Discrimination of papillary thyroid cancer from non-cancerous thyroid tissue based on lipid profiling by mass spectrometry imaging

Introduction: The distinction of papillary thyroid carcinomas from benign thyroid lesions has important implication for clinical management. Classification based on histopathological features can be supported by molecular biomarkers, including lipidomic signatures, identified with the use of high-throughput mass spectrometry techniques. Formalin fixation is a standard procedure for stabilization and preservation of tissue samples, therefore this type of samples constitute highly valuable source of clinical material for retrospective molecular studies. In this study we used mass spectrometry imaging to detect lipids discriminating papillary cancer from not cancerous thyroid directly in formalin-fixed tissue sections. Material and methods: For this purpose imaging and profiling of lipids present in non-malignant and cancerous thyroid tissue specimens were conducted. High resolution MALDI-Q-Ion Mobility-TOF-MS technique was used for lipidomic analysis of formalin fixed thyroid tissue samples. Lipids were identified by the comparison of the exact molecular masses and fragmentation pathways of the protonated molecule ions, recorded during the MS/MS experiments, with LIPID MAPS database. Results: Several phosphatidylcholines (32:0, 32:1, 34:1 and 36:3), sphingomyelins (34:1 and 36:1) and phosphatidic acids (36:2 and 36:3) were detected and their abundances were significantly higher in cancerous tissue compared to non-cancerous tissue. The same lipid species were detected in formalin-fixed as in fresh-frozen tissue, but [M + Na]+ions were the most abundant in formalin fixed whereas [M + K]+ions were predominant in fresh tissue. Conclusions: Our results prove the viability of MALDI-MSI for analysis of lipid distribution directly in formalin-fixed tissue, and the potential for their use in the classification of thyroid diseases

Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in several human carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression of AGR2 in PTC and its functional role

Zeros and the functional equation of the quadrilateral zeta function

In this paper, we show that all real zeros of the bilateral Hurwitz zeta function $Z(s,a):=\zeta (s,a) + \zeta (s,1-a)$ with $1/4 \le a \le 1/2$ are on only the non-positive even integers exactly same as in the case of $(2^s-1) \zeta (s)$. We also prove that all real zeros of the bilateral periodic zeta function $P(s,a):={\rm{Li}}_s (e^{2\pi ia}) + {\rm{Li}}_s (e^{2\pi i(1-a)})$ with $1/4 \le a \le 1/2$ are on only the negative even integers just like $\zeta (s)$. Moreover, we show that all real zeros of the quadrilateral zeta function $Q(s,a):=Z(s,a) + P(s,a)$ with $1/4 \le a \le 1/2$ are on only the negative even integers. On the other hand, we prove that $Z(s,a)$, $P(s,a)$ and $Q(s,a)$ have at least one real zero in $(0,1)$ when $0<a<1/2$ is sufficiently small. The complex zeros of these zeta functions are also discussed when $1/4 \le a \le 1/2$ is rational or transcendental. As a corollary, we show that $Q(s,a)$ with rational $1/4 < a < 1/3$ or $1/3 < a < 1/2$ does not satisfy the analogue of the Riemann hypothesis even though $Q(s,a)$ satisfies the functional equation that appeared in Hamburger's or Hecke's theorem and all real zeros of $Q(s,a)$ are located at only the negative even integers again as in the case of $\zeta (s)$.Comment: 12 pages. We changed the title. Some typos are correcte

Gene signature of the post-Chernobyl papillary thyroid cancer

Purpose: Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC. Methods: We investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized. Results: There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p &lt; 0.01), with 300 differently expressed probe sets (p &lt; 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples. Conclusion: Significant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure

Zalecenia Polskiej Grupy Mięsakowej w odniesieniu do postępowania diagnostyczno-terapeutycznego oraz kontroli u chorych na neurofibromatozę typu 1 (NF1) oraz związanego z nią złośliwego nowotworu osłonek nerwów obwodowych

