Replication study of THADA rs13429458 variant with PCOS susceptibility and its related traits in Indian women.

AIM: The aetiopathogenesis of the multigenic multifactorial endocrinopathy, polycystic ovary syndrome (PCOS) has been explored using linkage, candidate gene and genome-wide association studies. Contradictory reports of replication studies attributed to phenotypic, ethnic and geographic variations are available. In this study, we investigated the association of Han Chinese GWAS polymorphism (rs13429458) in thyroid adenoma-associated gene (THADA) with PCOS susceptibility and its related traits in Indian women. METHODS: We genotyped rs13429458 of THADA by direct sequencing and investigated its association with PCOS and its related traits in controls (N = 150) and PCOS women (N = 348). All women were extensively phenotyped in terms of anthropometric, hormonal and metabolic parameters. Association of polymorphism with PCOS risk and its related traits was carried out by regression analysis. RESULTS: Genotypic and allele frequencies for rs13429458 were not different between controls and PCOS. Women with PCOS carrying variant allele showed significantly reduced fasting glucose levels, and decreased free and bioavailable testosterone and free androgen index. CONCLUSION: To our knowledge, this is the first study to demonstrate that although this polymorphism does not alter PCOS susceptibility, it favorably impacts glucose metabolism and hyperandrogenism in Indian women with PCOS only. This study highlights that genetic predisposition markers for PCOS may differ with ethnicity and phenotypic variations.

Morphological and molecular data of two species of the rare genera Thada Thorne, 1941 and Tenunemellus Siddiqi, 1986 (Nematoda: Tylenchidae) from Iran.

Thada populus n. sp. was found in the rhizosphere of Populus euphratica in the city of Dezful, south-western Iran. The new species is characterized by its 365-453 µm body length, cuticle with transverse annuli 0.9-1.2 µm wide, lateral fields with four lines, lip region low with one or two annuli, 7.0-8.5 µm wide at base, longitudinal or slightly sigmoid amphidial slit, delicate stylet 8.4-9.8 µm long with posteriorly directed knobs, dorsal pharyngeal gland opening at 1.0-1.5 µm posterior to the stylet knobs, non-muscular and valve-less median bulb, pyriform and offset basal bulb, almost oval spermatheca, posterior position of vulva (V = 75-79%) without lateral membrane, short post-vulval uterine sac and conical tail with finely to broadly rounded terminus. Morphological differences of the new species with those of the type species, Thada striata, are discussed. Molecular phylogenetic studies of the new species using partial sequences of small subunit ribosomal DNA revealed that the new species formed a clade with Malenchus spp., Filenchus facultativus, F. fungivorus and Filenchus sp. in Bayesian inference. Morphological and molecular phylogenetic studies were also performed on Tenunemellus indicus, the second recovered species, the latter analysis using partial sequences of large subunit ribosomal DNA. In the inferred Bayesian tree, T. indicus formed a clade with Labrys fuzhouensis, Lelenchus leptosoma from the Netherlands, Malenchus spp. and Filenchus discrepans.

Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes.

Post-transcriptional tRNA modifications are critical for efficient and accurate translation, and have multiple different roles. Lack of modifications often leads to different biological consequences in different organisms, and in humans is frequently associated with neurological disorders. We investigate here the conservation of a unique circuitry for anticodon loop modification required for healthy growth in the yeast Saccharomyces cerevisiae. S. cerevisiae Trm7 interacts separately with Trm732 and Trm734 to 2'-O-methylate three substrate tRNAs at anticodon loop residues C32 and N34, and these modifications are required for efficient wybutosine formation at m(1)G37 of tRNA(Phe). Moreover, trm7Δ and trm732Δ trm734Δ mutants grow poorly due to lack of functional tRNA(Phe). It is unknown if this circuitry is conserved and important for tRNA(Phe) modification in other eukaryotes, but a likely human TRM7 ortholog is implicated in nonsyndromic X-linked intellectual disability. We find that the distantly related yeast Schizosaccharomyces pombe has retained this circuitry for anticodon loop modification, that S. pombe trm7Δ and trm734Δ mutants have more severe phenotypes than the S. cerevisiae mutants, and that tRNA(Phe) is the major biological target. Furthermore, we provide evidence that Trm7 and Trm732 function is widely conserved throughout eukaryotes, since human FTSJ1 and THADA, respectively, complement growth defects of S. cerevisiae trm7Δ and trm732Δ trm734Δ mutants by modifying C32 of tRNA(Phe), each working with the corresponding S. cerevisiae partner protein. These results suggest widespread importance of 2'-O-methylation of the tRNA anticodon loop, implicate tRNA(Phe) as the crucial substrate, and suggest that this modification circuitry is important for human neuronal development.

Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. METHODS: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested. RESULTS: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: p POE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: p POE = 0.01; HTB p POE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. CONCLUSIONS/INTERPRETATION: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.

CATEGORICAL DIAGNOSIS OF EXTREME HYPERACTIVITY, IMPULSIVITY, AND INATTENTION IN VERY YOUNG CHILDREN.

Severe hyperactivity and impulsivity are common reasons for referral to infant mental health services. Past versions of ZERO TO THREE's () diagnostic nosology, the Diagnostic Classification of Mental and Developmental Disorders in Infancy and Early Childhood (DC:0-3), did not address this clinical issue because it had been addressed in other nosologies. These general diagnostic nosologies describe attention deficit hyperactivity disorder (ADHD), but with little attention to developmentally specific aspects of the diagnosis in very young children. Categorical diagnosis related to hyperactivity and impulsivity in very young children warrants careful review of existing literature. Explicit attention must be paid to ensure that categorical diagnoses serve to describe syndromes that cause significant impairment to the family to allow children and families to access effective supports and ensure that behaviors typical of the developmental level are not described as pathologic. This article reviews proposed diagnostic criteria for ADHD and overactivity disorder of toddlerhood as well as the rationale for the criteria and evidence supporting validity and reliability of the diagnoses in very young children. Clinical implications also are presented.

DIAGNOSTIC CLASSIFICATION OF MENTAL HEALTH AND DEVELOPMENTAL DISORDERS OF INFANCY AND EARLY CHILDHOOD DC:0-5: SELECTIVE REVIEWS FROM A NEW NOSOLOGY FOR EARLY CHILDHOOD PSYCHOPATHOLOGY.

The Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood: Revised Edition (DC:0-5; ZERO TO THREE) is scheduled to be published in 2016. The articles in this section are selective reviews that have been undertaken as part of the process of refining and updating the nosology. They provide the rationales for new disorders, for disorders that had not been included previously in the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood: Revised Edition (DC:0-3R; ZERO TO THREE, 2005), and for changes in how certain types of disorders are conceptualized.

