[Correlation between common driver gene variations and clinicopathological typing in lung adenocarcinoma].

Objective: To correlate the common driver gene variations in primary lung adenocarcinoma with their clinical characteristics and histopathological subtypes. Methods: There were 4 995 cases of primary lung adenocarcinoma diagnosed at Weifang People's Hospital of Shandong Province from January 2015 to December 2021 which were retrospectively analyzed. Among them 1 983 cases were evaluated for their histopathological subtype; 3 012 were analyzed for the correlation of their histopathological subtypes and corresponding driver gene variations, including invasive non-mucinous adenocarcinoma (INMA) and invasive mucinous adenocarcinoma (IMA), and morphologically, poorly-differentiated, moderately-differentiated and well-differentiated adenocarcinomas. Next-generation sequencing was used to detect variations in EGFR, KRAS, ALK, RET, ROS1, MET, HER2, or BRAF driver genes. Results: There were 2 384 males and 2 611 females. EGFR and ALK variations were more commonly found in female patients aged 60 years or older, with EGFR mutation rate in clinical stage Ⅰ (25.80%) significantly higher than in other stages (P<0.05). KRAS mutations were more commonly detected in male smokers aged 60 years or older, HER2 mutations were more commonly in patients younger than 60 years, and RET mutations were more commonly in non-smokers (all P<0.05). No correlation was found between ROS1, MET, and BRAF gene variations and their clinical characteristics (P>0.05). For the histopathological subtypes, among the 1 899 cases of acinar adenocarcinoma, EGFR mutation rate was the highest (67.30%) compared to the other genes. Exon 21 L858R and exon 19 del were the main mutation sites in IMA and INMA, with a higher mutation rate at exon 20 T790M (11.63%) in micropapillary adenocarcinoma. In IMA, KRAS had the highest overall mutation rate (43.80%), with statistically significant difference in mutation rates of exon 2 G12D and exon 2 G12V in acinar adenocarcinoma, solid, and IMA (P<0.05). KRAS mutation at various sites were higher in poorly differentiated groups compared to moderately- and well-differentiated groups (P<0.05). HER2 mutations were more commonly observed in acinar adenocarcinoma, papillary, and micropapillary adenocarcinoma of INMA. BRAF mutation was higher in micropapillary adenocarcinoma compared with other types (P<0.05). Conclusions: Variations in EGFR, ALK, KRAS, HER2, and RET in primary lung adenocarcinoma are associated with patients' age, smoking history, and clinical stage, and driver gene mutations vary among different histopathological subtypes. EGFR mutations are predominant in INMA, while KRAS mutations are predominant in IMA.

[Multiple primary tumors in children: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

Molecular analysis of genetic mutations in non-small cell lung cancer in Morocco.

Non-small cell lung cancer (NSCLC) is a significant global health issue with diverse molecular profiles affecting treatment responses. Yet, NSCLC's molecular epidemiology in Morocco is largely unexplored. This study focuses on NSCLC genetic mutations, specifically in adenocarcinoma, among Moroccan patients to contribute to understanding NSCLC in this population. Ninety-four patients diagnosed with lung adenocarcinoma were analyzed. Formalin-fixed paraffin-embedded tissue samples were processed, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) was extracted using standardized protocols. Mutations were detected using the AmoyDx Pan Lung Cancer Polymerase Chain Reaction (PCR) Panel kit, and their frequencies were assessed through statistical analysis. Epidermal Growth Factor Receptor (EGFR) mutations were detected in 22.34% of patients, predominantly exon 19 deletions (66.66%) and exon 21 L858R mutations (23.80%). Anaplastic lymphoma kinase (ALK) gene fusion was observed in 3.19% of patients, and KRAS mutations in 1.06%. No mutations were found in other tested genes. A slightly higher mutation rate was noted in females (54.16%) compared to males (45.84%). The study reveals a distinct mutation profile in Moroccan NSCLC patients, with a notable prevalence of EGFR mutations, albeit lower than in some Asian populations. The significance of EGFR mutations in treatment response aligns with global findings, highlighting the importance of understanding regional molecular variations for personalized therapy. Despite limitations in sample size and clinical data, this study sheds light on the genetic landscape of NSCLC in Morocco. The observed mutation rates, particularly in EGFR, underscore the potential for targeted therapies in Moroccan NSCLC patients, emphasizing the need for further research to refine treatment strategies tailored to this population.

