Cancer Subtypes Research Articles

Advances in chitosan-based drug delivery systems in melanoma: A narrative review.

Melanoma accounts for the minority of skin cancer cases. However, it has the highest mortality rate among the subtypes of skin cancer. At the early stages of the disease, patients show a good prognosis after the surgery, but developing metastases leads to a remarkable drop in patients' 5-year survival rate. Despite the advances made in the therapeutic approaches to this disease, melanoma treatment is still facing several obstacles. Systemic toxicity, water insolubility, instability, lack of proper biodistribution, inadequate cellular penetration, and rapid clearance are some of the challenges that should be addressed in the field of melanoma treatment. While various delivery systems have been developed to circumvent these challenges, chitosan-based delivery platforms have indicated significant success. Chitosan that is produced by the deacetylation of chitin can be formulated into different materials (e.g., nanoparticle, film, and hydrogel) due to its characteristics. Both in vitro and in vivo studies have reported that chitosan-based materials can be used in drug delivery systems while offering a solution for the common problems in this area, such as enhancing biodistribution and skin penetration as well as the sustained release of the drugs. Herein, we reviewed the studies concerning the role of chitosan as a drug delivery system in melanoma and discussed how these drug systems are used for delivering chemotherapeutic drugs (e.g., doxorubicin and paclitaxel), genes (e.g., TRAIL), and RNAs (e.g., miRNA199a and STAT3 siRNA) successfully. Furthermore, we take a look into the role of chitosan-based nanoparticles in neutron capture therapy.

STK3 higher expression association with clinical characteristics in intrinsic subtypes of breast cancer invasive ductal carcinoma patients.

STK3 has a central role in maintaining cell homeostasis, proliferation, growth, and apoptosis. Previously, we investigated the functional link between STK3/MST2, and estrogen receptor in MCF-7 breast cancer cells. To expand the investigation, this study evaluated STK3's higher expression and associated genes in breast cancer intrinsic subtypes using publicly available data. The relationship between clinical pathologic features and STK3 high expression was analyzed using descriptive and multivariate analysis. Increased STK3 expression in breast cancer was significantly associated with higher pathological cancer stages, and a different expression level was observed in the intrinsic subtypes of breast cancer. Kaplan-Meier analysis showed that breast cancer with high STK3 had a lower survival rate in IDC patients than that with low STK3 expression (p < 0.05). The multivariate analysis unveiled a strongcorrelation between STK3 expression and the survival rate among IDC patients, demonstrating hazard ratios for lower expression. In the TCGA dataset, the hazard ratio was 0.56 (95% CI 0.34-0.94, p = 0.029) for patients deceased with tumor, and 0.62 (95% CI 0.42-0.92, p = 0.017) for all deceased patients. Additionally, in the METABRIC dataset, the hazard ratio was 0.76 (95% CI 0.64-0.91, p = 0.003) for those deceased with tumor. From GSEA outcomes 7 gene sets were selected based on statistical significance (FDR < 0.25 and p < 0.05). Weighted Sum model (WSM) derived top 5% genes also have higher expression in basal and lower in luminal A in association with STK3. By introducing a novel bioinformatics approach that combines GSEA and WSM, the study successfully identified the top 5% of genes associated with higher expression of STK3.

Molecular features and prognostic factors of locally advanced microsatellite instability-high gastric cancer.

Microsatellite instability-high (MSI-H) tumors are distinct molecular subtypes in gastric cancer. However, a few studies have comprehensively reported the molecular features of MSI-H tumors and their prognostic factors in locally advanced gastric cancer. This study aimed to clarify the molecular features and prognostic factors of locally advanced MSI-H gastric cancer. This study included 499 patients with locally advanced gastric cancer who underwent radical gastrectomy. We evaluated the MSI status and compared with previously published whole-exome sequencing, panel sequencing, and gene expression profiling data. Clinicopathological characteristics and molecular profiles were compared between patients with MSI-H and microsatellite stable (MSS) gastric cancer. A subgroup analysis of survival was performed in patients with MSI-H gastric cancer. MSI-H tumors were detected in 79 of 499 patients (15.8%). MSI-H tumors were associated with an increased tumor mutational burden, MLH1 downregulation, CD274 (PD-L1) upregulation, and enrichment of cell cycle pathways. Among patients with MSI-H gastric cancer, the disease-specific survival (DSS) tended to be better in the surgery plus tegafur, gimeracil, and oteracil potassium (S-1) adjuvant chemotherapy group than in the surgery alone group, especially for stage III patients. Furthermore, DSS was better in the T cell-inflamed gene expression signature-high group, and it tended to be worse in the non-solid type poorly differentiated adenocarcinoma group. The molecular features and prognostic factors of locally advanced MSI-H gastric cancer were clarified. S-1 adjuvant chemotherapy appears to be beneficial, and the T cell-inflamed gene expression signature and histopathological type are prognostic factors in MSI-H tumors.

Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

MDLC displays both ductal and lobular tumor regions. Our multi-omic profiling approach revealed that these morphologically distinct tumor regions harbor distinct intrinsic subtypes and oncogenic features that may cause prognostic uncertainty and therapeutic dilemma. Thus histopathological/molecular profiling of individual tumor regions may guide clinical decision making and benefit patients with MDLC, particularly in the advanced setting where there is increased reliance on next generation sequencing.

Cervicovaginal metabolome and tumor characteristics for endometrial cancer detection and risk stratification.

Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for non-invasive diagnostic and prognostic tests. Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n=66) and non-malignant conditions (n=108), and global untargeted metabolomics was performed. Using the metabolite data (n=920), we completed a multivariate biomarker discovery analysis. We analyzed grade 1/2 endometrioid carcinoma (n=53) and other endometrial cancer subtypes (n=13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (p<0.0001), tryptophan (p<0.0001), and glutamate (p<0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q<0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement into diagnosis. The metabolic dysregulation described in this paper linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighbouring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of non-invasive diagnostic can improve both the acceptability and accessibility of diagnosis.

Deep learning approach to identifying cancer subtypes using convolutional hyperbolic k nearest neighbours method

ABSTRACT To properly treat a cancer patient, radiologists must first review a large volume of cancer images. Based on this information, the appropriate treatment is prescribed. However, the manual cancer image classification is susceptible to errors due to the intricate nature of different tumours. This study introduces a novel convolutional hyperbolic k-nearest neighbours (ChkNN) method to address this challenge. Using deep learning algorithms, convolutional neural networks (CNN), hyperbolic mapping, and hyperbolic geometry, the proposed method effectively extracts and embeds features in hyperbolic space. This embedding not only enhances classification accuracy rates up to 99.92% but also facilitates informed decision-making in cancer diagnosis. The ChkNN method holds immense potential for radiologists worldwide, empowering them to make more accurate and timely treatment decisions, ultimately improving patient outcomes.

Prognostic implications of TOR1B expression across cancer types: a focus on basal-like breast cancer and cellular adaptations to hypoxia

The TOR1B gene is known to play a pivotal role in maintaining cellular homeostasis and responding to endoplasmic reticulum stress. However, its involvement in cancer remains relatively understudied. This study seeks to explore the prognostic implications of TOR1B across various cancers, with a specific focus on Basal-like Breast Cancer (BLBC) and its underlying cellular mechanisms. Through comprehensive analysis of data from TCGA, TARGET, GEO, and GTEx, we investigated TOR1B expression and its correlation with patient outcomes. Furthermore, in vitro experiments conducted on BLBC cell lines examined the impact of TOR1B modulation on cell viability, apoptosis, and metabolic activity under varying oxygen levels. Our statistical analysis encompassed differential expression analysis, survival analysis, and multivariate Cox regression. Our findings indicate that TOR1B is overexpressed in BLBC and other cancers, consistently correlating with poorer prognosis. Elevated TOR1B levels were significantly associated with reduced overall and disease-free survival in BLBC patients. In vitro experiments further revealed that TOR1B knockdown augmented apoptosis and influenced metabolic activity, particularly under hypoxic conditions, highlighting its potential role in cancer cell adaptation to stress. Overall, our study underscores the importance of TOR1B in cancer progression, particularly in BLBC, where it serves as a notable prognostic indicator. The interaction between TOR1B and metabolic pathways, as well as its regulation by HIF-1α, suggests its significance in adapting to hypoxia, thereby positioning TOR1B as a promising therapeutic target for aggressive breast cancer subtypes.

HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer

ABSTRACT Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString’s nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.

