Normal Tissues Of Patients Research Articles

Therapeutic response and safety of radioligand therapy with 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer patients.

Prostate cancer is one of the most common cancers and leading cause of death due to cancer across the globe. This persuaded researchers to devise innovative treatment modalities that may prove effective, safe, and demonstrate better outcomes in terms of patient morbidity and survival. The advancement in theranostics such as lutetium-177 (177Lu)-PSMA-617 radioligand therapies can target prostate cancer cells causing negligible or no damage to most of the normal tissues in patients. It has been proven to effectively improve the quality of life and progression-free survival. In this study, stage IV metastatic castration-resistant prostate cancer patients were treated with 177Lu-PSMA-617, and the therapeutic response and safety of 177Lu-PSMA-617 radioligand therapy were evaluated six months after the treatment. Additionally, molecular docking studies were also conducted to find the possible mechanism at the molecular level that causes the effectiveness of 177Lu-PSMA-617 in prostate cancer.

Similar usage of T-cell receptor β-chain between tumor and adjacent normal tissue in hepatocellular carcinoma.

In this study, we comprehensively profiled the T-cell receptor (TCR) repertoire of the tumor and adjacent normal tissue in patients with HBV-associated hepatocellular carcinoma (HCC) and determined the baseline characteristics and clinical significance of TCR. High-throughput sequencing was used to determine the profile of complementarity-determining region 3 (CDR3) of the TCR-β chain variable (TRBV) in the tumor and normal tissue samples of 14 HCC patients. At the same time, TRBV diversity and differences in expression between tumor and normal tissues were investigated. The cumulative frequency of top 100 CDR3 (CF100), clonality, and Shannon entropy as indices to evaluate diversity, RESULTS: The diversity of TRBV CDR3 showed no significant difference between tumor and normal tissues. Of the 58 V gene segments in TRBV, TRBV16 and TRBV7-6 had a significantly higher frequency in the tumor group than in the normal group (p < 0.05). The frequency of 14 J gene segments showed no significant difference between tumor and normal tissues. In contrast, the frequency of 22 TRBVx/BJx combinations was significantly higher in the tumor than in the normal tissue. In addition, the length and type of TRBV CDR3 were similar in tumor and normal tissues, and a Gaussian distribution was observed in both groups. This study provided a large amount of information about the TCR lineage in HBV-associated HCC, laying the foundation for further research. In addition, the fact that the immune repertoire (TRBV CDR3) hardly differs between tumor and adjacent normal tissue provides a new clue for exploring the mechanism of the liver as an organ with immune privileges.

DNA Repair Genetics and the Risk of Radiation Pneumonitis in Patients With Lung Cancer: A Systematic Review and Meta-analysis

AimsERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer. Materials and methodsSNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate. ResultsA total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001). ConclusionGenetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription.

A 3D-printed phantom for stereotactic body radiation therapy simulation.

In modern radiation therapy for lung cancer, examining the uncertainty between tumor motion and beam delivery is vitally important. To lower the radiation dose delivery to the patient's normal tissue, narrowing the irradiation field margin to hit the tumor accurately is critical. Thus we proposed a phantom that simulates the thorax and lung tumor's motions by employing a 3D printing technique. The lung tumor is controlled by a linear miniature Delta robot arm, with a maximum displacement of 20 mm in each direction. When we simulated the thoracic breathing movements at 12 mm in A-P (Anterior-Posterior), the control errors were within 10%. The average tracking errors of the prosthetic tumor were within 1.1 mm. Therefore, the 3D-printed phantom with a robot arm can provide a reliable simulation for training and dosimetry measurement before lung radiotherapy, especially SBRT.