Simultaneous Acquisition of T790M Mutation and SCLC Transformation during Targeted Therapy in EGFR-Mutated Lung Adenocarcinoma: A Rare Case Report.

BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.

A Comprehensive Prognostic Model for Colon Adenocarcinoma Depending on Nuclear-Mitochondrial-Related Genes.

Background: Colon adenocarcinoma (COAD) has increasing incidence and is one of the most common malignant tumors. The mitochondria involved in cell energy metabolism, oxygen free radical generation, and cell apoptosis play important roles in tumorigenesis and progression. The relationship between mitochondrial genes and COAD remains largely unknown. Methods: COAD data including 512 samples were set out from the UCSC Xena database. The nuclear mitochondrial-related genes (NMRGs)-related risk prognostic model and prognostic nomogram were constructed, and NMRGs-related gene mutation and the immune environment were analyzed using bioinformatics methods. Then, a liver metastasis model of colorectal cancer was constructed and protein expression was detected using Western blot assay. Results: A prognostic model for COAD was constructed. Comparing the prognostic model dataset and the validation dataset showed considerable correlation in both risk grouping and prognosis. Based on the risk score (RS) model, the samples of the prognostic dataset were divided into high risk group and low risk group. Moreover, pathologic N and T stage and tumor recurrence in the two risk groups were significantly different. The four prognostic factors, including age and pathologic T stage in the nomogram survival model also showed excellent predictive performance. An optimal combination of nine differentially expressed NMRGs was finally obtained, including LARS2, PARS2, ETHE1, LRPPRC, TMEM70, AARS2, ACAD9, VARS2, and ATP8A2. The high-RS group had more inflamed immune features, including T and CD4+ memory cell activation. Besides, mitochondria-associated LRPPRC and LARS2 expression levels were increased in vivo xenograft construction and liver metastases assays. Conclusion: This study established a comprehensive prognostic model for COAD, incorporating nine genes associated with nuclear-mitochondrial functions. This model demonstrates superior predictive performance across four prognostic factors: age, pathological T stage, tumor recurrence, and overall prognosis. It is anticipated to be an effective model for enhancing the prognosis and treatment of COAD.

Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation.

BACKGROUND: Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors. AIMS: In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses. METHODS AND RESULTS: We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K-AKT-mTOR signaling pathway in PAAD. CONCLUSION: After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.

Comprehensive analysis of T-cell regulatory factors and tumor immune microenvironment in stomach adenocarcinoma.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide and is associated with high morbidity and mortality rates. However, the specific biomarkers used to predict the postoperative prognosis of patients with gastric cancer remain unknown. Recent research has shown that the tumor microenvironment (TME) has an increasingly positive effect on anti-tumor activity. This study aims to build signatures to study the effect of certain genes on gastric cancer. METHODS: Expression profiles of 37 T cell-related genes and their TME characteristics were comprehensively analyzed. A risk signature was constructed and validated based on the screened T cell-related genes, and the roles of hub genes in GC were experimentally validated. RESULTS: A novel T cell-related gene signature was constructed based on CD5, ABCA8, SERPINE2, ESM1, SERPINA5, and NMU. The high-risk group indicated lower overall survival (OS), poorer immune efficacy, and higher drug resistance, with SERPINE2 promoting GC cell proliferation, according to experiments. SERPINE2 and CXCL12 were significantly correlated, indicating poor OS via the Youjiang cohort. CONCLUSIONS: This study identified T cell-related genes in patients with stomach adenocarcinoma (STAD) for prognosis estimation and proposed potential immunotherapeutic targets for STAD.

A Novel Gene Fusion YLPM1::PRKD1 Identified in a Cribriform Subtype of Polymorphous Adenocarcinoma.

