Neurofibromatosis type 1 (NF1) is a genetic condition that affects about 1 in 3000 individuals. Approximately 50% of individuals with NF1 have a family history of the condition. Individuals with NF1 experience variable symptoms that contribute to increased stress. This study investigated whether a family history of NF1 influences levels of stress and coping strategies in adults with NF1. Adults with NF1 who live in the United States and speak English were recruited through the Children's Tumor Foundation's (CTF) NF Registry, CTF's NF Clinic Network, and the Neurofibromatosis Network. Participants completed a survey about their personal and family history of NF1, the Perceived Stress Scale 10-Item Version (PSS-10), the Brief Coping Orientation to Problems Experienced Inventory (Brief-COPE), short response questions, and demographics. Overall, 547 of 646 responses met analysis criteria. Participants with affected parents were assigned to the inherited NF1 group (n = 222) and those with unaffected parents were assigned to the sporadic NF1 group (n = 325). No differences were found in mean PSS-10 scores between the two study groups (p = 0.568). Females had significantly higher PSS-10 scores than males (p < 0.001). After Bonferroni correction, no differences were found across Brief-COPE subscales or major coping styles between the two groups. A stagewise multivariable regression indicated that 42% of the variance in PSS-10 scores was accounted for by sex assigned at birth, age, problem-focused, and avoidant coping styles (R2 = 0.42, p < 0.001). Family history did not predict PSS-10 scores alone or as an interaction variable with major coping styles. This study showed no significant differences in stress or major coping styles between adults with inherited versus sporadic NF1. However, other factors may influence the stress and coping experiences of adults with NF1. Fostering discussions about patients' stressors and coping strategies could help promote stress management.

Bladder cancer (BC) remains a significant global health concern, with substantial sex and racial disparities in incidence, progression, and outcomes. BC is the sixth most common cancer among males and the seventeenth most common among females worldwide. Over 90% of BC cases are urothelial carcinoma (UC) with high degrees of pathological heterogeneity. Molecular subtyping of BC has also revealed distinct luminal, basal, and neuroendocrine subtypes, each with unique genetic and immune signatures. Emerging research uncovers the biasing effects of the sex hormones with androgens increasing BC risk through both tumor cell intrinsic and extrinsic mechanisms. The sex chromosomes, including both the X and Y chromosomes, also contribute to the sex differences in BC. The effect of sex chromosome is both independent from and synergistic with the effects of sex hormones. Loss of the Y chromosome is frequently observed in BC patients, while an extra copy of the X chromosome confers better protection against BC in females than in males. Advent of advanced technologies such as multiomics and artificial intelligence will likely further improve the understanding of sex differences in BC, which may ultimately lead to personalized preventative and treatment strategies depending on the biological sex of patients. This review delves into the impacts of biology of sex on BC, emphasizing the importance of further research into sex-specific biology to improve cancer prevention and care.

The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis.

Transcriptomic features of breast cancer locoregional recurrence (LRR) remain poorly understood. We therefore sought to investigate transcriptomic features associated with LRR in newly diagnosed invasive breast tumors from our institutional dataset.

Microvascular invasion (MVI) has been recognized as a risk factor for early recurrence after hepatectomy in patients with hepatocellular carcinoma (HCC). This study aimed to estimate the performance of an ultrasensitive chromosomal aneuploidy detector (UCAD) model for preoperative MVI prediction in operable HCC patients based on plasma cell-free DNA (cfDNA).

Super-enhancers (SEs) are critical regulators of tumorigenesis and represent promising targets for bromodomain and extra-terminal domain inhibitors (BETi). However, clinical studies across various solid tumors, including triple-negative breast cancer (TNBC), have demonstrated limited BETi efficacy. This study aims to investigate SE heterogeneity in TNBC and its influence on BETi effectiveness, with the goal of advancing BETi precision treatment strategies and enhancing therapeutic efficacy.

While metabolic pathway alterations are linked to colorectal cancer (CRC), the predictive value of pre-diagnostic metabolomic profiling in CRC risk assessment remains to be clarified. This study evaluated the predictive performance of a metabolomics risk panel (MRP) both independently and in combination with established risk factors.