Expression of GPR56 reflects a hypoactivated state of circulating B cells and is downregulated in B cell subsets in patients with early-stage lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, and the early detection and diagnosis of this disease are crucial in reducing mortality rates. The timely diagnosis of LUAD is essential for controlling tumour development and enabling early surgical treatment. GPR56 is a vital G protein-coupled receptor and its role in T lymphocytes has received considerable attention. However, its function in B cells remains unclear. This study aimed to investigate the significance of GPR56 in LUAD. We found that GPR56 exhibited a significant increase in circulating plasmablasts and a decrease in new memory B cells. GPR56 expression in B cells was significantly reduced after LPS stimulation and the proportion of HLA-DR+ and CD40+ proportions were also decreased in GPR56+ B cells after stimulation. Additionally, GPR56 exhibited significant down-regulation in circulating B cell subsets of early-stage LUAD patients, and there were significant correlations between GPR56+ B cell subsets and tumour markers. In conclusion, GPR56 could reflect the hypoactivation state of B cells and the decreased proportion of GPR56+ B cell subset in LUAD patients can signify the active humoral immunity in vivo. The expression of GPR56 in B cells could potentially hold value in the early diagnosis of LUAD.

Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group.

Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.

Exploring GZMK as a prognostic marker and predictor of immunotherapy response in breast cancer: unveiling novel insights into treatment outcomes

BackgroundGranzyme K (GZMK) is a crucial mediator released by immune cells to eliminate tumor cells, playing significant roles in inflammation and tumorigenesis. Despite its importance, the specific role of GZMK in breast cancer and its mechanisms are not well understood.MethodsWe utilized data from the TCGA and GEO databases and employed a range of analytical methods including GO, KEGG, GSEA, ssGSEA, and PPI to investigate the impact of GZMK on breast cancer. In vitro studies, including RT-qPCR, CCK-8 assay, cell cycle experiments, apoptosis assays, Celigo scratch assays, Transwell assays, and immunohistochemical methods, were conducted to validate the effects of GZMK on breast cancer cells. Additionally, Cox regression analysis integrating TCGA and our clinical data was used to develop an overall survival (OS) prediction model.ResultsAnalysis of clinical pathological features revealed significant correlations between GZMK expression and lymph node staging, differentiation grade, and molecular breast cancer subtypes. High GZMK expression was associated with improved OS, progression-free survival (PFS), and recurrence-free survival (RFS), as confirmed by multifactorial Cox regression analysis. Functional and pathway enrichment analyses of genes positively correlated with GZMK highlighted involvement in lymphocyte differentiation, T cell differentiation, and T cell receptor signaling pathways. A robust association between GZMK expression and T cell presence was noted in the breast cancer tumor microenvironment (TME), with strong correlations with ESTIMATEScore (Cor = 0.743, P < 0.001), ImmuneScore (Cor = 0.802, P < 0.001), and StromalScore (Cor = 0.516, P < 0.001). GZMK also showed significant correlations with immune checkpoint molecules, including CTLA4 (Cor = 0.856, P < 0.001), PD-1 (Cor = 0.82, P < 0.001), PD-L1 (Cor = 0.56, P < 0.001), CD48 (Cor = 0.75, P < 0.001), and CCR7 (Cor = 0.856, P < 0.001). Studies indicated that high GZMK expression enhances patient responsiveness to immunotherapy, with higher levels observed in responsive patients compared to non-responsive ones. In vitro experiments confirmed that GZMK promotes cell proliferation, cell division, apoptosis, cell migration, and invasiveness (P < 0.05).ConclusionOur study provides insights into the differential expression of GZMK in breast cancer and its potential mechanisms in breast cancer pathogenesis. Elevated GZMK expression is associated with improved OS and RFS, suggesting its potential as a prognostic marker for breast cancer survival and as a predictor of the efficacy of immunotherapy.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

YY1 mediated DCUN1D5 transcriptional activation promotes triple-negative breast cancer progression by targeting FN1/PI3K/AKT pathway

Triple-negative breast cancer (TNBC) is more aggressive and has a higher metastasis rate compared with other subtypes of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is now the only available systemic treatment for TNBC. However, some patients might still develop drug resistance and have poor prognosis. Therefore, novel molecular biomarkers and new treatment targets are urgently needed for patients with TNBC. To provide molecular insights into TNBC progression, we investigated the function and the underlying mechanism of Defective in cullin neddylation 1 domain containing 5 (DCUN1D5) in the regulation of TNBC. By TCGA dataset and surgical specimens with immunohistochemical (IHC) staining method, DCUN1D5 was identified to be significantly upregulated in TNBC tumor tissues and negatively associated with prognosis. A series of in vitro and in vivo experiments were performed to confirm the oncogenic role of DCUN1D5 in TNBC. Overexpression of FN1 or PI3K/AKT activator IGF-1 could restore the proliferative and invasive ability induced by DCUN1D5 knockdown and DCUN1D5 could act as a novel transcriptional target of transcription factor Yin Yang 1 (YY1). In conclusion, YY1-enhanced DCUN1D5 expression could promote TNBC progression by FN1/PI3K/AKT pathway and DCUN1D5 might be a potential prognostic biomarker and therapeutic target for TNBC treatment.

