Obstacle Numbers of Planar Graphs

Given finitely many connected polygonal obstacles $O_1,\dots,O_k$ in the plane and a set $P$ of points in general position and not in any obstacle, the {\em visibility graph} of $P$ with obstacles $O_1,\dots,O_k$ is the (geometric) graph with vertex set $P$, where two vertices are adjacent if the straight line segment joining them intersects no obstacle. The obstacle number of a graph $G$ is the smallest integer $k$ such that $G$ is the visibility graph of a set of points with $k$ obstacles. If $G$ is planar, we define the planar obstacle number of $G$ by further requiring that the visibility graph has no crossing edges (hence that it is a planar geometric drawing of $G$). In this paper, we prove that the maximum planar obstacle number of a planar graph of order $n$ is $n-3$, the maximum being attained (in particular) by maximal bipartite planar graphs. This displays a significant difference with the standard obstacle number, as we prove that the obstacle number of every bipartite planar graph (and more generally in the class PURE-2-DIR of intersection graphs of straight line segments in two directions) of order at least $3$ is $1$.Comment: Appears in the Proceedings of the 25th International Symposium on Graph Drawing and Network Visualization (GD 2017

Gene expression patterns that predict sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer cell lines and human lung tumors

BACKGROUND: Increased focus surrounds identifying patients with advanced non-small cell lung cancer (NSCLC) who will benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). EGFR mutation, gene copy number, coexpression of ErbB proteins and ligands, and epithelial to mesenchymal transition markers all correlate with EGFR TKI sensitivity, and while prediction of sensitivity using any one of the markers does identify responders, individual markers do not encompass all potential responders due to high levels of inter-patient and inter-tumor variability. We hypothesized that a multivariate predictor of EGFR TKI sensitivity based on gene expression data would offer a clinically useful method of accounting for the increased variability inherent in predicting response to EGFR TKI and for elucidation of mechanisms of aberrant EGFR signalling. Furthermore, we anticipated that this methodology would result in improved predictions compared to single parameters alone both in vitro and in vivo. RESULTS: Gene expression data derived from cell lines that demonstrate differential sensitivity to EGFR TKI, such as erlotinib, were used to generate models for a priori prediction of response. The gene expression signature of EGFR TKI sensitivity displays significant biological relevance in lung cancer biology in that pertinent signalling molecules and downstream effector molecules are present in the signature. Diagonal linear discriminant analysis using this gene signature was highly effective in classifying out-of-sample cancer cell lines by sensitivity to EGFR inhibition, and was more accurate than classifying by mutational status alone. Using the same predictor, we classified human lung adenocarcinomas and captured the majority of tumors with high levels of EGFR activation as well as those harbouring activating mutations in the kinase domain. We have demonstrated that predictive models of EGFR TKI sensitivity can classify both out-of-sample cell lines and lung adenocarcinomas. CONCLUSION: These data suggest that multivariate predictors of response to EGFR TKI have potential for clinical use and likely provide a robust and accurate predictor of EGFR TKI sensitivity that is not achieved with single biomarkers or clinical characteristics in non-small cell lung cancers

Vulnerable warriors: the atmospheric marketing of military and policing equipment before and after 9/11

In this article, we analyse changes in the circulation of advertisements of policing products at security expos between 1995 and 2013. While the initial aim of the research was to evidence shifts in terrorist frames in the marketing of policing equipment before and after 9/11, our findings instead suggested that what we are seeing is the rise of marketing to police as “vulnerable warriors”, law enforcement officers in need of military weapons both for their offensive capabilities and for the protection they can offer to a police force that is always under threat

MUC1 Is a Downstream Target of STAT3 and Regulates Lung Cancer Cell Survival and Invasion

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in human cancer including lung cancer and has been implicated in transformation, tumorigenicity, and metastasis. One putative downstream gene regulated by Stat3 is MUC1 which also has important roles in tumorigenesis. We determined if Stat3 regulates MUC1 in lung cancer cell lines and what function MUC1 plays in lung cancer cell biology. We examined MUC1 expression in non-small cell lung cancer (NSCLC) cell lines and found high levels of MUC1 protein expression associated with higher levels of tyrosine phosphorylated STAT3. STAT3 knockdown downregulated MUC1 expression whereas constitutive STAT3 expression increased MUC1 expression at mRNA and protein levels. MUC1 knockdown induced cellular apoptosis concomitant with reduced Bcl-XL and sensitized cells to cisplatin treatment. MUC1 knockdown inhibited tumor growth and metastasis in an orthotopic mouse model of lung cancer by activating apoptosis and inhibiting cell proliferation in vivo. These results demonstrate that constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis in vitro and in vivo. MUC1 appears to be a cooperating oncoprotein with multiple oncogenic tyrosine kinase pathways and could be an effective target for the treatment of lung cancer