Cribriform adenocarcinoma of the salivary gland (CASG) is an entity that is currently classified under polymorphous adenocarcinoma (PAC), cribriform subtype per the 2022 WHO classification of head and neck tumours. There is debate about whether CASG should be considered a separate diagnostic entity, as CASG differs from conventional PAC in anatomic site, clinical behaviors, and molecular patterns. Herein we describe a challenging and unique case which shares histologic and behavioral features between CASG and conventional PAC with a YLPM1::PRKD1 rearrangement not previously reported in the literature.

Assessing Mismatch Repair Expression by Immunohistochemistry in Colorectal Adenocarcinoma -Insight from a Tertiary Care Centre.

BACKGROUND: Microsatellite instability (MSI) is a pattern of hyper mutation that occurs at microsatellite level in the genome and result due to error in the mismatch repair system. MSI is caused by defective mismatch repair (MMR) genes associated with either hyper methylation of MMR genes or BRAF mutations. Anti-MLH-1, anti-MSH-2, anti-MSH-6 and anti-PMS2 monoclonal antibodies are used for Immunohistochemical analysis. METHODS: The immunohistochemical expression of MSI proteins were assessed in 72 cases of colorectal carcinoma. These were classified based on the expression of MLH1, MSH2, MSH6 and PMS2 proteins. RESULTS: There were 57 percent of cases showing loss of at least one antibodies, and 43 percent cases showing intact expression of all antibodies (MLH1, MSH2, MSH6 and PMS2). CONCLUSION: In conclusion, our study provides valuable insights into the expression of mismatch repair in colorectal adenocarcinoma through immunohistochemistry analysis conducted at our tertiary care centre. These findings hold significant clinical implications, suggesting further testing for BRAF and MLH1 Promoter Hypermethylation to confirm possibility of Lynch syndrome. KEY WORDS: IHC, MMR, CRC.

Development and assessment of an RNA editing-based risk model for the prognosis of cervical cancer patients.

RNA editing, as an epigenetic mechanism, exhibits a strong correlation with the occurrence and development of cancers. Nevertheless, few studies have been conducted to investigate the impact of RNA editing on cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). In order to study the connection between RNA editing and CESC patients' prognoses, we obtained CESC-related information from The Cancer Genome Atlas (TCGA) database and randomly allocated the patients into the training group or testing group. An RNA editing-based risk model for CESC patients was established by Cox regression analysis and least absolute shrinkage and selection operator (LASSO). According to the median score generated by this RNA editing-based risk model, patients were categorized into subgroups with high and low risks. We further constructed the nomogram by risk scores and clinical characteristics and analyzed the impact of RNA editing levels on host gene expression levels and adenosine deaminase acting on RNA. Finally, we also compared the biological functions and pathways of differentially expressed genes (DEGs) between different subgroups by enrichment analysis. In this risk model, we screened out 6 RNA editing sites with significant prognostic value. The constructed nomogram performed well in forecasting patients' prognoses. Furthermore, the level of RNA editing at the prognostic site exhibited a strong correlation with host gene expression. In the high-risk subgroup, we observed multiple biological functions and pathways associated with immune response, cell proliferation, and tumor progression. This study establishes an RNA editing-based risk model that helps forecast patients' prognoses and offers a new understanding of the underlying mechanism of RNA editing in CESC.

The value of dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting EGFR mutations.