Expression and prognostic analysis of AEG-1, NKD-1and β-catenin in gastric cancer tissues

Objective: To investigate the expressions of AEG-1, NKD-1 and β-catenin in gastric cancer (GC), and analyze their relationship with clinicopathological features and prognosis and the correlation among the three proteins.Methods: Fifty GC tissues and 50 adjacent normal tissues of patients who underwent radical gastrectomy in the Third Affiliated Hospital of Inner Mongolia Medical University during December 2015 to June 2017 were collected. The expressions of AEG-1, NKD-1 and β-catenin were detected by immunohistochemical SP method and qRT-PCR. The relationship between positive expression and clinical features and survival time of patients was analyzed, and the correlation between the three was analyzed.Results: The positive expression rates of AEG-1 and β-catenin in gastric cancer were 74% (37/50), 60% (30/50), respectively, which was significantly higher than that of paracancer tissue (18% [9/50] and 26% [13/50]). The positive expression rate of NKD1 in gastric cancer tissues was 20% (10/50), which was significantly lower than that in adjacent tissues [88% (44/50)]; and the differences were statistically significant (p &lt; . 05). AEG-1 mRNA expression level (1.0148±0.0019) and β-catenin mRNA expression level (1.0000±0.0005) in gastric cancer tissues were significantly higher than that of AEG-1 mRNA expression level (1.0002±0.0036) and β-catenin expression level in adjacent tissues mRMA expression level (0.9984±0.0012), and the differences were statistically significant (p &lt; .05). The expression level of NKD1 mRNA in gastric cancer tissues (1.0008±0.0073) was significantly lower than that in adjacent tissues (1.0291±0.0041), and the differences were statistically significant (p &lt; .05). The positive expression of AEG-1, NKD1 and β-catenin in gastric cancer tissues was not related to age, sex or tumor size (p &gt; .05), but was related to differentiation degree, TNM stage and lymph node metastasis (p &lt; .05). In gastric cancer, there was a positive correlation between AEG-1 and β-catenin protein expression (r = .678, p &lt; .001), and a negative correlation between AEG-1 and NKD1 protein expression (r = -.323, p = .012). β-catenin expression was negatively correlated with NKD1 expression (r = -.347, p = .007). The survival time of patients with positive expression of AEG-1 and β-catenin was significantly shortened compared with those with negative expression (p &lt; .05), while the survival time of patients with positive expression of NKD1 was longer than that of patients with negative expression of NKD1 (p &lt; .05).Conclusion: The abnormal expression of AEG-1, NKD-1 and β-catenin is closely related with the occurrence, development, invasion, metastasis and prognosis of gastric cancer, which provide a therapeutic target and may become markers for prognosis evaluation.

Branched-Chain Amino Acid Degradation Pathway was Inactivated in Colorectal Cancer: Results from a Proteomics Study.

Background: Colorectal cancer (CRC) ranks third in terms of cancer incidence and fourth in terms of cancer-related deaths worldwide. Identifying potential biomarkers of CRC is crucial for treatment and drug development. Methods: In this study, we established a C57B/6N mouse model of colon carcinogenesis using azoxymethane-dextran sodium sulfate (AOM-DSS) treatment for 14 weeks to identify proteins associated with colon cancer. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis was conducted on the cell membrane components enriched in the colonic mucosa. Additionally, tumor tissues and adjacent normal colon tissues were collected from patients with colon cancer for comparative protein and metabolite analyses. Results: In total, 74 differentially expressed proteins were identified in the tumor tissue samples from AOM/DSS-treated mice compared to both the adjacent tissue samples from AOM/DSS-treated mice and tissue samples from saline-treated control mice. Bioinformatics analysis revealed eight downregulated proteins enriched in the branched-chain amino acids pathway (valine, leucine, and isoleucine degradation). Moreover, these proteins are already known to be associated with the survival rate of patients with cancer. Targeted metabolomics showed increased levels of valine, leucine, and isoleucine in tumor tissues compared to those in adjacent normal tissues in patients with colon cancer. Furthermore, a real-time PCR experiment demonstrated that Aldehyde dehydrogenase, mitochondrial (short protein name ALDH2, gene name Aldh2) and Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial (short protein name HCDH, gene name Hadh) (two genes) in the pathway of branched-chain amino acids) were downregulated in patients with colon cancer (colon tumor tissues vs. their adjacent colon tissues). ALDH2 expression was further validated by western blotting in AOM/DSS-treated mouse model and in clinical samples. Conclusion: This study highlighted the inactivation of the branched-chain amino acid degradation pathway in colon cancer and identified ALDH2 and HCDH as potential biomarkers for diagnosing colon cancer and developing new therapeutic strategies.