M\"ossbauer Antineutrinos: Recoilless Resonant Emission and Absorption of Electron Antineutrinos

Basic questions concerning phononless resonant capture of monoenergetic electron antineutrinos (M\"ossbauer antineutrinos) emitted in bound-state beta-decay in the 3H - 3He system are discussed. It is shown that lattice expansion and contraction after the transformation of the nucleus will drastically reduce the probability of phononless transitions and that various solid-state effects will cause large line broadening. As a possible alternative, the rare-earth system 163Ho - 163Dy is favoured. M\"ossbauer-antineutrino experiments could be used to gain new and deep insights into several basic problems in neutrino physics

Антимікробна активність in vitro нанодисперсного кремнезему і композиту полігексаметиленгуанідину гідрохлориду для лікування місцевих інфекцій

The problem of antimicrobial drug resistance can be solved through the development of novel antimicrobial compounds and combination drugs. In order to enhance polyhexamethyleneguanidine hydrochloride (PHMG-HC) therapeutic benefits, a composite (code name CMU-211) of PHMG-HC with a nanoparticle-based sorbent of highly dispersed silica (HDS) was developed.Aim. To evaluate in vitro antimicrobial activity of highly dispersed silica and PHMG-HC (HDS + PHMG-HC) composite (CMU-211), highly dispersed silica (HDS) suspension (CMU-212), and PHMG-HC solution as a reference against standard test-strains.Materials and methods. HDS + PHMG-HC composite, HDS suspension, and PHMG-HC solution. Microbial test-strains (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Candida albicans). An antimicrobial activity of substances was studied with broth dilution method in LB liquid medium, minimum inhibitory concentrations (MIC) were obtained.Results. CMU-211 has been shown to have high activity against C. albicans and S. aureus with a minimum inhibitory concentration (MIC) of 48.83/9.77 μg/mL (HDS/PHMG-HC) and marked effect on E. coli (MIC of 97.66/19.53 μg/mL) and S. enterica (MIC of 195.31/39.06 μg/mL). The relatively low activity of CMU-211 was reported against K. pneumoniae (MIC of 390.63/78.13 μg/mL) and P. aeruginosa (MIC of 195.31/39.06 μg/mL), however, the effect on P. aeruginosa was consistent with the activity of PHMG-HC applied alone. The concentrations of CMU-211 had to be twice as high as the MICs to ensure bactericidal (fungicidal) effect on microorganisms studied, except of S. enterica and K. pneumoniae for which bacteriostatic concentration was also proved to be bactericidal.Conclusions. These results taken together with previous findings on CMU-211 high sorption activity suggest that the composite has double therapeutic activity and may be beneficial for local infections treatment.Резистентность к антимикробным препаратам является актуальной проблемой для всего мира, которая негативно влияет на результаты лечения больных. Решить поставленную проблему можно путем создания и внедрения новых антимикробных соединений и комплексных лекарственных средств. Актуальным остается разработка комбинированного антимикробного средства, которое бы проявляло выраженное антимикробное действие и сорбционные свойства. В качестве противомикробного компонента был избран полигексаметиленгуанидина гидрохлорид (ПГМГ-ГХ), который является высокомолекулярным катионным поверхностно-активным веществом группы гуанидина.Цель. Определить противомикробную активность суспензии нанодисперсного кремнезема (НДК), композита НДК и ПГМГ-ГХ и раствора полимера ПГМГ-ГХ.Материалы и методы. В работе были использованы 5 % суспензия НДК, модифицированная полимером ПГМГ-ГХ; 5 % суспензия НДК и 20 % водный раствор полигексаметиленгуанидина гидрохлорида. Исследование антимикробной активности веществ проводили на микроорганизмах: Escherichia coli; Staphylococcus aureus; Pseudomonas aeruginosa; Salmonella enterica; Klebsiella pneumoniae; Candida albicans.Результаты. Композит НДК/ПГМГ-ГХ обладает высокой активностью против C. albicans и S. aureus с МИК ~10 мкг/мл (в пересчете на ПГМГ-ГХ) и выраженной активностью против Е. coli (MIC ~20 мкг/мл), S. enterica (MIC ~40 мкг/мл) и P. aeruginosa (MIC ~40 мкг/мл). Относительно низкую активность композит НДК/ПГМГ-ГХ проявил к K. pneumoniae (MIC ~ 80 мкг/мл). Активность композита НДК/ПГМГ-ГХ была сходна с таковой у ПГМГ-ГХ.Выводы. Разработанный композит НДК/ПГМГ-ГХ проявляет выраженное антибактериальное действие по отношению к грамположительным, грамотрицательным микроорганизмам, а также C. albicans.Резистентність до антимікробних препаратів є актуальною проблемою для всіх країн світу, що негативно впливає на результати лікування хворих. Вирішити поставлену проблему можна шляхом створення та впровадження нових антимікробних сполук та комплексних лікарських засобів. Актуальним залишається розробка комбінованого антимікробного засобу, який би проявляв виражену антимікробну дію та сорбційні властивості. В якості антимікробного компоненту було обрано полігексаметиленгуанідину гідрохлорид (ПГМГ-ГХ), що є високомолекулярною катіонною поверхнево-активною речовиною групи гуанідинів.Мета. Визначити антимікробну активність суспензії нанодисперсного кремнезему (НДК), композиту НДК та ПГМГ-ГХ і розчину полімера ПГМГ-ГХ.Матеріали та методи. В роботі була використана 5 % суспензія НДК, модифікована полімером ПГМГ-ГХ; 5 % суспензія НДК та 20 % водний розчин полігексаметиленгуанідину гідрохлориду. Дослідження антимікробної активності речовин проводили на мікроорганізмах: Escherichia coli; Staphylococcus aureus; Pseudomonas aeruginosa; Salmonella enterica; Klebsiella pneumoniae; Candida albicans.Результати. Композит НДК/ПГМГ-ГХ має високу активність проти C. albicans і S. aureus з МІК ~10 мкг/мл (у перерахунку на ПГМГ-ГХ) і виражену активність проти Е. coli (MIC ~20 мкг/мл), S. enterica (MIC ~40 мкг/мл) і P. aeruginosa (MIC ~40 мкг/мл). Відносно низьку активність композит НДК/ПГМГ-ГХ проявив щодо K. pneumoniae (MIC ~80 мкг/мл). Активність композиту НДК/ПГМГ-ГХ була подібна до такої ж у ПГМГ-ГХ.Висновки. Розроблений композит НДК/ПГМГ-ГХ проявляє виражену антибактеріальну дію щодо грампозитивних, грамнегативних мікроорганізмів, а також C. albicans

