Functional and therapeutic significant of heat-shock protein 90 (HSP90) in reproductive cancers.

Reproductive cancers, such as ovarian, cervical, and endometrial carcinomas, have a poor prognosis in metastatic stages. Researchers are continuously seeking improved and safer methods to target cancer-related oncoproteins, addressing the limitations of current treatments, including their limited effectiveness, drug resistance, and off-target effects. Recent advancements in understanding the molecular mechanisms involved in the progress of reproductive cancers have provided valuable insights into potential targeted therapies. By engaging with oncoproteins and co-chaperones, heat-shock protein 90 (HSP90) regulates signaling networks and fixes protein folding errors in cancer cells. The potential of HSP90 inhibition as cancer-targeted treatments is underscored by the continuous discovery and testing of novel HSP90-targeted molecules for their antitumor properties in preclinical and clinical settings. Therefore, this study aims to shed light on the mechanism and recent research breakthroughs of HSP90, as well as provide an in-depth review of their therapeutic potential in reproductive cancers.

HLTF/SERPINE1 Axis Plays a Crucial Pro-Oncogenic Role in the Progression from Cervical Precancerous Lesions to Cervical Carcinoma in vitro.

OBJECTIVES: Cervical carcinoma (CC) is prevalent among women worldwide with increasing risk. Finding effective methods for treating CC is of utmost importance. The aim of this study was to investigate the effect of SERPINE1 on the progression of cervical precancerous lesions to CC. DESIGN: This study used transcriptome sequencing and in vitro cell line. Participants/Materials: Cervical precancerous lesions and CC samples and human cervical epithelial immortalized cell line H8, human CC cell lines HeLa, and CaSki were involved in this study. SETTING AND METHODS: Next-generation sequencing was applied to identify 100 differentially expressed genes from cervical precancerous lesions and CC samples. With the application of the Search Tool for the Retrieval of Interacting Genes (STRING) database, we carried out the protein-protein interaction network analysis, thus screening out serine protease inhibitor clade E member 1 (SERPINE1) with significant upregulation in CC cells. The helicase-like transcription factor (HLTF) was predicted as the upstream transcription factor using Human Transcription Factor Database (HumanTFDB). The chromatin immunoprecipitation (ChIP) experiment was conducted to validate the interaction between SERPINE1 and HLTF. The immunohistochemistry was employed to determine the expression of SERPINE1 and HLTF in CC tissues. Following the upregulation or downregulation of SERPINE1 and HLTF, the real-time quantitative reverse transcription polymerase chain reaction was carried out to assess mRNA expression levels of SERPINE1 and HLTF in cells. Cell viability, migration, and invasion were evaluated using MTT assay, cell scratch assay, and Transwell assay, respectively. Western blot analysis was conducted to assess changes in the expression levels of matrix metalloproteinases and proteins related to epithelial-mesenchymal transition (EMT). RESULTS: The ChIP experiment confirmed the interaction between HLTF and SERPINE1. HLTF and SERPINE1 were upregulated in CC tissues and cells, and silencing SERPINE1 inhibited the EMT process and viability, migration, and invasion of CC cells. However, overexpression of SERPINE1 in CC cells showed the opposite trend. Rescue experiments demonstrated that silencing HLTF repressed CC cell viability, migration, and invasion, which could be restored by overexpressing SERPINE1. LIMITATIONS: The effect of the HLTF/SERPINE1 axis on CC malignant progression has not been confirmed by in vivo experiments. CONCLUSION: HLTF transcriptionally activates SERPINE1, promoting the progression from cervical precancerous lesions to CC.

Anti-Cancer Potential of Isoflavone-Enriched Fraction from Traditional Thai Fermented Soybean against Hela Cervical Cancer Cells.

