A Pathogenic Th17/CD38+ Macrophage Feedback Loop Drives Inflammatory Arthritis through TNF-α.

The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis, involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. In this study, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations similar to those found in human RA. Notably, murine macrophage subtypes like those found in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNF-α induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis, and their depletion or blockade via TNF-α neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNF-α to drive inflammatory arthritis.

DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells.

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies.

Considerable ingenuity has been shown in the recent years in the discovery of novel xanthine oxidase (XO) inhibitors that fall outside the purine scaffold. The triazole nucleus has been the cornerstone for the development of many enzyme inhibitors for the clinical management of several diseases, where hyperuricemia is one of them. Here, we give a critical overview of significant research on triazole-based XO inhibitors, with respect to their design, synthesis, inhibition potential, toxicity, and docking studies, done till now. Based on these literature findings, we can expect a burst of modifications on triazole-based scaffolds in the near future by targeting XO, which will treat hyperuricemics, that is, painful conditions like gout that at present are hard to deal with.

Serotonin Transporter Deficiency Induces Metabolic Alterations in the Ileal Mucosa.

Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERT-/- mice ileal mucosa. However, the precise host or microbial metabolites altered by SERT deficiency that may contribute to the pleiotropic phenotype of SERT KO mice are not yet understood. This study investigated the hypothesis that SERT deficiency impacts lipid and microbial metabolite abundances in the ileal mucosa, where SERT is highly expressed. Ileal mucosal metabolomics was performed by Metabolon on wild-type (WT) and homozygous SERT knockout (KO) mice. Fluorescent-activated cell sorting (FACS) was utilized to measure immune cell populations in ileal lamina propria to assess immunomodulatory effects caused by SERT deficiency. SERT KO mice exhibited a unique ileal mucosal metabolomic signature, with the most differentially altered metabolites being lipids. Such changes included increased diacylglycerols and decreased monoacylglycerols in the ileal mucosa of SERT KO mice compared to WT mice. Further, the ileal mucosa of SERT KO mice exhibited several changes in microbial-related metabolites known to play roles in intestinal inflammation and insulin resistance. SERT KO mice also had a significant reduction in the abundance of ileal group 3 innate lymphoid cells (ILC3). In conclusion, SERT deficiency induces complex alterations in the ileal mucosal environment, indicating potential links between serotonergic signaling, gut microbiota, mucosal immunity, intestinal inflammation, and metabolic syndrome.

Sex differences in cognitive function among people with HIV-1 clade C infection in Northern India.

Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.

Quinoline derivatives volunteering against antimicrobial resistance: rational approaches, design strategies, structure activity relationship and mechanistic insights.

Emergence of antimicrobial resistance has become a great threat to human species as there is shortage of development of new antimicrobial agents. So, its mandatary to combat AMR by initiating research and developing new novel antimicrobial agents. Among phytoconstituents, Quinoline (nitrogen containing heterocyclic) have played a wide role in providing new bioactive molecules. So, this review provides rational approaches, design strategies, structure activity relationship and mechanistic insights of newly developed quinoline derivatives as antimicrobial agents.

Multispectroscopic studies on the molecular interactions between bovine γ-globulin and borohydride-capped silver nanoparticles.

Interactions between bovine γ-globulin (BGG) and borohydride-capped silver nanoparticles (BAgNPs) were studied using dynamic light scattering (DLS) and spectroscopic techniques such as UV-vis spectroscopy, fluorescence, and circular dichroism. The results were compared with earlier reported interactions between γ-globulin and citrate-coated AgNPs (CAgNPs). BAgNPs were synthesized and characterized. Irrespective of the coating on AgNPs, nanoparticles had formed ground-state complexes with the protein. CAgNPs, as well as BAgNPs had caused static quenching of tryptophan (Trp) fluorescence of the protein. The change in the capping agent from citrate to borohydride weakened the binding of nanoparticles with the protein. But the same change in capping agent had increased the fluorescence quenching efficiency of AgNPs. Hydrogen bonding and van der Waals interactions were involved in BGG-BAgNPs complex similar to the CAgNPs complex with γ-globulin. Polarity of the Trp microenvironment in BGG was not altered using BAgNPs as opposed to CAgNPs, as supported using synchronous and three-dimensional fluorescence. Resonance light scattering experiments also suggested nano-bio conjugation. Far-UV and near-UV circular dichroism (CD) spectra respectively pointed towards changes in the secondary and tertiary structure of BGG by BAgNPs, which was not observed for CAgNPs.

Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.