Integrated analysis of -omic landscapes in breast cancer subtypes

The subtypes of breast cancer exhibit diverse histology, molecular features, therapeutic response, aggressiveness, and patient outcomes. Multi-omics high-throughput technologies, which are widely used in cancer research, generated waste amounts of multimodal omic datasets calling for new approaches of integrated analyses to uncover patterns of transcriptomic, genomic, and epigenetic changes in breast cancer subtypes and connect them to disease clinical characteristics. Here, we applied multi-layer self-organizing map (ml-SOM) algorithms to PAM50-classified TCGA breast cancer samples to disentangle the diversity of the effects of gene expression, methylation, copy number, and somatic single nucleotide variation in the disease subtypes. Furthermore, we studied the association of perturbed gene modules with survival, prognosis, and other clinical characteristics. Our findings highlight the power of multi-omic analyses to offer a better understanding of the molecular diversity of breast cancer subtypes compared to single-omic analyses. Moreover, they highlight the complex subtype-characteristic associations between gene expression and epigenetic/genomic factors and their implications for survival and clinical outcomes.

Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition

BackgroundCirculating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk.MethodsWe analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics.ResultsCirculating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade.ConclusionsEstimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Optimus-Era Dose Finding for Rare Cancers.

Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line with evolving approaches to dose determination in the age of the US Food and Drug Administration's Project Optimus.

CRCDB: A comprehensive database for integrating and analyzing multi-omics data of early-onset and late-onset colorectal cancer

The incidence of early-onset colorectal cancer (EOCRC) has increased significantly worldwide. Uncovering biomarkers that are unique to EOCRC is of great importance to facilitate the prevention and detection of this growing cancer subtype. Although efforts have been made in the data curation about CRC, there is no integrated platform that gives access to data specifically related to young CRC patients. Here, we constructed a user-friendly open integrated resource called CRCDB (URL: http://crcdb-hust.com) which contains multi-omics data of 785 EOCRC, 4898 late-onset CRCs (LOCRC), and 1110 normal control samples from tissue, whole blood, platelets, and serum exosomes. CRCDB manages the differential analysis, survival analysis, co-expression analysis, and immune cell infiltration comparison analysis results in different CRC groups. Meta-analysis results were also provided for users for further data interpretation. Using the resource in CRCDB, we identified that genes associated with the metabolic process were less expressed in EOCRC patients, while up regulated genes most associated with the mitosis process might play an important role in the molecular pathogenesis of LOCRC. Survival-related genes were most enriched in oxidoreduction pathways in EOCRC while in immune-related pathways in LOCRC. With all the data gathered and processed, we anticipate that CRCDB could be a practical data mining platform to help explore potential applications of omics data and develop effective prevention and therapeutic strategies for the specific group of CRC patients.

Study on the mechanism of heterogeneous tumor-associated macrophages in three subtypes of breast cancer through the integration of single-cell RNA sequencing and in vitro experiments.

Tumor-associated macrophages (TAM) exert a significant influence on the progression and heterogeneity of various subtypes of breast cancer (BRCA). However, the roles of heterogeneous TAM within BRCA subtypes remain unclear. Therefore, this study sought to elucidate the role of TAM across the following three BRCA subtypes: triple-negative breast cancer, luminal, and HER2. This investigation aimed to delineate the variations in marker genes, drug sensitivity, and cellular communication among TAM across the three BRCA subtypes. We identified specific ligand-receptor (L-R) pairs and downstream mechanisms regulated by VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Experimental verification of these pairs was conducted by co-culturing macrophages with three subtypes of BRCA cells. Our findings reveal the heterogeneity of macrophages within the three BRCA subtypes, evidenced by variations in marker gene expression, composition, and functional characteristics. Notably, heterogeneous TAM were found to promote invasive migration and epithelial-mesenchymal transition (EMT) in MDA-MB-231, MCF-7, and SKBR3 cells, activating NF-κB pathway via P38 MAPK, TGF-β1, and AKT, respectively, through distinct VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Inhibition of these specific L-R pairs effectively reversed EMT, migration, and invasion of each cancer cells. Furthermore, we observed a correlation between ligand gene expression and TAM sensitivity to anticancer drugs, suggesting a potential strategy for optimizing personalized treatment guidance. Our study highlights the capacity of heterogeneous TAM to modulate biological functions via distinct pathways mediated by specific L-R pairs within diverse BRCA subtypes. This study might provide insights into precision immunotherapy of different subtypes of BRCA.

