Squamous Cell Cervical Cancer Research Articles

MiR-525-5p modulates cell proliferation, cell cycle, and apoptosis in Burkitt's lymphoma by targeting MyD88 and regulating the NF-κB signaling pathway.

MiR-525-5p functions as an oncomiRNA or tumor suppressor, and has been reported in various cancer types, including laryngeal squamous cell carcinoma, glioma, breast cancer, and cervical cancer. However, the biological functions and precise mechanisms of miR-525-5p remain unclarified in Burkitt's lymphoma (BL). This study aimed to explore the roles of miR-525-5p in BL, with the goal of ascertaining its regulatory effects on the nuclear factor-kappaB (NF-κB) signaling pathway by targeting Myeloid differentiation factor 88 (MyD88). The expression levels of miR-525-5p and MyD88 were measured by quantitative real-time PCR and immunohistochemical staining, respectively. The effects of miR-525-5p overexpression on BL cell proliferation, colony-forming, and migration were evaluated by cell counting kit-8, soft agar colony-forming, and transwell assays, while cell cycle and cell apoptosis were analyzed by flow cytometry. Possible interactions between miR-525-5p and MyD88 was examined via luciferase reporter assay. The expression of MyD88 and NF-κB signaling pathway-related proteins, including p65, p-p65, IκBa, and p-ΙκBa was determined by western blotting. BL cells overexpressing miR-525-5p were treated with phorbol 12-myristate 13-acetate (PMA), and Hoechst 33258 staining and Calcein AM/EthD-I staining were used to analyze the changes in chemotherapy sensitivity of BL cells to doxorubicin (DOX). Compared with reactive lymphoid hyperplasia, miR-525-5p was dramatically downregulated in BL tissues, while the rate of MyD88 protein positivity was significantly increased. Upregulation of miR-525-5p suppressed cell proliferation, colony-forming, and migration, induced cell cycle arrest and apoptosis, and enhanced the chemosensitivity to DOX in BL cells. MiR-525-5p targeted MyD88 to inhibit the activation of NF-κB signaling pathway. PMA treatment reactivated the NF-κB pathway and reversed apoptosis mediated by miR-525-5p overexpression. These findings revealed that miR-525-5p acts as a tumor suppressor, targeting MyD88 to modulate proliferation, cell cycle progression, and apoptosis in BL cells by regulation of NF-κB signaling pathway.

Abstract C120: Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities

Abstract Black persons have the highest mortality rates of both cervical cancer (CC) and pancreatic ductal adenocarcinoma (PDAC) in the United States. Differences in access to quality healthcare and socioeconomic status contribute to these cancer health disparities as well as ancestry and biology. In other cancer types, differences in the inflammatory tumor landscape across races and ancestral populations have been reported. However, the inflammatory tumor microenvironment (TME) as it relates to CC and PDAC health disparities is not well defined. Black patients are often underrepresented in PDAC studies. Meanwhile, CC health disparities studies primarily investigate socioeconomic status, screening, and vaccination rates. Therefore, we aim to characterize the inflammatory TME in these two cancer types with the long-term goal of informing prevention, prognostic, and therapeutic strategies. Clinicopathological characteristics were compared between Black (n = 144) and White (n = 198) patients with CC who received care at Johns Hopkins Medicine between 1995 and 2019. Surgically resected formalin-fixed paraffin embedded (FFPE) CC tissue samples were obtained from Non-Hispanic Black (n = 10), Non-Hispanic White (n = 10), Hispanic Black (n = 5), and Hispanic White (n = 5) women matched on grade, age, and subtype. Tissue microarrays (TMAs) were constructed using archival surgically resected FFPE PDAC tissues from Black (n = 45) and White (n = 45) patients, matched on sex, age, stage, and time of surgery. Multiplexing immunohistochemistry (mIHC) was used to assess markers for i) T cells (CD3, CD8, CD4, FoxP3), M2 macrophages (CD163), mast cells (Tryptase), and fibroblasts (FAP) in PDAC tissues and ii) B cells (CD79A), T cells (CD3, CD8, CD4, FoxP3), plasma cells (CD138/syndecan-1), programmed death-ligand 1 protein (PD-L1), macrophages (CD68, CD163), natural killer cells (NKP46/CD56/CD16), neutrophils (CD66ce), and mast cells (Tryptase) in CC tissues. HALO Image Analysis Platform (version 3.6.4134.137; Indica Labs) was used to quantify marker expression. GraphPad Prism Software (version 10.0.03), was used for graphing and statistical analysis. Squamous cell CC was the most frequent histological subtype in both Black (68%) and White (44%) women. Progression through treatment was more common among Black women (24%) compared to White women (7%). CD163+ M2 macrophages were significantly increased in PDAC tumors compared to benign tissues among Black patients (p = 0.0435), and in tumors from Black women compared to White women (p = 0.0067). FAP+ fibroblasts were also significantly increased in PDAC tumors compared to benign tissues among Black patients (p = 0.0001) and in tumors from Black women compared to White women (p = 0.0013). CD8+ cytotoxic T cells and FoxP3+ regulatory T cells were comparable between races. We observed differences in macrophage and fibroblast distribution between races supporting the effort for future studies that examine the significance of characterizing the TME to address cancer health disparities. Citation Format: Jelani Jarrett, Jae W Lee, Ali Dbouk, Vahinipriya Manoharan, Kennedy Rains, Terri Mason, Kimberly Levinson, Laura D Wood, Michael G Goggins, Janielle P Maynard. Characterization of the inflammatory tumor microenvironment and its association with cancer health disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C120.