Cervical cancer is a leading cause of gynecological malignancies and cancer-related deaths among women worldwide. This study investigates the anti-cancer activity of Thua Nao, a Thai fermented soybean, against HeLa cervical carcinoma cells, and explores its underlying mechanisms. Our findings reveal that the ethyl acetate fraction of Thua Nao (TN-EA) exhibits strong anti-cancer potential against HeLa cells. High-performance liquid chromatography (HPLC) analysis identified genistein and daidzein as the major isoflavones in TN-EA responsible for its anti-cancer activity. TN-EA and genistein reduced cell proliferation and induced G2/M phase arrest, while daidzein induced G1 arrest. These responses were associated with the downregulation of cell cycle regulators, including Cyclin B1, cycle 25C (Cdc25C), and phosphorylated cyclin-dependent kinase 1 (CDK-1), and the upregulation of the cell cycle inhibitor p21. Moreover, TN-EA and its active isoflavones promoted apoptosis in HeLa cells through the intrinsic pathway, evidenced by increased levels of cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3, loss of mitochondrial membrane potential, and the downregulation of anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), cellular inhibitor of apoptosis proteins 1 (cIAP), and survivin. Additionally, TN-EA and its active isoflavones effectively reduced cell invasion and migration by downregulating extracellular matrix degradation enzymes, including Membrane type 1-matrix metalloproteinase (MT1-MMP), urokinase-type plasminogen activator (uPA), and urokinase-type plasminogen activator receptor (uPAR), and reduced the levels of the mesenchymal marker N-cadherin. At the molecular level, TN-EA suppressed STAT3 activation via the regulation of JNK and Erk1/2 signaling pathways, leading to reduced proliferation and invasion of HeLa cells.

Uncommon Histopathological Subtypes and Variants of Cervical Carcinoma Diagnosed at a Tertiary Care Centre: A Case Series.

Introduction Cervical cancer ranks among the top gynaecological cancers worldwide. It is linked to lower socioeconomic status and high human papillomavirus (HPV) prevalence. This is a series of six cervical carcinoma cases analysed from 2021 to 2023 at our tertiary care centre to identify rare subtypes of cervical carcinoma. We document rare subtypes, which include glassy cell carcinoma, small cell neuroendocrine carcinoma, papillary squamous-transitional variant, basaloid squamous cell carcinoma and serous carcinoma of the uterine cervix. Immunohistochemistry (IHC) was helpful in confirmation of the subtypes and in diagnosing HPV-associated cases. Materials and methods This case series comprises six cases, including rare subtypes and variants of cervical carcinoma histopathologically diagnosed by the Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India, between 2021 and 2023. The demographic profile and patient details were obtained from the hospital information system and archival case files after obtaining informed consent from the patients. The H&E and relevant IHC slides along with histopathology reports of the included cases were analysed and studied. Results This series includes six cases of rare subtypes of cervical carcinoma, comprising glassy cell carcinoma, small cell neuroendocrine carcinoma, papillary squamous-transitional variant, basaloid squamous cell carcinoma (SCC), and serous carcinoma. Each subtype displays distinct clinicopathological features, emphasizing the need for specific diagnostic and treatment approaches, which are crucial in improving patient survival. Conclusion Six rare subtypes and variants of cervical carcinoma have been discussed in this case series, after correlating with histopathology reports and clinical and radiological findings. Understanding the histopathological characteristics of these rarer subtypes is essential for accurate diagnosis and timely intervention. This series highlights the importance of comprehensive screening strategies, early diagnosis and awareness of rarer subtypes and variants of cervical carcinoma among healthcare professionals. These factors can tailor therapeutic options and improve patient outcomes.

High-Dose-Rate Brachytherapy in Cervical and Endometrial Cancer Patients: A Retrospective Study From a Tertiary Cancer Center in the UAE.

