Circular RNAs (circRNAs) play a crucial role in the progression of malignant tumors such as breast cancer.

A circRNA microarray was used to detect key circRNAs in breast cancer. Expression of Circ72688 was verified by quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) assay. Transwell assay and in vivo assay were conducted to prove the function of Circ72688. Exploring the downstream mechanism, dual-luciferase reporter assay, western blotting, and tissue microarray were performed.

We sequenced and identified a circRNA, hsa-circ-0072688, also known as Circ72688. Our research found that Circ72688 enhanced tumor metastasis both in vivo and in vitro. Mechanistically, Circ72688 acted as a molecular sponge for hsa-miR-654-5p, thereby affecting the transcription of ORAI2. The expression levels of Circ72688 and ORAI2 were significantly higher in breast cancer tissues compared to adjacent normal tissues, and a notable positive correlation could be seen between them.

In summary, our study demonstrated the critical role of Circ72688 in breast cancer invasion and metastasis, and how Circ72688 partially regulated ORAI2 through hsa-miR-654-5p. Targeting Circ72688 might be a potential therapeutic strategy for breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and resistance to conventional therapies, including radiotherapy. Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance in TNBC. Identifying pathways sustaining CSCs in radioresistant TNBC is key for targeted therapies. This study examines SRC proto-oncogene (SRC) and the signal transducer and activator of transcription 3 (STAT3) activation in radioresistance and CSC maintenance.

A radioresistant MDA-MB-231 TNBC cell line (231RR) was developed and compared to the parental line for CSC activity and self-renewal. Western blotting assessed molecular changes; functional assays followed SRC and STAT3 inhibitor treatment. SRCY^530F overexpression and hexokinase-2 (HK2) knockdown evaluated roles in CSC activity and signaling. Pathways were analyzed via metabolic assays, The Cancer Genome Atlas (TCGA) breast cancer datasets, and Harmonizome gene sets.

231RR cells exhibited enhanced CSC traits and upregulated SRC/STAT3 signaling, with heightened sensitivity to SRC/STAT3 inhibitors. Forced expression of SRCY530F in parental cells boosted STAT3 activation and CSC activity. SRC/STAT3 inhibition reduced HK2 without impairing glycolysis. HK2 knockdown decreased MYC proto-oncogene (c-MYC) and octamer-binding transcription factor-4 (OCT4). Finally, the suppression of epidermal growth factor receptor (EGFR) activation by gefitinib resulted in the inhibition of the SRC/STAT3/HK2 axis. TCGA data linked SRC to glycolytic signatures in breast cancer.

The EGFR/SRC/STAT3/HK2 axis drives radioresistance and CSC maintenance in TNBC via HK2 upregulation. HK2 promotes stemness mainly through non-metabolic means, not broad metabolic shifts. Targeting this pathway could overcome radioresistance and enhance TNBC outcomes.

Radio-resistance hinders the effectiveness of radiotherapy for treating colorectal cancer (CRC) patients. Metadherin (MTDH) is proposed to exert a pivotal role in resistance to radiotherapy in various malignancies. This study aims to investigate the precise impact of MTDH on CRC radio-resistance.

Through a fusion of 14 machine learning algorithms and SHapley Additive exPlanations (SHAP) interpretability analysis, we pinpointed MTDH as a pivotal gene implicated in radio-resistance mechanisms. Subsequently, we investigated MTDH expression in CRC tissues using single-cell RNA sequencing data (scRNA-seq) and bulk transcriptomic data. MTDH level was also examined in tissues from 82 rectal cancer patients who were responsive or non-responsive to radiotherapy. We established radioresistant variants of SW480 and HT29 cells (designated SW480-R and HT29-R), then evaluated their characteristics using cell viability assays, apoptosis measurements, and γ-H2AX foci immunofluorescence. Then, MTDH silencing in radioresistant cells was applied to further investigate the impact of MTDH on regulating radiosensitivity for CRC cells.

