that human papillomavirus (HPV) infection was more likely to develop into cervical pre-cancer in women living with human immunodeficiency virus, according to research published in Cancer Epidemiology, Biomarkers &...

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### Abstract

Precision Tevatron and Linear Hadron Collider measurements at Fermilab and CERN have revealed the numerically accurate mass equality W + Z = t. This equality between two gauge bosons (gb) and the top quark t is only valid if reinterpreted as an energy equality, where E = mc 2, since energy is a shared property of particles and quarks. The experimental data indicate that the LHC particle excitation energy is quantized in the form of gauge boson energy packets E gb , which are created by factor-of-137 proton-quark energy increases denoted as α-boosts, where α ~ 1/137 is the fine structure constant. These α-boosts occur during the rare head-on quark–quark collisions in the proton beams. The α-boost energy quantization mechanism also occurs in low-energy electron–positron boson and fermion particle production channels, where it generates E b and E f energy packets. These α-boost energy channels link together coherently, as demonstrated by the accurate top quark energy equation E top = (18/α2) E electron. Particle production energy equations are derived which combine to create an overall energy pattern that accurately reproduces the energies of the (u,d), s, c, b, t fermion constituent quarks, the µ and τ leptons, and the proton.

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### Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan–Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (= 0.023, = 0.042, = 0.028, and = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (< 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32–3.37, = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31–2.93, = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.

Our study aims to investigate the prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for overall survival (OS) in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.

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### Objectives

The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.

### Material and methods

The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.

### Results

Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.

### Conclusions

The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.

### Clinical relevance

This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.

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### Marijuana Liberalization, Research, and Policy: Contributions to Current Knowledge and Practice

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### Physical and functional interactions between nuclear receptor LXRα and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells

Publication date: Available online 31 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Maria Kanaki, Ioanna Tiniakou, Efstathia Thymiakou, Dimitris Kardassis
Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand-activated LXRα/RXRα heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRα/RXRα and FOXA2. Physical and functional interactions between LXRα and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRα and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states.

### Graphical abstract

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### Summary

While the impact of interpersonal discrimination on mental health is well established, its effects on physical health outcomes have not been fully elucidated. This study systematically reviewed the literature on the prospective association between interpersonal discrimination and markers of adiposity. Medline, Web of Science, Scopus, PsycInfo, SciELO, LILACS, Google Scholar, Capes/Brazil and ProQuest databases were used to retrieve relevant information in November 2016. The results from the 10 studies that met the inclusion criteria support an association between interpersonal self-reported discrimination and the outcomes. In general, the most consistent findings were for weight and body mass index (BMI) among women, i.e. high levels of self-reported discrimination were related to increased weight and BMI. Waist circumference (WC) showed a similar pattern of association with discrimination, in a positive direction, but an inverted U-shaped association was also found. Despite a few inverse associations between discrimination and markers of adiposity, none of the associations were statistically significant. Overall, markers of adiposity were consistently associated with discrimination, mainly through direct and nonlinear associations. This review provides evidence that self-reported discrimination can play an important role in weight, BMI and WC changes.

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### Abstract

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.

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### Abstract

Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (N = 30) and in age-matched controls (N = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO.

Conclusion: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.

 What is Known: • The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years. • Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment. What is New: • Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.

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### Abstract

To assess risk factors for recurrent carbapenem-resistant Klebsiella pneumoniae bloodstream-infection (CR-KP BSI), we performed a prospective observational cohort study of all consecutive adult patients cured of a CR-KP BSI at our hospital over a six-year period (June 2010 to June 2016). Maximum follow-up per patient was 180 days from the index blood cultures (BCs). Recurrent CR-KP BSI was defined as new evidence of positive BCs in patients with documented clinical response after completing a course of anti-CR-KP therapy. Univariate and multivariate cause-specific Cox proportional hazards analysis were performed. During the study period 249 patients were diagnosed with a CR-KP BSI, 193 were deemed as cured within 14 days after index BCs and were analysed. Recurrence occurred in 32/193 patients (16.6%) within a median of 35 (IQR 25–45) days after index BCs. All but one of the recurrences occurred within 60 days after the index BCs. Comparison of recurrent and non-recurrent cases showed significant differences for colistin use (84.4% vs. 62.2%, p = 0.01), meropenem-colistin-tigecycline regimen (43.8% vs. 24.8%, p = 0.03) and length of therapy for the index BSI episode (median 18 vs. 14 days, p = 0.004). All-cause 180-day mortality (34.4% vs. 16.1%, p = 0.02) was higher in recurrent cases. In the multivariate analysis, the only independent variable was source control as a protective factor for recurrence. Recurrence is frequent among patients cured of a CR-KP BSI and is associated with higher long-term mortality. When feasible, source control is mandatory to avoid recurrence. The role of antibiotic treatment should be further investigated in large multicentre studies.

