Development Of Cervical Carcinoma Research Articles

Frequent Inactivation of Secreted Frizzled-Related Protein 2 during the Development of Cervical Carcinoma: Identification of Susceptible Alleles and Clinical Implications

ABSTRACT Background: In this study, importance of SFRP2, wnt stem cell renewal pathway antagonist, in the development of cervical cancer (CACX) was evaluated Aims and Objectives: Alterations (expression/ methylation/ deletion) of SFRP2 were analysed in primary cervical lesions of different clinical stages followed by their correlation with different clinicopathological parameters. Then, susceptible allele(s) of SFRP2 was identified through case control study followed by and in vitro validation. Results: The mRNA expression of SFRP2 was gradually reduced with progression of CACX. In immunohistochemistry, SFRP2 membrane expression was mainly present in the spinous layers of normal cervical epithelium and its reduced protein expression in CACX samples showed concordance with mRNA expression. Frequent deletion/ methylation of SFRP2 were seen to be associated with development of cervical cancer. Methylation of SFRP2 was prevalently associated with early invasive lesions (stage I/II) while, deletion with late invasive lesions (stage III/IV). Overall alterations (deletion/ methylation) of SFRP2 were significantly increased from premalignant CIN to stage-I/II samples followed by comparable change to the next stage (stage III/IV) samples. Moreover, deletion and/or methylation of SFRP2 were associated with poor prognosis of the patients. In a case control study, out of its seven microsatellite alleles infrequent SFRP_CA15/16 alleles along with frequent SFRP_CA17 allelewere found to be associated with CACX development. Comparatively reduced expression (mRNA/ protein) of SFRP2 was seen in the tumor adjacent normal cervical epithelium having SFRP_CA15/16 alleles than the other alleles. This has been further validated in in vitro luciferase promoter activity assay where SFRP_CA16 repeat showed high reduced activity followed by SFRP_CA15 repeat than the other repeats. Conclusion: Thus, our data showed that presence of the infrequent susceptible alleles along with deletion/methylation might have synergistic effect on frequent inactivation of SFRP2 during development of CACX.

Constructed competitive endogenous RNA network and patterns of immune infiltration revealing the prognostic signature for cervical cancer.

Aim: To investigate the relationship between potential abnormal epigenetic modification and immune cell infiltration in patients with cervical carcinoma. Materials & methods: RNA expression profiles from The Cancer Genome Atlas database were used to explore the relationship between key biomarkers and tumor-infiltrating immune cells and for clinical specimen validation. Results: Two nomogram models were developed, one with specific ceRNA and the other based on biological markers of related tumor-infiltrating immune cells. Moreover, a key biomarker (RIPOR2), which was significantly relevant to CD8 T cells. Conclusion: RIPOR2 and CD8T cells play a crucial role in the development and progression of cervical carcinoma, suggesting their potential as markers for guiding future therapeutic strategies.

The relationship between the expression of Stathmin and tumor immune cell infiltration in primary cervical carcinoma and its prognostic diagnostic value

