Search Results (97)

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC. Full article

The progressive decline in functional β-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed “dedifferentiation.” Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites—including Acetyl-CoA, α-ketoglutarate, and NAD+—serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a “Systemic epigenetic destabilization,” leading to the loss of lineage-specific markers and the formation of persistent “metabolic scars.” Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of β-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial–epigenetic axis offers a strategic window for re-differentiating failing β-cells and restoring glycemic homeostasis. Full article

Cheliped regeneration in the E. sinensis is a tightly regulated physiological process, yet the molecular regulatory mechanisms underlying sexual dimorphism during regeneration remain unclear. In this study, we combined morphological observation with transcriptomic analysis to systematically investigate the regenerative stage characteristics and sex-related differences. The papilla stage 4 dpa was identified as a pivotal transitional stage, bridging initial wound healing and cellular dedifferentiation (2 dpa) with subsequent redifferentiation and morphogenesis (7 dpa). Morphological sex-based differences characterized by larger regenerating chelipeds in males became prominent by the late stage (28 dpa). Notably, the molecular foundation of sexual dimorphism was found to be established at 4 dpa, significantly preceding the emergence of phenotypic differences. This early divergence was driven by sex-dimorphic endocrine networks: males exhibited preferential expression of genes such as Fem-1c-like, Cyp2L1-like, CpAMP1A-like and Nedd4-like, while females showed enrichment in elevated aromatase activity. Weighted gene co-expression network analysis (WGCNA) identified the Hox gene Antp as a core hub regulator, exhibiting high co-expression with key epidermal-related genes such as Cht6, Cht2-like and more. Its suppressed expression at 2 dpa aligned with the requirements for dedifferentiation, whereas its peak at 4 dpa indicated a crucial role in orchestrating appendage patterning and exoskeleton assembly. RNA interference (RNAi) knockdown of Antp resulted in obscured differentiation between the propodus and carpus in both sexes and confirmed its regulatory control over downstream targets including Ubx, Bmp2-like, and CpAMP1A-like. This study suggests a putative hierarchical regulatory model in which systemic hormonal signals may integrate Antp and other sex-biased regulators to potentially facilitate structured limb regeneration. These findings offer tentative novel insights into the interplay between developmental plasticity and sex-based regulatory divergence in decapod crustaceans. Full article

Background and aim: Recent preclinical studies have confirmed that inhibiting the MAP kinase pathway can induce the re-differentiation of radioiodine (RAI)-refractory (RAIR) follicular cell thyroid cancers (TCs). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myo-inositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells. Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into two groups: (1) a control group in which patients are treated with KIs (subgroup a: trametinib plus dabrafenib; subgroup b: lenvatinib); (2) a group in which patients (divided into the two subgroups) are treated with the same KIs in addition to MI. After 30 days of MI treatment, all patients, treated with levothyroxine (L-T4) at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). On day 35, the patients will be subjected to whole-body scintigraphy, with hybrid imaging where possible (SPECT/CT), after the administration of diagnostic activity (185–222 MBq of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0); after 30 days of MI therapy; and then on days 31, 32, 33, 34, and 35 after MI therapy. Quality of life (QoL) will be assessed at the beginning of the MI treatment and at the end of its administration. The primary endpoint is the restoration of 123-I uptake in RAIR-TC patients already on KI therapy alone and on KI therapy plus MI. The restoration of 123-I uptake in target lesions will be evaluated. Conclusions: MI may have a synergistic effect at the cellular level, and the possible increase in the re-differentiation of RAIR-TC in patients treated with KIs plus MI may have great clinical relevance. The re-uptake of RAI will be evaluated as the primary endpoint, and Tg values and QoL will be evaluated as the secondary endpoints. The main limitation of this study is that we do not investigate any clinical effects. We will have to postpone the clinical analysis to a later date after the administration of RAI for therapeutic purposes. Full article

