Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers doi: 10.3390/cancers10030061

Authors: Sergio Lamprecht Ina Sigal-Batikoff Shraga Shany Naim Abu-Freha Eduard Ling George Delinasios Keren Moyal-Atias John Delinasios Alexander Fich

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells.

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Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers doi: 10.3390/cancers10030060

Authors: Urska Kamensek Natasa Tesic Gregor Sersa Maja Cemazar

Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU.

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Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers doi: 10.3390/cancers10030059

Authors: David Corujo Marcus Buschbeck

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.

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Analysis of EML4-ALK rearrangement in non-small cell lung cancer in Argentina

Publication date: Available online 26 February 2018
Source:Annals of Diagnostic Pathology
Author(s): Verzura María, Batagelj Emilio, Bagnes Claudia, Martin Claudio, Enrico Diego, Richardet Eduardo, Paola De la Iglesia
IntroductionIdentification of EML4-ALK rearrangement by FISH test has become standard in advanced NSCLC patients. There is limited information about the prevalence and clinical characteristics of ALK translocation in Latin America. The aim of our study was to evaluate this lung cancer subtype features in Argentinian patients and the factibility of FISH test with different methods used for obtaining tissue samples.MethodsBetween August 2014 and February 2017, 183 non-squamous NSCLC patients were prospectively enrolled from five Argentinean institutions. Different techniques procedures were used to obtained tissue samples material. ALK determination was performed by FISH and IHC.Correlation with clinical-pathological information and the different biopsy procedures was assessed.ResultsFrom 183 non-squamous NSCLC samples, 131 could perform FISH test, finding 123 (93.9%) negative and 8 (6.1%) positive patients. Fifty-one samples were not evaluable by FISH, 35 because of technical problems and 16 due to not/weak signal.The difficulties in obtaining adequate FISH tests were observed significantly more frequently for fine-needle aspiration (FNA) and core-needle biopsy than for excisional and incisional biopsy (p = 0.009). Regarding the procedures, surgery was the most efficient obtaining only 12,7% (10/79) of not evaluable samples for FISH, while CT guided biopsy and transbronchial biopsy (TBB) failed in 43.8% (21/48) and 41.3% (19/46) of patients respectively (p < 0.001). We observed a significant association between ALK translocation and never smoking habit (p = 0.004).ConclusionOur ALK rearrangements frequency (6.1%) was similar to the reports worldwide. One of the major determinants for the ALK FISH test success is the quality of the tissue sample obtained.



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Diagnosis and endoscopic endonasal management of nontraumatic pseudoaneurysms of the cranial base

Background

Nontraumatic pseudoaneurysms of the cranial base are rare and present unique diagnostic and treatment dilemmas compared with both true aneurysms and pseudoaneurysms outside of the cranial base. There is a dearth of knowledge regarding the management of these complicated lesions.

Methods

Nontraumatic pseudoaneurysms of the cranial base internal carotid artery (ICA) were retrospectively identified at the University of Pittsburgh Medical Center through a key word search of cranial base cases from 2010 to 2017.

Results

Three cases were identified, demonstrating pseudoaneurysms of the cavernous and petrous ICA. Each patient underwent diagnostic work-up with computed tomography, magnetic resonance imaging, and angiography, followed by endovascular occlusion and endoscopic endonasal surgery, which resulted in relief of presenting complaints and ablation of the pseudoaneurysm.

Conclusion

Symptomatic cranial base pseudoaneurysms should undergo treatment to obliterate the aneurysm and relieve the mass effect. First, formal angiography is necessary for accurate diagnosis and treatment planning. Next, endovascular occlusion is performed, with a preference for coiling or endoluminal reconstruction with a flow diverter. Last, endoscopic intervention follows in cases where: (1) decompression of vital structures is indicated; (2) diagnosis of the pseudoaneurysm cannot be definitively confirmed with angiography; or (3) the etiology of the confirmed pseudoaneurysm requires further investigation.

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Management of long-lasting phantosmia: a systematic review

Background

Interest in the pathophysiology and management of phantom smells has increased rapidly over the last decade. A PubMed search for the term "phantosmia" demonstrated a near-doubling of articles published on phantosmia within the past 7 years. We aimed to systematically review the literature on the management of phantosmia.