To analyse the relationship between the Stathmin expression and the tumor immune cell infiltration in primary cervical carcinoma (CC), and its prognostic diagnostic value. Cervical tissue samples from 128 patients admitted to our hospital from February 2021 to February 2022 who underwent hysterectomy or cervical biopsy were selected as the observation objects, and then divided into control group (normal cervical tissue specimen, n = 30), cervical intraepithelial neoplasia (CIN) group (CIN neoplasia cervical tissue specimen, n = 30), and cervical cancer group (cervical tissue specimen of cervical cancer lesion, n = 68) according to pathological results. The expression of Stathmin was detected by Immunohistochemistry (IHC). The numbers of infiltrated neutrophils (TINs) were measured by the specific esterase staining. The pathological data of CC patients were collected, and the protein expression of Stathmin was compared with different pathological data. According to the protein expression of Stathmin, the samples were divided into Stathmin positive group and negative group. The infiltration numbers, the levels of CD3+T, CD4+T and CD8+T of TINs were compared in each group, and CD4+/CD8+ were calculated. Kaplan-Meier survival curve was used for the analysis of the relationship between the Stathmin expression and the clinical prognosis in CC. COX analysis was used to determine the factors affecting the prognosis of patients with CC. The proportion of positive expression of cervical tissue Stathmin in CIN group and cervical cancer group was significantly higher than that in the control group, and the proportion of positive expression of cervical tissue Stathmin in cervical cancer group was significantly higher than that in CIN group (P < 0.001). The ratio of the clinical stage II + III, tissue grade low and medium differentiation, and lymph node metastasis in Stathmin positive group was significantly higher than that in the Stathmin negative group (P < 0.05). Compared with the Stathmin negative group, the numbers of TINs infiltration and the level of CD4+/CD8+ were visibly higher, and the content of CD3+T, CD4+T and CD8+T were sharply lower in the Stathmin positive group (P < 0.001). Compared with the Stathmin negative group, the numbers of TINs infiltration were higher, but the content of CD4+T and CD8+T were lower in Stathmin-positive group (P < 0.001). The 68 CC patients were followed up, with a median follow-up time of 25 months (5–60 months) and an overall survival rate of 66.18 % (45/68). The results of Kaplan-Meier survival curve showed that the median survival time of patients with the Stathmin positive expression was 30 months, which was significantly lower than that of 46 months (P < 0.05) in patients with the Stathmin negative expression. Multivariate analysis of COX proportional regression risk model showed that the Stathmin positive expression, TINs infiltration numbers≥55, CD3+<5.5 %, CD4+<4.5 %, CD8+<3 %, CD4+/CD8+≥1.3 were independent factors affecting the prognosis of CC patients (P < 0.05). Stathmin in the primary tissue of CC had a significantly high expression state, which was involved in the occurrence and development of CC, thus affecting the immune microenvironment balance damaged by tumor immune cell infiltration. Detecting its expression level might help the diagnosis and prognosis assessment of CC, and Stathmin might become a new target of CC immunotherapy.

To Estimate the Levels of Serum Vitamins A, E, And C in Cervical Cancer Patients

Background&#x0D; Cervical cancer continues to be a leading cause of cancer-related mortality among women in developing nations, including India. Worldwide, cervical cancer is the third most frequent malignancy among women. In comparison to urban regions, cervical cancer is more common in rural communities. This investigation find the impact of vitamins (A, E, and C) on cervical cancer severity in SGT Hospital patients was the goal of this study.&#x0D; Aim and Objectives&#x0D; &#x0D; To determine the levels of serum vitamin A,C and E in cervical cancer patients and healthy controls&#x0D; To compare the serum level of vitamin A,C and E in patients with cervical cancer and healthy control&#x0D; &#x0D; Materials and Methods&#x0D; This study is conducted in Department of Biochemistry in collaboration with Department of Pathology, and Department of Gynaecology at SGT Hospital, Budhera, Gurugram's Faculty of Medicine and Health Sciences, this is hospital-based cross-sectional case control study. Subjects are 50 healthy volunteers who are age-matched from the general population as the control group. A signed and informed permission is obtained from each individual in both groups once they have been fully informed of the study's objectives. Before beginning the sample collection, institutional ethical committee approval is soughted. Samples are centrifuged at 3000 rpm for 10 minutes; the serum is separated from the clot in the plain tube. The plasma obtained after centrifuging the blood in the lithium heparin tube at 3000 rpm is decanted. Vitamins A and E is examined on zaivik by HPLC method and Vitamin C is examined by ELISA method&#x0D; Results&#x0D; Patients with cervical cancer had a significantly lower level of a parameter, such as serum vitamin A, C and E when compare with controls. Our study shows that serum vitamin A levels in the patients were 30.2 ±4.0 mcg/dl and 54.7 ±10.6 mcg/dl, respectively, with a p value of &lt;0.05 which are lower when compared with controls. Vitamin E levels were also decreased in study group (4.5±1.5 mcg/dl ) than controls (11.9±2.7 mcg/dl ) having p value &lt;0.05. Vitamin C levels in cases (1.83±0.3) mcg/dl were considerably lower than those in control groups 9.8±2.5 mcg/dl having p value &lt;0.05.&#x0D; Conclusion: Our results imply that lower antioxidant vitamin levels may contribute to the aetiology and development of cervical carcinoma, even if the precise mechanisms through which oxidative stress might cause cancer are still unclear.

RET/PTC rearrangement in papillary thyroid carcinoma arising in malignant struma ovarii with abdominal wall metastasis and cervical thyroid gland: a case report and review of the literature

BackgroundStruma ovarii refers to rare mature cystic teratomas containing at least 50% of thyroid tissue, and malignant transformation is known to be even rarer. The synchronous development of malignant struma ovarii and cervical thyroid carcinoma are also scarce and poorly understood due to limited data about molecular features. Here, we present the first report of RET/PTC 1 rearrangement in synchronous metastatic malignant struma ovarii to the abdominal wall and cervical thyroid cancer.Case presentationWe described a 47-year-old multigravida woman with bilateral adnexal and lower abdominal wall masses detected during the evaluation of abnormal uterine bleeding. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, and surgical removal of abdominal wall mass. Then, the pathological evaluation revealed papillary thyroid carcinoma (PTC) within struma ovarii and metastatic PTC in the abdominal wall fibro adipose tissue. Further, cervical thyroid gland physical examination and ultrasound illustrated a nodule within the left lobe. Subsequently, a total thyroidectomy was performed, and a histological examination revealed PTC. Furthermore, all affected tissue, i.e., struma ovarii, abdominal wall metastasis, and cervical thyroid gland tested for BRAF and RAS mutations and RET/PTC 1 rearrangement. RET/PTC 1 rearrangement was identified among all three different sites. Finally, after six years of follow-up, the patient had no evidence of recurrence or distant metastasis.ConclusionsIn light of these findings, malignant struma ovarii might yield a clue to cervical thyroid carcinoma, and the molecular analysis could provide valuable information for understanding the underlying mechanism, tumor clinicopathological behaviors, and prognosis.

Differential association of hedgehog pathway in development of cervical carcinoma and its chemo-tolerance

Cervical carcinoma (CACX) is still a dreadful threat to women in developing countries. Available conventional chemo-radiation therapies are not sufficient to restrict the disease recurrence. To unravel the mechanism of the disease recurrence, alteration of hedgehog self-renewal pathway was evaluated during development of CACX and in chemo-tolerance of the tumor. We have analyzed the alterations (expression/methylation/deletion) of some key regulatory genes (HHIP/SUFU/SHH/ SMO/GLI1) of hedgehog self-renewal pathway in cervical lesions at different clinical stages and compared with different datasets, followed by their clinico-pathological correlations. The changes in expression/methylation of the genes were then evaluated in two CACX cell lines (SiHa/HeLa) after treatment with chemotherapeutic drug cisplatin at different concentrations. Down regulation (mRNA/protein) of the antagonists HHIP and SUFU due to promoter methylation and/or deletion along with upregulation (protein) of agonists SHH, SMO and GLI1 was seen in early invasive lesions and subsequent clinical stages. Reduced protein expression of HHIP and SUFU showed significant association with high/intermediate expression of agonists SHH, SMO, GLI1 in the tumors and also poor prognosis of the patients. It was evident that cisplatin could restrict the growth of HeLa and SiHa cells through significant upregulation of antagonists HHIP and SUFU due to their promoter hypomethylation and down regulation of SHH in a concentration dependent manner without any significant changes in expression of SMO and GLI1, leading to the tumor cells in a dormant state. Thus, interplay of the agonists and antagonists has important role in activation of hedgehog pathway during development of CACX, whereas inactivation of the pathway due to upregulation of the antagonists is an important phenomenon in chemo-tolerance of the tumor. This suggests importance of epigenetic modification in chemo-resistance of CACX.

Expression and Significance of MTA2 and CPNE1 in Cervical Squamous Cell Carcinoma.

The aim of this study was to investigate the expression and clinical significance of MTA2 and CPNE1 proteins in cervical squamous cell carcinoma. In this study, high-risk human papillomavirus (HPV) typing was performed on cervical cancer tissues. Reverse transcription polymerase chain reaction and immunochemical EliVision method were used to examine the expressions of MTA2 and CPNE1 in the cervix, and their relationship with clinicopathologic features. We found that it is mainly distributed in these types, namely HPV-16 (23.8%), HPV-18 (20.9%), HPV-53 (17.1%), HPV-52 (15.5%), HPV-82 (11.7%), HPV-56 (10.8%). The expressions of MTA2 and CPNE1 in cervical squamous cell carcinoma tissues were significantly higher than those in normal tissues ( P <0.01). The expressions of MTA2 and CPNE1 were correlated with FIGO stage, degree of differentiation, and lymph node metastasis of cervical cancer ( P <0.05), but not with the patient's age ( P >0.05). The rank correlation coefficient of MTA2 and CPNE1 protein expression in cervical squamous cell carcinoma was 0.668 ( P <0.01), and the 2 expressions were positively correlated. MTA2 and CPNE1 are closely related to the occurrence and development of cervical squamous cell carcinoma and may play a synergistic role in the evolution of cervical squamous cell carcinoma.

Correlation and clinical significance of VISTA expression and cervical squamous cell carcinoma

Objective: To explore the relationship between the expression of the T-cell activation suppressor-immunoglobulin variable region (VISTA) and the development of cervical squamous cell carcinoma (CSCC), and the impact on the prognosis of CSCC patients. Methods: Cervical tissue samples from 116 CSCC, including 23 cervical intraepithelial neoplasia (CIN) grade I, 23 CIN grade Ⅱ-Ⅲ, and 23 chronic cervicitis patients, were collected from the First Hospital of Soochow University between March 2014 and April 2019. The expression of VISTA in each group was detected by immunohistochemistry (IHC). Survival data of CSCC patients were obtained by follow-up. The survival analysis was performed by Kaplan-Meier method, and survival differences between groups were compared by Log rank test. Prognostic impact factors were analyzed using a multifactorial Cox proportional hazards model. Results: The positive rate of VISTA expression in CSCC group was 32.8% (38/116), and which of grade Ⅱ-Ⅲ was 17.4% (4/23). VISTA expression results showed no positive expression patients in the cervical intraepithelial neoplasia grade I and chronic cervicitis groups. The differences between the CSCC group and other groups were statistically significant (P<0.01). In 116 CSCC patients, VISTA expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis (P<0.01). The mean survival time of patients in the VISTA positive expression group was 30.7 months, and the 3-year survival rate was 44.7% (17/38). However, the mean survival time of the patients in the VISTA negative expression group was 49.1 months, and the 3-year survival rate was 87.2% (68/78). The Cox regression model found that VISTA expression positivity (P=0.001) and FIGO stage (P=0.047) were prognostic factors for CSCC, and patients with VISTA-positive CSCC had a 4.130-fold risk of death higher than those with VISTA-negative expression. Conclusions: The VISTA protein is highly expressed in CSCC tissues, and its expression level is closely related to the occurrence and development of CSCC. The expression of VISTA can be used as an independent predictor of CSCC prognosis and can provide a strong basis for the treatment of CSCC with immune checkpoint inhibitors.

MiR-15a nanometric compound restrains the activity and adhesion of Hela cells through survivin signal pathway

We herein studied the mechanism of miR-15a nanometer compound (NMC) by assessing its activity and adhesion in Hela cells through survivin signal pathway. The miR-15a nanometer compound was prepared and Hela-S3 cells were divided into miR-15a group, miR-NC group and NC group for in vitro studies. Proliferative activity was detected with MTT method while invasive ability was detected with Transwell closet method. Adhesive capacity was compared and Survivin and Caspase-3 protein expressions were detected with Western blot assay. Results showed that, grain size of miR-15a NMC was reduced along with increased N/P value, and Zeta potential was negative, and was converted into positive charge along with increased N/P value. The particle size distribution was uniform and potential was moderated when the N/P value was twenty. The proliferation ability and invasive capacity in miR-15a group was reduced significantly along with lower A540 value and higher adhesive ability as well as reduced survivin and increased Caspase-3 level. The proliferative, invasive and adhesive capacity of Hela cells were all restrained by the miR-15a NMC, and apoptosis was prompted through restraining of the survivin signaling pathway, so as to affect the occurrence and development of cervical carcinoma.

Prognostic Value and Immune Infiltration of HPV-Related Genes in the Immune Microenvironment of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma

Mounting evidence has highlighted the immune environment as a critical feature in the development of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the relationship between the clinical characteristics of the immune environment and CESC remain unclear. Therefore, the aim of this study was to further characterize the relationship between the tumor and immune microenvironment and the clinical features of CESC using a variety of bioinformatic methods. Expression profiles (303 CESCs and three control samples) and relevant clinical data were obtained from The Cancer Genome Atlas. We divided CESC cases into different subtypes and performed a differential gene expression analysis. In addition, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed to identify potential molecular mechanisms. Furthermore, data from 115 CESC patients from East Hospital were used to help identify the relationship between the protein expressions of key genes and disease-free survival using tissue microarray technology. Cases of CESC (n = 303) were divided into five subtypes (C1-C5) based on their expression profiles. A total of 69 cross-validated differentially expressed immune-related genes were identified. Subtype C4 demonstrated a downregulation of the immune profile, lower tumor immune/stroma scores, and worse prognosis. In contrast, the C1 subtype showed an upregulation of the immune profile, higher tumor immune/stroma scores, and better prognosis. A GO analysis suggested that changes in CESC were primarily enriched nuclear division, chromatin binding, and condensed chromosomes. In addition, GSEA demonstrated that cellular senescence, the p53 signaling pathway, and viral carcinogenesis are critical features of CESC. Moreover, high FOXO3 and low IGF-1 protein expression were closely correlated with decreased clinical prognosis. In summary, our findings provide novel insight into the relationship between the immune microenvironment and CESC. As such, our results may provide guidance for developing potential immunotherapeutic targets and biomarkers for CESC.

Bacterial Infections and Cancer: Exploring This Association And Its Implications for Cancer Patients

Bacterial infections are common in the etiology of human diseases owing to the ubiquity of bacteria. Such infections promote the development of periodontal disease, bacterial pneumonia, typhoid, acute gastroenteritis, and diarrhea in susceptible hosts. These diseases may be resolved using antibiotics/antimicrobial therapy in some hosts. However, other hosts may be unable to eliminate the bacteria, allowing them to persist for long durations and significantly increasing the carrier's risk of developing cancer over time. Indeed, infectious pathogens are modifiable cancer risk factors, and through this comprehensive review, we highlight the complex relationship between bacterial infections and the development of several cancer types. For this review, searches were performed on the PubMed, Embase, and Web of Science databases encompassing the entirety of 2022. Based on our investigation, we found several critical associations, of which some are causative: Porphyromonas gingivalis and Fusobacterium nucleatum are associated with periodontal disease, Salmonella spp., Clostridium perfringens, Escherichia coli, Campylobacter spp., and Shigella are associated with gastroenteritis. Helicobacter pylori infection is implicated in the etiology of gastric cancer, and persistent Chlamydia infections present a risk factor for the development of cervical carcinoma, especially in patients with the human papillomavirus (HPV) coinfection. Salmonella typhi infections are linked with gallbladder cancer, and Chlamydia pneumoniae infection is implicated in lung cancer, etc. This knowledge helps identify the adaptation strategies used by bacteria to evade antibiotic/antimicrobial therapy. The article also sheds light on the role of antibiotics in cancer treatment, the consequences of their use, and strategies for limiting antibiotic resistance. Finally, the dual role of bacteria in cancer development as well as in cancer therapy is briefly discussed, as this is an area that may help to facilitate the development of novel microbe-based therapeutics as a means of securing improved outcomes.

Mechanistic analysis of endothelial lipase G promotion of the occurrence and development of cervical carcinoma by activating the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signalling pathway

Lipase G, endothelial type (LIPG) is expressed abundantly in tissues with a high metabolic rate and vascularisation. Research on LIPG has focussed on metabolic syndromes. However, the role of LIPG in providing lipid precursors suggests that it might function in the metabolism of carcinoma cells. Analysis in The Cancer Genome Atlas indicated that patients with cervical carcinoma with high LIPG expression had a lower survival prognosis compared with patients with low LIPG expression. The mechanism underlying the effects of LIPG in cervical carcinoma is unclear. The present study aimed to determine the role of LIPG in cervical carcinoma and its mechanism. The results showed that the LIPG expression level was higher in cervical cancer. Downregulation of LIPG expression inhibited cell migration, invasion, proliferation, and the formation of cell colonies, but increased the rate of apoptosis. The Human papillomavirus E6 protein might reduce the expression of miR-148a-3p, relieve the inhibitory effect of miR-148a-3p on LIPG expression, and promote the progression of cervical cancer through the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signalling pathway. IMPACT STATEMENT What is already known on this subject? LIPG provides lipid precursors, suggesting that it might function in the metabolism of carcinoma cells What do the results of this study add? LIPG might be regulated by HPV16 E6/miR-148a-3p and promote cervical carcinoma progression via the PI3K/AKT/mTOR signalling pathway. What are the implications of these finding for clinical practice and/or further research? The results indicated that novel treatment and diagnosis strategies for cervical carcinoma could be developed related to LIPG. However, the detailed relationship between LIPG and cervical carcinoma remains to be fully determined.

