A Higher-Order Colon Translation

A lambda-encoding such as the CPS transformation gives rise to administrative redexes. In his seminal article "Call-by-name, call-by-value and the lambda-calculus", 25 years ago, Plotkin tackled administrative reductions using a so-called colon translation. In "Representing control,a study of the CPS transformation", 15 years later, Danvy and Filinski integrated administrative reductions in the CPS transformation, making it operate in one pass. This one-pass transformation is higher-order, and can be used for other lambda-encodings, but we do not see its associated proof technique used in practice - instead, Plotkin's colon translation appears to be favored. Therefore, in an attempt to link the higher-order transformation and Plotkin's proof technique, we recast Plotkin's proof of Indifference and Simulation in a higher-order setting. To this end, we extend the colon translation from first order to higher order.Keywords: Call by name, call by value, lambda-calculus, continuation-passing style(CPS), CPS transformation, administrative reductions, colon translation, one-pass CPS transformation, Indifference, Simulation.

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex<sup>GM-CSF</sup>]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions

Molecular mechanisms of IL-18BP regulation in DLD-1 cells: pivotal direct action of the STAT1/GAS axis on the promoter level

Interleukin (IL)-18, formerly known as interferon (IFN)-γ-inducing factor, is a crucial mediator of host defence and inflammation. Control of IL-18 bioactivity by its endogenous antagonist IL-18 binding protein (IL-18BP) is a major objective of immunoregulation. IL-18BP is strongly up-regulated by IFN-γ, thereby establishing a negative feedback mechanism detectable in cell culture and in vivo. Here we sought to investigate in D.L. Dexter (DLD) colon carcinoma cells molecular mechanisms of IL-18BP induction under the influence of IFN-γ. Mutational analysis revealed that a proximal γ-activated sequence (GAS) at the IL-18BP promoter is of pivotal importance for expression by IFN-γ-activated cells. Use of siRNA underscored the essential role of the signal transducer and activator of transcription (STAT)-1 in this process. Indeed, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis proved STAT1 binding to this particular GAS site. Maximal expression of IL-18BP was dependent on de novo protein synthesis but unaffected by silencing of interferon regulatory factor-1. Altogether, data presented herein indicate that direct action of STAT1 on the IL-18BP promoter at the proximal GAS element is key to IL-18BP expression by IFN-γ-stimulated DLD-1 colon carcinoma cells

The micronutrient profile of the typical American diet enhances colorectal carcinogenesis

The typical Western dietary pattern is characterized by the consumption of energy-dense, nutrient-poor foods and has been linked to increased risk of colorectal cancer (CRC). Our research group previously developed the total Western diet (TWD) that emulates typical human dietary intakes of macro- (carbohydrates, proteins, and fats) and micronutrients (vitamins and minerals) on an energy density basis for rodents. In the present study, we sought to determine the impact of TWD on biomarkers of metabolic syndrome and obesity in comparison to a commercial 45% fat diet used for models of diet-induced obesity (DIO diet) and the standard basal AIN93G diet, which is optimized for rodent health. Also, we included 2 additional test diets to evaluate the contribution of the micronutrient (vitamin- and mineral-modified diet, [VMM]) or macronutrient (macro-modified diet [MM]) contents of the TWD in development of cancer, obesity, and glucose intolerance. A chemical carcinogenesis model of inflammation-associated colon cancer was employed to evaluate impact of diets on colon cancer in mice. As expected, mice consuming the DIO diet acquired an obesity/metabolic syndrome phenotype typified by increased food energy intake, greater rate of body weight gain, increased proportion of body composition as fat mass, higher fasting glucose, impaired glucose tolerance, and higher circulating levels of leptin. However, consumption of TWD did not alter any of these classic biomarkers of metabolic health, as these mice adjusted food intake so that energy consumption was similar to that for mice fed AIN93G. A different pattern was observed for colon carcinogenesis. Consumption of the TWD or VMM diet markedly increased colon tumor multiplicity and size compared to the AIN93G control, whereas consumption of the DIO or MM diets did not enhance colon tumorigenesis. Collectively, these observations point to a critical role of dietary micronutrients in colon carcinogenesis, and that this promoting effect is likely unrelated to the metabolic syndrome phenotype induced by a high fat diet. Moreover, our observations emphasize the need to take into account the micronutrient content of rodent basal diets when modeling typical U.S. nutrition in pre-clinical animal experiments in order to improve the translation of these studies to human nutrition and dietary intervention programs

Computer-assisted polyp matching between optical colonoscopy and CT colonography: a phantom study

Potentially precancerous polyps detected with CT colonography (CTC) need to be removed subsequently, using an optical colonoscope (OC). Due to large colonic deformations induced by the colonoscope, even very experienced colonoscopists find it difficult to pinpoint the exact location of the colonoscope tip in relation to polyps reported on CTC. This can cause unduly prolonged OC examinations that are stressful for the patient, colonoscopist and supporting staff. We developed a method, based on monocular 3D reconstruction from OC images, that automatically matches polyps observed in OC with polyps reported on prior CTC. A matching cost is computed, using rigid point-based registration between surface point clouds extracted from both modalities. A 3D printed and painted phantom of a 25 cm long transverse colon segment was used to validate the method on two medium sized polyps. Results indicate that the matching cost is smaller at the correct corresponding polyp between OC and CTC: the value is 3.9 times higher at the incorrect polyp, comparing the correct match between polyps to the incorrect match. Furthermore, we evaluate the matching of the reconstructed polyp from OC with other colonic endoluminal surface structures such as haustral folds and show that there is a minimum at the correct polyp from CTC. Automated matching between polyps observed at OC and prior CTC would facilitate the biopsy or removal of true-positive pathology or exclusion of false-positive CTC findings, and would reduce colonoscopy false-negative (missed) polyps. Ultimately, such a method might reduce healthcare costs, patient inconvenience and discomfort.Comment: This paper was presented at the SPIE Medical Imaging 2014 conferenc

Punctuation effects in English and Esperanto texts

A statistical physics study of punctuation effects on sentence lengths is presented for written texts: {\it Alice in wonderland} and {\it Through a looking glass}. The translation of the first text into esperanto is also considered as a test for the role of punctuation in defining a style, and for contrasting natural and artificial, but written, languages. Several log-log plots of the sentence length-rank relationship are presented for the major punctuation marks. Different power laws are observed with characteristic exponents. The exponent can take a value much less than unity ($ca.$ 0.50 or 0.30) depending on how a sentence is defined. The texts are also mapped into time series based on the word frequencies. The quantitative differences between the original and translated texts are very minutes, at the exponent level. It is argued that sentences seem to be more reliable than word distributions in discussing an author style.Comment: 13 pages, 7 figures (3x2+1), 60 reference

HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers

The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer