BackgroundThough the management of malignancies has improved vastly in recent years, many treatment options lack the desired efficacy and fail to adequately augment patient morbidity and mortality. It is increasingly clear that patient response to therapy is unique to each individual, necessitating personalised, or ‘precision’ medical care. This demand extends to thyroid cancer; ~ 10% patients fail to respond to radioiodine treatment due to loss of phenotypic differentiation, exposing the patient to unnecessary ionising radiation, as well as delaying treatment with alternative therapies.MethodsHuman thyroid tissue (n = 23, malignant and benign) was live-sliced (5 mm diameter × 350-500 μm thickness) then analysed or incorporated into a microfluidic culture device for 96 h (37 °C). Successful maintenance of tissue was verified by histological (H&E), flow cytometric propidium iodide or trypan blue uptake, immunohistochemical (Ki67 detection/ BrdU incorporation) and functional analysis (thyroxine [T4] output) in addition to analysis of culture effluent for the cell death markers lactate dehydrogenase (LDH) and dead-cell protease (DCP). Apoptosis was investigated by Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Differentiation was assessed by evaluation of thyroid transcription factor (TTF1) and sodium iodide symporter (NIS) expression (western blotting).ResultsMaintenance of gross tissue architecture was observed. Analysis of dissociated primary thyroid cells using flow cytometry both prior to and post culture demonstrated no significant change in the proportion of viable cells. LDH and DCP release from on-chip thyroid tissue indicated that after an initial raised level of release, signifying cellular damage, detectable levels dropped markedly. A significant increase in apoptosis (p < 0.01) was observed after tissue was perfused with etoposide and JNK inhibitor, but not in control tissue incubated for the same time period. No significant difference in Ki-67 positivity or TTF1/NIS expression was detected between fresh and post-culture thyroid tissue samples, moreover BrdU positive nuclei indicated on-chip cellular proliferation. Cultured thyroid explants were functionally viable as determined by production of T4 throughout the culture period.ConclusionsThe described microfluidic platform can maintain the viability of thyroid tissue slices ex vivo for a minimum of four days, providing a platform for the assessment of thyroid tissue radioiodine sensitivity/adjuvant therapies in real time.

Legendre transformations provide a natural symmetry on the space of solutions to the WDVV equations, and more specifically, between different Frobenius manifolds. In this paper a twisted Legendre transformation is constructed between solutions which define the corresponding dual Frobenius manifolds. As an application it is shown that certain trigonometric and rational solutions of the WDVV equations are related by such a twisted Legendre transform. F −→F1991 Mathematics Subject Classification. 11F55, 53B50, 53D45.

Background: Though the management of malignancies has improved vastly in recent years, many treatment options lack the desired efficacy and fail to adequately augment patient morbidity and mortality. It is increasingly clear that patient response to therapy is unique to each individual, necessitating personalised, or 'precision' medical care. This demand extends to thyroid cancer; ~10% patients fail to respond to radioiodine treatment due to loss of phenotypic differentiation, exposing the patient to unnecessary ionising radiation, as well as delaying treatment with alternative therapies.Methods: Human thyroid tissue (n=23, malignant and benign) was live-sliced (5mm diameter x 350-500µm thickness) then analysed or incorporated into a microfluidic culture device for 96hr (37°C). Successful maintenance of tissue was verified by histological (H&E), flow cytometric propidium iodide or trypan blue uptake, immunohistochemical (Ki67 detection/ BrdU incorporation) and functional analysis (thyroxine [T4] output) in addition to analysis of culture effluent for the cell death markers lactate dehydrogenase (LDH) and dead-cell protease (DCP). Apoptosis was investigated by Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Differentiation was assessed by evaluation of thyroid transcription factor (TTF1) and sodium iodide symporter (NIS) expression (western blotting).Results: Maintenance of gross tissue architecture was observed. Analysis of dissociated primary thyroid cells using flow cytometry both prior to and post culture demonstrated no significant change in the proportion of viable cells. LDH and DCP release from on-chip thyroid tissue indicated that after an initial raised level of release, signifying cellular damage, detectable levels dropped markedly. A significant increase in apoptosis (p<0.01) was observed after tissue was perfused with etoposide and JNK inhibitor, but not in control tissue incubated for the same time period. No significant difference in Ki-67 positivity or TTF1/NIS expression was detected between fresh and post-culture thyroid tissue samples, moreover BrdU positive nuclei indicated onchip cellular proliferation. Cultured thyroid explants were functionally viable as determined by production of T4 throughout the culture period. Conclusions:The described microfluidic platform can maintain the viability of thyroid tissue slices ex vivo for a minimum of four days, providing a platform for the assessment of thyroid tissue radioiodine sensitivity/adjuvant therapies in real time.

Abstract. From any given Frobenius manifold one may construct a so-called 'dual' structure which, while not satisfying the full axioms of a Frobenius manifold, shares many of its essential features, such as the existence of a prepotential satisfying the WDVV equations of associativity. Jacobi group orbit spaces naturally carry the structures of a Frobenius manifold and hence there exists a dual prepotential. In this paper this dual prepotential is constructed and expressed in terms of the elliptic polylogarithm function of Beilinson and Levin.

Background: Thyroid cancer is the most common endocrine malignancy worldwide. Primary treatment with surgery and radioactive iodine is usually successful, however, there remains a small proportion of thyroid cancers that are resistant to these treatments, and often represent aggressive forms of the disease. Since the 1950s, in vitro thyroid culture systems have been used in thyroid cancer research. In vitro culture models have evolved from 2-dimensional thyrocyte monolayers into physiologically functional 3-dimensional organoids. Recently, research groups have utilized in vitro thyroid cancer models to identify numerous genetic and epigenetic factors that are involved with tumorigenesis as well as test the efficacy of cytotoxic drugs on thyroid cancer cells and identify cancer stem cells within thyroid tumors. Objective of Review: The objective of this literature review is to summarize how thyroid in vitro culture models have evolved and highlight how in vitro models have been fundamental to thyroid cancer research. Type of Review: Systematic literature review. Search Strategy: The National Institute for Health and Care Excellence (NICE) Healthcare and Databases Advanced Search (HDAS) tool was used to search EMBASE, Medline and PubMed databases. The following terms were included in the search: "in vitro" AND "thyroid cancer". The search period was confined from January 2008 until June 2019. A manual search of the references of review articles and other key articles was also performed using Google Scholar. Evaluation Method: All experimental studies and review articles that explicitly mentioned the use of in vitro models for thyroid cancer research in the title and/or abstract were considered. Full-text versions of all selected articles were evaluated. Experimental studies were reviewed and grouped according to topic: genetics/epigenetics, drug testing/cancer treatment, and side populations (SP)/tumor microenvironment (TME). Results: Three thousand three hundred and seventy three articles were identified through database and manual searches. One thousand two hundred and sixteen articles remained after duplicates were removed. Five hundred and eighty nine articles were excluded based on title and/or abstract. Of the remaining 627 full-text articles: Chew et al. Thyroid Cancer in vitro Models 24 were review articles, 332 related to genetic/epigenetics, 240 related to drug testing/treatments, and 31 related to SP/TME. Conclusion: In vitro cell culture models have been fundamental in thyroid cancer research. There have been many advances in culture techniques-developing complex cellular architecture that more closely resemble tumors in vivo. Genetic and epigenetic factors that have been identified using in vitro culture models can be used as targets for novel drug therapies. In the future, in vitro systems will facilitate personalized medicine, offering bespoke treatments to patients.