If we build it they will come: targeting the immune response to breast cancer.

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance

Identifying Resistance Mechanisms against Five Tyrosine Kinase Inhibitors Targeting the ERBB/RAS Pathway in 45 Cancer Cell Lines

Because of the low overall response rates of 10-47% to targeted cancer therapeutics, there is an increasing need for predictive biomarkers. We aimed to identify genes predicting response to five already approved tyrosine kinase inhibitors. We tested 45 cancer cell lines for sensitivity to sunitinib, erlotinib, lapatinib, sorafenib and gefitinib at the clinically administered doses. A resistance matrix was determined, and gene expression profiles of the subsets of resistant vs. sensitive cell lines were compared. Triplicate gene expression signatures were obtained from the caArray project. Significance analysis of microarrays and rank products were applied for feature selection. Ninety-five genes were also measured by RT-PCR. In case of four sunitinib resistance associated genes, the results were validated in clinical samples by immunohistochemistry. A list of 63 top genes associated with resistance against the five tyrosine kinase inhibitors was identified. Quantitative RT-PCR analysis confirmed 45 of 63 genes identified by microarray analysis. Only two genes (ANXA3 and RAB25) were related to sensitivity against more than three inhibitors. The immunohistochemical analysis of sunitinib-treated metastatic renal cell carcinomas confirmed the correlation between RAB17, LGALS8, and EPCAM and overall survival. In summary, we determined predictive biomarkers for five tyrosine kinase inhibitors, and validated sunitinib resistance biomarkers by immunohistochemistry in an independent patient cohort. © 2013 Pénzváltó et al

Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies

Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2+/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2+/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2+/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CAH1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies

Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution

Breast cancers that occur in women 2–5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared with breast cancers diagnosed in young, premenopausal women. The molecular mechanisms underlying the malignant severity associated with postpartum breast cancers (ppBCs) are unclear but relate to stromal wound-healing events during postpartum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune–competent mice, we discovered that postpartum involution increases mammary tumor metastasis. Cell death was widespread, not only occurring in MECs but also in tumor epithelium. Dying tumor cells were cleared through receptor tyrosine kinase MerTK–dependent efferocytosis, which robustly induced the transcription of genes encoding wound-healing cytokines, including IL-4, IL-10, IL-13, and TGF-β. Animals lacking MerTK and animals treated with a MerTK inhibitor exhibited impaired efferocytosis in postpartum tumors, a reduction of M2-like macrophages but no change in total macrophage levels, decreased TGF-β expression, and a reduction of postpartum tumor metastasis that was similar to the metastasis frequencies observed in nulliparous mice. Moreover, TGF-β blockade reduced postpartum tumor metastasis. These data suggest that widespread cell death during postpartum involution triggers efferocytosis-induced wound-healing cytokines in the tumor microenvironment that promote metastatic tumor progression