Association of candidate gene (INSR & THADA) polymorphism with polycystic ovary syndrome: meta-analysis and statistical power analysis.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that impacts women before reaching menopause. In addition to notable features (irregular ovulation, elevated androgen levels, and the existence of numerous ovarian cysts), individuals with PCOS frequently encounter diverse metabolic, cardiovascular, and psychological conditions. The onset of PCOS is influenced by a combination of factors, and various genetic variations are believed to play a significant role in its progression. The objective of the current study was to explore the link between genetic variations in the candidate genes thyroid-adenoma-associated (THADA) gene and insulin receptor (INSR) and susceptibility to developing PCOS. We conducted an extensive search across various databases, including Google Scholar, PubMed, Science Direct, Scopus, and EMBASE, to compile relevant case-control studies and literature reviews for subsequent statistical analysis. In the present study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was followed, a guideline for Systematic Reviews and Meta-Analysis. While a previous meta-analysis explored the correlation between INSR rs1799817 and THADA rs13429458 and their association with susceptibility to PCOS, our current study did not integrate any findings from these prior investigations. Our research encompassed articles published between 2017 and 2023, and we employed MetaGenyo software to assess the collected data. Statistical power analysis was performed using G*Power 3.1 software. Odds ratios and their corresponding 95% confidence intervals were calculated for each genetic model. Fifteen studies that met the criteria were analyzed. Out of these, ten studies, involving 1,189 cases and 1,005 controls, examined the INSR rs1799817 gene polymorphism, while five studies, including 783 cases and 553 controls, investigated the THADA rs13429458 gene polymorphism. The meta-analysis results indicated that there was no statistically significant association between the INSR rs1799817 gene polymorphism and the risk of PCOS (p>0.05). In contrast, the THADA rs13429458 gene polymorphism showed a significant association with PCOS risk under the over-dominant model (p<0.05). The present meta-analysis demonstrated a notable association between the THADA rs13429458 gene polymorphism and the likelihood of developing PCOS. Further rigorous studies with expanded sample sizes and diverse ethnic representation will be important to comprehensively evaluate and validate these findings.

THADA inhibits autophagy and increases 5-FU sensitivity in gastric cancer cells via the PI3K/AKT/mTOR signaling pathway.

Objectives: 5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown. Materials and Methods: This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments. Results: Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative 5-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-3, ATG13, ULK1, and TFEB). Furthermore, the PI3K/AKT/mTOR signaling pathway and mTORC1 signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC1 signaling pathway (mLST8, RHEB, and TSC2). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to 5-FU through the PI3K/AKT/mTOR signaling pathway. Conclusion: The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to 5-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for 5-FU-related chemotherapy administered to GC patients with elevated THADA expression.

THADA-IGF2BP3 gene fusions in thyroid fine needle aspiration is involved in the pathway to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features".

BACKGROUND: The increased usage and adaptation of molecular testing of thyroid fine needle aspirations (FNA) has expanded the variety and number of gene fusions identified. While the identified number of molecular alterations is increasing, the definitive association between preoperative molecular analysis and phenotype has yet to be established. The aim of this study was to examine Thyroid adenoma-associated (THADA)-IGF2BP3 molecular fusions with FNA categorization, surgical pathology diagnosis, and other molecular alterations detected by ThyroSeq Genomic Classifier testing. METHODS: FNA cytology samples of thyroid nodules from 04/2017 to 01/2023 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) or follicular neoplasm suspicious for follicular neoplasm (FN/SFN; Bethesda IV) with associated ThyroSeqV3 testing were reviewed. Parameters including patient demographics, FNA diagnosis, ThyroSeq V3 results, and surgical pathology follow up were examined. RESULTS: 87 out of 249 (35%) FNA specimens of thyroid nodules displayed molecular alterations. 64 cases (74%) had a cytology diagnosis of AUS and 23 (26%) had FN. RAS mutation was observed in 48 cases. On surgical follow-up, 17 (35%) cases showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), while 14 (29%) patients had a malignant diagnosis. THADA-IGF2BP3 fusions were seen in 8 cases, all with NIFTP on surgical pathology follow-up (100%). CONCLUSIONS: Analysis of THADA-IGF2BP3 fusion, in our institutional series, shows close association with NIFTP cases. THADA-IGF2BP3 fusion, which seems to be a favorable prognostic indicator in general, may serve as a molecular marker for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

THADA-IGF2BP3 fusions detected in fine-needle aspiration specimens of thyroid nodules: An institutional experience.