Evaluation of Changes in miR-7113-3p, miR-6721-5p, and MAP2K1 gene expressions in tumor and normal tissues of patients with oral cancer

Background: Squamous cell carcinoma of the oral cavity (OSCC) is one of the most common cancers in the Head and Neck Squamous Cell Cancer (HNSCC) group. The increasing frequency of oral carcinomas and their late-stage appearance is a major worldwide health concern. MicroRNAs (miRNAs) play an important role in cancer growth and progression, as the available relevant data indicate. However, no information is available about the parts miR-7113-3p and miR-6721-5p taken in OSCC. In the present study, the expression of MAP2K1, miR-7113-3p, and miR-6721-5p was examined to determine their possible biological role in the advancement of oral squamous cell carcinoma. Methods: Quantitative Real-Time PCR was applied to investigate the mRNA expression of MAP2K1, miR-7113-3p, and miR-6721-5p in fresh frozen OSCC tissues and adjacent normal fresh frozen tissues of 30 patients and then, the relationship between MAP2K1 Expression and clinical parameters was studied. Results: MAP2K1 expression dramatically increased in tumor tissues compared to the normal tissues, while miR7113-3p and miR-6721-5p expression significantly decreased. Furthermore, a statistical correlation of p=0.04 was also observed between increased MAP2K1 expression and Perineural invasion. In addition, the downregulation of miR-7113-3p was positively correlated with the overexpression of MAP2K1 (p=0.0218), and a negative correlation was observed between the downregulation of miR-6721-5p and overexpression of MAP2K1 (p=0.7771). Conclusion: Based on the findings, miR-7113-3p, and miR-6721-5p might be prospective biomarkers for OSCC patients and can be utilized to detect OSCC at an early stage of its diagnosis. MAP2K1 overexpression is linked to the development of OSCC and Perineural invasion.

A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.

Studies have established a correlation between α2-macroglobulin-like 1 (A2ML1) and the prognosis of lung, pancreatic, and breast cancers; however, research on its involvement in the pathogenesis of esophageal carcinoma remains limited. Therefore, in this study, we aimed to investigate the role of A2ML1 in the progression of esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining was employed to assess the expression level of A2ML1 protein in both tumor and adjacent normal tissues of patients with ESCC. The Kaplan-Meier method, along with univariate and multivariate Cox risk ratio analyses, was used to determine survival rates and prognostic factors. Furthermore, two human ESCC cell lines, KYSE30 and KYSE150, were used to assess the effect of A2ML1 overexpression on cell proliferation and apoptosis. A human apoptosis antibody kit was also used to analyze the downstream action proteins of A2ML1, and a nude mouse xenotransplantation model was used to evaluate the effect of A2ML1 on ESCC tumorigenesis in vivo. The protein level of A2ML1 in ESCC tissues was significantly lower than that in normal esophageal tissues, and higher A2ML1 protein levels were associated with smaller ESCC tumor sizes and improved tumor-specific survival rates. Multivariate analysis established A2ML1 as a novel independent prognostic factor for ESCC. Moreover, A2ML1 overexpression significantly inhibited ESCC cell proliferation and promoted apoptosis. A2ML1 consistently inhibited tumor growth in mouse models. Furthermore, the human apoptotic antibody kit results showed increased expression of the proliferation-inhibiting protein p21 downstream of KYSE150 cells overexpressing A2ML1. Our findings demonstrate that a correlation exists between A2ML1 and ESCC prognosis and that A2ML1 plays an antitumor role in ESCC progression. This study underscores the potential of A2ML1 as a novel biomarker for predicting the prognosis of ESCC.

Tumor-associated microbiota in colorectal cancer with vascular tumor thrombus and neural invasion and association with clinical prognosis.

Neural invasion (NI) and vascular tumor thrombus (VT) are associated with poor prognosis in patients with colorectal cancer (CRC). In this study, we apply 16S rRNA amplicon sequencing to tumor tissues and adjacent normal tissues in patients with CRC to determine the microbial differences. A discovery cohort, including 30 patients with NI, 23 with VT, and 35 with double-negative CRC tissue, is utilized. Then, we analyze the relationship between the specific bacterial taxa and indicators of different dimensions in separate cohorts. In the discovery cohort, the diversity and composition of the gut microbiome distinctly differ between the tumor and nontumor tissues in the NI and VT groups. A high abundance of Cupriavidus is found to be related to a short survival time of NI CRC, while Herbaspirillum is a potential microbial biomarker predicting the prognosis of patients with CRC with NI or VT. Moreover, the abundance of Cupriavidus or Herbaspirillum is associated with some clinical patient characteristics and prognosis, respectively. In conclusion, this study is the first to comprehensively elaborate the differences in the gut microbiota of patients with CRC with different invasion statuses and to prove the relationship between some gut microbiota and clinical patient characteristics.