Machine learning analysis revealed a significant association between MTDH and radio-resistance. Furthermore, multi-omics data confirmed that MTDH expression was significantly upregulated in CRC tissues and, more notably, within the more malignant diploid single-cell subpopulation. Genes associated with MTDH were predominantly enriched in pathways related to damage repair, DNA damage response, epithelial-mesenchymal transition (EMT), and stem cell differentiation, which were known to be critically involved in radio-resistance. Experimental validation confirmed significantly elevated MTDH expression in both radioresistant rectal cancer specimens and corresponding cellular models. High level of MTDH was positively related to several clinicopathological parameters, including tumor stage, differentiation, and lymph node status. Silencing of MTDH inhibited proliferative ability, increased apoptosis, and increased γ-H2AX foci numbers in CRC cells with radiation treatment.

This study emphasizes the potential of MTDH as a promising prognostic and therapeutic target in response to radiotherapy for treating CRC patients.

In head and neck squamous cell carcinoma (HNSCC), solute carrier family 16 member 1 (SLC16A1) is associated with tumor advancement and reduced sensitivity to ferroptosis, yet the molecular basis of these effects remains unclear. This study seeks to uncover how SLC16A1 contributes to HNSCC tumorigenesis.

To elucidate how SLC16A1 drives HNSCC progression via ferroptosis resistance, we performed RNA sequencing on SLC16A1-knockdown HNSCC cells and controls, followed by functional validation. We next systematically assessed the role of the candidate molecule solute carrier family 7 member 11 (SLC7A11) in HNSCC progression and resistance to ferroptosis using loss- and gain-of-function experiments in vitro and xenograft-based assays in vivo. Finally, we applied RNA interference and validated expression changes by quantitative real-time polymerase chain reaction and immunoblotting to map the signaling pathway by which SLC16A1 controls SLC7A11 expression.

Integrated RNA sequencing and functional assays identified SLC7A11 as a key downstream effector of SLC16A1. SLC7A11 mediates SLC16A1-driven tumor cell proliferation, ferroptosis resistance, and tumorigenesis. Mechanistically, SLC16A1 activates signal transducer and activator of transcription 3 (STAT3) to transcriptionally upregulate SLC7A11 expression.

Our study defines a novel SLC16A1-STAT3-SLC7A11 signaling axis that promotes HNSCC progression by conferring robust resistance to ferroptosis. This axis may be leveraged as a therapeutic target to mitigate treatment resistance.

Approximately 1% of chronic lymphocytic leukemia (CLL) cases harbor a translocation juxtaposing the immunoglobulin heavy chain (IGH) and B-cell lymphoma 3 (BCL3) loci. Aiming at comprehensive molecular characterization of IGH::BCL3-positive B-cell neoplasms, we here investigated samples from 84 patients using fluorescence in situ hybridization (FISH), whole-genome and targeted sequencing, and DNA methylation analyses. Junctional sequences obtained in 27 patients showed breakpoints upstream of BCL3 in all CLL cases. IGH breaks were presumably driven by aberrant class-switch recombination in 26/27 cases, frequently involving IGHA (12/26). Notably, 95% (78/82) of patients carried an unmutated IGHV with significant CLL stereotype subset #8 enrichment. Trisomy 12 (61%, 51/83) and mutations affecting NOTCH1 (32%, 25/79), BRAF (14%, 11/79), and FBXW7 (14%, 11/79) were frequent aberrations. DNA methylation analysis assigned 77% (51/66) of patients with IGH::BCL3-translocation with at least 60% tumor cell content to the naive B-cell-like group but unraveled a distinct and during follow-up stable signature resembling in part plasma cell-like epigenetic features. A binary DNA methylation classifier using 20 CpGs could distinguish IGH::BCL3-translocated CLL samples from other CLL subtypes. In an efficacy cohort of 3832 previously untreated patients from GCLLSG trials, IGH::BCL3 was associated with shorter progression-free survival (PFS) and overall survival (OS) in 28 patients when treated with chemoimmunotherapy, but not in those receiving venetoclax. Our findings highlight the genetic and epigenetic homogeneity of IGH::BCL3-translocated CLL samples and their differences from other types of CLL, suggesting IGH::BCL3 leukemic B-cell neoplasms to be a biological distinct type within the spectrum of mature lymphatic leukemia/CLL.