Purpose This study evaluates the therapeutic outcomes and practical application of high-dose-rate (HDR) brachytherapy in managing cervical and endometrial cancers at a tertiary hospital in the UAE, focusing on treatment efficacy, safety, and patient-reported outcomes. Methods A retrospective analysis was conducted on 368 female patients treated between January 2008 and January 2022. Data included demographic information, cancer type, histopathology, treatment details, and survival outcomes. Statistical analyses were performed using descriptive and inferential statistics. Results The cohort comprised 275 cervical cancer patients (74.73%) and 93 endometrial cancer patients (25.27%). The majority were non-nationals (79.62%). The mean age was 57 years. Squamous cell carcinoma was the most common histopathological type (63.59%). HDR brachytherapy was administered to 290 patients (79.89%). The 12-month survival probability was significantly higher in the HDR-Brachy group (75%, 95% CI: 60% to 85%) compared to the noHDR-Brachy group (50%, 95% CI: 35% to 65%), with a hazard ratio of 0.953 (p=0.0035). At the last review, 86.68% of patients were alive, and disease progression was observed in 37.88% of patients. Conclusion HDR brachytherapy significantly improves survival outcomes in cervical and endometrial cancer patients. Continued efforts to enhance access and standardize brachytherapy protocols are essential to optimize treatment efficacy and patient outcomes in similar healthcare settings.

Analysis of miR-497/195 cluster identifies new therapeutic targets in cervical cancer.

OBJECTIVE: miR-497/195, located at 17p13.1, is a highly conserved miRNA cluster whose abnormal expression is a key regulator of carcinogenesis. We performed a comprehensive analysis of the miR-497/195 cluster to determine its prognostic utility and role in cervical cancer (CC) using publicly available datasets. RESULTS: In silico analysis and validation revealed that this cluster is downregulated in CC. A total of 60 target genes of miR-497/195 cluster were identified as differentially expressed between normal and CC samples. ShinyGO, STRING, CytoHubba, Timer 2.0, HPA, and HCMBD were used for functional enrichment, PPIN network construction, hub gene identification, immune infiltration correlation, histopathological expression, and determination of the metastatic potential of miR-497/195 cluster and their target genes. PPIN analysis identified CCNE1, CCNE2, ANLN, RACGAP1, KIF23, CHEK1, CDC25A, E2F7, CDK1, and CEP55 as the top 10 hub genes (HGs). Furthermore, the upregulation of RECK, ATD5, and BCL2, downregulation of OSBPL3, RCAN3, and HIST1H3H effected overall survival of CC patients. We identified 6 targets (TFAP2A, CLSPN, RASEF, HIST1H3H, AKT3, and ITPR1) of miR-497/195 cluster to influence metastasis. In addition, 8 druggable genes and 38 potential drugs were also identified. Our study identified miR-497/195 cluster target genes and pathways that could be used for prognostic and therapeutic applications in CC.

Computational insights into CRISP3 downregulation in cervical cancer and its cervical lineages pattern.

Background: Cysteine-rich secretory protein 3 (CRISP3) emerges as a potential biomarker in the study of many cancers, including cervical cancer (CC). This study aimed to analyze the expression pattern of CRISP3 in CC patients and CC cell lineages, following treatment with the epigenetic drugs: trichostatin A (TSA) and 5-aza-2'-deoxycytidine (5-aza). Methods: The differentially expressed genes identified in GSE63514 were used to construct a protein-protein interaction network. CRISP3 was selected for subsequent analyses. We utilized data from the TCGA and GENT2 projects to evaluate the expression profile and clinical behavior of CRISP3. Additionally, we conducted cell culture experiments to analyze the expression profile of CRISP3 in cells. Results: Low levels of CRISP3 were observed in squamous cell carcinoma (SCC) and human papillomavirus (HPV)16+, along with being associated with worse overall survival (OS). MIR-1229-3p was analyzed, and its high expression was associated with worse prognostic outcomes. In CC-derived cell lines, we observed low levels of CRISP3 in SiHa, followed by SW756, C33A, HeLa, and higher levels in CaSki. All cells were treated with TSA, 5-aza, or both. In all cell lines, treatment with TSA resulted in increased transcription of CRISP3. Conclusion: We identified a significant downregulation of CRISP3 in CC, particularly in cases with HPV16 infection and SCC, which was associated with poorer OS. Preliminary findings suggest that epigenetic treatments with TSA and 5-aza may modulate CRISP3 expression, warranting further research to elucidate its regulatory mechanisms and potential as a prognostic biomarker.