Wearing individualized 3D printed oral stent to protect normal tissues in patients with nasopharyngeal carcinoma during radiotherapy.

To demonstrate a new individualized 3D printed oral stent in radiotherapy of nasopharyngeal carcinoma (NPC) patients and carry out a comparative analysis combining with clinical case. Thirty NPC patients treated in our institution from September 2021 to October 2022 were prospectively enrolled. An individualized 3D printed oral stent was designed for each patient, and one set of computed tomography (CT) slices were obtained with /without wearing the oral stent, respectively. After delineation of target volumes and organs at risk (OARs) on the two CT slices, we finished two treatment plans by using the same target objectives, critical constraints and plan setup for each patient. Finally, the dose distribution and other dosimetric parameters of target volumes and OARs between the two plans were compared. Tongue volume and tongue length outside of mouth was 10.4±2.5cm3 and 2.8±0.6cm, respectively, distance between dorsal surface of oral tongue and plate increased from 0.3±0.3cm to 2.2±0.5cm by wearing the oral stent. For the target volume, there was no significant difference. However, Dmax of tongue, tongue tip and periglottis decreased significantly from 6352.6±259.9cGy to 5994.9±478.9cGy, 3499.8±250.6cGy to 3357.7±158.0cGy and 6345.5±171.0cGy to 6133.4±263.3cGy, respectively (p=0.000); Dmean of tongue, tongue tip and periglottis decreased significantly from 3714.7±204.2cGy to 3169.7±200.9cGy, 3060.8±216.2cGy to 2509.6±196.7cGy and 3853.3±224.9cGy to 3079.3±222.0cGy, respectively (p=0.000). The individualized 3D printed oral stent can reduce the dose of oral tissues and organs, so as to reduce the oral adverse reactions and improve the compliance of patients and the quality of their life. The technique can be used in radiotherapy of NPC patients.

Breast cancer-derived exosomal lncRNA SNHG14 induces normal fibroblast activation to cancer-associated fibroblasts via the EBF1/FAM171A1 axis.

Exosomes released from cancer cells can activate normal fibroblasts (NFs) into cancer-associated fibroblasts (CAFs), which promotes cancer development. Our study aims to explore the role and potential mechanisms of breast cancer exosomes-delivered long non-coding RNA (lncRNA) SNHG14 in regulating CAFs transformation. Adjacent normal tissues, cancerous and serum specimens were gathered in breast cancer patients. Exosomes and NFs were separated from breast cancer cells (SKBR-3) and normal tissues of patients, respectively. Cell viability and migration were measured with CCK-8 and Transwell assays. CAFs markers, fibroblast activation protein (FAP) and a-smooth muscle actin (α-SMA) were detected for assessing CAFs activation. The interactions between molecules were evaluated using dual luciferase reporter assay, RNA immunoprecipitation and chromatin immunoprecipitation. SNHG14 and FAM171A1 were upregulated in breast cancer. Exosomes secreted by SKBR-3 cells induced NFs activation in CAFs, as indicated by upregulating CAFs marker levels and facilitated cell viability and migration. Exosomal SNHG14 silencing in SKBR-3 cells inhibited CAFs activation. SNHG14 positively regulated FAM171A1 expression through EBF1. FAM171A1 overexpression eliminated the inhibition effect of exosomal SNHG14 silencing in CAFs transformation. Breast cancer-derived exosomal SNHG14 contributed to NFs transformation into CAFs by the EBF1/FAM171A1 axis.

A preliminary study on the effect of renal function on the metabolism of 18F-FDG in the human cerebellum.