Rational approaches for the design of various GABA modulators and their clinical progression.

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

Dissecting the sources of gene expression variation in a pan-cancer analysis identifies novel regulatory mutations.

Although the catalog of cancer-associated mutations in protein-coding regions is nearly complete for all major cancer types, an assessment of regulatory changes in cancer genomes and their clinical significance remain largely preliminary. Adopting bottom-up approach, we quantify the effects of different sources of gene expression variation in a cohort of 3899 samples from 10 cancer types. We find that copy number alterations, epigenetic changes, transcription factors and microRNAs collectively explain, on average, only 31-38% and 18-26% expression variation for cancer-associated and other genes, respectively, and that among these factors copy number alteration has the highest effect. We show that the genes with systematic, large expression variation that could not be attributed to these factors are enriched for pathways related to cancer hallmarks. Integrating whole genome sequencing data and focusing on genes with systematic expression variation we identify novel, recurrent regulatory mutations affecting known cancer genes such as NKX2-1 and GRIN2D in multiple cancer types. Nonetheless, at a genome-wide scale proportions of gene expression variation attributed to recurrent point mutations appear to be modest so far, especially when compared to that attributed to copy number changes - a pattern different from that observed for other complex diseases and traits. We suspect that, owing to plasticity and redundancy in biological pathways, regulatory alterations show complex combinatorial patterns, modulating gene expression in cancer genomes at a finer scale.

Haplotype data for 17 Y-STR loci in the population of Himachal Pradesh, India.

We report here the data of Y chromosome haplotypes of 259 unrelated males from the population of Himachal Pradesh, India, using the Yfiler® multiplex kit. A total of 188 haplotypes were detected, out of which 148 were unique. Three samples showed bi-allelic pattern on locus DYS448. The observed genetic diversity and discrimination capacity were 0.996 and 0.73, respectively. In order to compare the genetic distance of the studied population with the published populations, multidimensional scaling (MDS) plot was constructed. The reported data is expected to be valuable for both forensic and population genetics.

Characterization of isoflavonoids as inhibitors of ß-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Moraxella catarrhalis: Kinetics, spectroscopic, thermodynamics and in silico studies.

BACKGROUD: ß-hydroxyacyl-acyl carrier protein dehydratase (FabZ) is an essential component of type II fatty acid biosynthesis (FAS II) pathway in bacteria. It performs dehydration of ß-hydroxyacyl-ACP to trans-2-acyl-ACP in the elongation cycle of the FAS II pathway. FabZ is ubiquitously expressed and has uniform distribution, which makes FabZ an excellent target for developing novel drugs against pathogenic bacteria. METHODS: We focused on the biochemical and biophysical characterization of FabZ from drug-resistant pathogen Moraxella catarrhalis (McFabZ). More importantly, we have identified and characterized new inhibitors against McFabZ using biochemical, biophysical and in silico based studies. RESULTS: We have identified three isoflavones (daidzein, biochanin A and genistein) as novel inhibitors against McFabZ. Mode of inhibition of these compounds is competitive with IC50 values lie in the range of 6.85µΜ to 27.7µΜ. Conformational changes observed in secondary and tertiary structure marked by a decrease in the helical and the sheet content in McFabZ structure upon inhibitors binding. In addition, thermodynamic data suggest that biochanin A has a strong binding affinity for McFabZ as compare to daidzein and genistein. Molecular docking studies have revealed that these inhibitors are interacting with the active site of McFabZ and making contacts with catalytic and substrate binding tunnel residues. CONCLUSION AND GENERAL SIGNIFICANCE: Three new inhibitors against McFabZ have been identified and characterized. These biochemical and biophysical findings lead to the identification of chemical scaffolds, which can lead to broad-spectrum antimicrobial drugs targeted against FabZ, and modification to existing FabZ inhibitors to improve affinity and potency.

A randomised comparison of the effects of low-dose spinal or general anaesthesia on umbilical cord blood gases during caesarean delivery of growth-restricted foetuses with impaired Doppler flow.