Vaginal Ovule Loaded with Bismuth Lipophilic Nanoparticles and Cetylpyridinium Chloride Inhibits Human Cervical Carcinoma and Candida albicans Growth.

Bismuth lipophilic nanoparticles (BisBAL NPs) and cetylpyridinium chloride (CPC) are antineoplastic and antimicrobial in vitro. As a next pre-clinical step, a clinically viable dosage form for vaginal application was developed. Compendial pharmacopeial tests (mass uniformity, disintegration, and compressive mechanics) and inductively coupled plasma optical emission spectroscopy were conducted on in-house developed glycerinated gelatin (60:15 v/w) vaginal ovules containing BisBAL NP-CPC. The antimycotic activity of BisBAL NP-CPC vaginal ovules was analyzed using disk diffusion and cell viability XTT assays. The antitumor properties of BisBAL NP-CPC vaginal ovules were assessed by cell viability MTT tests. BisBAL NP-CPC and drug-free vaginal ovules deposited into ex vivo porcine vaginas disaggregated without signs of adverse cytotoxicity within the timespan of clinical efficacy. BisBAL NP-CPC vaginal ovules demonstrated antifungal efficacy comparable to miconazole: C. albicans growth inhibition haloes in diffusion tests were 23 ± 0.968 mm (n = 3) for BisBAL NP-CPC and 20.35 ± 0.899 mm (n = 3) for miconazole. Likewise, BisBAL NP-CPC vaginal ovules reduced HeLa cell growth by 81%, outperforming the clinical reference of 500 µM 5-fluouracil, which induced a 70% growth inhibition. BisBAL NP-CPC incorporated into glycerinated gelatin vaginal ovules constitute an innovative drug delivery system for topical antimycotic and anti-cervical carcinoma treatments.

Jackfruit Leaf Protein Hydrolysates Obtained by Enzymatic Hydrolysis of Leaf Protein Concentrate with Pepsin and Pancreatin: Molecular Weight, Cytotoxicity, Antiproliferative Activity, and Oxidative Stress.

Jackfruit leaf protein hydrolysates obtained from the enzymatic hydrolysis of leaf protein concentrate with gastrointestinal enzymes have shown good techno-functional properties and high antioxidant capacity. However, molecular weight, antiproliferative activity, cytotoxicity and the ability to reduce reactive oxygen species (ROS) are still unknown. Therefore, this study aimed to evaluate the effect of jackfruit leaf protein hydrolysates obtained by enzymatic hydrolysis with pepsin and pancreatin at different hydrolysis times (30-240 min) on molecular weights, cytotoxicity, antiproliferation of cancer cells, and the reduction of reactive oxygen species in H2O2-induced HaCaT cells. The electrophoretic profile indicated that H-Pep contains peptides with molecular weights between 25 - 20 kDa. Meanwhile, H-Pan is composed of molecular weight products between 25 - 20 kDa and < 20 kDa. H-Pan and H-Pep (125-500 µg/mL) did not show significant cytotoxicity on HaCaT (human keratinocytes) and J774A.1 (murine macrophage cells). Antiproliferative activity was achieved in human cervical, ovarian, and liver cancer cells. H-Pan-240 min (1000 µg/mL) reduced the cell viability of cervical cancer cells by 23% while H-Pan-60 min significantly reduced cell viability of ovarian and liver cancer cells by 14.5 (500 µg/mL) and 17% (1000 µg/mL), respectively (P < 0.05). The protective effect against oxidative stress on H2O2-stressed HaCaT cells was obtained with H-Pep-60 min, which reduced 25% of ROS at 250 µg/mL (P < 0.05). The findings demonstrate the safe use of green biomass as a source of plant protein hydrolysates.

An analysis of the vaginal microbiota and cervicovaginal metabolomics in cervical lesions and cervical carcinoma.