The cerebellum is less affected by normal aging or neurodegenerative diseases, the aim of this paper is to investigate the effect of renal function status on uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in human cerebellum based on independent creatinine (CRE) or blood urea nitrogen (BUN) levels. A total of 253 patients who underwent 18F-FDG PET/CT scans were included. The patients were divided into groups according to renal function status: 201 patients with normal renal function, 16 patients with increase CRE, 36 patients with decrease CRE, and 31 patients with abnormal BUN. The maximum standardized uptake values were obtained in regions of interest (ROIs) for multiple tissue types (right cerebellum, right lobe of liver, right lung, bone marrow and psoas muscle at the level of the fourth lumbar vertebra). Moreover, the selected normal CRE groups were pair-matched with CRE decrease group with respect to age, sex, body mass index and glucose, respectively. Among 253 patients who met the inclusion/exclusion criteria, the final analysis included 967 ROIs (244 cerebellum, 191 lungs, 230 muscles, 145 bone marrow, and 157 liver) from 18F-FDG PET/CT scans. Among patients grouped by CRE or BUN levels, the uptake of 18F-FDG by cerebellum was significantly decreased in patients with CRE decrease level (P=0.001). There were no statistically significant differences between the other groups. Matched-pair analysis indicated there were no significant changes in outcomes between the CRE decrease group and the age-, sex-, BMI-, and glucose-matched controls compared to pre-matching. In patients with normal renal function and reduced CRE concentration, decrease cerebellar glucose metabolism was observed; however, no abnormal uptake of 18F-FDG was found in the cerebellum and other normal tissues of patients with impaired renal function. Consequently, in the study of cerebellar 18F-FDG metabolism, it may be necessary to consider the influence of blood CRE level.

Dosimetric Comparative Analysis of Volumetric Modulated Arc Therapy and Intensity-Modulated Radiation Therapy in Cervical Cancer

Objective: To carry out dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) in cervical cancer. Methods: 50 postoperative cervical cancer patients were included in this study. The patients were admitted for treatment from January 2021 to January 2022. VMAT and IMRT plans were designed for each patient to analyze the dose distribution in the target area of the two treatment techniques. Results: Comparing the monitor unit for single treatment (638.21 ± 116.21 MU) and time of single treatment (143.21 ± 23.14 s) in the observation group and the monitor unit for single treatment (932.14 ± 74.11 MU) and time of single treatment (223.14 ± 17.26 s) in the control group, there was significant difference (P &lt; 0.05); there was also significant difference (P &lt; 0.05) between the normal tissue (bladder and rectum) of the observation group and that (bladder and rectum) of the control group. Conclusion: VMAT is more effective in cervical cancer, and it has a certain protective effect on normal tissues in patients and can reduce the radiation dose.

Study of the radioprotective properties of fumaric acid and 3-hydroxypyridine fumarate under the action of ionizing radiation on human cells

In the modern world, such a situation has developed that the development of nuclear energy and the use of sources of ionizing radiation in various fields of activity have created a potential threat of radiation hazard to humans. In this connection, the actual direction is the study of ways to increase the radioresistance of human cells and tissues to the action of ionizing radiation. In addition, radioprotective compounds are also important in radiotherapy, since normal tissues of patients must be protected from radiation damage when using high doses of radiation in the treatment of malignant neoplasms. However, the radioprotectors currently used have some disadvantages. The aim of this work is to study the radioprotective properties of fumaric acid and 3-hydroxypyridine fumarate under the action of gamma radiation and radiation of 12C ions on tumor (SK-N-BE neuroblastoma) and normal (hTERT fibroblasts) human cells. The effect of radiation was evaluated according to the criteria of cell survival in culture, doubling time and clonogenic activity. It has been shown that the use of fumaric acid and 3-hydroxypyridine fumarate has a radioprotective effect on normal and tumor cells when they are irradiated with gamma radiation at doses of 1, 4, 6 and 10 Gy. The use of fumaric acid and 3-hydroxypyridine fumarate does not have a radioprotective effect on tumor cells when they are irradiated with 12C ions. A comparative analysis of the results of the action of the preparations with gamma rays and 12C ions showed a significant dependence of the manifestation of modifying properties on the quality of radiation. The study of cell doubling time showed that the presence of drugs in the control did not increase this indicator. On the contrary, under the action of gamma radiation at a dose of 10 Gy, the preparations reduced the doubling time of fibroblasts by more than two times and the doubling time of neuroblastoma cells by almost 1.5 times. The data obtained indicate that the antioxidant properties of the studied preparations open up new possibilities for modifying the action of ionizing radiation in the treatment of oncological diseases. The use of fumaric acid and 3-hydroxypyridine fumarate will reduce the radiation load on healthy cells, including reducing the effect of secondary products on healthy cells beyond the Bragg peak under the action of carbon ion therapy.