INTRODUCTION: Though the clinical significance of THADA-IGF2BP3 fusions detected in thyroid nodules preoperatively is still under investigation, the limited literature suggests these lesions are clinically low-risk. METHODS: The pathology archives were searched from 2018 to 2022 for all thyroid nodules with a THADA-IGF2BP3 fusion detected via ThyroSeqV3® analysis. Patient demographics and tumor characteristics were collected. Statistical analyses were performed and p < .05 was considered statistically significant. This study was approved by the institutional review board. RESULTS: The case cohort included 34 thyroid nodules with THADA-IGF2BP3 fusions from 32 patients (average age-56.1 years, range: 30-86, male to female ratio-10:22). The average nodule size was 3.2 cm (range: 1.3-7.3 cm). At the time of biopsy, 21 cases were diagnosed as atypia of undetermined significance/follicular lesion of undetermined significance, 12 as follicular neoplasm/suspicious for follicular neoplasm and 1 as suspicious for malignancy. Surgical resection was performed in 29 patients (13 partial and 16 total thyroidectomies) to give a total of 31 nodules. Papillary thyroid carcinoma was diagnosed in 19/31 (61%) cases. No cases showed extrathyroidal extension or lymphovascular invasion. The remaining cases were considered either a low-risk neoplasm or benign. Four cases of NIFTP on final surgical pathology harbored concurrent incidental papillary thyroid microcarcinoma. One patient had the THADA-IGF2BP3 fusion detected in bilateral nodules. CONCLUSIONS: THADA-IGF2BP3 fusions can occur in malignant, low-risk and benign thyroid neoplasms, where malignant neoplasms show lack of aggressive features. Therefore, such entities can be classified as clinically low risk.

The Difference in Clinical Behavior of Gene Fusions Involving RET/PTC Fusions and THADA/IGF2BP3 Fusions in Thyroid Nodules.

BACKGROUND: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. METHODS: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing either RET/PTC or THADA/IGF2BP3 gene fusion. RESULTS: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had the RET/PTC fusion and seven had the THADA/IGF2BP3 fusion. Of the five nodules in the RET/PTC group, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the seven THADA/IGF2BP3 nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All the THADA/IGF2BP3 fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. CONCLUSIONS: RET/PTC nodules presented as Bethesda V/VI and potentially had more aggressive features, whereas THADA/IGF2BP3 nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment.

Association of rs13429458 and rs12478601 Single Nucleotide Polymorphisms of THADA Gene with Polycystic Ovary Syndrome.

BACKGROUND: It is thought that genetic factors are influential in the etiology of polycystic ovarian syndrome (PCOS), the most frequent endocrinological disorder of females in their reproductive age. This study was carried out to elucidate the association of rs13429458 and rs12478601 single nucleotide polymorphisms (SNPs) of the THADA gene and the risk of the PCOS among a population of Iranian female patients. MATERIALS AND METHODS: This case-control study contains 66 infertile women with PCOS (patient group) and 44 healthy women without PCOS (control group) that referred to the IVF Unit of the Infertility Research Center of the Academic Center for Education, Culture and Research (ACECR). The polymerase chain reaction (PCR) was utilized to amplify genome DNA as well as direct sequencing to determine SNPs. The THADA rs12478601 and rs13429458 genotypes were consequently examined with amplification refractory mutation system-PCR (ARMS-PCR). RESULTS: In this study, we observed that rs13429458 polymorphism was not associated with PCOS risk in two groups (P=0.42). On the other hand, data analysis indicated that the rs12478601 genotype significantly increased the risk of PCOS in the case group (P=0.032) in compared with control group. We found that the "T" allele of rs12478601 in the THADA gene had a significant relation to PCOS in the case group (odds ratio [OR]: 2.574, 95% confidence interval [CI]: 1.439-4.604, P=0.001). CONCLUSION: This study has presented further evidence that TT and CT genotype of THADA rs12478601 is associated with a high risk of PCOS.

Thada Is Dispensable for Female Fertility in Mice.