Silencing DTX3L Inhibits the Progression of Cervical Carcinoma by Regulating PI3K/AKT/mTOR Signaling Pathway.

Cervical carcinoma (CC) is the second most prevalent gynecologic cancer in females across the world. To obtain a better understanding of the mechanisms underlying the development of CC, high-resolution label-free mass spectrometry was performed on CC and adjacent normal tissues from eight patients. A total of 2631 proteins were identified, and 46 significant differently expressed proteins (DEPs) were found between CC and normal tissues (p < 0.01, fold change >10 or <0.1). Ingenuity pathway analysis revealed that the majority of the proteins were involved in the regulation of eIF4 and p70S6K signaling and mTOR signaling. Among 46 DEPs, Integrinβ6 (ITGB6), PPP1CB, TMPO, PTGES3 (P23) and DTX3L were significantly upregulated, while Desmin (DES) was significantly downregulated in CC tissues compared with the adjacent normal tissues. In in vivo and in vitro experiments, DTX3L knockdown suppressed CC cell proliferation, migration, invasion and xenograft tumorigenesis, and enhanced cell apoptosis. Combination of silencing DTX3L and cisplatin treatment induced higher apoptosis percentage compared to cisplatin treatment alone. Moreover, DTX3L silencing inhibited the PI3K/AKT/mTOR signal pathway. Thus, our results suggested DTX3L could regulate CC progression through the PI3K/AKT/mTOR signal pathway and is potentially a novel biomarker and therapeutic target for CC.

Britannin Induces Autophagy-Dependent Apoptosis via the Reactive Oxygen Species/Adenosine 5′-monophosphate-Activated Protein Kinase-unc-51-Like Autophagy Activating Kinase 1 Axis in Cervical Cancer as Detected Using Nanomagnetic Beads

Cervical cancer is a unique and common malignancy that occurs in women. Britannin has been proven to inhibit the progression of human liver and breast cancers. However, its efficacy in cervical cancer is still unclear. Human cervical squamous cell carcinoma SiHa cells were used to analyze the effect of britannin administration on cervical tumors by xenotransplantation of human tumor cells. The Cell Counting Kit-8 was used to determine the half maximal inhibitory concentration (IC50) of britannin on SiHa, and the cell invasion ability was measured using Transwell invasion assay. Cell migration was measured using the scratch-healing assay, while the clonogenic assay was performed to determine cell proliferation. Dichloro-dihydro-fluorescein diacetate was used to label reactive oxygen species (ROS) in cells or tissues. Intracellular autophages were stained with monodansylcadaverine. Western blotting assisted by nanomagnetic beads was performed to study the expression of p62, light chain 3 beta (LC3B), Beclin 1, and autophagy-related protein 5 (ATG5) in cells or tissues, as well as the phosphorylation of AMP-activated protein kinase (AMPK) and unc-51-like autophagy activating kinase 1 (ULK1). Hematoxylin and eosin staining was performed to analyze the pathological changes in the tumor cells. The expression of Ki-67, B-cell lymphoma 2 (Bcl-2), and Bax in the tumor cells was analyzed by immunohistochemistry. The IC50 obtained for britannin against SiHa was 10.01 μM. Britannin inhibited the proliferation, invasion, and migration of SiHa cells, and promoted the generation and autophagy of ROS in tumor cells and tissues. Furthermore, p-AMPK/AMPK and p-ULK1/ULK1, LC3B, Beclin 1, and ATG5 were upregulated, whereas p62 was downregulated in cells and tissues. Tumor development was inhibited; tissue inflammation was reduced; Ki-67 and Bcl-2 expression was downregulated; and Bax expression was upregulated. The expression of cleaved caspase-3, cleaved poly-ADP-ribose polymerases, and voltage-dependent anion-selective channel 1 was upregulated. These effects can be partially reversed by the AMPK inhibitor dorsomorphin dihydrochloride (BML-275). In vivo and in vitro studies showed that britannin upregulated the of ROS content of human cervical squamous cell carcinoma cells, leading to significant autophagy, thereby inhibiting the occurrence and development of cervical squamous cell carcinoma. The mechanism may be related to the ROS/AMPK/ULK1 signaling pathway.

