Preneoplastic Changes Research Articles

Molecular mechanisms underlying the effect of diacerein on trichloroacetic acid-induced hepatic pre-neoplastic lesions in rats.

IL-1β mediates angiogenesis indirectly, as it has been shown to induce hypoxia-inducible factor-1α (HIF-1α) which upregulates VEGF.

Follow the Metaplasia: Characteristics and Oncogenic Implications of Metaplasia's Pattern of Spread Throughout the Stomach.

The human stomach functions as both a digestive and innate immune organ. Its main product, acid, rapidly breaks down ingested products and equally serves as a highly effective microbial filter. The gastric epithelium has evolved mechanisms to appropriately handle the myriad of injurious substances, both exogenous and endogenous, to maintain the epithelial barrier and restore homeostasis. The most significant chronic insult that the stomach must face is Helicobacter pylori (Hp), a stomach-adapted bacterium that can colonize the stomach and induce chronic inflammatory and pre-neoplastic changes. The progression from chronic inflammation to dysplasia relies on the decades-long interplay between this oncobacterium and its gastric host. This review summarizes the functional and molecular regionalization of the stomach at homeostasis and details how chronic inflammation can lead to characteristic alterations in these developmental demarcations, both at the topographic and glandular levels. More importantly, this review illustrates our current understanding of the epithelial mechanisms that underlie the pre-malignant gastric landscape, how Hp adapts to and exploits these changes, and the clinical implications of identifying these changes in order to stratify patients at risk of developing gastric cancer, a leading cause of cancer-related deaths worldwide.

Protective effect of methanol extract of latex of Calotropis procera in an experimental model of colorectal cancer

Ethnopharmacological relevanceThe plant, Calotropis procera, has been used for treating various gastrointestinal disorders and cancer. Some of these medicinal properties have been attributed to the latex produced by the plant. Aim of the studyTo evaluate the efficacy of methanol extract of air-dried latex (MeDL) of C. procera in the rat model of colorectal cancer (CRC). Materials and methodsCRC was induced in the rats by 1,2-dimethylhydrazine (DMH) and the effect of MeDL was evaluated at two doses (50 and 150 mg/kg). MeDL and reference drug aspirin (60 mg/kg) were administered orally starting from 1 h before injecting DMH till 8 weeks after the second dose of DMH. The study also included experimental and normal control groups. Microscopic analysis was carried out to determine the count for aberrant crypt foci (ACF) and histology score whereas enzyme-linked immunosorbent assay and immunohistochemical analyses were performed for markers of carcinogenesis and angiogenesis. Other parameters that were evaluated include deoxyribonucleic acid (DNA) fragmentation, laddering, Bcl2 and Bax immunoreactivity, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity. ResultsSubcutaneous injection of DMH induced pre-neoplastic changes in the colon of rats with the appearance of ACF with multiple crypts (1–3, 4–6 or >6). In the experimental control group, total ACF count was 3.49 ± 0.23/cm of the colon length and the median histology score was 2.0 for architectural abnormalities, 2.0 for dilatation of crypts and 1.5 for hyperplasia/dysplasia against 1.0 for all the characteristics in normal rats. Oral administration of MeDL similar to aspirin, led to a reduction in ACF count and histology score of CRC concomitant with a decrease in the levels of markers of carcinogenesis - β-catenin and proliferating cell nuclear antigen (PCNA); markers of angiogenesis - matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF), and an increase in apoptotic DNA fragmentation. ConclusionMeDL confers protection in the rat model of CRC and the study suggests its therapeutic potential in this condition.

Xantomatosis. Xanthomas of the stomach

The article presents some information about xanthomatosis, as well as about xanthomas of the stomach, which are benign formations, but their etiopathogenesis is unknown. Some believe that there is a relationship between xanthomas of the stomach and hyperlipidymia, diabetes, preneoplastic changes in the mucous membrane, age-related features of the gastric mucosa.The clinical case described in this report confi rms the existing point of view about xanthomas as markers of preneopastic changes in the gastric mucosa and its precancerous diseases.

A Deep Learning Ensemble Method to Assist Cytopathologists in Pap Test Image Classification.

In recent years, deep learning methods have outperformed previous state-of-the-art machine learning techniques for several problems, including image classification. Classifying cells in Pap smear images is very challenging, and it is still of paramount importance for cytopathologists. The Pap test is a cervical cancer prevention test that tracks preneoplastic changes in cervical epithelial cells. Carrying out this exam is important in that early detection. It is directly related to a greater chance of curing or reducing the number of deaths caused by the disease. The analysis of Pap smears is exhaustive and repetitive, as it is performed manually by cytopathologists. Therefore, a tool that assists cytopathologists is needed. This work considers 10 deep convolutional neural networks and proposes an ensemble of the three best architectures to classify cervical cancer upon cell nuclei and reduce the professionals’ workload. The dataset used in the experiments is available in the Center for Recognition and Inspection of Cells (CRIC) Searchable Image Database. Considering the metrics of precision, recall, F1-score, accuracy, and sensitivity, the proposed ensemble improves previous methods shown in the literature for two- and three-class classification. We also introduce the six-class classification outcome.

Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251.

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.

Inflammatory bowel disease induces inflammatory and pre-neoplastic changes in the prostate.

Background:Inflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate.Methods:Using clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability.Results:A higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45+ leukocyte infiltration and elevation of three pro-inflammatory cytokines—TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest.Conclusions:These data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.

Survey on Reporting of Endometrial Biopsies From Women on Progestogen Therapy for Endometrial Atypical Hyperplasia/Endometrioid Carcinoma.

Histologic assessment of response to progestogen therapy is a cornerstone of nonsurgical management of atypical hyperplasia/low-grade endometrioid carcinoma. Pathologists are required to assess whether there is ongoing preneoplastic or neoplastic change in the biopsies (often multiple) taken during therapy. There have been few studies documenting the specific histologic changes induced by therapeutic progestogens and currently there are no guidelines on terminology used in this scenario. Given the need for uniformity in reporting and the lack of guidance in the current literature, we initiated an online survey (including questions, categories of reporting, and scanned slides for assessment) which was sent to all members of British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP) with the aim to assess the variability among pathologists in reporting these specimens and to come up with a consensus-based terminology for reporting of endometrial biopsies from women on progestogen therapy for endometrial atypical hyperplasia/endometrioid carcinoma. In total, 95 pathologists participated in this survey. This manuscript elaborates on the results of the survey with recommendations aimed at promoting uniform terminology in reporting these biopsies.

A Hierarchical Feature-Based Methodology to Perform Cervical Cancer Classification

Prevention of cervical cancer could be performed using Pap smear image analysis. This test screens pre-neoplastic changes in the cervical epithelial cells; accurate screening can reduce deaths caused by the disease. Pap smear test analysis is exhaustive and repetitive work performed visually by a cytopathologist. This article proposes a workload-reducing algorithm for cervical cancer detection based on analysis of cell nuclei features within Pap smear images. We investigate eight traditional machine learning methods to perform a hierarchical classification. We propose a hierarchical classification methodology for computer-aided screening of cell lesions, which can recommend fields of view from the microscopy image based on the nuclei detection of cervical cells. We evaluate the performance of several algorithms against the Herlev and CRIC databases, using a varying number of classes during image classification. Results indicate that the hierarchical classification performed best when using Random Forest as the key classifier, particularly when compared with decision trees, k-NN, and the Ridge methods.

Chronic stress caused by maternal separation is a possible risk factor for the development of 7,12-dimethyl benzo anthracene-induced breast tumors in rats

Background: Chronic stress has been investigated as a risk factor for breast cancer. Maternal separation (MS) of rats has been used as a chronic stress model that alters certain systemic functions, such as the immune response. Objective: The aim of this study was to determine the possible effect of MS on the development of breast tumors induced by 7,12-dimethyl benzo anthracene (DMBA). Methodology: postnatal day (PND) 1 female Wistar rats were divided into four experimental groups that either were or were not subjected to MS and either received or did not receive DMBA. For MS, PND 1 to 21 pups were separated from their mothers for 360 min/day. On PND 30, carcinomas were induced in mammary glands using DMBA. Body weight was evaluated, and the injected region was palpated. In addition, the mammary glands were subjected to histological examination, and corticosterone levels were determined in all groups. Results: DMBA-induced groups had significantly lower body weight gain compared with the non-DMBA-induced groups. Maternal separation increased the incidence of preneoplastic changes and breast carcinogenesis in DMBA-treated animals compared with control animals. Corticosterone levels were increased in both DMBA-induced and MS groups without interaction. Conclusion: MS is a possible risk factor for DMBA-induced preneoplastic changes and breast tumors in rats.

Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver.

Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.

Interleukin-1β Suppresses Gastrin via Primary Cilia and Induces Antral Hyperplasia.

Background & AimsHelicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum.MethodsMouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA.ResultsIFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin.ConclusionsOverexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184

Targeting Obesity-Induced Macrophages during Preneoplastic Growth Promotes Mammary Epithelial Stem/Progenitor Activity, DNA Damage, and Tumor Formation.

Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women. SIGNIFICANCE: Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophage-targeted therapies.

Impact ofhypothyroidism on early preneoplastic changes at the transcriptomic level in mammalian cells

Impact ofhypothyroidism on early preneoplastic changes at the transcriptomic level in mammalian cells

Keratin 36, a specific marker of tongue filiform papillae, is downregulated in squamous cell carcinoma of the mobile tongue.