Prognostic Value of IMP3 Expression in Squamous Cervical Cancer.

Cervical cancer remains one of the leading causes of death from malignant diseases in women worldwide. Primary and secondary prevention have led to better outcomes in developed countries, whereas in developing countries, cervical cancer continues to be responsible for an unjustifiably high number of fatalities. The discovery of new tumor biomarkers can lead to earlier diagnosis, better therapeutic decisions, and improved treatment methods. IMP3 is a protein responsible for invasiveness and other aggressive characteristics of tumor processes. Its highly specific expression has been proven in various malignant processes. The level of IMP3 expression in cervical cancer cells could be used as a prognostic factor for a worse disease course. In this study, IMP3 expression was examined in 80 patients who underwent surgery for squamous cell cervical cancer in the first FIGO stage of the disease, and its association with disease-free period and overall survival was investigated. Data analysis did not show a statistically significant association between IMP3 expression and the mentioned primary outcomes, despite its association with clinical-pathological indicators of advanced disease. In conclusion, the analysis of IMP3 protein expression in patients with early-stage cervical cancer is of limited utility.

HPV16 Genomes: In Silico Analysis of E6 and E7 Oncoproteins in 20 South American Variants.

Human papillomavirus (HPV) is the main risk factor for the development of squamous cell cervical cancer, and E6 oncoprotein and E7 oncoprotein are important components of the viral genome and its oncogenic potential. It is known that different viral variants of HPV16 have different pathology and impact on the development of neoplasia, although few studies have been performed on South American variants. Therefore, the present study aimed to analyze in silico the genomic diversity of HPV16 in 20 complete genome variants of South America in the National Center for Biotechnology Information (NCBI) database. We performed a descriptive study to characterize the polymorphic regions of the E6 and E7 genes in HPV16 variants, using software for genomic data and single nucleotide polymorphism (SNP) analysis and others for phylogenetic analysis. The variants analyzed included six SNPs linked to cancer (A131G, G145T, C335T, T350G, C712A, and T732C) and significant variation (798 nucleotide substitutions). Despite this, the variants showed low genetic diversity. Eighteen variants of unclear significance (VUS) were identified, 10 of which were in the coding E6 regions and 8 in the coding E7 regions. The prevalence of lineage D variants is of concern due to their pathology in cervical cancer and requires more research and epidemiological vigilance regarding their prevalence in the population. The data obtained in this study may contribute to future research on South American variants of HPV16, their pathogenicity, and the development of treatments.

Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer.

Cervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients. We investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A). This single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes. Among the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed. HPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.

Copy Number Profiling Implicates Thin High-Grade Squamous Intraepithelial Lesions as a True Precursor of Cervical Human Papillomavirus-Induced Squamous Cell Cancer