Determination of Risk Factors Associated with the Development of Cervical Cancer in Mirpur, AJK

Background: Cervical cancer is an important public health issue. Numerous factors are associated with the development of cervical cancer. Aim: To understand various contributory and risk factors associated with the development of cervical cancer in our area. Study design: Descriptive cross-sectional study. Duration and place of study: Mohi-ud-Din Islamic Medical College, Mirpur AJK from October 2021 to March 2022. Methods: Volunteering women were included in the study. A pre-tested questionnaire was used to collect data. The proforma included demographic and epidemiological information as well as about the various risk factors which were associated with the development of cervical carcinoma. A detailed medical history was taken and special emphasis was placed on the gynecological history including obstetrical and menstrual history as well as sexual and reproductive history together with contraception usage. Results: There were 753 study participants and their mean age was 56.80±10.51years. The mean age of first sexual intercourse was 17±2.80 years and the average number of pregnancies was two. About 14.61% of our study population was smoker. Hormonal contraception was practiced by 64.01% while 11.29% preferred intra-uterine contraceptive device as a mode of contraception. The prevalence of sexually transmitted diseases was 10.49% and out of these diseases, condylomatosis accounted for 05.84% of cases while syphilis and human immunodeficiency virus were responsible for 04.78% of cases collectively. Conclusion: There are various risk factors associated with the development of cervical cancer. Most important of them are younger age at marriage or sexual activity, use and duration of contraception usage and smoking. There is a need to arrange awareness campaigns among masses to raise awareness about the risk factors and also about the benefits of early screening so as to prevent the development of cervical cancer. Keywords: Human Papilloma Virus, Risk Factors, Cervical Cancer, Women, Contraception, Screening

The polymethoxylated flavone hexamethylquercetagetin suppresses NF-κB signaling and inhibits cell survival in cervical carcinoma

Nuclear factor-κB (NF-κB) contributes to the development and progression of cervical carcinoma. To construct a xenograft model, Ca Ski cells were subcutaneously inoculated into BALB/c nude mice. The relative protein expression of NF-κB p65, p-p65, IκBα, and p-IκBα were detected in hexamethylquercetagetin (HTQC) treated cervical carcinoma cells with or without tumor necrosis factor (TNF)α stimulation, or representative tumors tissues in xenograft mice. HTQC could prohibit NF-κB-derived luciferase activity in Ca Ski and C-33 A cells and inhibit the relative NF-κB p-p65 and p-IκBα expression with or without TNFα stimulation. At the same time, HTQC inhibited in vitro cell survival in a concentration-dependent manner and suppressed the tumor volume and weight in xenograft models. In summary, HTQC functions as an NF-κB inhibitor to prohibit the survival and proliferation of cervical carcinoma, which can be considered as an NF-κB target remedy in future clinical practice.

Frequency of Abnormal Pap Smear Cytology in Women with Post-Coital Bleeding

Risk of development of cervical carcinoma has been identified in patients with abnormal cytology on Pap smear. A long duration of prior to development of invasive cervical carcinoma is governed by a precancerous lesion. Consequently, screening and proper treatment reduces the overall risk of cervical carcinoma. Objective: Aim of study was to identify the frequency of abnormal cervical cytology detected by Papanicolaou smear in married child bearing female presenting with bleeding following coitus. Methods: A Descriptive, Cross-sectional study was carried from 15th November 2021 to 31st May 2022 in the Department of Obstetrics and Gynecology, Jinnah Post graduate Medical Centre, Karachi. A total of 218 females of reproductive age group (18-50 years) presenting with post-coital bleeding were included. Patients with previously histo pathological diagnosis, ablative or excisional treatment modalities of cervix and trauma to genital tract were excluded. All cases underwent Pap smear testing with standard technique by utilization of Ayre's spatula and were fixated with 95% ethanol on microscopic slides. Two specimens were prepared for each patient and were assessed for abnormalities. Results: Patients encountered were between 18 to 50 years with mean of 32.20 ± 7.80 years. Majority (139; 67.43%) of the patients were between 18 to 35 years. Mean parity was 3.53 ± 1.51. Mean BMI was 29.12 ± 2.37 kg/m2. Frequency of abnormal cervical cytology was found in 37 (16.97%). Conclusions: This study concluded that Pap smear is an easy, effective and a cheap method for detecting women with cervical pathology.