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### Indore: Students' drawings send out strong message against tobacco use - Free Press Journal

 Free Press Journal Indore: Students' drawings send out strong message against tobacco use Free Press Journal “Heart attacks, strokes, chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis), and cancer (particularly lung cancer, cancers of the larynx and mouth, and pancreatic cancer) are some of the common diseases,” Agrawal ...

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### Variants of lipopeptides and glycolipids produced by Bacillus amyloliquefaciens and Pseudomonas aeruginosa cultured in different carbon substrates

The quantitative and qualitative effect of water immiscible and miscible carbon-rich substrates on the production of biosurfactants, surfactin and rhamnolipids, by Bacillus amyloliquefaciens ST34 and Pseudomonas ...

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### Characterisation and antimicrobial activity of biosurfactant extracts produced by Bacillus amyloliquefaciens and Pseudomonas aeruginosa isolated from a wastewater treatment plant

Biosurfactants are unique secondary metabolites, synthesised non-ribosomally by certain bacteria, fungi and yeast, with their most promising applications as antimicrobial agents and surfactants in the medical ...

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### Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion [Research]

Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4–/– mice were protected from allergen-induced mucus overproduction and changes along the nerve–PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4–/– mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve–PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.—Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus-Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion.

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### Abstract

Nickel–zinc ferrites with the general chemical formula, $$\hbox {Ni}_{0.3}\hbox {Zn}_{0.7-x}\hbox {Mg}_{x}\hbox {Fe}_{2}\hbox {O}_{4}$$ with x varying from 0.00 to 0.25 in steps of 0.05, have been prepared by conventional solid-state method. Final sintering of the samples was carried out at $$1200{^{\circ }}\hbox {C}$$ for 6 h in air to investigate their structural and magnetic properties. X-ray diffraction patterns of all the samples confirm the cubic spinel structure. Percent porosity and lattice constants of the samples are similar for all the samples except for the sample with $$x=0.05$$ implying that the changes in magnetic properties could be solely attributed to the effects caused by substitutions only. The saturation magnetization has been observed to increase continuously with the substitution of $$\hbox {Mg}^{2+}$$ ions in the place of $$\hbox {Zn}^{2+}$$ ions. Curie temperature of the system was also found to increase from $$261{^{\circ }}\hbox {C}$$ ( $$x=0.00$$ ) to $$364{^{\circ }}\hbox {C}$$ ( $$x=0.25$$ ) with the increase in magnesium content. Smooth coercivity variation suggests better structural homogeneity. The results are discussed in the light of the distribution of the cations among octahedral and tetrahedral sites.

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### Abstract

The Saha equations for the photoionization process of hydrogen atoms and the creation of electron–positron pairs at high temperature are investigated in a reference frame undergoing a uniform accelerated motion. It is known as the Rindler space.

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### Abstract

A direct rational exponential scheme is introduced and applied to construct exact multisoliton solutions of the clannish random walker's parabolic and the Vakhnenko–Parkes equations. We discuss the nature of soliton solutions before and after their interactions, and present their fusion (non-elastic) and elastic collisions of the soliton solutions. These soliton solutions of the equations are connected to physical phenomena: weakly non-linear surface, internal waves in a rotating ocean and interacting population motions. In addition, some three-dimensional and contour plots of the soliton wave solutions are presented to visualize the dynamics of the models.