Genome-wide association studies (GWAS) have identified THADA as one of the susceptibility genes for polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) in the THADA gene showed significant over-transmission in PCOS and strong correlations with testosterone level. However, there was insufficient evidence to verify the effect of THADA in vivo on female reproductive system. In this study, we investigated the impacts of Thada ablation on ovarian function and reproductive outcomes with knockout (KO) mice. The results showed that the Thada deletion was insufficient to affect ovarian folliculogenesis, steroidogenesis, and female fertility. Additionally, we stressed the mice with high-fat-high-sugar diet (HFHS). In this case, the KO mice still merely had a negligible impact on ovarian function. These findings indicated that Thada deficiency was dispensable for female fertility in mice, which enriched our knowledge about in vivo functions of PCOS susceptibility genes.

Assessment of THADA gene polymorphisms in a sample of Colombian women with polycystic ovary syndrome: A pilot study.

Polycystic ovary syndrome (PCOS) is a multifactorial and polygenic endocrine-metabolic disorder in women of reproductive age. SNPs in the THADA gene have been identified as PCOS risk loci. In this study, we evaluated the frequency of five polymorphisms in a sample of Colombian women with PCOS, and their association with clinical and endocrine-metabolic parameters. Forty-nine women with PCOS and forty-nine healthy women were included. Allelic discrimination was performed in the THADA gene by iPLEX and the MassARRAY system (Agena Bioscience). Haploview software was conducted to analyze the linkage disequilibrium (LD) and haplotypes of polymorphisms. There was an association between the genotypes TT of rs12468394, CC + AA of rs12468394, and GG of rs6544661 and an increase in the levels of free testosterone. The CC + AA of rs12468394 genotype also was associated with an increase of androstenedione levels. THADA gene SNPs were not associated with PCOS risk. There was very strong LD among the SNPs. No significant differences in the frequency of haplotypes between groups were observed. The statistical power of this analysis is low because of the small number of samples analyzed. Additional studies involving large populations of Colombian women with PCOS are needed to verify the role of the THADA gene in this disorder.

Cytomorphologic features of thyroid nodules harboring thyroid adenoma-associated fusion: A single institutional review of 11 cases.

BACKGROUND: Thyroid adenoma-associated (THADA) fusions are being identified more frequently with increased preoperative molecular testing on indeterminate thyroid fine-needle aspirates (FNA). However, data on cytomorphologic features of THADA-fusion thyroid lesions are limited. We examined cytomorphologic features of a THADA-fusion thyroid FNA cohort with clinical, radiologic, and histologic data. METHODS: Our THADA fusion FNA cohort included 11 specimens from 11 patients with a mean age and F:M ratio of 56.5 years and 2.7:1, respectively. Ten cases had FNA slides available for review and five cases had histopathology. Air-dried Diff-Quik and alcohol-fixed Papanicolaou smears, and formalin-fixed cell blocks were reviewed and findings were correlated with the matched resection, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: THADA fusion thyroid lesions were hypoechoic or isoechoic (80%), solid (80%) with well-demarcated margins (100%) on ultrasound. Notable cytomorphologic features include crowded or prominent microfollicular groups (100%), scant colloid (91%), and mild nuclear atypia with nuclear grooves (100%), insignificant nuclear pleomorphism (100%), and without intranuclear pseudoinclusions (100%). All cases were classified as either atypia of undetermined significance (91%) or suspicious for follicular neoplasm (9%). Five resected cases were all low-risk lesions (benign and malignant) with no evidence of recurrence in the limited available follow-up. CONCLUSION: THADA-fusion thyroid FNAs show a crowded or prominent microfollicular pattern with mild nuclear atypia and without intranuclear pseudoinclusions, which overlaps with the cytomorphology of other RAS-like thyroid lesions. In our cohort, resected THADA lesions were low risk on histologic analysis.

Clinicopathologic Characteristics of Thyroid Nodules Positive for the THADA-IGF2BP3 Fusion on Preoperative Molecular Analysis.