CONTEXT: Hypotension following spinal anaesthesia for caesarean delivery may decrease uteroplacental perfusion and produce foetal acidosis. The optimal anaesthetic technique for mothers with foetal growth restriction and impaired Doppler flow is unclear. OBJECTIVE: To compare the effects of low-dose spinal anaesthesia and general anaesthesia on neonatal outcome and maternal haemodynamics. DESIGN: Prospective, randomised clinical trial. SETTING: Tertiary care hospital. PATIENTS: Forty pregnant women with foetal growth restriction and impaired Doppler flow scheduled for elective caesarean delivery. INTERVENTIONS: The women were allocated randomly to receive a low-dose spinal anaesthetic (8-mg hyperbaric bupivacaine 0.5% with fentanyl 20 µg) or standard general anaesthesia for elective caesarean delivery. SBP was maintained between 80 and 100% of baseline using bolus doses of phenylephrine. The total duration of hypotension, dose of phenylephrine used and any incidence of hypotension, nausea or vomiting were recorded. MAIN OUTCOME MEASURES: The primary outcome variable was arterial and venous umbilical cord base deficit. Neonatal outcome and maternal haemodynamics were analysed as secondary endpoints. RESULTS: The mean umbilical artery pH was significantly lower in the low-dose spinal anaesthesia group than in the general anaesthesia group (7.23 ± 0.06 vs. 7.27 ± 0.04, P = 0.01). Cord base deficit was similar in the two groups. Higher partial pressures of oxygen occurred in the general anaesthesia group (20.9 ± 6.5 kPa) than in the low-dose spinal anaesthesia group (13.6 ± 6.1 kPa, P = 0.001). No difference was observed between groups in 1 and 5-min Apgar scores. There appeared to be a greater need for immediate resuscitation of neonates in the general anaesthesia group, but the difference was not statistically significant (P = 0.51). Low-dose spinal anaesthesia was associated with hypotension of short duration (0.7 ±â€Š1.1 min). CONCLUSION: In this study, there was no difference in umbilical cord base deficit between the groups. Larger studies would be required to assess whether the mode of anaesthesia influences the incidence of clinically important neonatal acidosis in neonates with foetal growth restriction.

Life cycle assessment of municipal solid waste generated from hilly cities in India - A case study.

Improper disposal of waste poses a grave environmental threat, contributing to pollution of air, water, and soil. It is necessary to address this issue in order to mitigate the adverse effects of solid waste on both the environment and public health. In many developing nations, municipal authorities of bigger cities are enduring significant challenges in proper management of waste. The present study evaluates the impacts of various waste management alternative scenarios for environmental impacts for the selected study locations using Life Cycle Assessment (LCA) methodology. The methodology comprised of five different scenarios of waste management including an existing baseline scenario. In this context, the environmental impact categories analyzed were Global Warming potential (GWP), Acidification potential (AP), Eutrophication potential (EP) and Human Toxicity potential (HTP). The results indicated that amongst all the proposed scenarios, Scenario 1 and 4 exhibited the maximum and minimum environmental impacts respectively. The study revealed that least greenhouse gas emissions, acidification potential, eutrophication potential and human toxicity potential were comparatively lesser for scenario 4 varying from 5.65 to 11.36 kg CO2eq t-1; 1.24-3.345 kg SO2eq t-1, EP 0.19-0.68 kg PO4eq t-1, and 0.35-4.22 kg 1,4-DBeq t-1 respectively. Further, a sensitivity analysis was also performed to evaluate the influence of recycling rate of valuable resources in all the considered scenarios. The sensitivity analysis indicated an inversely proportional relation between change in recycling rate and total environmental burdens.

Poly(lactic-co-glycolic) Acid (PLGA) Nanoparticles and Transdermal Drug Delivery: An Overview.

BACKGROUND: Biodegradable polymeric nanoparticles have garnered pharmaceutical industry attention throughout the past decade. PLGA [Poly(lactic-co-glycolic acid)] is an excellent biodegradable polymer explored for the preparation of nanoparticles that are administered through various routes like intravenous and transdermal. PLGA's versatility makes it a good choice for the preparation of nanoparticles. OBJECTIVE: The main objective of this review paper was to summarize methods of preparation and characterization of PLGA nanoparticles along with their role in the transdermal delivery of various therapeutic agents. METHODS: A literature survey for the present review paper was done using various search engines like Pubmed, Google Scholar, and Science Direct. RESULTS: In comparison to traditional transdermal administration systems, PLGA nanoparticles have demonstrated several benefits in preclinical investigations, including fewer side effects, low dosage frequency, high skin permeability, and simplicity of application. CONCLUSION: PLGA nanoparticles can be considered efficient nanocarriers for the transdermal delivery of drugs. Nevertheless, the clinical investigation of PLGA nanoparticles for the transdermal administration of therapeutic agents remains a formidable obstacle.

Shikonin derivatives as potent xanthine oxidase inhibitors: in-vitro study.