Abstract 4982: The somatic mutation signature detected in gynecological mucosal melanoma

Abstract Background: Gynecological Mucosal Melanoma(GMM) is aggressive disease with a poor prognosis, where few studies focusing on its target drug and mutation signatures. Cancer as outcome of DNA mutagenesis process and can be inferred from somatic mutations signature by analyzing the genome sequence. Due to the rapid development of next-generation sequencing (NGS) and molecularly driven targeted therapy, discovering different mutation signature in cancer plays an important role in precision medicine. Methods: The study was conducted at a high-volume melanoma center, the Peking University Cancer Hospital. We enrolled female patients with melanoma (n = 22) from 2017 to 2021. Subsequently, whole-exome sequencing performed on the Formalin-fixed paraffin-embedded (FFPE) specimens from 22 GMM patients and match normal tissues of patients. Tumor mutational burden (TMB) was measured as the number of nonsynonymous somatic mutations of whole-exome sequence coding region. Mutation signature detection base pair of six substitution subtypes: C&amp;gt;A, C&amp;gt;G, C&amp;gt;T, T&amp;gt;A, T&amp;gt;C, and T&amp;gt;G. NMF can be used to decompose matrix A into two nonnegative matrices. Results: In all mutations of 22 GMM patients, we screen two mutation signatures. Signature 1 showed a strong correlation [0.77;cosine similarity value (CSV)] to the signature 3 from the COSMIC database, which represents failure of DNA double-strand break-repair by homologous recombination, which predominated in 55%(12/22) GMM patients. Signature 2 showed a strong correlation to Cosmic signature 1 (CSV = 0.791), which is has been found in all cancer types correlated with age cancer diagnosis. Patient-18 did not any treatment in our hospital, follow-up was lost. Kaplan-Meier revealed that Signature 2 was associated with longer overall survival in GMM patients and later recurrence or progression. Conclusions: This study aimed to identify prognostic markers and the development of targeted therapy for the treatment of GMM. Citation Format: Zhongwu Li, Lianyi Shen, Siyao Liu. The somatic mutation signature detected in gynecological mucosal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4982.

Vascular endothelial growth factor A is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Vascular endothelial growth factor A (VEGFA) is involved in regulating biological processes, such as angiogenesis and vascular permeability, and is very closely related to the pathogenesis of various tumours, especially vascular-rich, solid tumours. Clinical data of patients with HCC and other tumours were analysed through public databases, such as the TCGA database, Gene Expression Omnibus database, Human Protein Atlas database, STRING, Tumour Immune Estimation Resource and Kaplan-Meier Plotter. The tumour tissues and adjacent normal tissues of patients with HCC from Hunan Provincial People's Hospital were collected to verify the expression of VEGFA by immunohistochemistry, immunofluorescence, Western blotting and qPCR. VEGFA expression is elevated in multiple tumour types and correlates with the prognosis of tumour patients. VEGFA is involved in regulating the tumour microenvironment and immune cell function in tumour development. Inhibition of VEGFA reduces proliferation, invasion, and migration and promotes apoptosis in HCC cells. VEGFA is a potential predictive biomarker for the diagnosis and prognosis of HCC.

Effects of lncRNA-UCA1 targeting miR-204-5p on the proliferation, migration, apoptosis and immune escape of endometrial carcinoma cells