Type 1 neurofibromatosis (NF1 syndrome in von Recklinghausen’s disease) is inherited as an autosomal dominant disease, caused by mutations in the NF1 gene encoding the neurofibromin protein. NF1 patients are at an increased risk of the develop­ment of a malignant neoplasm and their life span is shorter by 20 years than that of the general population. National Institute of Health (NIH) criteria make a diagnosis possible from about 4 years of age. Examination of children and adults should encom­pass a physical and a subjective component, but also next-generation sequencing (NGS) genetic analysis, histopathological examination of skin lesions, neurological, ophthalmological and radiological examination. If a malignant peripheral nerve sheath tumor (MNPST) is diagnosed in a patient with NF1, the therapeutic procedure should not differ from the general principles of treating soft tissue sarcomas. Patients from the high risk group should be monitored at least once a year, the remaining patients once every 2–3 years by a specialized medical team, and every year by their primary physicians, internal medicine specialists and dermatologists. Patients should have access to genetic counselling.Neurofibromatoza typu 1 (zespół NF1 w chorobie Recklinghausena, nerwiakowłókniakowatość typu 1), jest dziedziczona au­tosomalnie dominująco, a odpowiadają za nią mutacje genu NF1 kodującego białko neurofibrominy. Pacjenci z NF1 są naraże­ni na zwiększone ryzyko rozwoju nowotworu złośliwego i żyją około 20 lat krócej niż populacja ogólna. Kryteria National Insti­tute of Health (NIH) umożliwiają postawienie diagnozy już około 4 roku życia. Badanie dzieci i dorosłych powinno objąć bada­nie przedmiotowe i podmiotowe, ale też badanie genetyczne techniką sekwencjonowania nowej generacji (NGS), badanie histopatologiczne zmian skóry, badanie neurologiczne, okulistyczne i radiologiczne. W przypadku postawienia roz­poznania złośliwego nowotworu osłonek nerwów obwodowych (malignant peripheral nerve sheath tumor – MPNST) u chorego na NF1 postępowanie terapeutyczne nie powinno odbiegać od ogólnych zasad leczenia mięsaków tkanek miękkich. Pacjenci z grupy wysokiego ryzyka powinni być monitorowani przynajmniej raz w roku, pozostali – raz na 2–3 lata – przez zespół lekarzy specjalistów, a co roku przez lekarzy podstawowej opieki zdrowotnej (POZ), chorób wewnętrznych i dermatologów. Pacjentom należy zapewnić poradnictwo genetyczne

Gene expression profiles for radiation-induced thyroid cancer.

The question whether radiation-induced thyroid cancer differs by its molecular biology from sporadic disease still remains. Studies on tissue from patients who developed thyroid cancer after the Chernobyl accident have provided a unique opportunity to look for biological consequences of low-dose irradiation by comparing the gene expression profile of sporadic papillary thyroid cancer (PTC), whose aetiology is unknown, and PTC induced by internal radiation. So far, four transcriptomic studies comparing radiation-induced and sporadic thyroid cancer have been reported. However, no final conclusion has been drawn regarding the presence of a radiation signature, as either no difference was noted or the reported differences were not sufficiently convincing due to the low number of cases analysed or to the presence of confounding factors. The list of putative biological and clinical factors that may influence the PTC gene expression profile is long, but there are sufficient data reported in the literature to link expression profiles with differing pathological variants of PTC. The comparison of expression profiles in the tumour samples allows the search for a radiation signature, whereas the comparison of expression profiles of the normal contralateral tissues offers a substantial opportunity for assessing the existence of a susceptibility to radiation that could be responsible for tumour development. We have undertaken this analysis as part of a European Union-funded project, GENRISK-T. Gene expression profiles were investigated in tumours that have arisen in the population exposed to fallout from Chernobyl (i.e. born before 26 April 1986) and were compared with profiles of tumours of similar pathology arising in an age-matched population, residing in the same geographical area (same ethnicity) and born after 1 January 1987. RNA samples from these tumours and their contralateral normal tissues were obtained from the Chernobyl Tissue Bank. Several lines of evidence suggest that the predisposition to developing cancer after radiation exposure is variable in the general population and may be measurable from gene expression.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells

BACKGROUND: Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as a gene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in several human carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression of AGR2 in PTC and its functional role. METHODS: Expression of AGR2 was studied by immunohistochemistry and real time PCR in normal thyroids and in PTC samples. The function of AGR2 was studied by knockdown in PTC cells and by ectopic expression in non-transformed thyroid cells. The role of AGR2 in the ER stress was analyzed upon treatment of cells, expressing or not AGR2, with Bortezomib and analyzing by Western blot the expression levels of GADD153. RESULTS: PTC over-expressed AGR2 at mRNA and protein levels. Knockdown of AGR2 in PTC cells induced apoptosis and decreased migration and invasion. Ectopic expression of AGR2 in non-transformed human thyroid cells increased migration and invasion and protected cells from ER stress induced by Bortezomib. CONCLUSIONS: AGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion and protection from ER stress

Additional file 4 of Transcriptomic population markers for human population discrimination

: Infinium Human OmniExpressExome microarray. (DOCX 11 kb