A Specificity Protein 1 assists the progression of the papillary thyroid cell line by initiating NECTIN4.

Papillary thyroid cancer (PTC) is one of the subtypes of thyroid cancer with increasing incidence worldwide, but the molecular mechanism is still unclear. Papillary thyroid cancer (PTC) is one of the subtypes of thyroid cancer with increasing incidence worldwide, but the molecular mechanism is still unclear. Studies have indicated that nectin cell adhesion molecule 4 (NECTIN4) was an oncogene and played an important role in the development and progression of PTC. Meanwhile, specificity protein 1 (SP1) expresses many important oncogenes and tumor suppressor genes. However, the relationship between NECTIN4 and SP1 in regulating PTC growth is unclear. In the present study, reverse transcription PCR was utilized to detect the mRNA expression of NECTIN4 and SP1 in thyroid cancer cell lines and normal thyroid cell lines. Chromatin immunoprecipitation assays and luciferase reporter assays were used to study whether SP1 could bind to the promoter region of NECTIN4 and activate its transcription. The biological functions of SP1 correlated with NECTIN4 were also performed in TPC-1 and KTC1 cell lines. The study revealed that the mRNA expression level of SP1 and NECTIN-4 showed a positive correlation and were upregulated in PTC cell lines. Moreover, the results of ChIP and luciferase reporter assays showed that SP1 could bind to the NECTIN4 promoter regions and activate the transcriptional level of NECTIN4. The experiments in vitro showed that SP1 could promote cell proliferation, colony formation, migration, and invasion by regulating NECTIN4 in PTC cells. In conclusion, our study, for the first time, demonstrated that SP1 could control the transcriptional regulation of NECTIN4 and accelerate the growth of PTC, which may provide a new potential therapeutic target for PTC patients.

Beyond the pain: Decoding opioid use in advanced cancer ED visits.

e24034 Background: Patients with advanced cancer often turn to the emergency department (ED) for pain treatment, impacting their quality of life and escalating healthcare costs. A crucial step in reducing avoidable ED visits is to identify the characteristics of this patient group and explore potential intervention points. This study aims to characterize the use of narcotics in the ED among patients with advanced cancer. Methods: This retrospective cross-sectional study involved adults aged 18 and older diagnosed with Stage IV solid cancers who passed away within one year of diagnosis (excluding those who died within 30 days). Participants had at least one ED visit within that year at one of 21 cancer centers within Kaiser Permanente Northern California from 2018 to 2020. Demographics, clinical variables, frequencies, and trends in ED visits were collected and compared based on opioid utilization. Pain management details for those receiving opioids during ED visits were also recorded. Results: The study encompassed 2,554 patients with 6,406 ED visits in their final year of life. Sixty-one percent of these patients received opioids during their ED visits, with a median of three visits per patient. In 56% of visits, patients had filled an opioid prescription within the last 30 days. Morphine (39%) and hydromorphone (29%) were the most commonly administered opioids, primarily intravenously (66%). The prevalent cancer subtypes receiving opioids during ED visits were breast, head and neck, and upper GI. Among patients in treatment with chemo, radiation, or both, 65% received opioids during ED visits, a higher rate compared to the 55% of patients not in treatment. For treated patients, chemotherapy was associated with increased ED visits requiring opioid pain management. Median survival did not differ significantly between those who received opioids during ED visits (130 days) and those who did not (123 days). Conclusions: This study emphasizes the dynamic pain needs of this patient population throughout their final year, leading them to seek pain management from the ED when their pain exceeds their home regimen. Factors influencing these needs include cancer subtype and current treatment status, particularly chemotherapy. Further studies are essential to understanding the variations in pain needs over the final year, enabling providers to better recognize and address changes in patients' pain requirements outside the ED.