Objective: To investigate the effect of long non-coding RNA urothelial carcinoma-associated 1 (UCA1) gene on the proliferation, migration, apoptosis and immune escape of endometrial cancer cells and its molecular mechanism. Methods: Endometrial cancer tissues and adjacent normal tissues of patients with endometrioid adenocarcinoma who underwent total or partial hysterectomy in Henan Provincial People's Hospital from 2017 to 2019 were collected. The expressions of UCA1 and miR-204-5p were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), and the cell proliferation, migration and apoptosis were detected by cell counting kit 8 (CCK8) method, Transwell method, flow cytometry, and dual-luciferase reporter assay was used to explore the target relationship between UCA1 and miR-204-5p. HEC-1A-sh-NC or HEC-1A-sh-UCA1 cells were co-cultured with peripheral blood mononuclear cells (PBMC) or cytokine-induced killer cells in vitro to explore the role of UCA1 in immune escape. Results: The expression level of UCA1 in endometrial cancer tissue (17.08±0.84) was higher than that in adjacent normal endometrial tissue (3.00±0.37), and the expression level of miR-204-5p (0.98±0.16) was lower than that in adjacent normal endometrial tissue (2.00±0.20, P<0.05). Pearson correlation analysis showed that the expression of miR-204-5p was negatively correlated with the expression of UCA1 (r=-0.330, P=0.030). The expressions of UCA1 and miR-204-5p were associated with the International Federation of Gynecology and Obstetrics stage of endometrial cancer, lymph node metastasis and vascular invasion (P<0.05). The relative ratio of absorbance (0.58±0.11) and the number of cell migration [(199.68±18.44)] in the sh-UCA1 group were lower than those in the sh-NC group (1.24±0.17 and 374.76±24.83), respectively. The apoptosis rate of sh-UCA1 group [(28.64±7.80)%] was higher than that of sh-NC group [(14.27±4.38)%, P<0.05]. After different ratios of effector cells and target cells were cultured, the cell survival rate of HEC-1A-sh-UCA1 group was lower than that of HEC-1A-sh-NC group, and the difference was statistically significant (P<0.05). UCA1 had a binding site for miR-204-5p. The relative ratio of absorbance (1.74±0.08) and the number of cell migration (426.00±18.00) cells in the UCA1+ anti-miR-204-5p group were higher than those in the control group [1.00±0.03 and (284.00±8.00) cells, respectively]. The apoptosis rate of UCA1+ anti-miR-204-5p group [(5.42±0.93)%] was lower than that of control group [(14.82±1.48)%, P<0.05]. HEC-1A-sh-UCA1 cells could induce higher interferon gamma (IFN-γ) expression when co-cultured with PBMC, and the levels of IFN-γ expression in PHA group and PHA+ pre-miR-204-5p group cells were 2.42±0.49 and 1.88±0.26, which were higher than that in the PHA+ pre-NC group (0.85±0.10, P<0.05). When co-cultured with cytokine-induced killer cells (different ratios) in vitro, the HEC-1A-sh-UCA1 group and the HEC-1A-pre-miR-204-5p group had lower survival rates than that in the HEC-1A-pre-miR-204-5p group. In the HEC-1A-pre-NC group, the differences were statistically significant (P<0.05). Conclusion: UCA1/miR-204-5p may play an important role in human endometrial cancer.

Abstract A011: Detection of disseminated tumor cells in advanced clear cell renal cell carcinoma through research autopsy

Abstract Background: The vast majority of cancer deaths can be attributed to tumor metastases. Disseminated tumor cells (DTCs) are thought to act as a reservoir of tumor clones which can lie dormant before causing overt metastases. Their presence has been shown to be a poor prognostic indicator in several tumor types. Despite their importance, the timing and source of DTCs is unclear across most solid cancers and even less is known about them in late-stage disease. The Posthumous Evaluation of the Advanced Cancer Environment (PEACE) post-mortem study enables extensive sampling of malignant lesions but also normal tissues, thereby allowing study of DTCs in patients with advanced cancer. Methods: We performed research autopsy sampling of macroscopically normal bone, lung and liver in 3 patients with advanced clear cell renal cell carcinoma (RCC). In addition, we performed bone marrow aspiration at autopsy from vertebral bodies and the ilium using an anterior approach. Mechanical disaggregation followed by collagenase digestion was used to generate single cell suspensions. Detection of tumor cells was carried out using antibodies against known tumor or epithelial markers carbonic anhydrase IX (CAIX). Epithelial cell adhesion molecule (EpCAM) was also used for bone marrow samples as native bone marrow cells do not express this marker. These sub-populations were then isolated using fluorescence activated cell sorting and DNA was extracted and amplified from single cells. Results: We performed and optimised collagenase-based digestion on all solid tissues collected. The percentage of viable cells generated varied significantly between subjects and tissues with bone marrow samples more viable than lung and liver. Rare and distinct populations of CAIX+ and EpCAM+ cells were detected in normal tissues between 0.5-2%. DNA amplification was successful on single cells isolated from normal lung and liver but not from bone tissue. Pilot shallow coverage whole genome sequencing revealed genomically aberrant cells ranging from single chromosome arm losses to widespread copy number aberrations. Conclusion: We demonstrate feasibility of sequencing single cells from autopsy study subjects. Rare populations of single cells with markers of clear cell RCC were detected and isolated both in normal tissues of patients with advanced disease. Genomic analyses of these cells will lead to insights into their relationship to the primary tumor and overt metastatic lesions. Citation Format: Haixi Yan, Cristina Cotobal Martin, Christie English, Annelien Verfaillie, Jonas Demeulemeester, Andrew Rowan, Annika Fendler, Anne-Laure Cattin, Sucheta Mahapatra, Lewis Au, Scott Shepherd, Ben Shum, Charlotte Spencer, Zayd Tippu, Ula Mahadeva, Anna Green, Eleanor Carlyle, Cristina Naceur-Lombardelli, PEACE consortium, Mariam Jamal-Hanjani, Charles Swanton, Samra Turajlic, Peter Van Loo. Detection of disseminated tumor cells in advanced clear cell renal cell carcinoma through research autopsy [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A011.

