Objective: Understanding the molecular mechanisms underlying papillary thyroid carcinoma (PTC) is crucial for identifying drug targets. This research aims to elucidate molecular interactions between transcriptional enhanced associate domain factor 1 (TEAD1) and cortactin-binding protein 2 N-terminal-like (CTTNBP2NL) in PTC cells and assess their effect on cell proliferation, apoptosis, and clonogenicity.
Material and methods: Transcriptome data were used to identify differences in TEAD1 and CTTNBP2NL in PTC tissues. The correlation of gene expression with overall patient survival was analyzed. Laboratory experiments were conducted using thyroid papillary carcinoma 1 (TPC1) cells, where the overexpression of TEAD1 and the downregulation of CTTNBP2NL were manipulated. The regulatory dynamics between the two genes were confirmed through molecular biochemistry experiments. The effects on cell proliferation were evaluated using cell proliferation assays, and the impact on clonogenicity was assessed through colony formation assays.
Results: Significant differences in TEAD1 and CTTNBP2NL were observed in PTC, with both genes showing strong correlations with overall patient survival. In TPC1 cells, the overexpression of TEAD1 remarkably mitigated the negative effects caused by CTTNBP2NL downregulation, reduced cell proliferation, and increased apoptosis. Quantitative polymerase chain reaction and Western blot analyses confirmed the regulatory relationship between TEAD1 and CTTNBP2NL. The overexpression of TEAD1 markedly enhanced the proliferative capacity of cells, while silencing CTTNBP2NL resulted in diminished cell growth. Clonogenic assays revealed that TEAD1 promoted colony formation, indicating its role in boosting cell survival and proliferation.
Conclusion: TEAD1 plays a critical compensatory role in PTC cells by alleviating the adverse effects of CTTNBP2NL deficiency, thereby promoting cell survival and growth. Hence, TEAD1 could serve as a potential therapeutic target.
The co-occurrence of uterine and adnexal malignancies poses significant diagnostic challenges in distinguishing synchronous primary tumors from metastatic lesions. This study presents a rare case of concurrent dedifferentiated endometrial carcinoma (DEC) and high-grade serous tubal carcinoma and highlights the critical role of integrated pathological and molecular analyses. A 58-year-old woman presented with a 2-month history of irregular vaginal bleeding. Transvaginal ultrasound demonstrated endometrial thickening (1 cm) with intrauterine fluid accumulation. Hysteroscopic biopsy confirmed endometrioid adenocarcinoma. The patient underwent laparoscopic radical hysterectomy with bilateral adnexectomy and pelvic lymphadenectomy. Histopathological examination identified two distinct neoplasms: (1) DEC (microsatellite instability-high subtype) located at the left uterine fundus and (2) High-grade serous carcinoma (SET subtype: solid, endometrioid-like, transitional patterns) in the right fallopian tube. Following surgery, six cycles of adjuvant chemotherapy with TP regimen (liposomal paclitaxel plus carboplatin) were administered. The patient remains disease-free at a 46-month follow-up. This case underscores the diagnostic complexity of synchronous gynecological malignancies. Comprehensive immunohistochemistry combined with molecular characterization is essential for accurate tumor classification, which directly determines staging precision and therapeutic decision-making. The favorable long-term outcome in this case suggests potential clinical implications for dual primary management strategies.
Objective: Cardiovascular (CV) diseases remain the leading cause of death in modern societies, with endothelial dysfunction being the common pathology of CV diseases with various etiologies. Therefore, effectively regulating the function of endothelial cells is considered the key to the future treatment of various CV diseases. Low levels of vitamin D and its analogs have been shown to be associated with endothelial dysfunction in various diseases. However, the underlying mechanism remains unknown. Here, we conducted an in vitro study to evaluate the effects of 1α,25-dihydroxyvitamin D3 (1α, 25(OH)2D3), the active form of vitamin D, on adhesion molecule expression in human endothelial cells. The possible mechanism involved in this process was also explored.