Full-thickness high-grade squamous intraepithelial lesions (HSIL) are precursors of invasive cervical squamous cell carcinoma (SCC). The World Health Organization and Lower Anogenital Squamous Terminology Standardization Project for human papilloma virus (HPV)–associated lesions divide full-thickness HSIL of the cervix into thin HSIL with thickness of 1 to 9 cell layers and the typical full-thickness HSIL of >10 cell layers. Although HPV oncogene transcripts and p16ink4a overexpression, as markers of transforming HPV infection, are detectable in thin HSIL, the biological significance of thin HSIL in cervical carcinogenesis remains poorly understood. To further characterize thin HSIL, we performed a comparative study of chromosomal copy number variations (CNV), an analysis of dysregulated genes present in the segments with CNV, and a generalized genetic complexity calculation for 31 thin HSIL, 31 thick HSIL, 24 microinvasive SCC (pT1a SCC), and 22 highly invasive SCC samples. Thin HSIL share various CNV and specific dysregulated gene pathways with thick HSIL and invasive SCC. Thin HSIL exhibited an average CNV of 11.6% compared with 14.1% for thick HSIL, 15.5% for pT1a SCC, and 26.6% for highly invasive SCC. The CNV included gains at 1q and 3q (40% and 43%, respectively), partial loss of 3p, and loss of chromosomes 11 (18%), 16 (50%), 20 (35%), and 22 (40%). Pathways affected solely in thin HSIL were those enhancing immune evasion and primarily involved the (interleukin) IL6, IL21, and IL23 genes. ILs are transiently upregulated in response to infection and play a crucial role in mounting antitumor T-cell activity. Deregulation reflects an attempt by the HPV to evade the initial immune response of the host. The primary pathways shared by thick HSIL and invasive SCC were interactions between lymphoid and nonlymphoid cells, NOTCH2 signaling, tight junction interactions (primarily of the claudin family), and FGR2 alternative splicing. Our results show that thin HSIL carry similar genetic changes as thick HSIL and SCC, indicating that thin HSIL are true precursor lesions that can progress to thick HSIL and SCC.

Whole-tumor histogram analysis of multiple non-Gaussian diffusion models at high b values for assessing cervical cancer.

To assess the diagnostic potential of whole-tumor histogram analysis of multiple non-Gaussian diffusion models for differentiating cervical cancer (CC) aggressive status regarding of pathological types, differentiation degree, stage, and p16 expression. Patients were enrolled in this prospective single-center study from March 2022 to July 2023. Diffusion-weighted images (DWI) were obtained including 15 b-values (0 ~ 4000s/mm2). Diffusion parameters derived from four non-Gaussian diffusion models including continuous-time random-walk (CTRW), diffusion-kurtosis imaging (DKI), fractional order calculus (FROC), and intravoxel incoherent motion (IVIM) were calculated, and their histogram features were analyzed. To select the most significant features and establish predictive models, univariate analysis and multivariate logistic regression were performed. Finally, we evaluated the diagnostic performance of our models by using receiver operating characteristic (ROC) analyses. 89 women (mean age, 55 ± 11 years) with CC were enrolled in our study. The combined model, which incorporated the CTRW, DKI, FROC, and IVIM diffusion models, offered a significantly higher AUC than that from any individual models (0.836 vs. 0.664, 0.642, 0.651, 0.649, respectively; p < 0.05) in distinguishing cervical squamous cell cancer from cervical adenocarcinoma. To distinguish tumor differentiation degree, except the combined model showed a better predictive performance compared to the DKI model (AUC, 0.839 vs. 0.697, respectively; p < 0.05), no significant differences in AUCs were found among other individual models and combined model. To predict the International Federation of Gynecology and Obstetrics (FIGO) stage, only DKI and FROC model were established and there was no significant difference in predictive performance among different models. In terms of predicting p16 expression, the predictive ability of DKI model is significantly lower than that of FROC and combined model (AUC, 0.693 vs. 0.850, 0.859, respectively; p < 0.05). Multiple non-Gaussian diffusion models with whole-tumor histogram analysis show great promise to assess the aggressive status of CC.

The role of neoadjuvant chemotherapy before radical surgery in stage IB2/IIA2 squamous cell cervical cancers

BackgroundThis study aimed to evaluate the outcomes of patients diagnosed with stage IB2/IIA2 cervical squamous cell carcinoma who underwent neoadjuvant chemotherapy (NACT) prior to radical hysterectomy compared to those who did not receive NACT before surgery.Materials and methodsThis is a multicenter study including data of 6 gynecological oncology departments. The study is approved from one of the institution’s local ethics committee. Patients were stratified into two cohorts based on the receipt of NACT preceding their surgical intervention. Clinico-pathological factors and progression-free survival were analyzed.ResultsTotally 87 patients were included. Lymphovascular space invasion (LVSI) was observed as 40% in the group receiving NACT, while it was 66.1% in the group not receiving NACT (p = 0.036). Deep stromal invasion (> 50%) was 56% in the group receiving NACT and 84.8% in the group not receiving NACT (p = 0.001). In the univariate analysis, application of NACT is statistically significant among the factors that would be associated with disease-free survival. Consequently, a multivariate analysis was conducted for progression-free survival, incorporating factors such as the depth of stromal invasion, the presence of LVSI, and the administration of NACT. Of these, only the administration of NACT emerged as an independent predictor associated with decreased progression-free survival. (RR:5.88; 95% CI: 1.63–21.25; p = 0.07).ConclusionsNACT shouldn’t be used routinely in patients with stage IB2/IIA2 cervical cancer before radical surgery. Presented as oral presentation at National Congress of Gynaecological Oncology & National Congress of Cervical Pathologies and Colposcopy (2022/ TURKEY).

