Alterations In Signaling Pathways Research Articles

Cyclin-dependent kinase 4/6 inhibitor resistance mechanisms and strategies for subsequent treatment in breast cancer: A comprehensive review

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the therapeutic landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, demonstrating significant efficacy in both early and advanced stages of the disease. Combined with endocrine therapy, these inhibitors have dramatically improved survival outcomes. However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant challenge in clinical management. Resistance to CDK4/6 inhibitors can develop through inherent and acquired fashions, and their mechanisms are explored in this comprehensive review. Inherent resistance arises from pre-existing genetic or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6 inhibitors. Acquired resistance, on the other hand, develops over time through mechanisms, such as the activation of alternative signaling pathways or changes in the tumor microenvironment. The review also examines potential biomarkers for predicting resistance, especially circulating tumor DNA markers, and discusses strategies to overcome resistance. These include combination therapies targeting multiple pathways simultaneously, sequential approaches to delay the onset of resistance, and the development of next-generation CDK4/6 inhibitors with improved efficacy and reduced resistance potential. Understanding resistance mechanisms and developing effective countermeasures are crucial for optimizing patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in cancer therapy. Leveraging these insights will enable clinicians to personalize treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6 inhibitors in managing breast cancer.

Single-cell landscape of dynamic changes in CD8+ T cells, CD4+ T cells and exhausted T cells in hepatocellular carcinoma

Hepatocellular carcinoma has a high incidence and poor prognosis. In this study, we investigated the value of T-cell-related genes in prognosis by single-cell sequencing data in hepatocellular carcinoma. Twelve cases of hepatocellular carcinoma single-cell sequencing were included in the study. The high dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify gene modules associated with CD4+ T cells, CD8+ T cells and exhausted T cells. Altered signaling pathway activity in exhausted T cells was uncovered by the AUCell algorithm. xCELL, TIMER, QUANTISEQ, CIBERSORT and CIBERSORT-abs were performed to explore immune cell infiltration. Immune checkpoint inhibitor genes and TIDE methods were used to predict immunotherapy response. Finally, immunohistochemistry and real-time PCR were used to verify gene expression. The hdWGCNA algorithm identified 40 genes strongly associated with CD4+ T cells, CD8+ T cells and exhausted T cells. Seven genes were finally selected for transcriptome data modeling. The results of the three independent datasets suggested that the model had strong prognostic value. Model genes were critical factors influencing CD4+ T cell and CD8+ T cell infiltration in patients. The efficacy of PD-1 immunotherapy was higher in patients belonging to the low-risk group. Alterations in signaling pathways’ activity within exhausted T cells were crucial factors contributing to the decline in immune function. Differential expression of seven genes in CD8+ T cells, CD4+ T cells and exhausted T cells were key targets for improving immunotherapy response in HCC.

AR and YAP crosstalk: impacts on therapeutic strategies in prostate cancer

Prostate cancer ranks as one of the most common types of cancer affecting men worldwide, and its progression is shaped by a diverse array of influencing factors. The AR signaling pathway plays a pivotal role in the pathogenesis of prostate cancer. While existing anti-androgen treatments show initial efficacy, they ultimately do not succeed in halting the advancement to CRPC. Recent studies have identified alterations in the Hippo-YAP signaling pathway within prostate cancer, highlighting intricate crosstalk with the AR signaling pathway. In this review, we examine the interactions and underlying mechanisms between AR and YAP, the key molecules in these two signaling pathways. AR regulates the stability and function of YAP by modulating its transcription, translation, and phosphorylation status, while YAP exerts both promotional and inhibitory regulatory effects on AR. Based on these findings, this paper investigates their significant roles in the onset, progression, and therapeutic resistance of prostate cancer, and discusses the clinical potential of YAP in prostate cancer treatment.

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial.