Cancers are complex diseases that have heterogeneous genetic drivers and varying clinical outcomes. A critical area of cancer research is organizing patient cohorts into subtypes and associating subtypes with clinical and biological outcomes for more effective prognosis and treatment. Large-scale studies have collected a plethora of omics data across multiple tumor types, providing an extensive dataset for stratifying patient cohorts. Network-based stratification (NBS) approaches have been presented to classify cancer tumors using somatic mutation data. A challenge in cancer stratification is integrating omics data to yield clinically meaningful subtypes. In this study, we investigate a novel approach to the NBS framework by integrating somatic mutation data with RNA sequencing data and investigating the effectiveness of integrated NBS on three cancers: ovarian, bladder, and uterine cancer.

Hypomethylating agents (HMAs), such as 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia (AML). Despite providing significant extensions in survival when used alone or in combination with BCL-2 inhibitors, resistance and eventual relapse is observed. Reported mechanisms of these outcomes are inconsistent when focusing on leukemic populations within bone marrow, indicating a need for studies on the impact of HMAs on non-leukemic cells in the blood and other tissue compartments.

Among the various types of breast cancer that endanger women's lives, triple-negative breast cancer (TNBC) stands out due to its extreme heterogeneity, aggressive nature, and high likelihood of recurrence. The absence of unique targets and targeted drugs is a major factor contributing to the failure of cancer treatments and the eventual death of patients.

Resisting anoikis is a prerequisite for cancer to spread and invade and a major cause of cancer-related deaths. Yet, the intricate mechanisms of how cancer cells evade anoikis remain largely unknown. There is a significant need to explore how these mechanisms play out in breast cancer (BC).

Cre-recombinase inducible model systems are extensively used in cancer research to manipulate gene expression in specific tissues and induce autochthonous tumor growth. These systems often involve the cross-breeding of genetically engineered organisms containing loxP-flanked alleles with those expressing Cre-recombinase. This approach, while effective, has the challenge of requiring high numbers of animals due to breeding requirements. Other frequently used tumor induction methods in cancer research involve the direct application of viral Cre-recombinase vectors. This approach presents the challenge of the accessibility of facilities that meet the necessary safety level. In this context, we perform a comprehensive comparison between TAT-CRE (biosafety level S1) and adenoviral Cre-recombinase induced (biosafety level S2) lung adenocarcinomas driven by KrasG12D expression and Trp53 depletion. We use in vivo lung tumor monitoring via computed tomography, single-cell RNA sequencing, immunohistochemistry and flow cytometry to elucidate similarities and differences between TAT-CRE and adenoviral Cre-recombinase induced lung adenocarcinomas. TAT-CRE induced lung tumors present differences in micro-vessels and macrophages but with corresponding tumor onset and growth characteristics compared to adenoviral-Cre recombinase induced lung tumors. Taken together, TAT-CRE is a valuable genetic engineering safety level S1 alternative for cancer induction and may be implemented in other cancer models than lung cancer.

Unrepaired DNA damage is the initiation of mutation and tumor-specific biological characteristics. Oxidative stress and base excision repair (BER) are the two main pathways to cope with oxidative DNA damage, which is closely related to the heterogeneity of Lung adenocarcinoma (LUAD), but their relationship with tumor biological characteristics is unclear, and a molecular subtyping based on comprehensive BER and oxidative stress gene expression is lacking. 501 samples from The Cancer Genome Atlas (TCGA) were classified into three subtypes based on genes related to BER and oxidative stress through hierarchical agglomerative cluster analysis. By integrating the nearest template prediction (NTP), four GEO datasets and 52 samples from our institution were analyzed for validation. Bioinformatic analysis was performed to define the diverse molecular characteristics, mutation background, tumor microenvironment, and prognosis. Three subtypes with distinct gene signatures were identified: relatively high BER and low oxidative stress gene expression (C1), low BER gene and high oxidative stress gene expression (C2), and high expression of both BER and oxidative stress genes (C3). C2 was characterized by a low mutation frequency in TP53 (29%) and a high mutation frequency in EGFR (20%), whereas a high frequency of mutation was seen in C3 in STK11 and KEAP1 genes. Additionally, differentially expressed genes among the three subtypes were particularly enriched in immune-related pathways, and the abundance of immune cells and Immunophenoscore were significantly higher in C2, while the Tumor Immune Dysfunction and Exclusion (TIDE) score was lower in C2, indicating a better response to immunotherapy. C2 was also associated with an improved survival outcome compared with C1 and C3, and this finding was validated in 978 samples from four independent GEO datasets and 52 samples at our institution by the NTP algorithm. The three-subtype classifications based on BER and oxidative stress gene expression offers potential for predicting the survival and response to immunotherapy of LUAD patients.