Background: To explore the role of vaginal microbiota and metabolomics in the progression of cervical dysplasia. Methods: The patient group consists of female patients with low-grade, high-grade cervical dysplasia, and cervical cancer. Normal cervix samples from health volunteers were used as controls. The metabolic fingerprints of cervicovaginal lavage were analyzed using liquid chromatography-mass spectrometry, while the vaginal microbiota was examined through 16S rRNA sequencing. Bioinformatic analysis was adopted to investigate the interplay between hosts and microbes. The vaginal metabolic and microbiota profiles of 90 female patients with cervical dysplasia and 10 controls were analyzed to discover the biological characteristics underlying the progression of cervical cancer. Results: We found that Valyl-Glutamate, N, N'-Diacetylbenzidine, and Oxidized glutathione, which were involved in oxidative stress response, were discriminators to distinguish the normal cervix, invasive cervical carcinomas, and CIN3 from others. Cervical carcinoma was characterized by a large variety of vaginal microbes (dominated by non-Lactobacillus communities) compared to the control. These microbes affected amino acid and nucleotide metabolism, producing metabolites with cervical carcinoma and genital inflammation compared to the control group. Conclusions: This study revealed that cervicovaginal metabolic profiles were determined by cervical cancer, vaginal microbiota, and their interplays. ROS metabolism can be used to discriminate normal cervix, CIN3, and invasive cervical carcinoma.

Study on the relationship between Methylation of Neuregulin (NRG) Gene and Cervical Carcinoma.

Objective: To investigate the relationship between the DNA methylation state of NRG1 promoter and its expression changes, and to analyze the clinical significance of its regulatory mechanism of DNA methylation in cervical carcinoma. Methods: This was a retrospective study. One-hundred and twenty patients from the Department of Gynecology of Cangzhou People's Hospital from September 2017 to September 2019 were selected, including 40 cases of cervical SCC, 40 cases of high grade squamous intraepithelial lesions(HSIL) and 40 cases of control cervical tissues. RT-qPCR, immunohistochemistry and DNA methylation-specific PCR(MSP) were used to detect the mRNA and protein expression of NRG1 and DNA methylation status in different tissue types. Results: Immunohistochemical results showed that the positive protein expression rate of NRG1 gene in the SCC group was lower than that in both HSIL and Control groups. RT-qPCR results showed that the mRNA gene of NRG1 gradually decreased in expression with the increase of cervical tissue lesions, with a statistically significant difference. Similarly, it also found that the mRNA expression level of NRG1 in the SCC group was independent of patients' age (p>0.05), but significantly correlated with tumor pathological staging, surgical pathology staging and lymphatic metastasis (p<0.05). Furthermore, methylation-specific PCR results revealed a significantly higher DNA methylation rate of NRG1 gene in the SCC group than in both HSIL and Control groups, with a statistically significant difference. Moreover, the methylation degree of NRG1 gene in SCC tissues was negatively correlated with its mRNA expression (p<0.05). Conclusions: Abnormal DNA hypermethylation of NRG1 gene inhibits the expression of mRNA and protein in the progression of cervical tissue from normal to cancerous state, which is involved in the occurrence and development of cervical carcinoma.

Cervical Tuberculosis Mimicking Tumor Persistence: A Case Report.

Tuberculosis can coexist with malignancy in the same organ, but cancer with TB in the cervix is rare. This is a case of cervical tuberculosis diagnosed in a cervical cancer patient after concurrent chemoradiotherapy and brachytherapy. This is the case of a 38-year-old G2P2 (2002) diagnosed with squamous cell carcinoma, large cell non-keratinizing cervix, Stage IIIB. The patient underwent concurrent chemoradiotherapy and brachytherapy. One month after the last brachytherapy dose, the attending physician noted a nodularity on the anterior lip of the cervix. A cervical punch biopsy was done to rule out tumor persistence. The histopathology revealed chronic granulomatous inflammation with Langhan's type multinucleated giant cells consistent with tuberculous infection. She was diagnosed with cervical tuberculosis, postulated to be from latent TB reactivation, and was given Anti-Koch's medication for six months. After receiving Anti-Koch's treatment, the cervical nodularity was no longer appreciated, and the rest of the cervix was smooth on palpation. Her Pap Test was negative for any intraepithelial lesion and was declared with no evidence of carcinoma. A possible latent TB infection should always be screened in cancer patients from high-burden areas or those with close contact treated for tuberculosis because immunosuppression during cancer treatment can cause the reactivation of tuberculous disease. Cervical tuberculosis complicating cervical malignancy is treatable with Anti-Koch's therapy and has not been shown to affect the course of the carcinoma.