OBJECTIVES: 18F-fluorodeoxyglucose (FDG) PET/CT has been widely used for the differential diagnosis of cancer. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may make it difficult to differentiate between benign and malignant lesions. It is crucial to find reliable quantitative metabolic parameters to further support the diagnosis. This study aims to evaluate the value of the quantitative metabolic parameters derived from dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting epidermal growth factor receptor (EGFR) mutation status. METHODS: We included 147 patients with lung lesions to perform FDG PET/CT dynamic plus static imaging with informed consent. Based on the results of the postoperative pathology, the patients were divided into benign/malignant groups, adenocarcinoma (AC)/squamous carcinoma (SCC) groups, and EGFR-positive (EGFR+)/EGFR-negative (EGFR-) groups. Quantitative parameters including K1, k2, k3, and Ki of each lesion were obtained by applying the irreversible two-tissue compartmental modeling using an in-house Matlab software. The SUV analysis was performed based on conventional static scan data. Differences in each metabolic parameter among the group were analyzed. Wilcoxon rank-sum test, independent-samples T-test, and receiver-operating characteristic (ROC) analysis were performed to compare the diagnostic effects among the differentiated groups. P < 0.05 were considered statistically significant for all statistical tests. RESULTS: In the malignant group (N = 124), the SUVmax, k2, k3, and Ki were higher than the benign group (N = 23), and all had-better performance in the differential diagnosis (P < 0.05, respectively). In the AC group (N = 88), the SUVmax, k3, and Ki were lower than in the SCC group, and such differences were statistically significant (P < 0.05, respectively). For ROC analysis, Ki with cut-off value of 0.0250 ml/g/min has better diagnostic specificity than SUVmax (AUC = 0.999 vs. 0.70). In AC group, 48 patients further underwent EGFR testing. In the EGFR (+) group (N = 31), the average Ki (0.0279 ± 0.0153 ml/g/min) was lower than EGFR (-) group (N = 17, 0.0405 ± 0.0199 ml/g/min), and the difference was significant (P < 0.05). However, SUVmax and k3 did not show such a difference between EGFR (+) and EGFR (-) groups (P>0.05, respectively). For ROC analysis, the Ki had a cut-off value of 0.0350 ml/g/min when predicting EGFR status, with a sensitivity of 0.710, a specificity of 0.588, and an AUC of 0.674 [0.523-0.802]. CONCLUSION: Although both techniques were specific, Ki had a greater specificity than SUVmax when the cut-off value was set at 0.0250 ml/g/min for the differential diagnosis of lung cancer. At a cut-off value of 0.0350 ml/g/min, there was a 0.710 sensitivity for EGFR status prediction. If EGFR testing is not available for a patient, dynamic imaging could be a valuable non-invasive screening method.

Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications.

BACKGROUND: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. METHODS: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. RESULTS: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. CONCLUSION: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

Identification of extracellular matrix-related biomarkers in colon adenocarcinoma by bioinformatics and experimental validation.

Backgrounds: Extracellular matrix (ECM) is an important component of tumor microenvironment, and its abnormal expression promotes tumor formation, progression and metastasis. Methods: Weighted gene co-expression network analysis (WGCNA) was used to identify ECM-related hub genes based on The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) data. COAD clinical samples were used to verify the expression of potential biomarkers in tumor tissues, and siRNA was used to explore the role of potential biomarkers in cell proliferation and epithelial-mesenchymal transition (EMT). Results: Three potential biomarkers (LEP, NGF and PCOLCE2) related to prognosis of COAD patients were identified and used to construct ERGPI. Immunohistochemical analysis of clinical samples showed that the three potential biomarkers were highly expressed in tumor tissues of COAD patients. Knockdown of LEP, NGF or PCOLCE2 inhibited COAD cell proliferation and EMT. Dictamnine inhibited tumor cell growth by binding to these three potential biomarkers based on molecular docking and transplanted tumor model. Conclusion: The three biomarkers can provide new ideas for the diagnosis and targeted therapy of COAD patients.

Bioinformatics Analysis Reveals Prognostic Significance of the Macrophage Marker Gene Signature in Gastric Adenocarcinoma.

BACKGROUND: Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor microenvironment. METHODS: Herein, single-cell RNA sequencing (scRNA-seq) profiles from the Gene Expression Omnibus (GEO) and bulk RNA-seq data from the Cancer Genome Atlas (TCGA) database were utilized to construct a macrophage marker gene signature (MMGS) to predict the prognosis of GAC patients. Subsequently, a risk score model based on the MMGS was built to predict the prognosis of GAC patients; further, this was validated in the GEO cohort. The risk score categorized patients into the high- and low-risk groups. A nomogram model based on the risk score and clinic-pathological characteristics was developed. RESULTS: Seven genes, ABCA1, CTHRC1, GADD45B, NPC2, PLTP, PRSS23, and RNASE1, were included in the risk score model. Patients with a low-risk score showed a better prognosis. The MMGS had good sensitivity and specificity for predicting the prognosis inGAC patients. The risk score was an independent prognostic factor. The constructed nomogram exhibited favorable predictability and reliability for predicting GAC prognosis. CONCLUSION: In conclusion, the risk score model based on the seven MMGSs performed well in the predicting prognosis of GAC patients. Our study may provide new insights into clinical decision-making for the personalized treatment of patients with gastric cancer (GC).