LUAD, a prevalent lung cancer with high mortality, has seen increased focus on molecular targeted therapies due to patient heterogeneity. Among these prospects, dystrophin-associated protein 2 (DRP2), a critical component of the dystrophin complex, underpins membrane-associated structures vital for intercellular interactions in vertebrates. Aberrations in DRP2 function have been linked to the occurrence and development of multiple diseases, prompting an inquiry into its potential link with LUAD progression. To delve into the potential roles of DRP2 in LUAD, we initiated a comprehensive investigation. First, we analyzed DRP2 expression patterns in LUAD using bioinformatics tools. This was subsequently validated through immunohistochemical staining, quantitative PCR, and Western blot analyses. Furthermore, we assessed the functional implications of DRP2 in LUAD cells, both in vitro and in vivo, utilizing assays such as cell cycle analysis, CCK-8 proliferation assay, Colony formation assay EdU incorporation, Transwell migration test, scratch wound healing assay, flow cytometry, and mouse models for tumor xenograft and metastasis. Results showed a strong correlation between high DRP2 expression in LUAD and poorer survival. Notably, DRP2 knockdown accelerated LUAD progression via the EMT pathway. These findings highlight DRP2's crucial role in LUAD and its potential as a therapeutic target.

Recent studies indicate that Secretogranin V (SCG5) is aberrantly expressed in various cancers and may be linked to tumor progression and prognosis. This study aims to evaluate the potential of SCG5 as a prognostic biomarker for non-small cell lung cancer (NSCLC). We employed a combination of bioinformatics analysis, Western blotting, and immunofluorescence techniques to investigate the role of SCG5 in NSCLC. A comprehensive analysis of TCGA and GEO pan-cancer datasets revealed a consistent upregulation of SCG5 across multiple cancer types. In NSCLC, SCG5 expression was significantly higher in tumor tissues compared to normal lung tissues (p < 0.001). Kaplan-Meier survival analysis demonstrated that patients with elevated SCG5 expression exhibited lower overall survival rates, suggesting a strong association with poor prognosis. Univariate and multivariate COX regression analyses, conducted on both TCGA cases and our collected patient data, confirmed SCG5 as an independent prognostic factor for NSCLC. Furthermore, immune infiltration analysis indicated a significant correlation between SCG5 expression and various immune cell subpopulations, underscoring its potential role as a biomarker for adverse outcomes. Western blot analysis further validated the elevated levels of SCG5 in NSCLC tissues and cell lines compared to their normal counterparts. Based on our findings, we hypothesize that SCG5 may serve as a valuable biomarker for predicting the prognosis of non-small cell lung cancer, thereby guiding future research in the fields of diagnosis, progression, therapy, and prognosis of NSCLC.