Epidemiological data link a lack of breastfeeding with an increased risk of breast cancer. Breast tissue remodels after pregnancy through involution. Long-term breastfeeding results in gradual involution (GI), and a lack of breastfeeding leads to abrupt involution (AI). AI causes increased mammary gland estrogen signaling, causing adipocyte redifferentiation through neutrophil infiltration. Adipocyte differences and metabolic implications of involution have not been explored between AI and GI. As breast cancer is characterized as highly metabolic, we explored how adipocyte differences and metabolism during involution may support breast cancer risk. FVB/n was randomized to AI/GI and standardized to 6 pups on day 0/birth. AI mice had pups removed on day 7. GI mice had 3 pups removed on days 28 and 31. Mammary glands were harvested at 28, 56, and 120 days. A subset of AI mice were given tamoxifen for 21 days. Day 28 AI glands had upregulation of estrogen signaling, neutrophil degranulation, and glucose metabolism and downregulation of adipogenesis and glycolysis compared to Day 56 GI. Day 120 AI glands had downregulation of oxidative phosphorylation and upregulation of mitochondrial dysfunction similar to estrogen receptor-negative (ER−) pregnancy-associated breast cancer (PABC). AI with tamoxifen resulted in a similar metabolic phenotype to GI. Early metabolic phenotypes in AI and GI glands may be related to estrogen signaling. AI long-term transcriptional metabolic effects were similar to breast cancer. Full article

Induction of callus is an important step to produce high-quality seedlings, to promote the large-scale production of seedings, and to establish stable transgenic methods. To establish an efficient callus-based regeneration system for lily, in this study, we used the scales of Lilium regale as explants and employed plant tissue thin-layer culture to induce callus tissues. To examine the effects of different types and concentrations of plant growth regulators (PGRs) on the induction of lily callus tissues and plant regeneration, we designed orthogonal experiments using three PGRs: 6-BA, NAA, and PIC, with each regulator at three concentration levels. The results indicated that a suitable medium for inducing callus under the experimental conditions was 1.00 mg/L 6-BA + 0.05 mg/L NAA + 2.00 mg/L PIC, pH = 5.8 because in this medium, callus tissue showed a good balance of induction and contamination rate, as well as very low redifferentiation into bulbs. Under the experimental conditions, a suitable medium for callus expansion was 1 mg/L 6-BA + 0.5 mg/L NAA, pH = 5.8. We also showed that the induced callus tissues could develop into seedlings. These findings provide important references for optimizing in vitro culture systems of Lilium regale and offer supports for tissue culture studies of other lily species. Full article

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

Follicular-cell-derived thyroid carcinoma, while typically associated with a favorable prognosis, can undergo dedifferentiation into poorly differentiated (PDTC) or anaplastic thyroid carcinoma (ATC), leading to enhanced aggressiveness and radioiodine resistance. This review systematically examines the genetic and molecular mechanisms driving this pathological progression, highlighting the roles of key mutations—such as BRAF, RAS, TERT, and TP53—and the disregulation of signaling pathways, including MAPK and PI3K/AKT. These alterations promote the loss of thyroid-specific functions, including iodide metabolism, and correlate with poor clinical outcomes. In recent years, therapeutic strategies aimed at tumor redifferentiation have emerged as a promising approach for radioiodine-refractory disease. We summarize recent advances in the use of targeted agents, particularly BRAF and MEK inhibitors, to restore radioiodine avidity and improve treatment response. While early clinical studies show encouraging results, including tumor shrinkage and restored RAI uptake in selected patients, challenges such as treatment resistance and patient selection remain. Future efforts should focus on refining molecular stratification, developing rational combination therapies, and integrating novel modalities such as immunotherapy to overcome resistance. A deeper understanding of redifferentiation mechanisms not only provides insights into thyroid cancer progression but also supports the development of personalized treatment strategies for high-risk patients. Full article

Deep alterations in tumor cell gene profiles resulting in the loss of their specific functions are frequently the cause of resistance to traditional cancer treatments. Therefore, reprogramming the expression pattern of cancer cells toward a differentiated phenotype represents a promising therapeutic strategy. In this study, we investigated whether resveratrol (RSV) and its natural analogs—3,4′,5-trimethoxystilbene (3-MET-OX) and isorhapontigenin (ISOR-H-PG)—can modulate the SOX2/SOX17 balance and promote re-differentiation in anaplastic thyroid cancer (ATC) cells. Two human ATC cell lines (SW1736 and 8505c) and non-tumoral thyroid cells (Nthy-ori 3-1) were cultured in two-dimensional (2D) or three-dimensional (3D) systems and treated with polyphenols at sub-cytotoxic doses. In 2D cultures, cell viability and cell cycle analyses confirmed a cytostatic effect characterized by G1 arrest. In 3D cultures, polyphenol treatment caused morphological disruption of ATC spheroids and significantly modulated the gene expression profile. RSV and 3-MET-OX reduced stemness markers (SOX2, NANOG), increased the thyroid lineage transcription factor (SOX17), and enhanced differentiation genes (TTF-1, TPO, NIS). Overall, these results support our hypothesis that modulation of the SOX2/SOX17 ratio by polyphenols provides a mechanistic basis for re-differentiation, thereby improving therapeutic responsiveness in ATC. Full article