Naringenin as potent anticancer phytocompound in breast carcinoma: from mechanistic approach to nanoformulations based therapeutics.

The bioactive compounds present in citrus fruits are gaining broader acceptance in oncology. Numerous studies have deciphered naringenin's antioxidant and anticancer potential in human and animal studies. Naringenin (NGE) potentially suppresses cancer progression, thereby improving the health of cancer patients. The pleiotropic anticancer properties of naringenin include inhibition of the synthesis of growth factors and cytokines, inhibition of the cell cycle, and modification of several cellular signaling pathways. As an herbal remedy, naringenin has significant pharmacological properties, such as anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. The inactivation of carcinogens following treatment with pure naringenin, naringenin-loaded nanoparticles, and naringenin combined with anti-cancer agents was demonstrated by data in vitro and in vivo studies. These studies included colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancers, bladder neoplasms, gastric cancer, and osteosarcoma. The effects of naringenin on processes related to inflammation, apoptosis, proliferation, angiogenesis, metastasis, and invasion in breast cancer are covered in this narrative review, along with its potential to develop novel and secure anticancer medications.

First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with other solid tumors: Safety and efficacy results from a phase I study.

e14593 Background: IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein which could block PD-1 checkpoint and rejuvenate exhausted tumor-specific T cells by cis-activating α-bias IL-2. It was well tolerated and showed encouraging efficacy in patients (pts) with advanced melanoma, non-small cell lung cancer and colorectal cancer. Herein, we report a phase I study of IBI363 in patients (pts) with other solid tumors. Methods: Eligible pts with advanced biliary tract cancer (BTC), head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC) and ovarian cancer (OC) who failed or intolerant to standard therapy were enrolled. IBI363 was intravenously administered at different dose levels ranging from 600 to 1500 μg/kg QW/Q2W/Q3W. Primary objective of the study was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 26, 2024, 24 pts were enrolled including 13 pts with BTC, 3 pts with HNSCC, 4 pts with CC and 4 pts with OC. In BTC, 6 (46.2%) pts received IBI363 treatment for more than 3 months and the maximum treatment duration was 7 months. In HNSCC, CC and OC, the maximum treatment duration was 4.6, 6.2 and 6.5 months respectively. Pts with at least 1 tumor assessment were included in efficacy evaluable set (n = 18). The overall ORR was 22.2% and DCR was 77.8%. In 11 evaluable pts with BTC, best overall response (BOR) was confirmed partial response (cPR) in 1 pt (600 μg/kg Q2W, immunotherapy (IO)-failed), stable disease (SD) in 9 pts (including 6 pts with tumor regression) and progressive disease (PD) in 1 pt. ORR was 9.1% and DCR was 90.9%. In 2 evaluable pts with HNSCC, 1 pt had cPR (600 μg/kg Q2W, IO-naïve, PD-L1 expression negative) and 1 pt had PD. In 3 evaluable pts with CC, 1 pt had cPR (1000 μg/kg Q2W, IO-failed), 1 pt had SD and 1 pt had PD. In 2 evaluable pts with OC, 1 pt had cPR (1000 μg/kg Q2W, platinum-resistant) and 1 pt had PD. All cPR pts had previous 1-2 lines of treatments and had tumor regression ranging from 45% to 87%. Durable tumor responses were observed with cPR remained at week 30 in BTC and remained at week 24 in HNSCC, CC and OC. In 4 pts with cPR, 3 pts still on treatment and 1 pt with HNSCC received curative resection. No new safety signals of IBI363 were observed. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI363 showed promising and durable efficacy in pts with various solid tumors including refractory tumors such as BTC and IO or platinum-resistant tumors such as CC and OC. Further clinical investigations on these tumors using IBI363 alone or in combination with other treatments are ongoing. Clinical trial information: NCT05460767 .

Interim results from a prospective multicenter phase II trial of stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC trial).

e16089 Background: Definitive concurrent chemoradiotherapy (dCRT) is the standard treatment for cervical esophageal squamous cell cancer (CESCC). However, salvage esophagectomy poses significant technical challenges in dCRT failures, and optimizing patient selection for dCRT remains an unsolved concern. In this context, we propose a stratified screening strategy by incorporating induction immunochemotherapy, aiming to identify suitable candidates for organ-sparing dCRT and timely surgical treatment. Methods: This prospective multicenter interventional phase II study (ChiCTR2200057732) enrolled patients with clinical stage T2-4NanyM0 (AJCC TNM 8th) resectable CESCC. Eligible participants received induction therapy of intravenous PD-1 inhibitor tislelizumab (200mg, day 1) plus nab-paclitaxel (100 mg/m2, day 1,8,15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles. Treatment response was evaluated 4 weeks after the completion of induction therapy, according to the criteria of the CROC trial: Grade 1, remarkable response (RR); Grade 2, limited partial response (LPR); and Grade 3, poor response (POR). Stratified patients would receive different follow-up treatments: dCRT was administered to RR patients, and radical surgery was performed in LPR and POR patients. Tislelizumab was maintained after dCRT in RR patients, and the postoperative adjuvant therapy was dependent on the doctors in the surgery groups. The primary endpoint was the 2-year event-free survival with a planned enrollment of 36 patients in this study. Results: From Jul 2022 to Jan 2024, 28 patients were enrolled. Of these, 22 patients completed the full two-cycle induction therapy and response evaluation. The response after induction immunochemotherapy were RR in 50.0% (11/22), LPR in 31.8% (7/22), and POR in 18.2% (4/22). All of the RR population underwent subsequent dCRT. Among 11 non-RR patients, only 7 cases received esophagectomy, other 4 selected dCRT according to their will. Up to Jan 2024, the median follow-up was 11.0 months (3.5-17.7), all of the RR patients with dCRT were in disease-free survival, 1 LPR and 1 POR patients received dCRT had progression in the primary lesion, and 4 patients underwent surgery had locoregional or distant recurrences. Overall, 24 patients (96%) had any-grade treatment-related adverse events with the most common being leukocytopenia. Four patients (16%) had adverse events of grade 3 or worse, and no treatment-related death occurred. Conclusions: The 1-year survival of RR followed by dCRT appears promising compared to historical data. The strategy of induction immunochemotherapy showed effective in identifying candidates suitable for dCRT in patients with resectable CESCC. Enrollment is ongoing. Clinical trial information: ChiCTR2200057732.

Peroxiredoxin 2 as a potential prognostic biomarker associated with angiogenesis in cervical squamous cell cancer.

Peroxiredoxins (Prxs) are a ubiquitously expressed family of antioxidant enzymes that either facilitate or inhibit tumorigenesis, depending on the cancer type and Prx isoform. Prx2 is a typical Prx that has a dual role in tumorigenesis and tumor progression. However, the expression of Prx2 and its precise role in cervical cancer remains to be elucidated. Therefore, the present study aimed to investigate the expression of Prx2 and its association with the progression and prognosis of cervical squamous cell cancer (CSCC). In the present study, the clinicopathological data of 105 patients diagnosed with CSCC were collected from the medical record system at Jingzhou Central Hospital, Tongji Medical College of Huazhong University of Science and Technology (Jingzhou, China). Prx2 protein was also detected in 105 CSCC tissues and 40 adjacent peri-tumoral tissues by immunohistochemical staining. The relationships between Prx2 expression and clinicopathological features, vascular endothelial growth factor A (VEGF-A) expression and micro-vessel density (MVD) in CSCC were then analyzed. Progression-free survival (PFS) was also assessed using both univariate and multivariate analyses. The results of the present study demonstrated that the expression of Prx2 was upregulated in CSCC tissues compared with the adjacent peri-tumoral tissues (P<0.001). In addition, higher Prx2 expression was associated with greater depth of stromal invasion (P=0.023) and positive lymph vascular space invasion (P=0.044), while the Prx2 expression level was not associated with age, tumor size, histological grade, lymph node (LN) metastasis or International Federation of Gynecology and Obstetrics (FIGO) stage (all P>0.05). Furthermore, increased Prx2 expression was associated with high MVD (P=0.016), while expression of VEGF-A was not associated with Prx2 expression (P>0.05). Kaplan-Meier analysis showed that patients with high Prx2 expression (log-rank test, P=0.039), high MVD (log-rank test, P=0.015), a higher FIGO stage (log-rank test, P=0.021) and LN metastasis (log-rank test, P=0.022) had a shorter PFS time than patients with low Prx2 expression, low MVD, a lower FIGO stage and without LN metastasis, respectively. Cox proportional hazard regression analysis revealed that expression of Prx2 [hazard ratio (HR), 2.551; 95% confidence interval (CI), 1.056-6.162; P=0.037], MVD (HR, 2.436; CI, 1.034-5.735; P=0.042) and FIGO stage (HR, 1.543; CI, 1.027-2.319; P=0.037) were independent factors for PFS time. In conclusion, the results of the present study suggested that Prx2 could act as a potential biomarker for predicting CSCC progression and prognosis and could be a novel target for antiangiogenic therapy of CSCC.

The Role of Wheatgrass in Colorectal Cancer: A Review of the Current Evidence.

The etiology of colon cancer is either genetic in nature or results from inflammatory bowel diseases such as ulcerative colitis and Crohn's disease; nevertheless, dietary habits play a crucial role in the disease. Wheatgrass is a dietary supplement that is rich in vitamins, minerals, and antioxidants which contribute to health promotion in cardiovascular diseases, liver disease, blood diseases, diabetes, and inflammatory bowel diseases, as well as in several types of cancers, such as oral squamous cell cancer, cervical cancer, and breast cancer. In colorectal cancer (CRC), the prospect that wheatgrass possesses anti-inflammatory, antioxidant, and anticancer properties, and its use as an adjunctive therapy, have been minimally investigated and evidence is still limited. In this review, we compiled the available evidence pertaining to wheatgrass and its likely impact on CRC, described the pathways of inflammation in which wheatgrass could possibly play a role, and identified future research needs on the subject.

Understanding the age-related epithelial shifts at the uterine cervix and the area of risk for squamous cell cervical cancer

Understanding the age-related epithelial shifts at the uterine cervix and the area of risk for squamous cell cervical cancer

Synthesis of substituted terpyridine nickel nitrate complexes and their inhibitory selectivity against cancer cell lines

Six terpyridine‑nickel complexes 1–6 were formed by the coordination of 4′-(4-R-phenyl)-2,2′:6′,2″-terpyridine (R = hydroxyl (L1), methoxyl (L2), methylsulfonyl (L3), fluoro (L4), bromo (L5), iodo (L6)) derivatives to nickel nitrate. The compositions and structures of these complexes were analyzed by Fourier Transform infrared spectroscopy (FT-IR), elemental analyses, electrospray ionization mass spectra (ESI-MS), solid-state ultraviolet-visible (UV–Vis) spectroscopy, and single crystal X-ray diffraction (1, 2 and 4) studies. In vitro anticancer cell proliferation experiments against SiHa (human cervical squamous cancer cell line) cells, Bel-7402 (human hepatoma cancer cell line), Eca-109 (human esophageal cancer cell line) and HL-7702 (human normal hepatocyte cell line) indicate that they have more excellent anti-proliferation effects than the cis-platin against Siha cells, Bel-7402 cells and Eca-109 cells. Especially, complex 5 showed a rather outstanding inhibitory effect against the SiHa cell line and was less toxic than the other compounds to the HL-7702 cell line, implying an obvious specific inhibitory effect. Therefore, complex 5 has the potential value to be developed as an anticancer cell-specific drug against human cervical squamous carcinoma. Molecular docking simulation, UV–vis absorption spectroscopy and circular dichroism experiments show that they prefer to bind to DNA part in an embedded binding manner.

MRNA vaccines in cancer clinical trials: HPV16 tumor-derived antigens (e6 and e7 oncoproteins) associated with head and neck squamous cell carcinoma (HNSCC), oropharyngeal and cervical cancers

Human papillomavirus (HPV) induces the most common sexually transmitted disease and has been classified in the Alphapapillomavirus genus, Papillomaviridae family. They are non‒enveloped viruses presenting a closed circular double‒stranded non‒segmented DNA genome of approximately 8 kb that infect the anogenital epithelium causing cervical cancer, anal and penis cancer. There are viral groups based on their oncogenic activity as high‒risk types, low‒risk types and types of undetermined‒risk. mRNA vaccines are being evaluated in people with HPV-related cancers. This study described how mRNA cancer vaccines work and their applications recruiting several strategies for HPV cancer immunotherapy. Several biopharmaceuticals are developing mRNA vaccines encoding neoepitopes that can induce immune responses against target tumors. One trial is testing a personalized mRNA vaccine in combination with an immune checkpoint inhibitor in patients with advanced head and neck cancer. The production of therapeutic mRNA proteins for development of vaccine cancer have been manufactured by upstream and downstream methods. Several stages are processed in bioreactors using input and output parameters to measure the quality control of purified substance. Thus, novel technologies using different mRNA delivery system can be able to be integrated in clinical trials of HPV16 tumor-derived antigens associated cervical intraepithelial lesions of different stages until head and neck squamous cell carcinoma, oropharyngeal and cervical cancers.