A predictive study of genes related to lactic acid metabolism in cervical carcinoma.

OBJECTIVES: Lactic acid metabolism, a hallmark of carcinogenesis, may play potential roles in cervical carcinoma, assisting the prognosis prediction. MATERIALS AND METHODS: A regression analysis was conducted to identify the ones with the most frequent variation in mutations and CNV changes in lactate metabolism-related (L-related) genes, after which a prognostic nomogram was built based on selected genes and clinical features by machine learning methods. RESULTS: EGLN1, IL1, IL12RB1, ENO1, and 10 other genes had the most frequent changes and prognostic differences in overall survival (OS). The lactated associated risk (LAR) score model can distinguish the patients in OS (p = 0.046, HR = 101.9, 95%CI 1.1-9447.6), and together with clinical features has a higher AUC (AUC = 0.839). Furthermore, CD8+ T, activated CD4+ memory T and resting mast cells were significantly negatively associated with the LAR score. CONCLUSIONS: Lactic acid metabolism is closely related to the prognosis of cervical carcinoma, where the immune microenvironment may play an important role.

A case of metastatic HPV-related cervical small cell neuroendocrine carcinoma with varying cytomorphology found in cytological specimens of a solid organ transplant recipient.

Small cell neuroendocrine carcinoma (NEC) of the cervix is a rare gynecological malignancy, constituting 2%-5% of all such cases. As high-risk Human Papilloma Virus (HR-HPV) infections contribute to 85% of these tumors, small cell NEC poses a significant risk for solid organ transplant recipients, increasing their risk of progressive disease. We present a case of an uterine cervix small cell NEC with metastasis to the bladder and pleural cavities in a 53-year-old woman with a past medical history of kidney transplantation, who presented with abnormal uterine bleeding. The initial liquid preparation (ThinPrep) cytology stained with Papanicolaou (Pap) showed an adenocarcinoma not otherwise specified. At the time of diagnosis, the patient had diffusely metastatic disease. A subsequent uterine cervix biopsy was consistent with a small cell NEC. Despite treatment with chemotherapy, the patient's condition deteriorated, evidenced by a worsening right-sided pleural effusion one-month postdiagnosis. A pleural effusion showed a tumor with glandular features, with immunohistochemistry suggestive of metastatic adenocarcinoma. HR HPV E6/E7 RNA in situ hybridization (ISH) was positive. Bladder washing showed cytopathologic findings consistent with bladder involvement by small cell carcinoma. The patient's lesions in both urine and pleural fluids showed distinct cytomorphology. Within a year of diagnosis, the patient was declared deceased. This case highlights the existence of carcinoma admixed with NEC tumor, such as an HPV associated adenocarcinoma admixed with a NEC and underscores the elevated risk of HPV-related genital lesions in renal transplant patients. In patients with a history of solid organ transplant or other immunosuppressive conditions, there is an increased necessity for enhanced surveillance and appropriate cancer screening.

A novel prognostic signature based on cancer stemness and metabolism-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma.