Triple-negative breast cancer (TNBC) metastasis is driven, in part, by the epithelial-to-mesenchymal transition (EMT), a process critical for cancer cell migration and invasion. Current treatment options, including immunotherapies and targeted therapies, demonstrate limited efficacy in this aggressive disease, underscoring the need for innovative therapeutic approaches. Here, we present a novel approach integrating oncolytic virotherapy with RNA interference by engineering two variants of vesicular stomatitis virus (VSVd51) expressing pri- or pre-miR-199a-5p, a microRNA implicated in the regulation of EMT. We demonstrate that both viral constructs are functional and capable of overexpressing mature miR-199a-5p. In the human TNBC cell line MDA-MB-231, both viral variants inhibited the expression of ZEB1, a transcription factor central to EMT. However, in the mouse TNBC cell line 4T1, miR-199a-5p delivered via VSVd51 failed to disrupt EMT-related gene expression. In vivo testing of VSVd51-pre-miR-199 in the syngeneic BALB/c-4T1 mouse model revealed no significant survival benefits or reduction in tumor growth, even when coupled with primary tumor resection. Additional in vivo testing in immunodeficient mice using the MDA-MB-231 xenograft model showed no effect on tumor reduction. Our study highlights the challenges of integrating miRNA-based strategies with oncolytic viruses in a cancer context-specific manner and underscores the importance of vector selection and tumor model compatibility for therapeutic synergy.

The tumor microenvironment (TME) plays a critical role in ovarian cancer (OC) progression, yet the relationship between immune and stromal scores within the TME and prognostic outcomes remains poorly understood. Immune and stromal cell scores were computed using the "estimate" R package, which enabled the assessment of immune and stromal components in OC samples. We then performed univariate and multivariate Cox regression analyses to identify prognostic factors associated with these scores using data from The Cancer Genome Atlas (TCGA). Additionally, LASSO Cox regression were employed to identify key prognostic genes linked to immune infiltration. Our analysis of OC expression data identified 1,667 differentially expressed genes (DEGs) associated with immune and stromal scores. From these, we developed a 6-gene risk model, consisting of ALOX5AP, FCGR1C, GBP2, IL21R, KLRB1, and PIK3CG, which effectively stratified OC patients into high-risk and low-risk groups. Survival analysis and area under the curve (AUC) assessment confirmed the model's strong predictive accuracy. Furthermore, drug sensitivity predictions indicated that sorafenib was particularly effective in high-risk patients, with this finding validated through in vitro experiments. The 6-gene TME-related risk model offers robust prognostic capabilities for OC and could serve as a valuable tool for clinical stratification and personalized treatment approaches.

The efficacy of immune checkpoint inhibitors in colon cancer has been established, and there is an urgent need to identify new molecular markers for colon cancer immunotherapy to guide clinical decisions. Using the "EPIC" and "MCPcounter" R packages to conduct cancer-associated fibroblast (CAF) infiltration scoring on colon cancer samples from the TCGA database and the GEO database, the WGCNA analysis was performed on the two databases' samples based on the CAF infiltration scores to screen for CAF-related genes. LASSO regression analysis was used to construct a risk model with these genes. Comprehensive bioinformatics analysis was conducted on the constructed model to evaluate the stability of its prediction of CAF infiltration abundance and the stability of its prediction of immunotherapy efficacy. The newly constructed risk model could well reflect the abundance of CAF infiltration in colon cancer, with a correlation coefficient of 0.91 in the training cohort TCGA-COAD and 0.88 in the validation cohort GSE39582. GSEA analysis revealed that CAF is closely related to functions associated with extracellular matrix remodeling. The constructed risk model can predict the efficacy of immunotherapy in colon cancer well, with the high-risk group showing significantly poorer immunotherapy response than the low-risk group, with an expected effective rate of immunotherapy of 68 vs. 24% in the training group (P < 0.001) and 64 vs. 26% in the validation group (P < 0.001). The AUC value for predicting immunotherapy response by the risk model in the training group was 0.780 (95% CI 0.736-0.820), and in the validation group, the AUC value was 0.774 (95% CI 0.735-0.810). Drug sensitivity analysis showed that the expected chemotherapeutic effect in the low-risk group was superior to that in the high-risk group. CAF is associated with immunosuppression and drug resistance. Predicting the efficacy of immunotherapy in colon cancer based on the abundance of CAF infiltration is a feasible approach. For the high-risk population identified by our model, clinical consideration should be given to prioritizing non-immunotherapy approaches to avoid potential risks associated with immunotherapy.

In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9-110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%; p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110).

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA+ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.