Next generation of mRNA and lncRNAs based-vaccines platforms: Highlighted for HPV in head and neck squamous cell carcinoma, cervical and colorectal cancers and oncogenic viruses HBV/HCV in hepatocellular carcinoma

More than 200 HPV genotypes and several HPV types associated with particular diseases as oral lesions (Hecks disease, oropharyngeal carcinoma, laryngeal papillomas), anogenital warts (Bowenoid papulosis, Buschike‒Lowenstein tumor), Epidermodysplasia verruciformis (plane warts, Pityriasis‒ like plaques, squamous cell carcinomas of sun‒exposed skin) have been described. Several advances in the genomics era and the development of new technological tools for next-generation sequencing have been showed that approximately 98% of RNAs are not translated into proteins. This study aims to succinctly describe long non-coding RNAs (lncRNAs) and their correlation with the hallmark of cancers since they comprise a class of RNAs that do not code for proteins. Oncogenic mutations occur with higher prevalence in non-coding regions, and the correlation of lncRNAs is extremely important for better understanding the biology of cancer cells as well as elucidating the molecular mechanisms underlying cancer. Thus, these may be promising tumor biomarkers and potential therapeutic targets exemplified in hepatocellular carcinoma, cervical and colorectal cancer induced by oncogenic viruses. Future studies are need to delve deeper into the cellular signaling pathways involved in biological processes. This theme addresses innovative issues on the ONU 2030 agenda from the perspective of global one health.

Validation of the 2018 FIGO staging system for stage IIIC cervical cancer by determining the metabolic and radiomic heterogeneity of primary tumors based on 18F-FDG PET/CT.

This study aimed to validate the 2018 FIGO staging system of cervical cancer (CC) by determining the metabolic and radiomic heterogeneity of primary tumors between stage IIIC1 and IIIC2. 168 patients with squamous cell CC underwent pre-treatment fluorine-18 fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and were randomly allocated to training and testing cohorts with a 7:3 ratio. Radiomics features were extracted from the primary tumors based on CT and PET data. Ten metabolic parameters of the primary tumors were also assessed. After feature selection, three logistic regression radiomics models, involving (1) 2 CT features, (2) 3 PET features, and (3) 2 CT features + 3 PET features, respectively, and one random forest model were established. Finally, area under the curve (AUC) values and calibration curves were used to evaluate the 4 models. The IIIC1 and IIIC2 groups did not differ significantly in age, weight, height, or the 10 major metabolic parameters (P > 0.05). The AUCs of the 4 models were 0.577, 0.639, 0.763, and 0.506, respectively, in the training cohort, and 0.789, 0.699, 0.761, and 0.538, respectively, in the testing cohort. The model fit of the logistic regression model based on CT + PET data was good in both the training and testing cohorts. Our study offers additional diagnostic options for PALN metastasis, which could impact treatment decisions. Our results indirectly support the conclusions of previous studies recommending that primary tumors should be considered during IIIC staging.

Abstract 4007: AIC100 CAR-T cells targeting ICAM-1 are efficacious against solid tumors in xenograft mouse models of non-small cell lung cancer (NSCLC) and cervical cancer (CC)