BACKGROUND: CESC is the second most commonly diagnosed gynecological malignancy. Given the pivotal involvement of metabolism-related genes (MRGs) in the etiology of multiple tumors, our investigation aims to devise a prognostic risk signature rooted in cancer stemness and metabolism. METHODS: The stemness index based on mRNA expression (mRNAsi) of samples from the TCGA dataset was computed using the One-class logistic regression (OCLR) algorithm. Furthermore, potential metabolism-related genes related to mRNAsi were identified through weighted gene co-expression network analysis (WGCNA). We construct a stemness-related metabolic gene signature through shrinkage estimation and univariate analysis, thereby calculating the corresponding risk scores. Moreover, we selected corresponding DEGs between groups with high- and low-risk score and conducted routine bioinformatic analyses. Furthermore, we validated the expression of four hub genes at the protein level through immunohistochemistry (IHC) in samples obtained from our patient cohort. RESULTS: According to the findings, it was found that six genes-AKR1B10, GNA15, ALDH1B1, PLOD2, LPCAT1, and GPX8- were differentially expressed in both TCGA-CSEC and GEO datasets among 23 differentially expressed metabolism-related genes (DEMRGs). mRNAsi exhibited a notable association with the extent of key oncogene mutation. The results showed that the AUC values for forecasting survival at 1, 3, and 5 years are 0.715, 0.689, and 0.748, individually. We observed a notable association between the risk score and different immune cell populations, along with enrichment in crucial signaling pathways in CESC. Four genes differentially expressed between different risk score groups were validated by IHC to be highly expressed in the CESC samples at the protein level. CONCLUSION: The current investigation indicated that a 3-gene signature based on stemness-related metabolic and 4 hub genes with differential expression between high and low-risk score subgroups may serve as valuable prognostic markers and potential therapeutic targets in CESC.

Case Report: Low-Risk HPV associated Verruco-Papillary squamous cell carcinoma of the cervix.

•Cervical cancer plays a large role in morbidity and mortality for gynecologic cancer.•Most cases are involved with high-risk HPV, rare cases of low-risk HPV associated cancer exists.•Low risk HPV associated cervical cancers have increased difficulty in diagnosis.•No distinction exists in treatment between low and high risk HPV associated cervical cancer.

Double-layer hollow mesoporous silica nanoparticles for ultrasound-guided photodynamic treatment.

Cervical carcinoma persists as a major global public health burden. While conventional therapeutic modalities inevitably cause ablation of adjacent non-tumorous tissues, photodynamic therapy (PDT) offers a targeted cytotoxic strategy through a photosensitizing agent (PS). However, the hydrophobicity and lack of selective accumulation of promising PS compounds such as zinc(II) phthalocyanine (ZnPc) impedes their clinical translation as standalone agents. The present study sought to incorporate ZnPc within double-layer hollow mesoporous silica nanoparticles (DHMSN) as nanocarriers to enhance aqueous dispersibility and tumor specificity. Owing to their compartmentalized design, the hollow mesoporous silica nanoparticles (HMSN) demonstrated enhanced ultrasonic imaging contrast. Combined with the vaporization of the perfluorocarbon perfluoropentane (PFP), the HMSN-encapsulated ZnPc enabled real-time ultrasound monitoring of PDT treatment.In vivo, the innate thermal energy induced vaporization of the DHMSN-carried PFP to significantly amplify ultrasound signals from the tumor site. Results demonstrated biocompatibility, efficient PFP microbubble generation, and robust photocatalytic activity. Collectively, this investigation establishes ultrasound-guided PDT utilizing multi-layer HMSN as a targeted therapeutic strategy for cervical malignancies with mitigated toxicity.

DBD-FISH Using Specific Chromosomal Region Probes for the Study of Cervical Carcinoma Progression.

Genomic instability is an important biomarker in the progression of cervical carcinoma. DBD-FISH (DNA breakage detection-fluorescence in situ hybridization) is a sensitive method that detects strand breaks, alkali-labile sites, and incomplete DNA excision repair in cells of the cervical epithelium. This technique integrates the microgel immersion of cells from a vaginal lesion scraping and the DNA unwinding treatment with the capacity of FISH integrated into digital image analysis. Cells captured within an agarose matrix are lysed and submerged in an alkaline unwinding solution that generates single-stranded DNA motifs at the ends of internal DNA strand breaks. After neutralization, the microgel is dehydrated and the cells are incubated with DNA-labeled probes. The quantity of a hybridized probe at a target sequence corresponds to the measure of the single-stranded DNA produced during the unwinding step, which is equivalent to the degree of local DNA breakage. DNA damage does not show uniformly throughout the entire DNA of a cell; rather, it is confined to specific chromosomal sites. In this chapter, an overview of the technique is supplied, focusing on its ability for assessing the association between DNA damage in specific sequences and in the progressive stages of cervical carcinoma.