Methods

The PubMed, EMBASE, and Cochrane databases were searched for articles published since January 1990, using terms combined with pertinent Boolean search operators. We included articles evaluating management of phantosmia written in the English language, with original data and a minimum of 6 months of follow-up, on at least 2 patients and with well-defined and measurable outcomes.

Results

A total of 2151 unique titles were returned upon the initial search. Of these, 146 abstracts were examined, yielding 7 articles meeting the inclusion criteria. All articles were predominantly level 4 evidence. One prospective level 3 study was included. The studies included a total of 96 patients, with follow-up ranging from 6 months to 11 years. Endpoints were primarily based on subjective patient responses. Management options included observation and medical and surgical therapy. Olfactory mucosa excision was the only surgical intervention studied, with short-term symptomatic improvement in 10 of 11 patients. Forty-one patients were treated medically, which included antipsychotic, antimigraine, and antiseizure medications, transcranial stimulation, and topical cocaine application.

Conclusion

Despite increasing interest in the treatment of phantosmia and reports of successful therapies, there remains a paucity of data and lack of consensus regarding optimal management of this difficult condition.

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A challenge-response endoscopic sinus surgery specific checklist as an add-on to standard surgical checklist: an evaluation of potential safety and quality improvement issues

Background

The goal of this study was to develop and evaluate the impact of an aviation-style challenge and response sinus surgery–specific checklist on potential safety and equipment issues during sinus surgery at a tertiary academic health center. The secondary goal was to assess the potential impact of use of the checklist on surgical times during, before, and after surgery. This initiative is designed to be utilized in conjunction with the "standard" World Health Organization (WHO) surgical checklist. Although endoscopic sinus surgery is generally considered a safe procedure, avoidable complications and potential safety concerns continue to occur. The WHO surgical checklist does not directly address certain surgery-specific issues, which may be of particular relevance for endoscopic sinus surgery.

Methods

This prospective observational pilot study monitored compliance with and compared the occurrence of safety and equipment issues before and after implementation of the checklist. Forty-seven consecutive endoscopic surgeries were audited; the first 8 without the checklist and the following 39 with the checklist. The checklist was compiled by evaluating the patient journey, utilizing the available literature, expert consensus, and finally reevaluation with audit type cases. The final checklist was developed with all relevant stakeholders involved in a Delphi method.

Results

Implementing this specific surgical checklist in 39 cases at our institution, allowed us to identify and rectify 35 separate instances of potentially unsafe, improper or inefficient preoperative setup. These incidents included issues with labeling of topical vasoconstrictor or injectable anesthetics (3, 7.7%) and availability, function and/or position of video monitors (2, 5.1%), endoscope (6, 15.4%), microdebrider (6, 15.4%), bipolar cautery (6, 15.4%), and suctions (12, 30.8%).

Conclusion

The design and integration of this checklist for endoscopic sinus surgery, has helped improve efficiency and patient safety in the operating room setting.

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Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Abstract

Background

In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results

Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions

This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.

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Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis

Abstract

Background

Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis.

Results

Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h.

No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO₃⁻ were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h.

Conclusion

Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

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Books Received

ALEXANDER, ZEYNEP ÇELIK. Kineasthetic Knowing: Aesthetics, Epistemology, and Modern Design. (Chicago: University of Chicago Press). 2017. pp. 311. £40.54 (hbk).

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Journals Received

JTLA, Journal of the Faculty of Letters, The University of Tokyo: Aesthetics.

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Notes on Contributors

CHRISTOPHER BARTEL is an Associate Professor in Philosophy at Appalachian State University. His research interests primarily lie within aesthetics with a special focus on philosophy of music and philosophy of video games. He has published essays on the ontology of musical works, the ethics of video games, and historical inaccuracies in works of fiction. His essays have appeared in the British Journal of Aesthetics, Ethics and Information Technology, the European Journal of Philosophy, and the Journal of Aesthetics and Art Criticism.