Beyond established risk factors such as genetics and hormones, the human microbiome has emerged as a pivotal player in breast cancer pathogenesis. This review delineates the technological evolution in breast microbiome research, spanning traditional culture methods to high-throughput sequencing and cutting-edge spatial omics. We elucidate the role of the gut-breast axis in modulating breast cancer development through its influence on estrogen metabolism, immune responses, and microbial metabolites. Furthermore, we analyze the distinctive compositional features of the intratumoral microbiota and their dual, context-dependent roles in promoting invasion, inducing immunosuppression, and driving metabolic reprogramming within the tumor microenvironment. Novel microbiome-based therapeutic strategies, including targeted microbiota depletion, engineered microbial therapeutics, and dietary interventions, are summarized. Finally, we discuss the translational potential of microbiome research in refining breast cancer risk prediction, evaluating treatment responses, and advancing personalized prevention and treatment strategies, ultimately contributing to improved patient outcomes.

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. Previous studies have reported that interleukin enhancer-binding factor 3 (ILF3) is involved in the regulation of multiple cancers. This study investigated the molecular mechanisms whereby ILF3 promotes HCC progression.

ILF3 expression levels were determined through immunohistochemistry (IHC) and Western blot (WB) analyses. The biological functions of ILF3 in HCC were evaluated using both in vitro assays and in vivo animal models. Co-immunoprecipitation (Co-IP) was carried out to identify HMGCL as a binding partner of ILF3. To clarify the potential molecular pathways underlying ILF3-mediated regulation of HCC malignant behaviors, protein stability assays and in vitro ubiquitination experiments were performed.

ILF3 was significantly upregulated in HCC. The patients with high expression of ILF3 showed poor prognosis in our cohort. ILF3 knockdown inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo in this study. Mechanistically, ILF3 was found to be bound to HMGCL and to accelerate its protein degradation. Additionally, we found that ILF3 promotes HCC cell proliferation and metastasis through HMGCL. Overexpression of HMGCL in ILF3-upregulated HCC cells could significantly reverse the proliferation and invasion role of ILF3 on HCC cells. Moreover, USP38 was identified as a deubiquitinating enzyme that participates in promoting the stability of HMGCL. ILF3 disrupted the interaction between USP38 and HMGCL, thereby enhancing HMGCL ubiquitination and accelerating its degradation.

ILF3 promotes the proliferation and metastasis of HCC by enhancing the ubiquitination of HMGCL by interfering with the interaction between the deubiquitinase USP38 and HMGCL.

Natural killer (NK) cells play a pivotal role in anti-tumor immunity; however, the prognostic significance of genetic variants in NK cell-related genes in gastric cancer (GC) remains largely uncertain.

We systematically evaluated 12,476 single-nucleotide polymorphisms (SNPs) in 151 NK cell-related genes for their associations with overall survival (OS) in 2,211 Chinese GC patients with pathological tumor-node-metastasis (TNM) stage I-III, who were enrolled in the Shanghai genome-wide association study (GWAS). Significant variants were further validated in an independent Jiangsu GWAS cohort comprising 1,049 GC patients with TNM stage I-III. The prognostic value of independent SNPs was evaluated. Bioinformatic annotations were performed through expression QTL, splicing QTL, histone modification QTL, and methylation QTL analyses, as well as transcription factor binding, differential expression, functional enrichment, and immune infiltration analyses.

Three independent SNPs (CD160 rs9728526 A>G, MERTK rs114788905 G>A, and IL15 rs140007893 T>A) were significantly associated with GC OS, with adjusted hazard ratios of 1.16 (95% CI = 1.05-1.29, P = 0.006), 0.89 (95% CI = 0.81-0.99, P = 0.033), and 0.77 (95% CI = 0.62-0.97, P = 0.028), respectively. A combined analysis demonstrated a dose-dependent association between the number of unfavorable genotypes and poorer OS. Incorporating these SNPs improved the C-index, time-dependent AUC, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) for OS prediction. Functional annotation indicated that the variant alleles exerted tissue- and immune cell-specific regulatory effects on gene expression, splicing, and transcription factor binding. The expression levels of CD160, MERTK, and IL15 were correlated with immune cell infiltration within the tumor microenvironment in GC.