Material and methods: Human umbilical vein endothelial cells were cultured and treated according to the experimental requirements. Western blotting and reverse transcription polymerase chain reaction were used to evaluate the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Chromatin immunoprecipitation (ChIP) assays, immunofluorescence, Western blotting, and coimmunoprecipitation were used to assess the effects of 1α, 25(OH)2D3 on nuclear factor kappa-B (NF-κB) signaling.
Results: 1α, 25(OH)2D3 inhibited VCAM-1 and E-selectin mRNA and protein expression after tumor necrosis factor-α (TNF-α) stimulation. Moreover, 1α, 25(OH)2D3 affected TNF-α-induced IκBα phosphorylation and p65 NF-κB activation, leading to the inhibition of p65 expression. A ChIP assay revealed that TNF-α increased p65 binding to the promoters of VCAM-1 and E-selectin, which was suppressed by 1α, 25(OH)2D3. These effects were abrogated by a specific vitamin D receptor siRNA (VDR-siRNA). Coimmunoprecipitation revealed that 1α, 25(OH)2D3 induced increased binding of the vitamin D receptor to p65, which inhibited the ability of p65 to bind to target gene promoters.
Conclusion: 1α, 25(OH)2D3 regulates adhesion molecule expression in endothelial cells through the TNF-α/NF-κB pathway, laying the foundation for the clinical application of 1α, 25(OH)2D3 in the treatment of CV diseases.
Objective: Ovarian cancer (OC) is the most common and deadliest cancer in women worldwide. The high incidence and mortality rates highlight the serious threat that OC poses to women's health. Regulator of chromosome condensation (RCC1) and broad-complex, tramtrack and bric a brac ( BTB) domain-containing protein 1 (RCBTB1), which includes the RCC1 and BTB domains, is a cell proliferation-related protein. This study aims to reveal the role of RCBTB1 in OC and its possible pathway.
Material and methods: The expression of RCBTB1 in OC cells was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Transwell assay, wound-healing assay, clone formation assay, IHC, immunofluorescence, and methylthiazolyldiphenyl-tetrazolium bromide assay were used to evaluate the effect of silencing RCBTB1 in vivo and in vitro. The neurofibromin 1 (NF1)/rat sarcoma (Ras) signal axis was determined by Western Blot, qRT-PCR, and immunofluorescence.
Results: The A2780 cells had increased RCBTB1 expression (P < 0.01). By suppressing Ras signaling, RCBTB1 silencing hindered the proliferation of OC cells with Kirsten rat sarcoma viral oncogene (KRAS) mutations. RCBTB1 activated protein kinase kinase Cε, which degrades NF1. RCBTB1 also plays a key role in the Ras/ extracellular regulated protein kinase (ERK) signal axis by inhibiting Ras GTPase. RCBTB1 knockdown may alleviate mitogen-activated protein kinase kinase ( MEK) inhibitor resistance in KRAS-mutated OC by inhibiting Ras/ERK signaling.
Conclusion: RCBTB1 may regulate the NF1/Ras signaling axis, which is critical for OC and MEK inhibitor resistance. This research offers a unique therapeutic approach for ovaries with KRAS mutations and uncovers a previously unknown connection between RCBTB1 and NF1/Ras signaling.
Objective: Gestational diabetes mellitus (GDM) has significant implications for maternal and neonatal health and constitutes a considerable health challenge that requires intervention. The primary factors contributing to GDM are oxidative stress and dysbiosis of the gut microbiota. Alginate oligosaccharides (AOS), known for their antioxidant properties and ability to modulate the balance of gut microbiota, may offer a promising therapeutic option for managing GDM. In this investigation, we aim to clarify the specific therapeutic effects and underlying mechanisms of AOS in GDM.
Material and methods: Mice with GDM were administered various agents, including AOS and deltamethrin, to investigate the impact of AOS on gut microbiota composition, insulin resistance (IR), pancreatic cell apoptosis, and hepatic gluconeogenesis. Biochemical markers associated with GDM, IR, and hepatic gluconeogenesis were analyzed. Cell experiments were introduced to confirm the effects of AOS on high-glucose-induced liver cell damage.