Background: Thyroid adenoma-associated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms. However, the prevalence of this gene fusion and associated phenotypical and clinical features are not well defined. The aim of this study was to characterize thyroid nodules positive for THADA-IGF2BP3 fusions on preoperative molecular analysis, review surgical outcomes, and explore potential impact of the fusion detection on patient management. Methods: Thyroid nodules positive for THADA-IGF2BP3 fusion on ThyroSeq v3 genomic classifier (GC) testing of fine needle aspiration (FNA) (n = 30) samples from November 2017 to August 2019 were identified. Demographic and clinical data were obtained by retrospective chart review; pathology slides were re-examined. Results: Thirty nodules positive for THADA-IGF2BP3 fusion on FNA were identified, representing ∼2% of 1280 nodules that underwent molecular analysis. Of the 27 nodules with available cytology diagnosis data, 22 (81%) were diagnosed as atypia of undetermined significance, 3 (11%) as follicular neoplasm, and 1 (4%) each were benign, and suspicious for malignancy. No additional mutations or gene fusions were identified in any of the nodules. Of the 24 cases with available clinical data, 22 (92%) THADA-IGF2BP3-positive nodules were managed surgically, 14 (64%) by thyroid lobectomy, and 8 (36%) by total thyroidectomy. Of the patients who had initial lobectomy, 3 (21%) had completion surgery. On surgical pathology, 7 (32%) THADA-IGF2BP3-positive nodules were malignant (six encapsulated follicular variant papillary thyroid carcinomas (EFVPTC), one minimally infiltrative FVPTC), 10 (45%) noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 5 (23%) follicular adenomas (FA). THADA-IGF2BP3-positive malignancies were intrathyroidal, without aggressive histology. Nodule size was similar between malignant nodules, NIFTP, and FA (2.6, 2.7, and 2.3 cm, respectively; p = 0.77). On limited follow-up (mean, 18 months) available for six patients with malignant fusion-positive nodule and 4 patients with NIFTP, no tumor recurrences were found. Conclusions: In this series of patients, 77% of THADA-IGF2BP3 fusion-positive thyroid nodules were thyroid tumors requiring surgery, either papillary carcinoma or NIFTP. However, all cancers were low risk, predominantly encapsulated FVPTCs and thus can likely be adequately treated with lobectomy.

Pilot study on evaluation and determination of the prevalence of Polycystic Ovarian Syndrome (PCOS) associated gene markers in the South Indian population.

Background: Polycystic ovarian syndrome (PCOS) is typically characterized by a spectrum of manifestations that include menstrual irregularities, anovulation, cysts, hyperandrogenic features like hirsutism, acne, alopecia, and various metabolic complications. The pathology of PCOS is complex and several mechanisms have been potentially involved in the genetic abnormalities/dysfunctions. Hence, the present study aims to examine the prevalence and association of polymorphisms in candidate genes (thyroid adenoma-associated gene [THADA], luteinizing hormone and human chorionic gonadotropin receptor [LHCGR], DENN domain containing 1A [DENND1A], follicle-stimulating hormone receptor [FSHR], Connexin37 [CX37], angiotensin-converting enzyme [ACE], insulin receptor [INSR] and calpain 10 [CAPN10]) in PCOS patients of the South Indian regional population. Methods: The study group included 20 PCOS cases and 10 controls, whose deoxyribonucleic acid (DNA) were genotyped by the polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (RFLP), and PCR product sequencing to determine the prevalence of the DENND1A (rs10818854), LHCGR (rs13405728), FSHR (rs2349415), THADA (rs13429458), CX37 (rs1764391), ACE (rs1799752), INSR (rs1799817), and CAPN10 (rs2975760) polymorphisms. Clinical examinations including anthropometric measurements, biochemical investigations relevant to glucose metabolism, and hormones were measured. Results: A significant difference was observed in the DENND1A (rs10818854) polymorphism between the control and PCOS patients (P = 0.001). The variants of LHCGR, FSHR, THADA, CX37, ACE, INSR, and CAPN10 were not statistically significant with PCOS. The body mass index (BMI) (P = 0.01), triglycerides (P = 0.01), and dehydroepiandrosterone sulfate (DHEAS) (P = 0.05) were significantly different between the PCOS patients and controls. Significant results were observed in rs1799817 single nucleotide polymorphisms (SNP) of INSR with elevated levels of triglycerides and rs10818854 of DENND1A, rs13429458 of THADA, rs2349415 of FSHR with the high levels of DHEAS. Conclusion: In the study population, the presence of rs10818854 of DENND1A polymorphism may be associated with the risk of PCOS and high levels of DHEAS.