MR-based radiomics predictive modelling of EGFR mutation and HER2 overexpression in metastatic brain adenocarcinoma: a two-centre study.

OBJECTIVES: Magnetic resonance (MR)-based radiomics features of brain metastases are utilised to predict epidermal growth factor receptor (EGFR) mutation and human epidermal growth factor receptor 2 (HER2) overexpression in adenocarcinoma, with the aim to identify the most predictive MR sequence. METHODS: A retrospective inclusion of 268 individuals with brain metastases from adenocarcinoma across two institutions was conducted. Utilising T1-weighted imaging (T1 contrast-enhanced [T1-CE]) and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, 1,409 radiomics features were extracted. These sequences were randomly divided into training and test sets at a 7:3 ratio. The selection of relevant features was done using the least absolute shrinkage selection operator, and the training cohort's support vector classifier model was employed to generate the predictive model. The performance of the radiomics features was evaluated using a separate test set. RESULTS: For contrast-enhanced T1-CE cohorts, the radiomics features based on 19 selected characteristics exhibited excellent discrimination. No significant differences in age, sex, and time to metastasis were observed between the groups with EGFR mutations or HER2 + and those with wild-type EGFR or HER2 (p > 0.05). Radiomics feature analysis for T1-CE revealed an area under the curve (AUC) of 0.98, classification accuracy of 0.93, sensitivity of 0.92, and specificity of 0.93 in the training cohort. In the test set, the AUC was 0.82. The 19 radiomics features for the T2-FLAIR sequence showed AUCs of 0.86 in the training set and 0.70 in the test set. CONCLUSIONS: This study developed a T1-CE signature that could serve as a non-invasive adjunctive tool to determine the presence of EGFR mutations and HER2 + status in adenocarcinoma, aiding in the direction of treatment plans. CLINICAL RELEVANCE STATEMENT: We propose radiomics features based on T1-CE brain MR sequences that are both evidence-based and non-invasive. These can be employed to guide clinical treatment planning in patients with brain metastases from adenocarcinoma.

Differential Tumor Gene Expression Profiling of Patients With Prostate Adenocarcinoma on the Basis of BMI.

PURPOSE: An increased BMI is linked to increased prostate adenocarcinoma incidence and mortality. Baseline tumor gene expression profiling (GEP) can provide a comprehensive picture of the biological processes related to treatment response and disease progression. We interrogate and validate the underlying differences in tumor GEP on the basis of BMI in patients with prostate adenocarcinoma. METHODS: The inclusion criteria consisted of histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data obtained from treatment-naïve primary prostate tissue. RNA sequencing was performed by a Clinical Laboratory Improvement Amendments-certified laboratory (Tempus or Caris Life Sciences). The Tempus cohort was used for interrogation and the Caris cohort for validation. Patients were stratified on the basis of BMI at the time of prostate cancer diagnosis: BMI-high (BMIH; BMI ≥30) and BMI-low (BMIL; BMI <30). Differential gene expression analysis between the two cohorts was conducted using the DEseq2 pipeline. The resulting GEPs were further analyzed using Gene Set Enrichment software to identify pathways that exhibited enrichment in each cohort. RESULTS: Overall, 102 patients were eligible, with 60 patients in the Tempus cohort (BMIL = 38, BMIH = 22) and 42 patients in the Caris cohort (BMIL = 24, BMIH = 18). Tumor tissues obtained from patients in the BMIL group exhibited higher expression of genes associated with inflammation pathways. BMIH displayed increased expression of genes involved in pathways such as heme metabolism and androgen response. CONCLUSION: Our study shows the upregulation of distinct genomic pathways in BMIL compared with BMIH patients with prostate cancer. These hypothesis-generating data could explain different survival outcomes in both groups and guide personalized therapy for men with prostate cancer.

Evaluating the predictive value of angiogenesis-related genes for prognosis and immunotherapy response in prostate adenocarcinoma using machine learning and experimental approaches.