Abstract Purpose: Establish preclinical proof of concept efficacy with CAR T cells (AIC100) in xenograft models of solid tumors (NSCLC and CC) expressing high levels of surface ICAM-1. Experimental: AIC100 is a third generation CAR T cell with micromolar affinity to ICAM-1, tuned lower than most CARs used to date in pre-/clinical studies. Affinity tuned AIC100 drug product is expected to selectively bind and kill tumor cells while safely sparing healthy cells. AIC100 also co-expresses somatostatin receptor 2 (SSTR2), which enables in vivo monitoring of AIC100 distribution and expansion by DOTATATE PET/CT imaging. To test preclinical efficacy of AIC100 in NSCLC and CC, four xenograft mouse models were generated using tumor cell lines known to have ICAM-1 expression (verified by flow cytometry) to test efficacy of AIC100. Reporter cell lines transfected with Luciferase were H226 NSCLC adenocarcinoma, H441 NSCLC squamous cell carcinoma, HeLa CC adenocarcinoma and SW756 CC squamous cell carcinoma. AIC100 efficacy was established by in vitro cytotoxicity prior to in vivo studies. NSG mice (n=10 per cell line) were inoculated via tail vein injection (1.0x106 cells) in cell growth media. Mice were imaged to ensure solid tumor formation which occurred in all mice within 3-5 days in the lung. At D0, mice were randomized into 2 groups (n=5 per group) of vehicle (PBS) and AIC100. At D1, mice were injected with AIC100 (1.0x107 live T cells) or vehicle. Mice were followed by weight and clinical observations 2x weekly and imaging by IVIS weekly. The study continued until vehicle group was euthanized due to tumor related co-morbidities at which time the study concluded. Results: AIC100 showed clear treatment benefit in both models of NSCLC and CC. In CC HeLa model, in mice treated with AIC100, primary tumors were significantly reduced by D8 and eliminated in 5/5 mice by D22. In CC SW756 model, in mice treated with AIC100, tumor growth was reduced in size by D22. In NSCLC H441 model, in mice treated with AIC100, primary tumors were largely eliminated in 5/5 mice by D15. In NSCLC H226 model, in mice treated with AIC100, tumors were significantly reduced by D8 and largely eliminated by D57 (4/5 mice). A clear survival benefit was observed in AIC100 treated mice in NSCLC H226 xenograft model. These results show treatment benefit by AIC100 in 2 tumor models per indication and establish proof of concept for the potential development of AIC100 as a treatment for ICAM-1 expressing NSCLC and CC cancers. Conclusions: AIC100 has significant treatment benefit in NSCLC and CC tumors with ICAM-1 expression in in vivo preclinical studies. Citation Format: Alyssa Birt, Serene Josiah, Kelsey L. Joyce, Srinija Alla, Michael P. Gallagher, Janusz Puc, Hanh Nguyen, Emily Walsh Martin, Sonal Gupta. AIC100 CAR-T cells targeting ICAM-1 are efficacious against solid tumors in xenograft mouse models of non-small cell lung cancer (NSCLC) and cervical cancer (CC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4007.

CLCN3 in mediating the proliferation of human ovarian cancer cells.

Chloride channel-3 (CLCN3), a crucial component of the voltage-gated chloride channel family, is implicated in numerous physiological and pathophysiological processes. This study aimed to investigate the characteristics of CLCN3 in pancancer and its influence on the immune response through the use of a range of databases. Concurrently, we assessed the impact of CLCN3 on the proliferation of ovarian cancer (OC) cells and explored its potential mechanisms. We employed the Tumor Immune Estimation Resource (TIMER) 2.0 and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to examine the messenger RNA (mRNA) and the protein expression of CLCN3 across various cancers. The prognostic significance of CLCN3 was evaluated using the Gene Expression Profiling Interactive Analysis 2.0 (GEPIA 2.0) database. The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) facilitated the analysis of CLCN3 promoter methylation levels. The association between CLCN3 expression and tumor-infiltrating immune cells was investigated using various algorithms. The cBioportal database facilitated the analysis of CLCN3 mutations and mutation sites across various cancers. The Tumor-Immune System Interactions Database (TISIDB) database was employed to explore the correlation between CLCN3 expression and immune or molecular subtypes across a variety of cancer types. We collected ovarian tissue samples, encompassing both normal ovarian and OC tissues. The human OC cell lines, SKOV3 cells and OVCAR433 cells, were cultured. CLCN3 expression was determined via reverse-transcription quantitative polymerase chain reaction (RT-qPCR), while phosphatidylinositol 3-kinase/Akt kinase (PI3K/AKT) expression was detected using Western blot. We utilized small interfering RNA (siRNA) technology to suppress CLCN3 expression. The proliferative capacity of SKOV3 and OVCAR433 cells was assessed using the Cell Counting Kit 8 (CCK-8) assay. CLCN3 demonstrated an aberrant expression in a number of cancer types and was markedly reduced in OC tissues. Poor prognosis in cervical squamous cell cancer and myeloid leukemia was linked to excessive expression of CLCN3. The examination of immune cell infiltration, which included CD8+ T cells, B cells, T regulatory cells, and cancer-associated fibroblast cells, showed a strong association with aberrant CLCN3 expression. Following the use of siRNA technology, the ability of the ovarian carcinoma cell line SKOV3 and OVCAR433 to proliferate as well as the expression of PI3K/AKT both increased. CLCN3 is a possible biomarker for immune-related processes and the prognosis of cancer, and the PI3K/AKT signaling pathway may affect OC cells' ability to proliferate.