Jan Geliebter

Background/Objectives: Papillary thyroid cancer (PTC) is the most common endocrine malignancy and is generally associated with favorable clinical outcomes. However, a subset of tumors develops aggressive phenotypes characterized by increased proliferation, migration, therapeutic resistance, and disease progression. Long non-coding RNAs (lncRNAs) have emerged as important regulators of tumor biology, yet the role of Long Intergenic Non-Protein Coding RNA 1614 (LINC01614) in PTC remains poorly understood. This study investigated the functional role of LINC01614 in PTC and its potential involvement in ferroptosis-associated molecular pathways. Methods: RNA sequencing data from a repository of 44 paired PTC and adjacent normal thyroid tissue samples were analyzed to identify differentially expressed lncRNAs. LINC01614 expression was evaluated in thyroid cell lines, and CRISPR interference (CRISPRi) was used to generate stable LINC01614 knockdown K1 cell lines. Cellular proliferation, migration, clonogenicity, intracellular iron accumulation, lipid peroxidation, cytokine secretion, and ferroptosis-associated gene expression were assessed using qRT-PCR, RNA sequencing, Western blotting, cytokine array analysis, iron quantification assays, and BODIPY C11 lipid peroxidation imaging. Results: LINC01614 was significantly overexpressed in PTC tissues and thyroid cancer cell lines. CRISPRi-mediated repression of LINC01614 reduced cellular proliferation, migration, and clonogenic capacity. Mechanistically, LINC01614 knockdown resulted in an 8.8-fold increase in miR-4521 expression and a 23-fold decrease in IGF2 expression, supporting a potential competing endogenous RNA mechanism. Reduced LINC01614 expression was associated with decreased AKT, GPX4, SLC7A11, and SLC3A2 expression, increased IL-6 secretion, a 3.4-fold increase in intracellular ferrous iron accumulation, and a marked increase in lipid peroxidation following erastin treatment, indicating enhanced sensitivity to ferroptosis. Conclusions: These findings identify LINC01614 as a novel regulator of aggressive PTC phenotypes and ferroptosis resistance. The data support a model in which LINC01614 contributes to thyroid cancer progression through modulation of a miR-4521/IGF2/PI3K/AKT signaling axis and downstream anti-ferroptotic pathways. LINC01614 may represent a promising biomarker and potential therapeutic target in papillary thyroid cancer.

Staphylococcus aureus (S. aureus), a primary exacerbating factor in eczema, remains a prevalent pathogenic public-health threat. The mechanism of mast cell/basophil degranulation in the context of S. aureus-exacerbated eczema remains unclear. We sought to investigate the direct effect of mast cell/basophil activation by S. aureus isolated from patients with severe eczema undergoing topical steroid withdrawal (TSW) and understand the mechanism of berberine (BBR) in inhibiting this activation. Clinical S. aureus strains (N = 8) were isolated from skin swabs of severe eczema patients and confirmed by sequencing. Human basophils (KU812), rat basophils (RBL-2H3) and murine mast cells (MC/9) were pre-treated with BBR for 48 h. and stimulated with heat-killed standard S. aureus- and clinical strains for 45 min, and degranulation was measured. BBR’s molecular-targets on basophils were identified by computational modeling and validated by qRT-PCR. BBR prevented degranulation following standard S. aureus stimulation in KU812, RBL-2H3 and MC/9 cells. BBR dose-dependently inhibited degranulation in KU812. BBR inhibited TNF-α and IL-4 release, and markedly suppressed the expression of FcεR1 (α, β, γ), TNFα, MAPK1, MAPK3, AKT2, CASP9, and CCND1 following standard S. aureus stimulation. BBR dose-dependently inhibited KU812 cell degranulation, markedly reduced TNF-α, IL-4, and MAPK1 and enhanced NFκB1A expression following clinical S. aureus strain stimulation. BBR inhibition of S. aureus-induced KU812 activation was at least associated with inhibition of MAPK-associated gene expression. This study provides novel insights into BBR’s effect in preventing S. aureus and human basophil interaction.