Background: Angiogenesis, the process of forming new blood vessels from pre-existing ones, plays a crucial role in the development and advancement of cancer. Although blocking angiogenesis has shown success in treating different types of solid tumors, its relevance in prostate adenocarcinoma (PRAD) has not been thoroughly investigated. Method: This study utilized the WGCNA method to identify angiogenesis-related genes and assessed their diagnostic and prognostic value in patients with PRAD through cluster analysis. A diagnostic model was constructed using multiple machine learning techniques, while a prognostic model was developed employing the LASSO algorithm, underscoring the relevance of angiogenesis-related genes in PRAD. Further analysis identified MAP7D3 as the most significant prognostic gene among angiogenesis-related genes using multivariate Cox regression analysis and various machine learning algorithms. The study also investigated the correlation between MAP7D3 and immune infiltration as well as drug sensitivity in PRAD. Molecular docking analysis was conducted to assess the binding affinity of MAP7D3 to angiogenic drugs. Immunohistochemistry analysis of 60 PRAD tissue samples confirmed the expression and prognostic value of MAP7D3. Result: Overall, the study identified 10 key angiogenesis-related genes through WGCNA and demonstrated their potential prognostic and immune-related implications in PRAD patients. MAP7D3 is found to be closely associated with the prognosis of PRAD and its response to immunotherapy. Through molecular docking studies, it was revealed that MAP7D3 exhibits a high binding affinity to angiogenic drugs. Furthermore, experimental data confirmed the upregulation of MAP7D3 in PRAD, correlating with a poorer prognosis. Conclusion: Our study confirmed the important role of angiogenesis-related genes in PRAD and identified a new angiogenesis-related target MAP7D3.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.

BACKGROUND: Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM: To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS: RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS: In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION: We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.

Human plasma can modulate micronucleus frequency in TK6 and OE33 cells in vitro.

In this paper, we studied the potential genotoxic effects of human plasma from healthy volunteers, as well as patients with gastro-oesophageal reflux disease, Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) using the oesophageal adenocarcinoma cell line (OE33) and the lymphoblastoid cell line (TK6). Both TK6 and OE33 cells were treated with plasma (10 % volume, replacing foetal bovine serum (FBS) or horse serum (HS)) at different time points of 4 h (for the micronucleus (Mn) assay and the invasion assay) and 24 h (for the cell cycle studies). Plasma-induced effects on DNA damage levels, cell viability and the cell cycle were studied by the micronucleus assay, cytokinesis block proliferation index (CBPI) and flow cytometry respectively. The expression of IL-8 in supernatants of TK6 cells and IFN-ß in OE33 cells was also analysed by enzyme-linked immunosorbent assay (ELISA). Finally, we carried out an assessment of cellular invasion of OE33 cells following plasma treatment. The results of the micronucleus assay confirmed the genotoxicity of direct plasma treatment from some participants through the increase in DNA damage in TK6 cells. Conversely, some individual patient plasma samples reduced background levels of TK6 cell Mn frequency, in an anti-genotoxic fashion. In TK6 cells, (on average) plasma samples from patients with Barrett's oesophagus induced higher micronucleus levels than healthy volunteers (p= 0.0019). There was little difference in Mn induction when using plasma versus serum to treat the cells in vitro. Cell cycle results showed that direct plasma treatment had a marked impact on OE33 cells at 24 h (p=0.0182 for BO and p=0.0320 for OAC) by decreasing the proportion of cells in the S phase, while plasma exposure was less impactful on the cell cycle of TK6 cells. Invasion of OE33 cells was also seen to be non-significantly affected by plasma treatment of OE33 cells. The addition of N-acetyl cysteine NAC in a dose-dependent matter did not alter the formation of Mn in TK6 cells, suggesting that reactive oxygen species (ROS) are not the root cause of plasma's genotoxicity. The concentration of IL-8 in TK6 cells and IFN-ß in OE33 cells was significantly higher in cells treated with OAC-derived plasma than in the untreated negative control. Collectively, our results demonstrate that plasma-specific effects are detectable which helps us better understand some important aspects of the biology of blood-based biomarkers under development.