Downregulation of CEMIP enhances radiosensitivity by promoting DNA damage and apoptosis in colorectal cancer.

Colorectal cancer (CRC) is the third leading malignancy worldwide in both new cases and deaths. Neoadjuvant radiotherapy is the standard preoperative regimens for locally advanced patients. However, approximately 50% of patients develop recurrence and metastasis after radiotherapy, which is largely due to the radiation resistance properties of the tumor, and the internal mechanism has not been elucidated. Here we found that CEMIP expression is up-regulated in a variety of tumor types, particularly in CRC. Public databases and clinical samples revealed that CEMIP expression is significantly higher in tumor tissues than in adjacent normal tissues in patients with locally advanced CRC who received neoadjuvant chemoradiotherapy, and it is closely related to the poor prognosis. Functional characterization uncovered that downregulation of CEMIP expression can enhance the radiosensitivity of CRC cells, which is confirmed to be achieved by promoting DNA damage and apoptosis. In vivo studies further verified that CEMIP knockdown can significantly improve the radiosensitivity of subcutaneously implanted colorectal tumors in mice, suggesting that CEMIP may be a radiation-resistant gene in CRC. Mechanistically, EGFR/PI3K/Akt signaling pathway is hypothesized to play a key role in CEMIP mediating radiation resistance. These results provide a potential new strategy targeting CEMIP gene for the comprehensive treatment of locally advanced CRC patients.

Self-assembled nanoparticles based on cationic mono-/AIE tetra-nuclear Ir(III) complexes: long wavelength absorption/near-infrared emission photosensitizers for photodynamic therapy.

Cyclometalated Ir(III) complexes as photosensitizers (PSs) have attracted widespread attention because of their good photostability and efficient 1O2 production ability. However, their strong absorption in the UV-vis region severely limits their applications in photodynamic therapy (PDT) because the short wavelength illuminating light can be easily absorbed by the skin and subcutaneous adipose tissue causing damage to the patient's normal tissue. Herein, mono- and tetra-nuclear Ir(III) complex-porphyrin conjugates are rationally designed and synthesized, especially [TPP-4Ir]4+ exhibits obvious aggregation-induced emission (AIE) characteristics. PSs comprising Ir(III) complex-porphyrin conjugates self-assembled as nanoparticles (NPs) are successfully achieved. The obtained [TPP-Ir]+ NPs and [TPP-4Ir]4+ NPs exhibit long wavelength absorption (500-700 nm) and near-infrared emission (635-750 nm), successfully overcoming the inherent defects of short wavelength absorption of traditional Ir(III) complexes. Moreover, [TPP-4Ir]4+ NPs exhibit good biocompatibility, high 1O2 generation ability, low half-maximal inhibitory concentration (IC50) (0.47 × 10-6 M), potent cytotoxicity toward cancer cells and superior cellular uptake under white light irradiation. This work extends the scope for transition metal complex PSs with promising clinical applications.