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Nahlowsky’s Psychological Aesthetics

Abstract

My article aims to revisit the aesthetic thought of the Austrian psychologist and philosopher Joseph Wilhelm Nahlowsky (1812–1885), as expounded in his formerly famous monograph Das Gefühlsleben. I show that although Nahlowsky was a direct heir of Herbart, his ideas were in keeping with both the contemporary debate about form and content and the then-emerging paradigm of psychological aesthetics. I describe his developments on aesthetic feelings and his remarkable attempt to elaborate a general psycho-affective theory on the experience of the aesthetic object. I also discuss the importance of the notion of form, inherited from Herbart, in his psychological aesthetics. Finally, I demonstrate that, in addition to having marked an 'affective' turn in Herbartianism, Nahlowsky was a key actor in the evolution of ideas in psychological aesthetics in the second half of the nineteenth century.

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The Value of Fidelity in Adaptation

The adaptation of literary works into films has been almost completely neglected as a philosophical topic. I discuss two questions about this phenomenon:

• What do we mean when we say that a film is faithful to its source?
• Is being faithful to its source a merit in a film adaptation?

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Appearance and History: the Autographic/Allographic Distinction Revisited

Abstract

Nelson Goodman notoriously distinguished between autographic works, whose instances should be identified by taking history of production into account, and allographic works, whose instances can be identified independently of history of production. Scholars such as Jerrold Levinson, Flint Schier, and Gregory Currie have criticized Goodman's autographic/allographic distinction arguing that all works are such that their instances should be identified by taking history of production into account. I will address this objection by exploiting David Davies' distinction between e-instances and p-instances of a work, thereby restating the autographic/allographic distinction. Then, I will show that this way of restating this distinction leads us to effective accounts of relevant related phenomena such as forgery, plagiarism, and digital technologies. Finally, I will show the theoretical advantages of my account of the autographic/allographic distinction in comparison with an alternative account recently proposed by Jason D'Cruz and P.D. Magnus.

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Body Aesthetics

Body AestheticsIrvinSherri (ed.)OUP. 2016. pp. 352. £40.00 (hbk).

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‘Nothing but Nonsense’: A Kantian Account of Ugliness1

Abstract

What does it mean for something to be judged ugly? On Kant's account of aesthetic judgment, an object judged beautiful brings about a 'free play of the imagination and the understanding', and is thus given as though 'purposive without purpose'; but ugliness, Kant claims, is the 'contrary to beauty'. Assuming Kant is correct on all counts, we would have to conclude that the object judged ugly would bring about a dynamic that is contrary to this ' free play', but that is nevertheless not its mere absence—since its absence is what is exhibited in usual cognitive, non-aesthetic judgment. Likewise, an ugly object is one that would have to be given as though contrapurposive, yet without running counter to any specific end of ours. In this essay, I try to clear up what this can mean, in order to clarify the judgment of ugliness.

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‘It’s Just a Story’: Pornography, Desire, and the Ethics of Fictive Imagining

Abstract

Is it ever morally wrong for a consumer to imagine something immoral? Brandon Cooke has recently argued that it cannot be. On Cooke's account, fictive imagining is immune to moral criticism because such cases of imagining do not amount to the consumer's endorsement of the immoral content, nor do they imply that the authors of such fictions necessarily endorse their contents. We argue against Cooke that in fact fictively imagining something immoral can be morally blameworthy for the consumer, specifically in cases where fictive imagining is engaged in the service of immoral desires. Taking one potent case—namely, rape-fantasy pornography—we argue that the proper engagement with pornography requires the engagement of the consumer's desires, and that consumers often engage with works of pornography as a way of 'trying on' desires. Insofar as it is morally wrong to desire something immoral, then it is also morally wrong to cultivate an immoral desire; and for some consumers, fictive imagining is a means of cultivating immoral desires. In this restricted sense, we argue that it can be morally wrong for a consumer to engage in fictively imagining immoral things.

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Eat this Book: A Carnivore’s ManifestoTaste as Experience. The Philosophy and Aesthetics of Food

Eat This Book: A Carnivore's ManifestoLestelDominique, Trans. Gary Steiner.Columbia University Press. 2016. pp. 160. £14.95 (pbk).

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Strange Tools: Art and Human Nature

Strange Tools: Art and Human NatureNoëAlvaHill and Wang. 2015. pp. 304. £;21.81 (hbk).

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