Exploring FGFR signaling inhibition as a promising approach in breast cancer treatment.

As our grasp of cancer genomics deepens, we are steadily progressing towards the domain of precision medicine, where targeted therapy stands out as a revolutionary breakthrough in the landscape of cancer therapeutics. The fibroblast growth factor receptors (FGFR) pathway has been unveiled as a fundamental instigator in the pathophysiological mechanisms underlying breast carcinoma, paving the way for the exhilarating development of precision-targeted therapeutics. In the pursuit of exploring inhibitors that specifically target the FGFR signaling pathways, a multitude of kinase inhibitors targeting FGFR has been assiduously engineered to address the heterogeneous landscape of human malignancies. This review offers an exhaustive exploration of aberrations within the FGFR pathway and their functional implications in breast cancer. Additionally, we delve into cutting-edge therapeutic approaches for the treatment of breast cancer patients bearing FGFR alterations and the management of toxicity associated with FGFR inhibitors. Furthermore, our contemplation of the evolution of cutting-edge FGFR inhibitors foresees their potential to spearhead innovative therapeutic approaches in the ongoing combat against cancer.

PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities.

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly enhanced the treatment outcomes in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, the occurrence of acquired resistance to EGFR-TKIs is an unavoidable outcome observed in these patients. Disruption of the PI3K/AKT/mTOR signaling pathway can contribute to the emergence of resistance to EGFR TKIs in lung cancer. The emergence of PIK3CA mutations following treatment with EGFR-TKIs can lead to resistance against EGFR-TKIs. This review provides an overview of the current perspectives regarding the involvement of PI3K/AKT/mTOR signaling in the development of lung cancer. Furthermore, we outline the state-of-the-art therapeutic strategies targeting the PI3K/AKT/mTOR signaling pathway in lung cancer. We highlight the role of PIK3CA mutation as an acquired resistance mechanism against EGFR-TKIs in EGFR-mutant NSCLC. Crucially, we explore therapeutic strategies targeting PIK3CA-mediated resistance to EGFR TKIs in lung cancer, aiming to optimize the effectiveness of treatment.

Combining Radiotherapy with Immunotherapy in Cervical Cancer: Where Do We Stand and Where Are We Going?

OPINION STATEMENT: Combining immunotherapy and radiotherapy as a treatment strategy for cervical cancer has attracted increasing attention. The primary objective of this review is to provide an up-to-date summary of the knowledge regarding the combined use of radiotherapy and immunotherapy for treating cervical cancer. This review discusses the biological rationale combining immunotherapy with radiotherapy in a clinical setting and presents supporting evidence for the combination strategy based on both safety and effectiveness data. Additionally, we discuss the potential and challenges of combining radiotherapy and immunotherapy in clinical practice.

Phase separation in cancer at a glance.

Eukaryotic cells are segmented into multiple compartments or organelles within the cell that regulate distinct chemical and biological processes. Membrane-less organelles are membrane-less microscopic cellular compartments that contain protein and RNA molecules that perform a wide range of functions. Liquid-liquid phase separation (LLPS) can reveal how membrane-less organelles develop via dynamic biomolecule assembly. LLPS either segregates undesirable molecules from cells or aggregates desired ones in cells. Aberrant LLPS results in the production of abnormal biomolecular condensates (BMCs), which can cause cancer. Here, we explore the intricate mechanisms behind the formation of BMCs and its biophysical properties. Additionally, we discuss recent discoveries related to biological LLPS in tumorigenesis, including aberrant signaling and transduction, stress granule formation, evading growth arrest, and genomic instability. We also discuss the therapeutic implications of LLPS in cancer. Understanding the concept and mechanism of LLPS and its role in tumorigenesis is crucial for antitumor therapeutic strategies.

Intratumoral microbiota: implications for cancer onset, progression, and therapy.

Significant advancements have been made in comprehending the interactions between the microbiome and cancer. However, prevailing research predominantly directs its focus toward the gut microbiome, affording limited consideration to the interactions of intratumoral microbiota and tumors. Within the tumor microenvironment (TME), the intratumoral microbiome and its associated products wield regulatory influence, directing the modulation of cancer cell properties and impacting immune system functionality. However, to grasp a more profound insight into the intratumoral microbiota in cancer, further research into its underlying mechanisms is necessary. In this review, we delve into the intricate associations between intratumoral microbiota and cancer, with a specific focus on elucidating the significant contribution of intratumoral microbiota to the onset and advancement of cancer. Notably, we provide a detailed exploration of therapeutic advances facilitated by intratumoral microbiota, offering insights into recent developments in this burgeoning field.

Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities.

Hepatocellular carcinoma is one of the leading causes of cancer mortality globally, and its incidence is increasing. Immune checkpoint therapy has revolutionized the treatment of hepatocellular carcinoma over the past few years. However, only a limited proportion of patients with hepatocellular carcinoma respond to immunotherapy. Despite the significant breakthroughs, the molecular mechanisms that drive immune responses and evasion are largely unresolved. Predicting tumor response and resistance to immune checkpoint inhibitors is a significant challenge. In this review, we focus on the current research progress of immune checkpoint inhibitors in hepatocellular carcinoma. Importantly, this review highlights the underlying mechanisms of resistance to immune checkpoint inhibitors and summarizes potential strategies to overcome the resistance to immune checkpoint inhibitors in hepatocellular carcinoma.

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.

Oncogenic Neuregulin 1 gene (NRG1) fusions in cancer: A potential new therapeutic opportunities.

It is widely established that chromosomal rearrangements induce oncogenesis in solid tumors. However, discovering chromosomal rearrangements that are targetable and actionable remains a difficulty. Targeting gene fusion or chromosomal rearrangement seems to be a powerful strategy to address malignancies characterized by gene rearrangement. Oncogenic NRG1 fusions are relatively rare drivers that infrequently occur across most tumor types. NRG1 fusions exhibit unique biological properties and are difficult to identify owing to their large intronic regions. NRG1 fusions can be detected using a variety of techniques, including fluorescence in situ hybridization, immunohistochemistry, or next-generation sequencing (NGS), with NGS-based RNA sequencing being the most sensitive. Previous studies have shown that NRG1 fusion protein induces tumorigenesis, and numerous therapies targeting the ErbB signaling pathway, such as ErbB kinase inhibitors and monoclonal antibodies, have initially demonstrated encouraging anticancer efficacy in malignant tumors carrying NRG1 fusions. In this review, we present the characteristics and prevalence of NRG1 fusions in solid tumors. Additionally, we discuss the laboratory approaches for diagnosing NRG1 gene fusions. More importantly, we outline promising strategies for treating malignancies with NRG1 fusion.

Dietary intake of fructose increases purine de novo synthesis: A crucial mechanism for hyperuricemia.

Background: Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine de novo synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine de novo synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine de novo synthesis in a hepatic cell line and livers of mice. Materials and methods: RNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay. Results: Metabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA. Conclusion: This study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.

Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives.

Circulating tumor DNA (ctDNA) is cell-free DNA (cfDNA) fragment in the bloodstream that originates from malignant tumors or circulating tumor cells. Recently, ctDNA has emerged as a promising non-invasive biomarker in clinical oncology. Analysis of ctDNA opens up new avenues for individualized cancer diagnosis and therapy in various types of tumors. Evidence suggests that minimum residual disease (MRD) is closely associated with disease recurrence, thus identifying specific genetic and molecular alterations as novel MRD detection targets using ctDNA has been a research focus. MRD is considered a promising prognostic marker to identify individuals at increased risk of recurrence and who may benefit from treatment. This review summarizes the current knowledge of ctDNA and MRD in solid tumors, focusing on the potential clinical applications and challenges. We describe the current state of ctDNA detection methods and the milestones of ctDNA development and discuss how ctDNA analysis may be an alternative for tissue biopsy. Additionally, we evaluate the clinical utility of ctDNA analysis in solid tumors, such as recurrence risk assessment, monitoring response, and resistance mechanism analysis. MRD detection aids in assessing treatment response, patient prognosis, and risk of recurrence. Moreover, this review highlights current advancements in utilizing ctDNA to monitor the MRD of solid tumors such as lung cancer, breast cancer, and colon cancer. Overall, the clinical application of ctDNA-based MRD detection can assist clinical decision-making and improve patient outcomes in malignant tumors.

Atractyloside Protect Mice Against Liver Steatosis by Activation of Autophagy via ANT-AMPK-mTORC1 Signaling Pathway.

