The mass spectrometry-based molecular profiling can be used for better differentiation between normal and cancer tissues and for the detection of neoplastic transformation, which is of great importance for diagnostics of a pathology, prognosis of its evolution trend, and development of a treatment strategy. The aim of the present study is the evaluation of tissue classification approaches based on various data sets derived from the molecular profile of the organic solvent extracts of a tissue. A set of possibilities are considered for the orthogonal projections to latent structures discriminant analysis: all mass spectrometric peaks over 300 counts threshold, subset of peaks selected by ranking with support vector machine algorithm, peaks selected by random forest algorithm, peaks with the statistically significant difference of the intensity determined by the Mann-Whitney U test, peaks identified as lipids, and both identified and significantly different peaks. The best predictive potential is obtained for OPLS-DA model built on nonpolar glycerolipids (Q 2 = 0.64, area under curve [AUC] = 0.95); the second one is OPLS-DA model with lipid peaks selected by random forest algorithm (Q 2 = 0.58, AUC = 0.87). Moreover, models based on particular molecular classes are more preferable from biological point of view, resulting in new explanatory mechanisms of pathophysiology and providing a pathway analysis. Another promising features for OPLS-DA modeling are phosphatidylethanolamines (Q 2 = 0.48, AUC = 0.86). Journal of MASS SPECTROMETRY 4 | CONCLUSION ESI-MS shotgun lipidomics of a tissue takes about 25 minutes including sample preparation. It is somewhat faster than the common cervical cancer identification methods such as histology and can give significantly more information. Thus, it has a potential for precise and personalized characterization of cancer as a supplement for histological examination. Influence of pre-analytical experimental data processing on the classification model predictive potential is analyzed.The OPLS-DA model based on nonpolar glycerolipids demonstrated the best predictive power. These data sets together with ethanolamines are the most promising for tissue classification among the data bearing essential biochemical information.
Cervicovaginal fluid (CVF) is a valuable source of clinical information about the female reproductive tract in both nonpregnant and pregnant women. The aim of this study is to specify the CVF proteome at different stages of cervix neoplastic transformation by label-free quantitation approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The proteome composition of CVF from 40 women of reproductive age with human papillomavirus (HPV)-associated cervix neoplastic transformation (low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], and CANCER) was investigated. Hierarchical clustering and principal component analysis (PCA) of the proteomic data obtained by a label-free quantitation approach show the distribution of the sample set between four major clusters (no intraepithelial lesion or malignancy [NILM], LSIL, HSIL and CANCER) depending on the form of cervical lesion. Multisample ANOVA with subsequentWelch's t test resulted in 117 that changed significantly across the four clinical stages, including 27 proteins significantly changed in cervical cancer. Some of them were indicated as promising biomarkers previously (ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B). CVF proteomic data from the discovery stage were analyzed by the partial least squares-discriminant analysis (PLS-DA) method to build a statistical model, allowing to differentiate severe dysplasia (HSIL and CANCER) from the mild/normal stage (NILM and LSIL), and receiver operating characteristic (ROC) area under the curve (AUC) were obtained on an independent set of 33 samples. The sensitivity of the model was 77%, and the specificity was 94%; AUC was equal to 0.87. CVF proteome proved to be reflect the stage of cervical epithelium neoplastic process.
The role of human papillomavirus (HPV) in the development of cervical cancer and other diseases of the anogenital area has been proven and well known. Despite this, the incidence of cervical cancer is growing every year. Specific methods of HPV treatment are not developed, and the only effective method of cervical cancer prevention is to prevent infection itself. A number of randomized clinical trials have demonstrated extremely high (up to 100%) effectiveness of HPV vaccines. Currently, the HPV vaccine is approved by WHO and included in the National Immunization Program of 86 countries, 17 counties use gender-neutral program. In the clinical practice of Australia, USA and countries of the European Union, in particular Italy, Germany and France, high efficiency of vaccination for 10 or more years is reported.