ThyroSeq v3 for Bethesda III and IV: An institutional experience.

BACKGROUND: The ThyroSeq v3 genomic classifier is a commercial molecular test that examines a wide spectrum of genomic alterations in a thyroid fine-needle aspiration (FNA) sample and reports test results as either negative or positive. The authors report their institutional experience with ThyroSeq v3. METHODS: Thyroid FNA specimens diagnosed as either atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) (Bethesda category III [Bethesda III] according to The Bethesda System for Reporting Thyroid Cytopathology) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (Bethesda IV) that had ThyroSeq v3 results available from December 2017 through October 2019 were retrieved for analysis. FNA diagnoses were correlated with ThyroSeq v3 results and follow-up histopathology. RESULTS: In total, 415 cases (AUS/FLUS, n = 251; FN/SFN, n = 164) were retrieved: 294 (71%) were reported as ThyroSeq v3-negative, and 121 (29%) were reported as ThyroSeq v3-positive. The benign call rate (BCR) of ThyroSeq v3 for AUS/FLUS (82%; 206 of 251 cases) was significantly higher (P < .001) than that for FN/SFN (BCR, 54%; 88 of 164 cases). Histopathologic follow-up was available for 127 cases (ThyroSeq v3-positive, 96; ThyroSeq v3-negative, 31), of which 57 were benign and 70 were malignant (including noninvasive follicular thyroid neoplasm with papillary-like nuclear features). The negative predictive value of ThyroSeq v3 was significantly higher for AUS/FLUS (99.5%) than for FN/SFN (95.4%; P < .0294), given malignancy rates of 10% for AUS/FLUS and 30% for FN/SFN. Forty-five unique combinations of genetic alterations were detected in the operated ThyroSeq-positive cases, and there were only 5 false-negative cases, comprised of 4 low-risk neoplasms. CONCLUSIONS: The high BCR of ThyroSeq v3 for AUS/FLUS prevents surgery in a majority of patients. The ThyroSeq v3 genomic classifier reveals the complexity of the genetic signature of indeterminate nodules.

Genotype based Risk Predictors for Polycystic Ovary Syndrome in Western Saudi Arabia.

Polycystic ovary syndrome (PCOS) is the most common endocrine disease among premenopausal women. The genetic risk of PCOS in the Saudi population is still unclear. Therefore, it is of interest to study the genotype and allele frequency for six gene variants (THADA rs13429458, TOX3 rs4784165, FSHR rs2268361, YAP1 rs1894116, RAB5B rs705702, and HMGA2 rs2272046) in patients with PCOS in western Saudi population. The study included 95 PCOS patients and 94 normal ovulatory females as controls. Genotyping was performed using TaqMan™ real-time polymerase chain reaction assays. There was significant link between the THADA rs13429458 variant and PCOS. Homozygosity in allele A of the rs13429458 variant was correlated with hyperandrogenism (HA) risk. Homozygosity in the T allele of the FSHR rs2268361 variant was associated with normal levels of AMH among non-PCOS women. The THADA rs13429458 and TOX3 rs4784165 variants were significantly associated with the combined oligo/amenorrhea (OA) and polycystic ovarian morphology subgroups while the HMGA2 rs2272046 variant was significantly associated with the combined HA and OA subgroup. Thus, results show the genetic risk of the THADA rs13429458, TOX3 rs4784165, and HMGA2 rs2272046 variants on PCOS patients in the western Saudi population.