Induction of hypersensitivity reactions (may be fatal too) by specific XO inhibitors has led to development of new molecules that are efficacious and have safer ADME profile. Among natural compounds, biologically active Alkannin/Shikonin (A/S) derivatives have unexplored XO inhibition potential. Therefore, their iso-hexenylnaphthazarin nucleus was studied and found that the nucleus is similar to that of allopurinol, signifying the XO inhibitory potential of these derivatives. For confirmation of their potential, ß,ß-dimethylacrylshikonin and deoxyshikonin were successfully isolated and characterised from Arnebia euchroma (Royle.) Johnst. (Boraginaceae) and were evaluated for in vitro XO inhibitory potential. ß,ß-dimethylacrylshikonin and deoxyshikonin showed a good XO inhibition potential with IC50 values of 7.475 ± 1.46 µg/mL and 4.487 ± 0.88 µg/mL, respectively. Results also validated the pharmacophore hypothesis, and it was concluded that nucleus iso-hexenylnaphthazarin can be remodelled for optimising the efficacy.

Mucosal Metabolomic Signatures in Chronic Colitis: Novel Insights into the Pathophysiology of Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) involve complex interactions among genetic factors, aberrant immune activation, and gut microbial dysbiosis. While metabolomic studies have focused on feces and serum, fewer investigations have examined the intestinal mucosa despite its crucial role in metabolite absorption and transport. The goals of this study were twofold: to test the hypothesis that gut microbial dysbiosis from chronic intestinal inflammation leads to mucosal metabolic alterations suitable for therapeutic targeting, and to address gaps in metabolomic studies of intestinal inflammation that have overlooked the mucosal metabolome. The chronic DSS colitis was induced for five weeks in 7-9-week-old wild-type C57BL/6J male mice followed by microbial profiling with targeted 16srRNA sequencing service. Mucosal metabolite measurements were performed by Metabolon (Morrisville, NC). The data were analyzed using the bioinformatic tools Pathview, MetOrigin, and Metaboanalyst. The novel findings demonstrated increases in several host- and microbe-derived purine, pyrimidine, endocannabinoid, and ceramide metabolites in colitis. Origin analysis revealed that microbial-related tryptophan metabolites kynurenine, anthranilate, 5-hydroxyindoleacetate, and C-glycosyltryptophan were significantly increased in colon mucosa during chronic inflammation and strongly correlated with disease activity. These findings offer new insights into the pathophysiology of IBD and provide novel potential targets for microbial-based therapeutics.

Potential Dietary and Therapeutic Strategies Involving Indole-3-Carbinole in Preclinical Models of Intestinal Inflammation.

Diet-microbiota interactions are emerging as important contributors in the pathogenesis of inflammatory bowel diseases (IBD), characterized by chronic inflammation of the GI tract. The aryl hydrocarbon receptor (AhR) transcription factor regulates xenobiotic metabolism and is activated by exogenous ligands, including indole-3-carbinole (I3C), which is found in cruciferous vegetables. However, studies investigating the impact of dietary I3C and AhR in preclinical models resembling human IBD are lacking. Mice (WT or AhR KO in IECs, 6-8 weeks) or SAMP/YitFC and AKR/J control (4 weeks, m/f) were fed an AhR ligand-depleted or I3C (200 ppm)-supplemented diet. There were increased levels of LPS and exacerbated inflammation, resulting in increased mortality in AhRΔIEC mice fed the AhR ligand-depleted diet in response to chronic DSS. The mechanisms underlying the protective effects of I3C supplementation during colonic colitis involved amelioration of intestinal inflammation and restoration of the altered gut microbiota, particularly the families of clostridicae and lachnospriaceae. Furthermore, the AhR-depleted diet led to the emergence of pathobiont Parvibacter caecicola in WT mice. SAMP/YitFc mice with spontaneous ileitis showed significant recovery in epithelial abnormalities when fed dietary I3C. These data demonstrate the critical role of AhR and the mechanisms of dietary I3C in maintaining epithelial homeostasis and ameliorating inflammation.

Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease. AIM: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy. MATERIALS AND METHODS: In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we are proposing biomarkers that could indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. RESULTS: Normal and tumour thyroid tissue from DTC patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumour cells. The consistency of the DTC metabolic profile allowed us to build a bioinformatic classification model capable of clearly distinguishing normal from tumor thyroid tissues, which might help diagnose thyroid cancer. Moreover, based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intra-tumour heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. DISCUSSION: Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. CONCLUSIONS: Well-designed, prospective translational clinical trials will ultimately show the value of this integrated multi-omics approach and early diagnosis of DTC and potential metastatic PTC.