Objective: Adenine nucleotide translocase (ANT) can transport ADP from cytoplasm to mitochondrial matrix and provide raw materials for ATP synthesis by oxidative phosphorylation. Dysfunction of ANT leads to limitation of ADP transport and decrease of ATP production. Atractyloside (ATR) is considered as a cytotoxic competitive inhibitor binding to ANT, making ANT vulnerable to transport ADP, and reduces ATP synthesis. Moreover, the blockage of ANT by ATR may increase ADP/ATP ratio, activate AMPK-mTORC1-autophagy signaling pathway, and promote lipid degradation in steatosis hepatocytes. The present study was conducted to investigate the mechanism of ATR, regulate ANT-AMPK-mTORC1 signaling pathway to activate autophagy, and promote the degradation of lipid droplets in high-fat diet (HFD) induced liver steatosis. Methods: ICR mice were fed with HFD for 8 weeks to induce liver steatosis, and ATR solution was given by intraperitoneal injection. Intracellular triglyceride level and oil red O staining-lipid droplets (LDs) were assessed, the expression of proteins related to ANT-AMPK-mTORC1 signaling pathway and autophagy were determined, and the colocalization of LC3B and Perilipin 2 was performed. Results: ATR treatment decreased the serum AST level, relative weight of liver and epididymal fat, and body weight of HFD mice. The LDs in HFD mice livers were reduced in the presence of ATR, and the TG level in serum and liver of HFD mice was significantly reduced by ATR. In addition, ATR inhibited ANT2 expression, promoted the activation of AMPK, then increased Raptor expression, and finally decreased the mTOR activity. Furthermore, ATR increased the protein level of LC3A/B and ATG7, and a strong colocalization of LC3B and PLIN2 was observed. Conclusion: ATR treatment blocks ANT2 expression, promotes the activation of AMPK, then decreases the mTOR activity, and finally promotes autophagosomes formation, thus accelerating the degradation of HFD-induced accumulated lipids in the liver. This will provide new therapeutic ideas and experimental data for clinical prevention and treatment of non-alcoholic fatty liver disease.

Relationship between gene expressions of aquaporin 3 and 4 and various degrees of spleen-stomach dampness-heat syndrome in chronic superficial gastritis.

OBJECTIVE: To explore the relationship between gene expressions of aquaporin (AQP) 3 and 4 and various degrees of spleen-stomach dampness-heat syndrome in chronic superficial gastritis (CSG). METHODS: Twenty-four CSG patients were divided into three groups according to the degrees of spleen-stomach dampness-heat syndrome: mild, moderate and severe groups. There were 8 patients in each group, and another 8 healthy persons were selected as normal control. Samples of mucosa of upper stomach in the included patients and normal persons were collected by gastroscopy, and then were stored in liquid nitrogen. The gene expressions of AQP3 and AQP4 in gastric tissue were examined by fluorescence quantitative polymerase chain reaction. RESULTS: The gene expressions of AQP3 and AQP4 in the moderate and severe groups were higher than that in the mild group and normal group (P<0.05, P<0.01). The gene expression of AQP3 in the severe group was higher than that in the moderate group (P<0.05). CONCLUSION: The gene expressions of AQP3 and AQP4 in gastric mucosa are different in patients with various degrees of spleen-stomach dampness-heat syndrome of CSG. There is a relationship between expressions of AQP3 and AQP4 genes and the degrees of spleen-stomach dampness-heat syndrome, and the gene expressions will increase with the aggravation of the dampness-heat syndrome.

[Study on correlation between aquaporin 3, 4 gene expression in gastric mucosa and severity of Pi-Wei damp-heat syndrome in patients with chronic superficial gastritis].

OBJECTIVE: To explore the relationship between aquaporin 3,4 (AQP3, AQP4) gene expression in gastric mucosa and severity of Pi-Wei damp-heat syndrome (PWDHS) in patients with chronic superficial gastritis (CSG). METHODS: Gastric mucosa taken from the upper part of gastric corpus was collected under gastroscope and preserved in liquid nitrogen. The gene expression of AQP3 and AQP4 was determined quantitatively by fluorescent PCR. RESULTS: The gene expression of AQP3 and AQP4 in patients with PWDHS of moderate and severe degree was higher than that in those of mild degree and in healthy persons respectively (P <0.05 and P <0.01); and the gene expression of AQP3 in patients with PWDHS of severe degree was higher than that in those of moderate degree (P<0.05). CONCLUSION: The gene expression of AQP3 and AQP4 in gastric mucosa was correlative with the severity of PWDHS in patients with chronic superficial gastritis, the severer the syndrome, the higher the gene expression.