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### Abstract

In order to further understand a self-exciting Faraday disc dynamo (Hide et al, in Proc. R. Soc. A 452, 1369 1996), showing chaotic attractors with very complicated topological structures, we present codimension one and two (degenerate) Hopf bifurcations and prove the existence of periodic solutions. In addition, numerical simulations are given for confirming the theoretical results.

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### Intervention for CPAP adherence in OSAS: a choice to patient or technique?

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### Objectives

The observer score of the trabecular pattern on panoramic radiographs is known to be a strong predictor of bone fractures. The aim of this study was to enhance the predictive power of panoramic radiographs by means of texture analysis methods.

### Material and methods

The study followed 304 postmenopausal women during 26 years. At the beginning of the study, panoramic radiographs were obtained. One observer assessed the trabecular pattern in the premolar region as dense, sparse, or alternating dense and sparse. In addition, on each radiograph, a region of interest was selected in the molar/premolar region and analyzed with texture analysis procedures. During 26 years of follow-up, 115 women suffered a fracture of the hip, spine, leg, or arm. Logistic regression was applied to test the predictive power of various variables with respect to fractures.

### Results

Of all variables, the observer score of the trabecular pattern correlated strongest with the occurrence of fractures. By itself, the score yielded an ROC curve with an area of 0.80 under the curve. Combining the observer score with the texture analysis features increased the area under the ROC curve to 0.85.

### Conclusions

The trabecular pattern on panoramic radiographs provides a strong predictor of fractures, at least for postmenopausal women. The assessment by an observer combined with texture analysis procedures yields a predictive power that parallels best known predictions in literature.

### Clinical relevance

This study illustrates that panoramic radiographs are state of the art predictors of postcranial fractures.

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### Abstract

There is conflicting evidence of the effectiveness of montelukast in preschool wheeze. A recent Cochrane review focused on its use in viral-induced wheeze; however, such subgroups are unlikely to exist in real life and change with time, recently highlighted in an international consensus report. We have therefore sought to investigate the effectiveness of montelukast in all children with preschool wheeze (viral-induced and multiple-trigger wheeze). The PubMed, Cochrane Library, Ovid Medline and Ovid EMBASE were screened for randomised controlled trials (RCTs), examining the efficacy of montelukast compared with placebo in children with the recurrent preschool wheeze. The primary endpoint examined was frequency of wheezing episodes. Five trials containing 3960 patients with a preschool wheezing disorder were analysed. Meta-analyses of studies of intermittent montelukast showed no benefit in preventing episodes of wheeze (mean difference (MD) 0.07, 95% confidence interval (CI) −0.14 to 0.29; mean for montelukast 2.68 vs placebo 2.54 (p = 0.5)), reducing unscheduled medical attendances (MD −0.13, 95% CI −0.33 to 0.07; mean for montelukast 1.62 vs placebo 1.78 (p = 0.21)) and reducing oral corticosteroids (MD −0.06, 95% CI −0.16 to 0.02; mean for montelukast 0.35 vs placebo 0.36 (p = 0.25)). The pooled results of the continuous regimen showed no significant difference in the number of wheezing episodes between the montelukast and placebo groups (MD −0.40, 95% CI −1.00 to 0.19; mean for montelukast 2.05 vs placebo 2.37 (p = 0.18)).

Conclusions: This review highlights that the currently available evidence does not support the use of montelukast in preschool children with recurrent wheeze. We recommend further studies to investigate if a ‘montelukast responder’ phenotype exists, and how these can be easily identified in the clinical setting.

 What is Known: • Current guidelines recommend montelukast use in preschool children with recurrent wheeze. • A recent Cochrane review has found montelukast to be ineffective at reducing courses of oral corticosteroids for viral-induced wheeze. What is New: • This meta-analysis has examined all children with preschool wheeze and found that montelukast was not effective at preventing wheezing episodes or reducing unscheduled medical attendances. • A specific montelukast responder phenotype may exist, but such patients should be sought in larger multicentre RCTs.