Lymphocyte Subsets in Cervicovaginal Lavage Specimens of HIV-Infected Women: A Surrogate Risk Marker of HPV-Associated Cervical Lesions

Introduction: To better understand the role of mucosa immunity in the development of cervical carcinoma in HIV infection, cervical lymphocyte subsets were characterized in HIV+ and HIV− women, as well as their relation to HPV-associated cervical lesions. Methods: Eighty-three (52 HIV+, 31 HIV−) cell suspensions of cervicovaginal lavage (CVL) and 52 HIV+ peripheral blood (PB) samples were assessed by flow cytometry to evaluate lymphoid populations. High-risk (HR) HPV was assessed in liquid-based cytology and HIV mRNA in PB in the same patients. Results: Cervical CD4⁺ T cells and CD4⁺/CD8⁺ ratio were decreased (p < 0.0001) and cervical CD8⁺ T cells were increased (p = 0.0080) in HIV+ women. These patients had lower CD4⁺ T-cell percentages in CVL compared to PB (p = 0.0257), and the opposite was true for CD8⁺ T cells (p = 0.0104). They also had a higher prevalence of high-grade squamous intraepithelial lesions (SILs) with an increased prevalence of HR HPV. Cervical CD8⁺ T cells were increased in HR HPV+ patients (p = 0.0300) and related to higher prevalence of SILs (p = 0.0001). Discussion/Conclusion: Cervical lymphoid populations can be characterized by flow cytometry, showing a distinct cervical T-cell compartment in HIV+ women. This may represent a surrogate risk marker of HPV-associated cervical lesions in this population and prompt further research on this subject, contributing to improving patients’ management.

Identifying anal and cervical tumorigenesis-associated methylation signaling with machine learning methods.

Cervical and anal carcinoma are neoplastic diseases with various intraepithelial neoplasia stages. The underlying mechanisms for cancer initiation and progression have not been fully revealed. DNA methylation has been shown to be aberrantly regulated during tumorigenesis in anal and cervical carcinoma, revealing the important roles of DNA methylation signaling as a biomarker to distinguish cancer stages in clinics. In this research, several machine learning methods were used to analyze the methylation profiles on anal and cervical carcinoma samples, which were divided into three classes representing various stages of tumor progression. Advanced feature selection methods, including Boruta, LASSO, LightGBM, and MCFS, were used to select methylation features that are highly correlated with cancer progression. Some methylation probes including cg01550828 and its corresponding gene RNF168 have been reported to be associated with human papilloma virus-related anal cancer. As for biomarkers for cervical carcinoma, cg27012396 and its functional gene HDAC4 were confirmed to regulate the glycolysis and survival of hypoxic tumor cells in cervical carcinoma. Furthermore, we developed effective classifiers for identifying various tumor stages and derived classification rules that reflect the quantitative impact of methylation on tumorigenesis. The current study identified methylation signals associated with the development of cervical and anal carcinoma at qualitative and quantitative levels using advanced machine learning methods.

WDR5 drives the development of cervical squamous cell carcinoma by inducing epithelial-mesenchymal transition and cancer-associated fibroblasts formation

BackgroundWD repeat domain 5 (WDR5) has been indicated to be involved in tumor progression, however, its role in cervical cancer (CC) has not been investigated yet. MethodsA total of 350 pairs of CC tissues and para-carcinoma tissues (PCT) were collected. Primary human cervical epithelial cells (hCECs) and cancer-associated fibroblasts (CAFs) were isolated from cervical cancer tissues. MM102 was used to block the interaction between WDR5 and mixed lineage leukemia protein-1 (MLL1), and it was used in vivo to investigate its therapeutic value. ResultsWDR5 was up-regulated in cervical squamous cell carcinoma (CSCC) tissues compared to that in PCT. C-X-C motif chemokine ligand 8 (CXCL8) was indicated to be the target gene of WDR5. Highly expressed CXCL8 promoted epithelial-mesenchymal transition (EMT) to form CAFs, and enhanced the cytokine secretions in CAFs to promote CSCC progression. CXCL8 expression was regulated by the interaction between WDR5 and MLL1, and blocking the interaction between these two proteins using MM102 significantly suppressed tumor growth in mice models. ConclusionsWDR5 plays a key role in CSCC progression by inducing CXCL8 expression and promoting the transformation of CAFs from epithelial cells.