LBA125 Background: Colorectal cancer (CRC) affects 1.9 million individuals globally each year. Among patients with stage II-III CRC, 20-40% develop metastatic disease. Aspirin lowers the incidence of adenomas and CRC in high-risk patients. In addition, observational studies suggest that post-diagnosis aspirin treatment improves disease-free survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response, but requires validation in randomized trials. Methods: The ALASCCA trial was a randomized, double-blind, multicenter, placebo-controlled trial with two parallel arms, across 33 hospitals in Sweden, Denmark, Finland, and Norway. Patients with stage I-III rectal cancer or stage II-III colon cancer exhibiting somatic alterations in the PI3K signaling pathway were included. Patients were randomized to receive either 160 mg of aspirin daily or placebo, initiated within three months post-surgery and continued for three years. To detect a hazard ratio (HR) of 0.36 for the primary outcome of time to recurrence (TTR) assessed at 3 years, with 80% power and a two-sided alpha of 0.05, 150 patients with PIK3CA mutations in exon 9 and/or 20 (“Group A”) were required per arm. An additional 300 patients with other somatic PI3K pathway driver alterations (PIK3CA outside exon 9/20, PIK3R1, or PTEN; "Group B") were required for secondary analyses. A stratified Cox proportional hazards model was fitted for the primary efficacy analysis. Results: A total of 3508 patients were screened for somatic alterations in the PI3K pathway. Of the 2980 patients with conclusive genomic analyses, 1103 patients (37%) had an alteration in the PI3K pathway: 515 patients (17.3%) in Group A and 588 patients (19.7%) in Group B. In total, 626 patients were randomized. After three years of follow-up, the HRs for TTR comparing aspirin to placebo were 0.49 (95% CI; 0.24-0.98; p=0.044) in Group A and 0.42 (95% CI; 0.21-0.83; p=0.013) in Group B. For DFS, the HRs were 0.61 (95% CI; 0.34-1.08; p=0.091) in Group A, and 0.51 (95% CI; 0.29-0.88; p=0.017) in Group B. Three patients experienced aspirin-related severe adverse events (one GI-bleeding, one hematoma, one allergic reaction). Conclusions: Primary endpoint was met. Adjuvant treatment with 160 mg aspirin daily for three years reduced recurrence rate in CRC patients with somatic alterations in the PI3K signaling pathway. These findings could lead to immediate changes in clinical praxis for about a third of CRC patients. Clinical trial information: NCT02647099 .

High-intensity acute noise exposure causes anxiety in female rats by inducing hippocampal neuron apoptosis.

The increasing prevalence of acute noise exposure poses a significant threat to mental health. Identifying the intensity of noise that impair health is crucial for developing effective interventions. The study aimed to determine the acute noise intensity thresholds that elicit anxiety-like behaviors and brain damage in female rats, and then to elucidate the underlying neurobiological mechanisms. Female rats were subjected to acute noise exposure at levels of 105, 115, 125, and 135 dB to determine the intensity thresholds that elicit anxiety-like behaviors and brain damage were assessed at the 3th day and 1 month post-exposure. We found that acute noise exposure at 135 dB induced significant anxiety-like behaviors and hippocampal neuron apoptosis on the third day, with these effects persisting up to one month after exposure. KEGG enrichment analysis of differentially expressed genes (DEGs) revealed alterations in the PI3K-AKT signaling pathway, as confirmed by Western blot analysis. Our findings indicate that acute noise exposure at 135 dB elicits anxiety-like behaviors in female rats on the third day post-exposure, with these effects persisting up to one month. This sustained anxiety is attributed to the inhibition of the PI3K-AKT signaling pathway and the subsequent activation of the apoptotic Caspase-3/BCL-2/BAX pathway, culminating in hippocampal neuron apoptosis.

Integrated analysis of the transcriptome and hormone metabolome elucidates the regulatory mechanisms governing walnut bud germination

The walnut (Juglans regia) is an important oilseed tree species characterized by its extensive distribution, high oil yield, and nutrient-dense kernels, which provide substantial economic benefits. However, the rising incidence of late-spring frosts, exacerbated by global climate change, has adversely affected walnut yields. A comprehensive understanding of the regulatory mechanisms involved in bud dormancy, germination, and development is essential for developing strategies to mitigate the effects of late-spring frosts and for breeding frost-resistant cultivars. This study focused on W13, a protogynous walnut variety with early germination of dormant buds in spring, employing a combination of transcriptomic and hormone metabolomic analyses. Our results emphasized four key biological processes—cellular response to ethylene stimulus, phenylpropanoid metabolic process, ethylene-activated signaling pathway, and monooxygenase activity—along with several relevant pathways, including plant hormone signal transduction, flavone and flavonol biosynthesis, biosynthesis of secondary metabolites, and MAPK signaling pathway, all crucial for walnut bud germination. Additionally, bud germination is closely associated with alterations in various hormone signaling pathways, including abscisic acid, auxin, cytokinin, ethylene, gibberellins, jasmonic acid, and salicylic acid. By assessing hormone levels and gene expression at different developmental stages, we pinpointed potential regulatory genes and critical hormones associated with bud germination. Furthermore, through weighted correlation network analysis, we constructed a co-expression network, identifying gene modules specifically expressed during dormancy, germination, budding, and leafing phases. The hub genes within these modules are likely pivotal in regulating walnut bud germination. Our analysis also revealed that genes from various transcription factor families are central within the co-expression network, indicating their significant roles in the bud germination process. Correlation network analysis of hormone and gene further illuminated the mechanisms through which genes and hormones jointly influence walnut bud germination. These findings establish a crucial molecular basis for a more comprehensive understanding of the mechanisms governing germination and development in dormant walnut buds.

SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection.

Understanding the neurobiological mechanisms underlying HIV-associated neurocognitive decline in people living with HIV is frequently complicated by an inability to analyze changes across the course of the infection and frequent presence of comorbid psychiatric and substance use disorders. Preclinical non-human primate simian immunodeficiency virus (SIV) models help address these shortcomings. However, SIV studies frequently target protracted endpoints, limiting our understanding of the neuromolecular alterations during the early post-infection window. To begin to address this knowledge gap, we utilized single nuclei transcriptomics to examine frontal cortex samples of rhesus macaques 10- and 20-days post-SIV infection, compared to non-infected controls. We identify and validated a decrease in inhibitory neurons during the early post infection window, representing a potential substrate of longer-term injury and neurocognitive impairment in people living with HIV. Differential expression identified alterations in cellular subtype gene expression that persisted over the 20-day time course and short-lived differences only detected at 10-days post-SIV infection. In silico predicted regulatory mechanisms and dysregulated neural signaling pathways are presented. Analysis of cell-cell interaction networks identify altered signal pathways in the frontal cortex that may represent regional alterations in cell-cell communications. In total, these results identify cell type-specific molecular mechanisms putatively capable of underlying long-term neurocognitive alterations in persons living with HIV.

Nitrate induced hepatic fibrosis in tadpoles of Bufo gargarizans by mediating alterations in toll-like receptor signaling pathways.

The nitrate pollution has become an increasingly serious environmental problem worldwide, and the toxic effects of elevated nitrate levels in the environment on aquatic animals remain to be elucidated. The purpose of the present study was to investigate the mechanisms of liver injury to tadpoles after exposure to nitrate from embryonic to metamorphic climax and to assess the recovery process of liver function after cessation of exposure. In the group with continuous nitrate exposure, the livers and thyroid of tadpoles showed remarkably histological lesions, of this with structural disorganization of the hepatocytes, cellular atrophy, and fibrosis, as well as significant reduction in the follicular and colloidal area of the thyroid. Meanwhile, the expression levels of genes related to inflammatory signaling pathways, such as TLR2, TLR6 and NF-κB, were significant elevated. After termination of exposure at Gs23, liver damage (histologic, ultrastructural, and molecular levels) was almost completely recovered, whereas thyroid gland damage was irreversible. Overall, this study shed light on the harmful effects of nitrate pollution on amphibian health and emphasizes the importance of controlling nitrate emissions in the environment.

Genes and proteins expression profile of 2D vs 3D cancer models: a comparative analysis for better tumor insights.

When juxtaposed with 2D cell culture models, multicellular tumor spheroids demonstrate a capacity to faithfully replicate certain features inherent to solid tumors. These include spatial architecture, physiological responses, the release of soluble mediators, patterns of gene expression, and mechanisms of drug resistance. The morphological and behavioural similarities between 3D-cultured cells and cells within tumor masses highlight the potential of these models in studying cancer biology and drug responses. The liquid overlay method, hanging drop technique, and ultra-low adhesion plates are among the various methods for generating tumor spheroids, each with its advantages and applications. Gene expression studies, employing advanced methods such as microarrays, suppression subtractive hybridization, qRT-PCR, and mass-spectrometry-based proteomics revealed distinct expression patterns in 3D spheroids compared to 2D cultures, uncovering upregulation and downregulation of genes associated with tumor development, metastasis, and drug resistance. Protein expression studies identified alterations in key signaling pathways, metabolic characteristics, and phosphorylation levels, highlighting the impact of 3D culture on cellular responses. This study explores genes and proteins expression variations in various cancer cell lines cultivated in 3D spheroids, shedding light on the complexity of interactions in a more tumor-mimicking environment. The fusion of these analytical approaches not only advances scientific understanding but also holds promise for the development of more effective cancer treatments.