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### Neurobehavioral changes in mice offspring exposed to green tea during fetal and early postnatal development

Green tea extract (GTE) has various health promoting effects on animals and humans. However, the effects of perinatal exposure to GTE on the behavioral aspects of offspring have not been elucidated thus far. G...

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### Abstract

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### Abstract

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed.

Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG-1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge.

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### Abstract

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### Abstract

Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed pre-diagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin, and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988.

We conducted a nested case-control study including 127 non-cardia gastric adenocarcinoma (NCGA), 41 esophago-gastric junctional adenocarcinoma (EGJA), and 60 esophageal squamous cell carcinoma (ESCC) incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection, and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower pre-diagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7 to 12.6 for lowest compared to highest quartile, p-trend < 0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population.

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### Abstract

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5, and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n=244) or a control set (FIRE3-Bev, n=246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n=76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, P=0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, P=0.005, multivariate: HR 2.02, 95% CI: 1.14–3.55, P=0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients. This article is protected by copyright. All rights reserved.

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### Three Mile Island nuke accident linked to thyroid cancer - USA TODAY

 USA TODAY Three Mile Island nuke accident linked to thyroid cancer USA TODAY A new Penn State Medical Center study has found a link between the 1979 Three Mile Island nuclear accident and thyroid cancer cases in south-central Pennsylvania. The study marks the first time the partial meltdown of Unit 2's reactor can be connected ... Possible correlation shown between the partial meltdown at TMI and thyroid cancersScience Daily 'Possible' link between thyroid cancers and 1979 Three Mile Island nuclear accident reportedLancasterOnline Hershey researcher believes new study makes first connection between TMI and cancerPennLive.com York Daily Record/Sunday News -ABC27 all 8 news articles »

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### Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination

Oncolytic viruses selectively lyse tumor cells, disrupt immunosuppression within the tumor and reactivate anti-tumor immunity, but they have yet to live up to their therapeutic potential. Immune checkpoint modulation has been efficacious in a variety of cancer with an immunogenic microenvironment, but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies would likely result in both effective and specific cancer therapy. To test the hypothesis, we first constructed oncolytic adenovirus Delta-24-RGDOX expressing the immune co-stimulator OX40 ligand (OX40L). Like its predecessor Delta-24-RGD, Delta-24-RGDOX induced immunogenic cell death and recruit lymphocytes to the tumor site. Compared to Delta-24-RGD, Delta-24-RGDOX exhibited superior tumor-specific activation of lymphocytes and proliferation of CD8+ T cells specific to tumor-associated antigens, resulting in cancer-specific immunity. Delta-24-RGDOX mediated more potent anti-glioma activity in immune-competent C57BL/6 but not immune-deficient athymic mice, leading to specific immune memory against the tumor. In order to further overcome the immune suppression mediated by programmed death-ligand 1 (PD-L1) expression on cancer cells accompanied with virotherapy, intratumoral injection of Delta-24-RGDOX and an anti-PD-L1 antibody showed synergistic inhibition of gliomas and significantly increased survival in mice. Our data demonstrate that combining an oncolytic virus with tumor-targeting immune checkpoint modulators elicits potent in situ autologous cancer vaccination, resulting in an efficacious, tumor-specific and long-lasting therapeutic effect.

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### Pharmacokinetics and drug-interactions determine optimum combination strategies in computational models of cancer evolution

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression - a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multi-scale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting non-intuitive strategies for combination therapies. We applied our approach to an ongoing phase-Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the maximally tolerated dose are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials.

MAJOR FINDINGS

Drugs used in cancer treatment exhibit varied temporal dynamics of absorption and clearance, summarized by their pharmacokinetic (PK) parameters. Typically these dynamics are neglected in evolutionary models of cancer progression under combination therapy. By developing a computational framework to incorporate PK and drug interaction effects, we showed that the complex interplay of dynamics of drugs and various cancer clones significantly affect dosing strategies. Applied to an ongoing phase-Ib clinical trial, our framework predicted efficacies of different dosing schedules and suggested new strategies to significantly improve cancer cell eradication and reduce associated toxicities.

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