Propagation of rubber tree (Hevea brasiliensis) via secondary somatic embryogenesis (SSEis) is a reliable method. However, its efficiency is relatively low. The aim of this study was to understand more about the factors related to SSEis in rubber trees, trying to improve the efficiency of somatic embryo (SE) yield. Our study showed that the orientations of explants, i.e., the fragments of primary SE (PSE), on the medium affected secondary SE (SSE) yield significantly. Among five experimental tests, the highest yield was 2.6 ± 0.9 secondary somatic embryos (SSEs) per explant, which was achieved by orienting the abaxial side of the explant in contact with the medium and then the adaxial side after a period of culture time. Based on histological evidence, SSEis was induced from the epidermal cells and adjacent cells on the adaxial side of the explants. A remarkable difference in embryogenic capacity difference existed among individual PSE. The concentrations of soluble proteins, starch, soluble sugars, and the superoxide dismutase activity (SOD) levels in the explants were measured during a 25-day long SSEis induction treatment and compared between explants of high and low embryogenic capacity. This study proves that the explant orientation toward the culture medium plays a crucial role in SSEis, while the concentration changes of these biochemical compounds correlate to morphological changes in the explants during induction, as do the changes in SOD activity. Furthermore, the trend of the dynamic changes in the explants reflected a process of de-differentiation and re-differentiation, which started from mature SE tissues during SSE induction. Full article

Quercus suber L. (Q. suber) is an ecologically and industrially valuable species, yet faces challenges in propagation in China. This study optimized somatic embryogenesis (SE) protocols using two-year-old Q. suber leaves, focusing on petioles and leaf veins as the most responsive explants, with May as the optimal sampling time. The MSSH medium (a combination of Murashige and Skoog Medium (MS) major elements and Schenk and Hildebrandt Medium (SH) minor elements and vitamins) under darkness maximized transdifferentiation. Additionally, the highest callus induction was achieved with 0.50 mg/L 6-benzyladenine (6-BA) and 1.00 mg/L 1-Naphthaleneacetic acid (NAA). Liquid culture with 1.00 g inoculum and 0.50 mg/L 6-BA + 0.20 mg/L NAA achieved the best proliferation. Redifferentiation peaked at 0.15 mg/L NAA + 0.20 mg/L 6-BA. Transcriptome profiling identified 4534 differentially expressed genes (DEGs) between embryogenic callus (E1) and global embryos (E2), with key pathways linked to cell wall remodeling, stress responses, and photosynthesis. Key regulators identified during the early stage of callus redifferentiation include cytokinin oxidase 3 (CKX3), gibberellin-responsive protein (GH3.6), and pectin lyase 5 (PL5), among others. This study provides insights into efficient SE of Q. suber and the genes underlying early callus redifferentiation, laying the groundwork for future research. Full article

Cell-based immunotherapy is a promising treatment strategy for cancer. Particularly in the case of solid tumors, however, this strategy only benefits a minority of patients. A critical limitation to immunotherapy is T cell exhaustion, a terminal differentiation state characterized by loss of self-renewal and cytotoxic capacity. For over a decade, regenerative immunology approaches to overcome exhaustion and restore stem-like features of T cells have been pursued. The reprogramming of tumor-specific T cells back to a less-differentiated, stem-like state using induced pluripotent stem cell (iPSC) technology has been viewed as a powerful and highly appealing strategy to overcome the limitations imposed by exhaustion. However, clinical translation of these approaches has been stymied by the requirement for subsequent iPSC-to-T cell re-maturation strategies, vanishingly low efficiencies, and resource-intensive cell culture protocols. In this review, we discuss the emergence of transcription factor reprogramming to iPSCs, contemporary techniques for T cell reprogramming, as well as techniques for re-differentiation into mature T cells. We discuss the potential clinical utility of T cell reprogramming and re-maturation strategies alongside progress and major roadblocks toward clinical translation. If these challenges can be addressed, transcription factor reprogramming of T cells into iPSCs and subsequent re-maturation into tumor-specific stem-like T cells may represent an incredibly efficacious approach to cancer immunotherapy. Full article