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive follicular cell-derived malignancy characterized by rapid progression, profound dedifferentiation, and marked resistance to conventional therapy. Despite frequent involvement of major oncogenic pathways, ATC does not exhibit a universal driver mutation, suggesting that its pathogenesis reflects convergence upon shared biological hallmarks rather than dependence on a single molecular event. This review describes the principal mechanistic programs that define the ATC phenotype: disruption of cell-cycle and apoptotic control through alterations in TP53, CDKN2A/B, and aberrant MAPK activation; metabolic adaptations involving glycolysis, glutaminolysis, and mitochondrial one-carbon metabolism; reprogramming of canonical stress response pathways including ER stress and hypoxia signaling; and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation. Collectively, these processes cooperate to generate a highly proliferative, stress-tolerant, immune-inflamed yet immunosuppressed tumor state. A mechanistic understanding of these convergent pathways is essential for rational therapeutic development and for overcoming the profound clinical resistance that defines ATC.

Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This molecular phenotype narrows the availability of targeted therapies and contributes to high rates of early relapse, therapeutic resistance, and poor clinical outcomes. Mounting evidence pinpoints the tumor microenvironment (TME) as a central driver of TNBC progression, immune evasion, and resistance to treatment. The TME encompasses a complex and dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that collectively shape tumor behavior and influence therapeutic response. Notably, TNBC often displays an immunologically active microenvironment, marked by high levels of tumor-infiltrating lymphocytes and immune checkpoint expression, opening a window for immune-based therapeutic strategies. This narrative review summarizes current knowledge on the cellular, molecular, and structural features of the TNBC tumor microenvironment, with particular focus on immunosuppressive mechanisms mediated by tumor-associated macrophages, myeloid-derived suppressor cells, cancer-associated fibroblasts, and dysfunctional T cells. We describe the clinical development and therapeutic impact of monoclonal antibodies, including immune checkpoint inhibitors and antibody–drug conjugates. Additionally, we discuss strategies aimed at modulating the TME to enhance monoclonal antibody efficacy, including immune cell reprogramming, extracellular matrix remodeling, cytokine/chemokine blockade, and combination treatment strategies. Finally, we highlight the role of biomarker-driven patient stratification and personalized therapeutic strategies, addressing current challenges and future directions in TME-targeted drug development. Together, these insights underscore the potential of integrating immune modulation and monoclonal antibody-based therapies to improve outcomes for TNBC patients.

Ferroptosis is a non-apoptotic, iron-dependent form of cell death. The characteristic accumulation of membrane lipid peroxides that occurs is controlled by several different mechanisms including redox homeostasis, the intracellular labile iron pool, and amino acid metabolism. In cancer, ferroptosis can contribute to either tumor progression or tumor suppression. When promoted in cancer cells, ferroptosis plays an innately tumor-suppressive role; however, it can negatively affect anticancer immunity, allowing for tumor growth and progression. Cells that are traditionally known to be resistant to apoptosis and other forms of cell death have demonstrated susceptibility to ferroptosis, making this form of cell death particularly useful in terms of cancer therapeutics. This narrative review will focus on the role of ferroptosis in cancer promotion or prevention and how it can be manipulated therapeutically—whether it be induced or inhibited.

Background: Long non-coding RNAs (lncRNAs) are regulatory molecules that have multifaceted impacts on the carcinogenic molecular landscape—with pathologic consequences when aberrantly expressed. Anaplastic thyroid cancer (ATC) is a rapidly progressing and highly lethal malignancy, with mortality rates approaching 100%. The molecular/transcriptomic signature of ATC has significant gaps in understanding; thus, a comprehensive study of ATC non-coding RNA transcript regulation is necessary. Results: The lncRNA Double Homeobox A Pseudogene 10 (DUXAP10) was identified in patient genomic datasets as a highly upregulated transcript in ATC vs. normal thyroid tissue. DUXAP10 expression was transcriptionally repressed with CRISPR-interference (CRISPRi), and data supports an extensive role of DUXAP10 in several cancer-promoting phenotypes in ATC, both in vitro and in vivo. Our two DUXAP10-CRISPRi cell lines significantly reduced the rapid growth and metastatic behaviors characteristic of ATC, affecting proliferation, viability, clonogenicity, apoptosis, invasion, migration, tumorigenesis, and metastasis. Conclusion: Thus, DUXAP10 is a proposed prognostic marker and therapeutic target for ATC disease propagation and progression.