We identified three novel SNPs in NK cell-related genes that independently predict GC survival, providing potential prognostic biomarkers for risk stratification in GC, although further validation is warranted.

Acute respiratory tract infections (ARTIs) are among the most common reasons for pediatric primary care visits and antibiotic receipt. Telemedicine outside of primary care settings has been associated with overuse of antibiotics for ARTIs in children. The quality of telemedicine when integrated within primary care for children is not clear.

To compare antibiotic management during primary care visits conducted through telemedicine vs in-person.

This retrospective, cross-sectional study analyzed visits for ARTIs in children younger than 18 years between January 1 and December 31, 2023, at 694 US primary care practices (including community health organizations, independent pediatric practices, and practice networks affiliated with large health systems). Analyses were performed between October 1, 2024, and February 12, 2026.

Primary care telemedicine vs primary care in-person index visits.

The primary outcomes were percentage of index visits with antibiotics prescribed and percentage with antibiotic management concordant with guidelines for visit diagnosis. Secondary outcomes included index visit diagnosis, follow-up visits within 14 days, and antibiotic prescription within 14 days. Weighted analyses were conducted using a propensity score model to estimate the probability of an ARTI index visit being conducted via telemedicine and estimated the average treatment effect associated with telemedicine.

This study included 438 148 in-person and 11 482 telemedicine index ARTI visits at primary care practices by 302 817 children (mean [SD] age: 6.6 [4.7] years; 51.4% male). Antibiotic prescription occurred during 46.8% (95% CI, 45.1%-48.4%) of primary care in-person visits vs 34.6% (95% CI, 27.0%-42.3%) of primary care telemedicine visits in the propensity score-weighted model, with a difference of -12.1 (95% CI, -19.3 to -5.0) percentage points. Antibiotic management was guideline concordant for 86.2% (95% CI, 85.1%-87.3%) of primary care in-person visits vs 85.5% (95% CI, 80.5%-90.4%) of primary care telemedicine visits, with a difference of -0.7 (95% CI, -5.3 to 3.8) percentage points. The proportion of follow-up visits and antibiotic prescription within 14 days after initial visit did not vary significantly by index visit modality.

In this cross-sectional study of primary care practices caring for children, telemedicine integrated within primary care was associated with judicious antibiotic prescribing without increased follow-up visits or subsequent antibiotics prescribed. Supporting primary care practices in offering telemedicine for acute concerns may be a strategy to limit unnecessary antibiotic receipt.

Primary care improves population health, yet access is a challenge in the US. It is unclear how primary care use, access, and access disparities have changed since widespread adoption of telemedicine during the pandemic.

To quantify trends in primary care use and determine the role of telemedicine in primary care access and access disparities for traditional Medicare beneficiaries.

Serial cross-sectional study using 2017-2023 100% claims and administrative data for traditional Medicare beneficiaries continuously enrolled and alive for the given year. Data were analyzed from October 2024 to July 2025.

Primary care visits per beneficiary, primary care access (defined as ≥1 virtual or in-person primary care visit in the year), and primary care continuity (Bice-Boxerman Index).

Among 258 324 127 person-years from 2017 to 2023, primary care visit rates decreased from 2.54 per person-year in 2017 to 2.27 per person-year in 2023, and access dropped from 61.9% to 59.8%. In 2023, virtual visits comprised 7% of primary care visits and 14% of beneficiaries who accessed primary care used telemedicine to do so. Disparities in access by race, geography, and income increased slightly from 2019 to 2023, and beneficiaries in historically underserved groups by race, geography, and income who accessed primary care were more likely than others to use telemedicine to do so. Primary care continuity decreased from 0.72 in 2019 to 0.65 in 2023; in 2023, continuity was slightly higher for those using telemedicine for primary care than for those who were not.

This serial cross-sectional study found that across all traditional Medicare beneficiaries, primary care visit rates and access decreased, with virtual visits comprising a small share of previously in-person visits. Access disparities widened while those in underserved groups were more likely than others to use telemedicine for this access. Results suggest that telemedicine plays a small but potentially important role in primary care access.