Caffeine is a nitrogenous base that naturally occurs in coffee (Cafea arabica), tea (Thea sinensis), and cocoa (Theobroma cacao). Chemically, caffeine is 1,3,5-trimethylxanthine, a purine analogue. Due to significant human consumption, caffeine effects have been widely studied. Being a natural xanthine derivative, the key degradative enzyme is xanthine oxidase, converting caffeine into 1-methyluric acid. Ecologically, caffeine is believed to act as a repellent molecule against insect feeding behavior. Caffeine’s chemical similarity to purines and plant hormones motivated this study, establishing the potential for cellular de-differentiation and re-differentiation. For this, a highly hormone-responsive plant species, Ornithogalum dubium, was used. As caffeine has been shown to induce endoreplication, the potential for new germlines in O. dubium is attractive. Using tissue culture, a range of caffeine concentrations were used (0.0125 mg/L to 2.0 mg/L) without additional hormones. A significant difference (p > 0.05) was observed for intermediate concentrations of 0.0125, 0.025, and 0.05 mg/L when compared to the control (no hormones). The highest rates of callus induction were obtained at a concentration of 0.025 mg/mL. Higher concentrations were phytotoxic (1.0 mg/L or greater). To conclude, caffeine-regenerated plants were not dissimilar to those obtained from canonical hormones. Full article

Since the 1940s, 131-I radioiodine therapy (RIT) has been the primary treatment for metastatic differentiated thyroid cancer (DTC). Approximately half of these patients respond favorably to RIT, achieving partial or complete remission or maintaining long-term stable disease, while the other half develop radioiodine-refractory DTC (RAI-R DTC). The main genomic alteration involved in radioiodine resistance is the activated mitogen-activated protein kinase (MAPK) pathway, which results in the loss of sodium iodide symporters (NIS). Therefore, RAI-R DTC requires alternative treatment options such as tyrosine kinase inhibitors. Over the past decade, several studies have investigated pharmacological induction or enhancement of NIS expression through “redifferentiation” therapies, mainly targeting the MAPK pathway. These novel approaches can restore radioiodine sensitivity in previously refractory patients and, therefore, potentially reestablish the efficacy of RIT. This review discusses various redifferentiation strategies, including their molecular mechanisms and clinical implications. Full article

VX-770 is a small-molecule CFTR potentiator that is highly efficacious in individuals with cystic fibrosis caused by mutations in CFTR that result in a defect in channel gating. While studies have reported on the mechanism of action of VX-770, there is still more to learn about the impact that it has on CFTR function in various contexts. The aim of the present study was to examine the longevity and stability of the effect of VX-770 on CFTR function in cultured airway epithelia and to measure the consequences of this interaction. The responses to acute and chronic VX-770 exposure were measured in cultures of expanded and re-differentiated primary human nasal epithelial cells. Acute VX-770 exposure resulted in an increase in CFTR-mediated currents in the absence of exogenous compounds that induce the phosphorylation/activation of CFTR, with acute exposure having the same effect as chronic exposure. The functional impact of VX-770 on CFTR was long-lasting in cultured airway epithelia, as they maintained an electrophysiological profile consistent with the saturation of CFTR with VX-770 over time periods of up to 4 days following a short (0.5 min) or low-dose (100 nM) exposure to VX-770 during an analysis in an Ussing chamber. Rinsing the apical surface prior to VX-770 exposure or exposure during the analysis in the Ussing chamber increased the interaction between VX-770 and the CFTR. Importantly, after short, low-dose exposures to VX-770, the CFTR channels in cultured epithelia appeared to remain saturated with VX-770 for extended periods of time, despite the repetitive rinsing of the apical surface. This finding has implications for patients discontinuing the use of VX-770-containing therapies. Full article