Current therapeutic strategies for IgE-mediated diseases are limited. The drawbacks include adverse reactions, ineffectiveness, and relapses. Natural compound berberine (BBR) may combat this therapeutic gap through sustained transcriptional regulation of IgE. Human tonsil cells were cultured in the presence or absence of BBR to establish dose-dependent effects on IgE, IgG, and cell viability. IgE-producing plasma cells (U266, IgE plasma cells) and IgG-producing plasma cells (ARH-77, IgG plasma cells) were used as surrogate cells to validate dose-dependent effects on IgE and IgG production, respectively. At 10 μg/mL BBR, cell viability and proliferation were determined, and cells were harvested for protein, RNA, and miRNA and analyzed by Western blot and qPCR. BBR treatment of human tonsil samples resulted in reduced IgE production (p < 0.001) with no effect on IgG levels or cell viability. BBR demonstrated sustained, dose-dependent inhibition of IgE production by IgE plasma cells (p < 0.001), without affecting IgG production by IgG plasma cells. There was no significant reduction in cell viability of either cell type. Proliferation was reduced in IgE plasma cells (p = 0.02), but not IgG plasma cells. Assessment of IgE regulation and cell cycle at the RNA level revealed that BBR reduced IgE heavy chain expression and CCND1 (p < 0.01), with increased the GADD45A expression of IgE plasma cells, only (p = 0.016). At the protein level, BBR increased p53 (p = 0.02) and CDKN1C (p = 0.03), and decreased CDK2 (p = 0.01) expression of IgE plasma cells, only. Investigation of miRNAs implicated in B cell and p53 regulation demonstrated increased p53 and GADD45A activator, miR-34a (p = 0.04). miRNAs that are present in IgE plasma cells allow for specific effects on B cells and cell cycle genes by BBR, that are not present in IgG plasma cells. A novel mechanism for specific suppression of IgE by BBR highlights miR-34a, involved in the p53 pathway and B cell development, and may be crucial to pathological IgE production.

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after surgery, with a five-year survival rate exceeding 90%. Nevertheless, recurrence can occur, and the ten-year survival rate for the advanced PTC is below 50%. Even after effective successful surgical intervention, many still require ongoing surveillance, additional treatment, and lifelong thyroid hormone replacement, while facing the potential adverse effects such as hormone fluctuations, surgical complications, and sequelae of radioactive iodine exposure. Naturally occurring compounds have demonstrated anti-cancer properties and hence the potential to be used as therapeutic options, impacting the same drivers and pathways involved in the tumorigenesis of thyroid cancer. This narrative review focuses on the natural compounds’ convergence on molecular nodes of PI3K/Akt, MAPK, and JAK/STAT to overcome therapeutic resistance and restore apoptosis, highlighting their potential in advanced and recurrent PTC.

Metastases are responsible for the majority of cancer-related deaths and remain one of the most complex and therapeutically challenging hallmarks of cancer. The metastatic cascade involves a multistep process by which cancer cells invade local tissue, enter and survive in circulation, extravasate, and ultimately colonize distant organs. Increasingly, the tumor microenvironment (TME), particularly the extracellular matrix (ECM), has emerged as a central regulator of these steps. Far from being a passive scaffold, the ECM actively influences cancer progression through its biochemical signals, structural properties, and dynamic remodeling. Among ECM components, collagens play a particularly pivotal role by mediating tumor cell adhesion, migration, invasion, survival, immune evasion, and therapeutic resistance. This narrative review synthesizes current knowledge of the dual roles of collagen in the metastatic process, with a focus on the cellular and molecular mechanisms. We highlight how altered ECM architecture and signaling contribute to metastatic niche formation and explore the potential of targeting ECM components as a strategy to enhance cancer therapy and improve patient outcomes.

The thyroid is a vital endocrine organ that regulates metabolism, heart rate, respiration, digestion, body temperature, brain development, skin and bone maintenance, and reproduction and fertility. Thyroid cancer (TC) is the most common endocrine malignancy, with an estimate of 44,020 new cases in 2025. Incidence has been increasing, most notably at 4–5% per year in young adults. Papillary thyroid cancer (PTC), the most common TC subtype, accounts for approximately 80% of newly diagnosed TC cases. Furthermore, 2290 deaths are expected from the disease in 2025, with survival at over 98% with treatment. However, as PTC occurs most frequently in young women, recurrences are frequent and the 10-year disease-specific survival rate for advanced PTC is less than 50%. This narrative review aims to describe the current understanding of the thyroid gland, the incidence and subtypes of thyroid cancer, and specifically the diagnosis, prognosis, treatment, and recurrence of PTC. This is supplemented by the role of molecular pathways and biomarkers in PTC.