Characteristics of genomic alterations and heavy metals in hypertensive patients with non‑small cell lung cancer.

Both lung cancer and cardiovascular disease (CVD) are prevalent diseases that contribute to global mortality rates. Although individuals with CVD may face an elevated risk of cancer based on the presence of shared risk factors (such as tobacco smoking and excessive body weight), the roles of somatic mutations and heavy metal distributions remain unknown. The present study aimed to explore the differences in somatic mutations and heavy metal distributions between hypertensive patients and non-hypertensive patients in a cohort of patients with non-small cell lung cancer (NSCLC). Tumor tissue samples from 64 patients were analyzed using a next-generation sequencing panel consisting of 82 tumor-related genes through hybrid capture. Serum samples were also analyzed to determine the levels of 18 heavy metals using inductively-coupled plasma mass spectrometry. Among the 16 hypertensive patients, all patients (16/16; 100.00%) harbored 47 somatic mutations in 14 mutant genes, whereas 45 patients without hypertension (45/48; 93.75%) harbored 113 somatic mutations across 26 mutant genes (no mutations were detected in the remaining 3 patients). Among the 32 identified mutant genes in these two groups, FBXW7, CBR3, CDKN2A, HRAS, SMO and UGT1A1 were exclusively observed in patients with hypertension, while 18 mutant genes were only observed in patients without hypertension. No significant mutually exclusive interactions were found in hypertensive patients, but mutually exclusive interactions were observed between EGFR and STK11 (P=0.0240) and between STK11 and KRAS (P=0.0169) in non-hypertensive patients. 'Non-small cell lung cancer' was the top Kyoto Encyclopedia of Genes and Genomes pathway in hypertensive patients, whereas 'central carbon metabolism in cancer' was the top pathway in patients without hypertension. Moreover, the proportions of altered key signaling pathways and biological function categories shared between these two groups were 54.37% (56/103) and 21.62% (8/37), respectively. Furthermore, the levels of chromium (Cr) in the serum of hypertensive patients were notably elevated compared with those in patients without hypertension. In addition, significant negative correlations were observed between Cr and CEA, between CYFRA21-1 and Zn, and between NSE and As in hypertensive patients but not in non-hypertensive patients, indicating differing interactive profiles among the traditional serum biomarkers and heavy metals between these two patient groups. In summary, there were differences in genomic alterations, somatic interactions and the serum levels of Cr between patients with NSCLC with hypertension and patients with NSCLC without hypertension. Furthermore, patients with hypertension exhibited significant negative correlations between Cr and CEA, between CYFRA21-1 and Zn, and between NSE and As, suggesting that heavy metals may contribute to the occurrence of NSCLC with different hypertensive status.

Nicotine's impact on platelet function: insights into hemostasis mechanisms.

Traditional Miao and Dai Chinese medicines have used nicotine-rich leaf tobacco to treat traumatic injuries by promoting hemostasis. While nicotine is known to enhance platelet aggregation, its effects on other platelet functions and underlying mechanisms remain unclear. This study aimed to thoroughly investigate nicotine's effects on human platelets and its pharmacological mechanisms, using thromboelastography to assess nicotine's impact on platelet function during coagulation. This study aimed to investigate the functional effects of nicotine on human platelets and elucidate its pharmacological mechanisms. The impact of nicotine on platelet function during the coagulation process was assessed using thromboelastography. Further studies showed that nicotine fully activates washed platelets, promoting aggregation, granule release, adhesion, spreading, and plaque retraction. Concurrently, nicotine was found to enhance the intracellular concentration of calcium ions in platelets ([Ca2+]i). To explore the underlying mechanisms, molecular docking software was employed to identify the platelet membrane receptors PAR1 and PAR4, which exhibited the highest docking scores with nicotine. Intervention with two receptor inhibitors demonstrated that only the PAR4 inhibitor could reverse the stimulatory effects of nicotine on platelet granule release. Through the examination of alterations in the downstream signaling pathways of PAR4 receptors, it was determined that nicotine promo-facilitates the phosphorylation of PI3K, AKT, and ERK1/2 proteins, subsequently contributing to the activation of αIIbβ3 receptors in platelets. Conversely, the application of PAR4 inhibitors was found to reverse these effects. In conclusion, nicotine activates αIIbβ3 receptors and significantly enhances platelet function by promoting the phosphorylation of the platelet PAR4 receptor signaling pathway. These findings suggest the potential utility of nicotine as a hemostatic agent.