Metachronous Squamous Cell Carcinomas of the Uterine Cervix and Lung: True Metachrony or Metastasis.

Human papillomaviruses (HPV) are a big group of infection agents with oncogenic potential, especially regarding squamous epithelium. Some high-risk variants are key in the development of squamous cell carcinomas (SCC) across multiple systems, the most affected of which is the female reproductive system, but also parts of the gastrointestinal tract, head, and neck SCC, and cutaneous and pulmonary (bronchogenic) SCCs. In cases where a patient develops two SCCs in different systems, often the main question is whether these tumors are synchronous, metachronous, or if one of the tumors is a metastasis from the other, with HPV testing and stereotype identification often being of aid in differentiating between these. Herein, we report the case of a female patient in her 50s, initially diagnosed with SCC of the uterine cervix. The patient remained stable for three calendar years after completing preoperative radiotherapy, surgical resection, and postoperative chemo-radiotherapy. At that point, she developed respiratory symptoms, and radiography suggested a pulmonary malignancy. After undergoing surgical resection of the pulmonary lesion, histological specimens were initially interpreted to be a metachronous pulmonary SCC. Immunohistochemical testing proved that both the cervical and pulmonary lesions were HPV-associated, with further testing proving that both lesions were associated with high-risk HPV (genotype 16). Based on the clinical history and aggregated data, the pulmonary lesion was interpreted as a metastatic and not a metachronous one, and the patient is currently undergoing treatment for metastatic disease.

Human serum albumin-bound paclitaxel nanoparticle inhibits cervical carcinoma cell proliferation and oxidative damage through CYP3A4 and CYP2C8.

Background: Cervical cancer (CC) is currently the most common malignant tumour in the female reproductive tract, and paclitaxel (PTX) is a commonly used chemotherapeutic agent, but tumour cell resistance will seriously affect the therapeutic efficacy of PTX. Nanoparticle human serum albumin-bound paclitaxel (Nano-HSA-PTX) is a novel drug delivery modality that may have superior effects to PTX alone. Objective: To clarify the effect of Nano-HSA-PTX on cervical carcinoma (CC) cells and the underlying mechanisms. Methods: After the preparation of Nano-HSA-PTX, its morphology was observed by electron transmission microscope (TEM), and its entrapment efficiency (EE%) and drug loading rate (DL%) were detected. Nano-HSA-PTX was compared with conventional PTX for drug metabolism. Additionally, CC HeLa and SiHa cells were purchased and divided into three groups to treat with Nano-HSA-PTX, PTX and normal saline, respectively. MTT, cell cloning, Transwell and cell scratch assays were carried out to determine cell proliferation, invasion and migration, flow cytometry and Western blotting were performed to detect apoptosis rate and apoptosis-related protein expression, and PCR was conducted to quantify oxidative damage indicators. Further, CYP3A4 and CYP2C8 expression patterns in CC cells (HeLa and SiHa) and human normal cervical epithelia (End1/E6E7) and the changes of their levels under the intervention of Nano-HSA-PTX were measured. Subsequently, C57BL/6mice were purchased for subcutaneous tumorigenesis experiment to observe the impact of Nano-HSA-PTX on tumor growth. Results: Under TEM, Nano-HSA-PTX was complete and arranged compactly, with a stable structure and markedly higher EE% and DL% than PTX (P < 0.05). Under Nano-HSA-PTX intervention, the proliferation, invasion, migration and oxidative damage of HeLa and SiHa were significantly decreased compared with the control and PTX groups, while the apoptosis was increased (P < 0.05). Besides, elevated CYP3A4 and CYP2C8 levels were observed in CC cells, which were inhibited by Nano-HSA-PTX and PTX (P < 0.05). Finally, tumorigenesis experiments in nude mice revealed that Nano-HSA-PTX could inhibit tumor growth. Conclusion: Compared with PTX, Nano-HSA-PTX has a superior effect of inhibiting CC activity. And this mechanism of action was carried out by inhibiting the expression of CYP3A4 and CYP2C8.