Human keratin 36 (K36) is a member of the hair keratin family and is a marker of hair cortex differentiation. The human KRT36 gene is located on the long arm of chromosome 17 and belongs to the cluster of structurally unrelated acidic hair keratins. Recently, it has been reported that KRT36 mRNA is specifically expressed in normal tongue epithelium and downregulated in squamous cell carcinomas of the mobile tongue. Furthermore, KRT36 levels have been reported to be downregulated in clinically normal mobile tongue tissue that is adjacent to tumours, suggesting it could be a marker of pre-neoplastic changes. However, the exact role and the potential role of K36 in tongue tumour formation remains unclear. The aim of the present study was to investigate expression of K36 in a series of squamous cell carcinomas of the mobile tongue, normal mobile tongue and a small panel of other human tissues (normal tissue from the appendix, cervix, hair, lip, mamilla, nail, oesophagus, skin, thymus and vagina) and selected cancer tissue (cervical cancer, melanoma and basal cell carcinoma). Affinity purified polyclonal antibodies against K36 were generated and used for immunohistochemical analysis. The results revealed that in the normal tongue, K36 was detected specifically in the filiform papillae of the dorsal surface of the tongue. Additionally, none of the tongue cancer tissue samples were K36-positive. Immunostaining also revealed that K36 was expressed in nail beds, Hassal's corpuscles in the thymus and the hair cortex. However, K36 was not expressed in the squamous epithelia of the skin, cervix and oesophagus, and the squamous cells of cervical carcinomas, basal cell carcinoma or melanoma. The present data indicated that K36 may be inactivated in tumours of the tongue. However, whether this is part of the tumoural process or if it is an effect of the tumour itself remains to be elucidated.

MiR130b from Schlafen4+ MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer

The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter-induced spasmolytic polypeptide-expressing metaplasia (SPEM).ObjectiveTo identify the gene products expressed by Slfn4+-MDSCs...

How to Manage a Patient With Gastric Intestinal Metaplasia: An International Perspective

How to Manage a Patient With Gastric Intestinal Metaplasia: An International Perspective

Non-invasive laboratory markers assessing efficacy of Helicobacter pylori eradication therapy

Effective eradication of Helicobacter pylori infection is an important means to reduce the risk of precancerous changes in the gastric mucosa and prevention of gastric cancer. A search for non-invasive diagnostic tools for Helicobacter pylori infection, evaluation of the effectiveness of eradication remains of high importance.The aim of the study was to assess an informative value of detecting pepsinogen I and II as well as serum antibodies to Helicobacter pylori while assessing an efficacy of treated chronic Helicobacter gastritis and identifying preneoplastic changes in the stomach mucosa. There enrolled 113 male patients with chronic gastritis aged 41 to 76, average age- (56.7±0.7) years. Examination of patients was carried out at admission to the clinic, as well as at 2 and 12 months after administering a standard eradication therapy. It was found that Helicobacter pylori infection was detected in 101 (89.4%) patients. Groups of patients with effective eradication therapy were noted. A time-dependent level of antibodies to Helicobacter pylori, as well as measured concentration of pepsinogen I and II after the onset of eradication treatment were determined. Which were analyzed in connection with the results of histology examination of gastric mucosa biopsy specimens and expression of oncoproteins Ki-67, Bcl-2, c-erbB-2, p16 in the gastric mucosa depending on efficacy of eradication therapy. It is shown that effective eradication therapy was characterized by significantly decreased serum level of IgG antibodies to Helicobacter pylori 2 months after the onset of treatment. Moreover, a significantly decreased pepsinogen II and serum IgG antibodies to Helicobacter pylori during eradication therapy were accompanied by a significant decrease in Ki-67 expression in the gastric epithelium. Decreased concentration of pepsinogen II within the first year after Helicobacter pylori eradication therapy was due to a greater decrease in activity of inflammatory changes in the gastric mucosa than to dynamic changes in gastric atrophy and metaplasia. An inverse relation between the serum level of pepsinogen I and atrophy as well as intestinal metaplasia within the gastric mucosa were found.

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa.

Background & AimsGastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context.MethodsHippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated.ResultsLATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other’s expression. Loss-of-function experiments showed that LATS2 restricts H pylori–induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori–induced preneoplastic changes.ConclusionsH pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host–pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.

Relationship between Oxidative Stress and Physical Activity in Women with Squamous Intraepithelial Lesions in a Cervical Cancer Control Program in the Brazilian Amazon

Human papillomavirus (HPV) infection is recognized as the most common sexually transmitted disease in the world, and there is a consensus on its role in the etiology of preneoplastic epithelial changes in the cervix. Through the process of lipid peroxidation, oxidative stress is found in the course of premalignant and malignant changes. Moreover, the level of physical activity can exert an influence on markers of oxidative stress, lowering the serum levels of these markers. Objective. To determine the relationship between levels of malondialdehyde (MDA) and the level of physical activity in women with squamous intraepithelial lesion (SIL) of the cervix. Methods. A cross-sectional study was conducted with 46 women participating in a cervical cancer control program. The women had been submitted to the cytopathological exam and were divided into two groups: 18 with SIL and 28 controls. MDA concentrations were determined, and the International Physical Activity Questionnaire (IPAQ) was administered on the same day as the gynecological appointment (prior to the Papanicolaou test). Results. The SIL group had higher MDA levels than the control group (mean: 47.63 ± 9.57 vs. 9.32 ± 4.79, respectively) and a lower IPAQ score (median: 713.5 vs. 1875, respectively). A weak correlation was found between the MDA level and IPAQ score (r2 = −0.34, p = 0.018). Conclusion. The women with SIL had higher levels of oxidative stress and were less physically active than the women in the control group. These findings suggest that physical exercise exerts an influence on markers of oxidative stress in the development of intraepithelial squamous lesions.