Metabolic reprogramming and signaling adaptations in anoikis resistance: mechanisms and therapeutic targets.

Anoikis, a form of programmed cell death triggered by detachment from the extracellular matrix (ECM), maintains tissue homeostasis by removing mislocalized or detached cells. Cancer cells, however, have evolved multiple mechanisms to evade anoikis under conditions of ECM detachment, enabling survival and distant metastasis. Studies have identified differentially expressed proteins between suspended and adherent cancer cells, revealing that key metabolic and signaling pathways undergo significant alterations during the acquisition of anoikis resistance. This review explores the regulatory roles of epithelial-mesenchymal transition, cancer stem cell characteristics, metabolic reprogramming, and various signaling pathway alterations in promoting anoikis resistance. And the corresponding reagents and non-coding RNAs that target the aforementioned pathways are reviewed. By discussing the regulatory mechanisms that facilitate anoikis resistance in cancer cells, this review aims to shed light on potential strategies for inhibiting tumor progression and preventing metastasis.

Venlafaxine induces Teratogenesis and alters SHH Gene Expression and Protein Biochemistry of Developing Gallus sp. Embryos

The use of antidepressant drugs during pregnancy is increasing globally. SNRIs and SSRIs are most widely used for treating panic disorders. Venlafaxine is an antidepressant that inhibits serotonin and norepinephrine reuptake. Given the increasing prevalence of antidepressant use during pregnancy, Venlafaxine exposure during the early stages of development could lead to changes in protein dynamics and disrupt essential gene pathways, raising concerns about the potential teratogenic effects of antidepressant exposure during pregnancy. This study explores the developmental impact of Venlafaxine, a commonly prescribed serotonin-norepinephrine reuptake inhibitor (SNRI), on protein biochemistry and gene expression in the developing Gallus gallus domesticus embryos. Significant changes in protein profiles were observed among control and Venlafaxine-treated groups. Sonic Hedgehog (SHH) gene, a key regulator of embryonic patterning and organogenesis, specifically neural tube formation, and limb development, is known for its crucial role in embryonic development. qRT-PCR analysis of Venlafaxine-treated embryos showed changes in SHH gene expression suggesting that Venlafaxine may target SHH gene expression, and potentially alter signalling pathways crucial for normal embryogenesis. However, detailed studies are needed to understand the long-term consequences of prenatal and foetal antidepressant exposure on embryonic growth and development. These changes may lead to abnormal growth patterns or congenital defects, emphasizing the need for caution when prescribing Venlafaxine during pregnancy. Keywords: Antidepressants, Venlafaxine, SNRI, Gallus gallus domesticus, Sonic Hedgehog (SHH), Protein Biochemistry, qRT-PCR

Precision medicine in gynecological cancer (Review).

The advent of personalized and precision medicine has revolutionized oncology and treatment of gynecological cancer. These innovative approaches tailor treatments to individual patient profiles beyond genetic markers considering environmental and lifestyle factors, thereby optimizing therapeutic efficacy and minimizing adverse effects. Precision medicine uses advanced genomic technologies such as next-generation sequencing to perform comprehensive tumor profiling. This allows identification of distinct genetic mutations, expression patterns and signaling pathway alterations, revealing the complex molecular landscape of gynecological cancer such as ovarian, cervical and uterine cancer. A major challenge in treating these cancers is their inherent molecular heterogeneity, which can influence tumor behavior, therapy response and prognosis. Precision medicine aims to overcome this by identifying biomarkers and molecular drivers for targeted therapy selection. For example, the identification of breast cancer (BRCA) gene mutations in ovarian cancer has guided the use of poly (ADP-ribose) polymerase inhibitors, leading to more effective treatments with fewer side effects. Similar targeted therapies and immunotherapies have also been developed for cervical and uterine cancer, marking progress toward personalized care. Future directions in gynecological oncology emphasize the importance of molecular profiling and development of targeted therapies. By understanding the unique molecular features of each patient, clinicians can select the most effective personalized treatment strategies to improve patient outcomes and quality of life.