A dramatic increase in cervical diseases associated with human papillomaviruses (HPV) in women of reproductive age has been observed over the past decades. An accurate differential diagnosis of the severity of сervical intraepithelial neoplasia and the choice of the optimal treatment requires the search for effective biomarkers with high diagnostic and prognostic value. The objective of this study was to introduce a method for rapid shotgun lipidomics to differentiate stages of HPV-associated cervix epithelium transformation. Tissue samples from 110 HPV-positive women with cervicitis (n = 30), low-grade squamous intraepithelial lesions (LSIL) (n = 30), high-grade squamous intraepithelial lesions (HSIL) (n = 30), and cervical cancers (n = 20) were obtained. The cervical epithelial tissue lipidome at different stages of cervix neoplastic transformation was studied by a shotgun label-free approach. It is based on electrospray ionization mass spectrometry (ESI-MS) data of a tissue extract. Lipidomic data were processed by the orthogonal projections to latent structures discriminant analysis (OPLS-DA) to build statistical models, differentiating stages of cervix transformation. Significant differences in the lipid profile between the lesion and surrounding tissues were revealed in chronic cervicitis, LSIL, HSIL, and cervical cancer. The lipids specific for HPV-induced cervical transformation mainly belong to glycerophospholipids: phosphatidylcholines, and phosphatidylethanolamines. The developed diagnostic OPLS-DA models were based on 23 marker lipids. More than 90% of these marker lipids positively correlated with the degree of cervix transformation. The algorithm was developed for the management of patients with HPV-associated diseases of the cervix, based on the panel of 23 lipids as a result. ESI-MS analysis of a lipid extract by direct injection through a loop, takes about 25 min (including preparation of the lipid extract), which is significantly less than the time required for the HPV test (several hours for hybrid capture and about an hour for PCR). This makes lipid mass spectrometric analysis a promising method for express diagnostics of HPV-associated neoplastic diseases of the cervix.
Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. академика В.И. Кулакова; 117997, Россия, Москва, ул. Академика Опарина, д. 4 Резюме Среди гинекологических заболеваний у женщин репродуктивного возраста ведущее место занимают воспалительные заболевания нижнего отдела генитального тракта (70%), значительную долю которых составляют воспалительные процессы влагалища и шейки матки. У ⅔ женщин цервицит чаще всего протекает бессимптомно, поэтому они не обращаются за лечением, а у 65-77,6% отмечается переход в хроническую форму. Так, хронический цервицит диагностируется почти у каждой третьей женщины, обращающейся за помощью к гинекологу в связи с лейкореей, тенденции к снижению частоты заболевания не отмечается. В статье представлен актуальный взгляд на проблему воспалительных заболеваний нижнего отдела полового тракта. Проведен анализ ряда исследований, посвященных влиянию локального иммунитета и состояния микрофлоры влагалища на развитие хронических воспалительных заболеваний. Представлены результаты протеомных исследований цервиковагинальной жидкости в ранней диагностике воспалительных заболеваний нижнего отдела полового тракта и возможность использования цитокиновых биомаркеров в клинической практике с целью прогнозирования патологического состояния и выбора дальнейшей тактики лечения пациентки. Рассмотрена эффективность использования комбинированного препарата на основе хлоргексидина и декспантенола, обладающего выраженным противомикробным, регенерирующим и метаболическим действием и применяемым в терапии острых и хронических вагинитов; бактериального вагиноза; эндо-, экзоцервицитов, что является актуальным в терапии воспалительных заболеваний нижнего отдела генитального тракта.Ключевые слова: вагинит, цервицит, хлоргексидин, декспантенол, лейкорея Для цитирования: Назарова Н.М., Некрасова М.Е., Довлетханова Э.Р., Абакарова П.Р. Вагиниты и цервициты: выбор эффективного метода терапии (обзор литературы). Медицинский совет. 2020;(3):17-23. AbstractAmong gynaecological diseases in women of reproductive age the leading place is occupied by inflammatory diseases of the lower part of the genital tract (70%), a significant proportion of which are inflammatory processes of the vagina and cervix uteri. In ⅔ of women, cervicitis is most often asymptomatic, so they do not seek medical treatment, and 65-77.6% have a transition to a chronic form. Thus, chronic cervicitis is diagnosed in almost one in three women who seek assistance from a gynaecologist due to leukorrhea, and there is no tendency for a decrease in frequency. The article presents an actual view on the problem of inflammatory diseases of the lower genital tract. The analysis of some researches devoted to the influence of local immunity and the state of vaginal microflora on the development of chronic inflammatory diseases is carried out. The results of proteomic researches of cervicovaginal fluid in early diagnostics of inflammatory diseases of the lower genital tract and the possibility of using cytokine biomarkers i...
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