A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive.

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort.

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis.

Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied.

Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets.

Context: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3.

Objective: To investigate underlying genetic defects in patients with hypophosphataemic rickets.

Methods: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis.

Attenuation Limits Progression of -Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAF Inhibitor PLX4720.

CYP24A1, the primary inactivating enzyme for vitamin D, is often overexpressed in human cancers, potentially neutralizing the antitumor effects of calcitriol, the active form of vitamin D. However, it is unclear whether CYP24A1 expression serves as a functional contributor versus only a biomarker for tumor progression. In this study, we investigated the role of CYP24A1 on malignant progression of a murine model of -induced papillary thyroid cancer (PTC).

IL-12 immunotherapy of Braf(V600E)-induced papillary thyroid cancer in a mouse model.

Papillary thyroid carcinoma (PTC) accounts for >80% thyroid malignancies, and BRAF(V600E) mutation is frequently found in >40% PTC. Interleukin-12 (IL-12) is a proinflammatory heterodimeric cytokine with strong antitumor activity. It is not known whether IL-12 immunotherapy is effective against Braf(V600E)-induced PTC.

KRAS(G12D)-mediated oncogenic transformation of thyroid follicular cells requires long-term TSH stimulation and is regulated by SPRY1.

KRAS(G12D) can cause lung cancer rapidly, but is not sufficient to induce thyroid cancer. It is not clear whether long-term serum thyroid stimulating hormone (TSH) stimulation can promote KRAS(G12D)-mediated thyroid follicular cell transformation. In the present study, we investigated the effect of long-term TSH stimulation in KRAS(G12D) knock-in mice and the role of Sprouty1 (SPRY1) in KRAS(G12D)-mediated signaling.

Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma.

Background: RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC.

Increased CYP24A1 expression is associated with BRAF(V600E) mutation and advanced stages in papillary thyroid carcinoma.

Objective: 1α, 25(OH)2 D3 (calcitriol), the active form of vitamin D, has been shown to exert antiproliferative effects in many cancers. Overexpression of CYP24A1, the primary vitamin D-inactivating enzyme, is also observed in a variety of human cancers, thus potentially neutralizing the antitumour effect of 1α, 25(OH)2 D3. This study investigates the expression of CYP24A1 and the effect of BRAF(V600E) on its expression in thyroid cancer.

Novel and de novo PHEX mutations in patients with hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is the most common inherited rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in 10 patients from 6 unrelated Turkish families by PCR-sequence analysis.

Molecular characterization of a novel p.R118C mutation in the insulin receptor gene from patients with severe insulin resistance.

Context: Mutations of the insulin receptor gene (INSR) can cause genetic syndromes associated with severe insulin resistance.

Objectives: We aimed to analyse INSR mutations in Saudi patients with severe insulin resistance.

Design: Ten patients with Type A insulin resistance syndrome from five unrelated Saudi families were investigated.

A novel deletion of the MEN1 gene in a large family of multiple endocrine neoplasia type 1 (MEN1) with aggressive phenotype.

Context: The MEN1 syndrome is associated with parathyroid, pancreatic and pituitary tumours and is caused by mutations in the MEN1 gene. In general, there is no genotype-phenotype correlation.

Objectives: To characterize a large family with MEN1 with aggressive tumour behaviour: malignant pancreatic endocrine tumours were present in five affected subjects and were the presenting features in three subjects.

Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations.

Vitamin D-dependent rickets type 1 (VDDR-I) is caused by mutation in CYP27B1. The glycine residue at codon 102 is not conserved between human (G(102)) and rodent (S(102)). G102E mutation results in 80% reduction in its enzymatic activity but PolyPhen predicts benign change.

A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1.

Context: Mutations in the CYP27B1 gene, which encodes vitamin D 1alpha-hydroxylase, are the genetic basis for vitamin D-dependent rickets type 1 (VDDR-I).