Genomic and Clinicopathological Characterization of CRLF2-Rearranged Mixed Phenotype Acute Leukemia.

Rearrangements of cytokine receptor-like factor 2 gene (CRLF2) are present in ∼50% of B-lymphoblastic leukemia/lymphoma (B-ALL) with BCR::ABL1-like features. Herein, we report three patients with CRLF2-rearranged mixed phenotype acute leukemia (MPAL). All three cases were B/myeloid MPAL in young patients harboring P2RY8::CRLF2 or IGH::CRLF2 with additional genomic alterations in signaling (JAK and RAS) and cell cycle (CDKN2A/B) pathways, a genomic profile similar to that in BCR::ABL1-like B-ALL. Our study is the first case series to demonstrate clinicopathological and genomic features of this underrecognized entity. We recommend upfront genetic/molecular testing to timely diagnose and further characterize MPAL with BCR::ABL1-like features.

Dysfunction in amino acid synthesis pathways: Potential biomarkers for early glaucoma detection

Aims/Purpose: Amino acids have been proposed as preclinical biomarkers of the risk of developing neurodegenerative and metabolic diseases. We used proton nuclear magnetic resonance (1H‐NMR) in tears for the first time to investigate alterations in essential amino acids in patients with primary open‐angle glaucoma (POAG).Methods: We planned an analytical pilot case‐control study for 30 participants aged 40‐80 years, divided into: POAG group (n = 11) and control group (CG; n = 19). Tears were obtained from each eye using capillarity. The samples were studied using 1H‐NMR spectroscopy, acquiring one‐dimensional spectra for each sample, and assigning the peaks according to their chemical shift (profiling) and information from various databases. The data from the chemometric analysis are shown as mean and standard deviation.Results: A total of 40 metabolites were assigned based on their chemical shifts, multiplicity, and scalar coupling between J cores. Our multivariate model included 11 to discriminate between POAG and CG: phenylalanine, phenylacetate, leucine, taurine, glycine, urea, glucose, N‐acetylated compounds, unsaturated fatty acid, formic acid, and uridine. Thus, the most relevant metabolites were phenylalanine, phenylacetate, leucine, taurine, glycine, urea, and glucose, showing a significant reduction in concentration in the tears of the POAG group for phenylalanine, phenylacetate, leucine, N‐acetylated compounds, formic acid, and uridine, compared to the CG.Conclusions: Our results suggested that the alteration in phenylalanine, tyrosine, and tryptophan signaling pathways and their effects are associated with an increased risk for POAG. Their decrease in tears maybe considered a potential biomarker to identify patients in the early stages of glaucoma.

The Role of Cuproptosis Key Factor FDX1 in Gastric Cancer.

Gastric cancer is a common malignant tumor of the digestive tract, both domestically and internationally. It has high incidence and mortality rates, posing a significant threat to human health. The levels of blood copper are elevated in patients with gastric cancer. However, the exact relationship between copper overload and the malignant phenotype of gastric cancer is still unclear. This study aims to investigate the role of the Cuproptosis-related factor FDX1 in the conversion of gastric cancer to a malignant phenotype. Firstly, the relative mRNA and protein expression levels of FDX1 in gastric cancer were detected. Secondly, lentiviral transfection of gastric cancer cell lines was performed, and the effects of FDX1 functional intervention on the proliferation, invasion and migration of gastric cancer cells were assessed by CCK-8, colony formation, EdU proliferation, cell scratch and Transwell assays. Thirdly, the differential alteration of genes after overexpression of FDX1 was also analyzed by transcriptome sequencing. Finally, we assessed the tumour-forming capacity in vivo by the xenograft model. FDX1 is significantly upregulated in gastric cancer. The inhibition of FDX1 function results in the suppression of malignant phenotypic transformation in gastric cancer cells. Conversely, overexpression of FDX1 function leads to alterations in tumor-related signaling pathways and the tumor microenvironment. FDX1 plays a significant role in the malignant phenotypic transformation of gastric cancer cells. Further investigation into the regulatory mechanism of FDX1 in the malignant transformation of gastric cancer will enhance our understanding of the involvement of Cuproptosis in gastric cancer.

The pathway alteration load is a pan-cancer determinant of outcome of targeted therapies: results from the Drug Rediscovery Protocol (DRUP).

Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP). DRUP is a prospective, pan-cancer, non-randomized clinical trial (NCT02925234) that treats patients with therapy-refractory metastatic cancer and an actionable molecular profile using matched off-label targeted and immunotherapies. All patients treated with TT with available clinical outcomes and whole genome sequencing were included. PAL was determined based on driver gene alterations and correlated with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Outcomes were validated in the independent Hartwig Medical database of metastatic cancers. In 154 patients treated with TT, the median PAL was 3. Patients with a PAL below median (n= 60) demonstrated a higher CBR (41.7% versus 25.5%, odds ratio 0.48, P= 0.051), longer PFS [median 4.7 versus 2.9 months, adjusted hazard ratio (aHR) 1.70, P= 0.020] and OS (median 13.7 versus 5.6 months, aHR 3.80, P < 0.001) compared with those with PAL ≥3. Two hundred and fifty-eight patients in the Hartwig database showed similar results for CBR (54.2% versus 36.7%, odds ratio 2.04, P= 0.009) and PFS (7.0 versus 4.2 months, aHR 1.55, P= 0.009). In our population, PAL emerged as a pan-cancer determinant of outcome to TT. Our findings support refined patient selection for TT and highlight the rationale for combinatorial treatment strategies in patients with multiple affected pathways.

Activation of S1PR2 on macrophages and the hepatocyte S1PR2/RhoA/ROCK1/MLC2 pathway in vanishing bile duct syndrome.

Immunologic bile duct destruction is a pathogenic condition associated with vanishing bile duct syndrome (VBDS) after liver transplantation and hematopoietic stem-cell transplantation. As the bile acid receptor sphingosine 1-phosphate receptor 2 (S1PR2) plays a critical role in recruitment of bone marrow-derived monocytes/macrophages to sites of cholestatic liver injury, S1PR2 expression was examined using cultured macrophages and patient tissues. Bile canaliculi destruction precedes intrahepatic ductopenia; therefore, we focused on hepatocyte S1PR2 and the downstream RhoA/Rho kinase 1 (ROCK1) signaling pathway and bile canaliculi alterations using three-dimensional hepatocyte culture models that form obvious bile canaliculus-like networks. Multiplex immunohistochemistry revealed increased numbers of S1PR2+CD45+CD68+FCN1+ inflammatory macrophages and S1PR2+CD45+CD68+MARCO+ Kupffer cells in liver tissues showing ductopenia due to graft-versus-host disease and rejection post-liver transplant compared with normal liver. Macrophage expression of proinflammatory cytokines, including MCP1, was reduced following S1PR2 inhibition. Taurocholic acid and S1P2 agonist induced hepatocyte S1PR2 and reduced RhoA/ROCK1 expression, resulting in bile canaliculi dilatation. S1PR2 inhibition reversed the effect on RhoA/ROCK1 expression, resulting in maintenance of bile canaliculi through myosin light chain 2 (MLC2) phosphorylation. Activation of S1PR2 on macrophages and S1PR2 on hepatocytes may disrupt bile canaliculi dynamics in VBDS under regulation by RhoA/ROCK1 through MLC2 phosphorylation.

Microplastic and Extracellular Vesicle Interactions: Recent Studies on Human Health and Environment Risks

Microplastics (MPs) are widespread environmental pollutants that have drawn significant attention due to their possible health risks to humans and animals, as well as their extensive presence in ecosystems. Recent growing evidence highlights a remarkable relationship between MPs and extracellular vesicles (EVs), nanoscale particles involved in intercellular communication. The purpose of this review was to investigate how the relationships between MPs and EVs can affect cellular functions and how this interaction could impact environmental conditions leading to broader ecological risks. The interaction patterns and bioactivity of both MPs and EVs are strongly influenced by biophysical characteristics such as hydrophobicity, surface charge, and particle size, which have received particular attention from the scientific community. Recent studies indicate that MPs affect EV distribution and their capacity to function appropriately in biological systems. Additionally, MPs can modify the molecular cargo of EVs, which may result in alterations of cell signaling pathways. Understanding the interactions between MPs and EVs could provide important opportunities to comprehend their potential effects on human health and environmental systems, especially when it comes to cancer development, endocrine, metabolic, and inflammatory disorders, and ecological disruptions. This review emphasizes the necessity of multidisciplinary research to clarify the molecular and biophysical mechanisms regulating the interaction between MPs and EVs.