Results: Mice with GDM exhibited an imbalance in the gut microbiota, increased IR, enhanced liver gluconeogenesis, and activated the nuclear factor-erythroid 2 related factor 2/heme oxygenase-1 pathway in the liver. The administration of AOS restored gut microbiota equilibrium and reduced cell apoptosis in pancreatic cells, oxidative stress, IR, and hepatic gluconeogenesis, leading to improvements in parameters associated with islet β-cell functionality and insulin sensitivity. AOS also increased cell viability and decreased the inflammatory cytokine release induced by high glucose in QSG 7701 liver cells.
Conclusion: Treatment with AOS offers protection against IR, and hepatic gluconeogenesis by diminishing oxidative stress and modulating the gut microbiota in mice with GDM. Hence, AOS is a promising intervention for GDM.
Kikuchi's lymphadenitis (KL) is a benign, self-limited, reactive condition with unknown etiology, usually seen in young women of Asian descent. It is most commonly seen in the cervical lymph nodes; however, in rare cases, axillary lymph nodes are involved. Cytological diagnosis is possible with adequate lymph node sampling by fine needle aspiration in the proper clinical setting. Pathologists face some difficulties in making the diagnosis of KL due to overlapping findings among other conditions, such as tuberculosis, lupus lymphadenitis, non-specific reactive conditions, and even malignant lymphoma. Diagnosis by cytopathology has the advantage of using minimally invasive interventions, which avoid the unnecessary excision of the lymph node for this benign condition. Herein, we report a case of KL in a patient who presented with right axillary lymphadenopathy.
Objective: The immunosuppressive tumor microenvironment (TME) limits the treatment effectiveness of immunotherapy in gastric cancer (GC). This study investigated the role of membrane-spanning four domains subfamily A member 4A (MS4A4A) in the regulation of macrophage polarization and its effect on the immune response in GC, with the aim of enhancing the effectiveness of immunotherapy by addressing the immunosuppressive TME.
Material and methods: A GC ectopic tumor model was initiated in C57BL/6 mice with subcutaneous MKN-45 injection. Five groups were formed by randomly dividing the mice: model, MS4A4A recombinant protein, MS4A4A antibody, programmed cell death protein 1 (PD-1) antibody, and MS4A4A recombinant protein + PD-1 antibody groups. MKN-45 cells and bone marrow-derived macrophages (BMDMs) were cocultured with the MS4A4A protein or antibody. Macrophage polarization was analyzed through flow cytometry, gene expression through quantitative real-time polymerase chain reaction (qRT-PCR), cytokine levels through enzyme-linked immunosorbent assay, protein expression through Western blot, and tumor morphology through hematoxylin and eosin staining.
Results: In the GC mouse model, the MS4A4A recombinant protein markedly enhanced tumor growth (P < 0.001), and the MS4A4A antibody exhibited an inhibitory effect (P < 0.001). MS4A4A recombinant protein decreased the levels of inflammatory cytokine concentrations and increased those of anti-inflammatory mediator concentrations (P < 0.001). By contrast, the MS4A4A antibody treatment group displayed the opposite effect. Inhibition of MS4A4A enhanced the accumulation of macrophages, CD4+ T cells, and CD8+ T cells in the tumor (P < 0.001). Flow cytometry and qRT-PCR analyses showed that MS4A4A promoted M2 macrophage polarization, and MS4A4A antibody induced M1 polarization (P < 0.001). MS4A4A played a key role in inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells subunit p50 (p50) during M1 polarization. Furthermore, the PD-1 antibody reversed the pro-tumor effects of MS4A4A, which reestablished pro-inflammatory cytokine levels while lowering anti-inflammatory cytokines (P < 0.001).
Conclusion: This study shows that MS4A4A promotes tumor growth by inducing M2 macrophage polarization and suppressing immune responses, while MS4A4A antibody enhances anti-tumor immunity by inducing M1 polarization. PD-1 antibody reverses MS4A4A's pro-tumor effects, restoring anti-tumor immunity. MS4A4A inhibitors or their combination with PD-1 antibodies may offer a promising strategy for GC immunotherapy.
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