Objective: The aim of this study was to investigate the CYP27B1 mutation in a large family with VDDR-I and characterize the genotype-phenotype correlation.

Patients And Methods: The index patient was a 23-yr-old female who had a progressive form of rickets and growth retardation since the age of 9 months.

Biallelic p.R2223H mutation in the thyroglobulin gene causes thyroglobulin retention and severe hypothyroidism with subsequent development of thyroid carcinoma.

Context: Dyshormonogenesis due to genetic defect in thyroglobulin (Tg) synthesis and secretion can lead to congenital hypothyroidism.

Objectives: The aim of the study was to analyze the TG gene for the presence of mutations and to study the underlying mechanisms leading to dyshormonogenesis.

Cases: Two siblings aged 25 and 31 yr presented with recurrent goitrous hypothyroidism with undetectable serum Tg.

Aberrant BRAF splicing as an alternative mechanism for oncogenic B-Raf activation in thyroid carcinoma.

Activating BRAF mutations have recently been reported in 28-83% of papillary thyroid carcinomas (PTCs). However, it is not known whether aberrant BRAF splicing occurs in thyroid carcinoma. To investigate aberrant BRAF splicing and its association with BRAF mutation in thyroid tumours, we studied aberrant BRAF splicing and BRAF mutation from 68 thyroid tumours.

Oncogenic activation of MAP kinase by BRAF pseudogene in thyroid tumors.

Activating BRAF mutations have been reported in 40% of papillary thyroid carcinomas (PTCs). The involvement of BRAF pseudogene in thyroid tumorigenesis has not previously been studied. We investigated BRAF pseudogene expression in 68 thyroid tumors: 16 multinodular goiters, 43 classic PTCs, 6 follicular variants of PTC, and 3 anaplastic thyroid carcinomas.

Diagnosis by serendipity: Cushing syndrome attributable to cortisol-producing adrenal adenoma as the initial manifestation of multiple endocrine neoplasia type 1 due to a rare splicing site MEN1 gene mutation.

Objective: To report a case that highlights the potential for Cushing syndrome to be the first manifestation of multiple endocrine neoplasia type 1 (MEN 1) syndrome and to describe the rare underlying genetic mutation and the heterogeneous manifestations of the syndrome within the same family.

Methods: We present a case report including biochemical and radiologic findings, review family data, and discuss the results of genetic analyses.

Results: A 16-year-old girl who was not known to have any medical illness and had no known family history of MEN 1 syndrome presented with Cushing syndrome attributable to a cortisol-producing adrenal adenoma.

Genotype-phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Objective: Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-alpha (GR-alpha) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance.

Thiamine transporter mutation: an example of monogenic diabetes mellitus.

Objective: Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome.

Case: The patient is an 18-year-old girl who was born to non-consanguous parents.

Ribonucleic acid interference targeting S100A4 (Mts1) suppresses tumor growth and metastasis of anaplastic thyroid carcinoma in a mouse model.

Context: The characteristic feature of malignant neoplasm is invasion and metastasis. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality.

Objective: Our objective was to examine the effects of S100A4 expression knockdown by RNA interference on the growth and metastasis of human anaplastic thyroid carcinoma cells (ARO) and the sensibility of ARO to paclitaxel after S100A4 knockdown.

Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene.

Context: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only a few mutations in the Tg gene have been described.

Objectives: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation.

Microarray analysis of metastasis-associated gene expression profiling in a murine model of thyroid carcinoma pulmonary metastasis: identification of S100A4 (Mts1) gene overexpression as a poor prognostic marker for thyroid carcinoma.

Tumor cell invasion and metastasis are the hallmark of malignant neoplasm. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality. To gain new insights into this complex process in thyroid carcinoma, we established a thyroid carcinoma cell line (ARO-met2) with high metastatic capacity to the lung by sequential passage of a human anaplastic thyroid cancer cell line (ARO) through the lung of a nude mouse.