| 1. |
- Castro Wersäll, Ofra, et al.
(författare)
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Dietary Habits and Daily Routines as Prognostic Factors in Endometrial Cancer : A Machine Learning Approach
- 2023
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Ingår i: Nutrition and Cancer. - : Routledge. - 0163-5581 .- 1532-7914. ; 75:1, s. 310-319
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer (EC) is becoming more common worldwide, primarily due to an increase in life expectancy and obesity. As several modifiable factors may affect EC incidence and progression, we aimed to elucidate how dietary habits and daily routines influence recurrence and survival among women with EC, using a Random Survival Forest (RSF) approach. 481 women who previously underwent hysterectomy due to EC completed two extensive questionnaires on dietary habits and daily routines, and we used RSF to identify risky or protective variables. Among the 186 variables considered, consumption of sugar-sweetened beverages and fried potatoes increased the risk of EC recurrence and death, while physical activity decreased the risk of death. We conclude that RSF is a suitable approach to study survival in multivariable datasets.
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| 2. |
- Govorov, Igor, et al.
(författare)
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Blood inflammatory and endothelial markers in women with von Willebrand disease
- 2019
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls.Materials and methods: The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI.Results: Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle.Conclusions: Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia—common complication of VWF deficiency. The latter statement requires confirmation in larger studies.
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| 3. |
- Govorov, Igor, et al.
(författare)
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STK4 protein expression pattern follows different trends in endometrioid and serous endometrial adenocarcinoma upon tumor progression
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study, we showed that serine/threonine-protein kinase 4 (STK4) is involved in the control on proliferation and migration of endometrial cancer (EC) cells in vitro. In the present paper, we studied STK4 expression in EC tissues from a large cohort of patients to determine whether STK4 can serve as a marker for the aggressiveness and prognosis of EC. Tissue samples from patients with EC were examined for tumor type, grade, and stage. The STK4 protein expression in EC cells was assessed by immunohistochemistry and related to clinicopathological data of patients, such as progression and patient survival rate. The STK4 mRNA levels and its relation to the survival rate were analyzed also in publicly available databases. The STK4 gene expression was low at both, the mRNA and protein levels in EC, especially in serous tumors. Comparison of STK4 expression with the patient survival rate shows that the higher expression is associated with worse prognosis in serous EC, while no such dependence was found in endometrioid EC. Hence, the determination of the SKT4 expression pattern could be used as a putative prognostic marker for serous EC.
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| 4. |
- Govorov, Igor, et al.
(författare)
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Upregulation of PKN1 as a Prognosis Biomarker for Endometrial Cancer
- 2022
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Ingår i: Cancer Control. - : Sage Publications. - 1073-2748 .- 1526-2359. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several markers of survival among endometrial cancer (EC) patients have been proposed, namely, the oncoprotein stathmin, RAF kinase inhibitor (RKIP), Cyclin A, GATA-binding protein 3 (GATA3), and growth and differentiation factor-15 (GDF-15). Their elevated expression correlated significantly with a high stage, serous papillary/clear cell subtypes, and aneuploidy. In a previous study, we reported the elevated expression of the serine/threonine protein kinase N1 (PKN1) in cancerous cells. In the present paper, we studied PKN1 expression in EC tissues from a large cohort of patients, to determine whether PKN1 can serve as a marker for the aggressiveness and prognosis of EC, and/or as a marker of survival among EC patients.METHODS: Tissue samples from EC patients were examined retrospectively for tumor type, tumor size, FIGO stage and grade, depth of invasion in the myometrium, and presence of lymph node metastasis. The PKN1 protein expression in EC cells was assessed by immunohistochemistry. PKN1 mRNA levels were analyzed in publicly available databases, using bioinformatic tools.RESULTS: We found that expression of PKN1 at the mRNA and proteins levels tended to increase in high-grade EC samples (P = .0001 and P = .06, respectively). In addition, patients with metastatic disease had higher PKN1 mRNA levels (P = .02). Moreover, patients with high PKN1 expression could be characterized by poorer survival.CONCLUSIONS: We have shown a trend of the higher PKN1 expression levels in EC patients with poor prognosis. Therefore, PKN1 might be considered as a candidate prognostic marker for EC.
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| 5. |
- Govorov, Igor
(författare)
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von Willebrand disease in women : heavy menstrual bleeding and obstetrical bleeding
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Von Willebrand disease is the most common inherited bleeding disorder worldwide with a prevalence, reaching 1% of general population. vWD is equally distributed between genders. However, vWD-affected females experience specific hemostatic challenges during menstruation and childbirth. Despite intensive research within the field, there are still many unsolved issues, related to the fundamental mechanisms of the increased bleeding tendency. This thesis was divided into clinical part (Study I and Study II) and fundamental part (Study III and Study IV). The former has explored current management options for vWD-patients, suffering from excessive menstrual bleeding and postpartum hemorrhage (PPH), respectively. Fundamental part aimed to enhance our understanding of the dynamics of hemostasis contributing to excessive menstrual bleeding in women with VWD. Study I explored the prevalence of heavy menstrual bleeding (HMB) among vWD affected females, its impact on everyday life activities and overall health-related quality of life. Information was obtained using self-administered forms and medical records. Of the 30 women (18-52 years) included in the study, a half (50%) suffered from HMB. This occurred despite the fact, that the majority of women received treatment for HMB. Almost all women had limitations in their everyday life activities, caused by HMB. The overall health-related quality of life was lower with regards to ‘bodily pain’ in women with HMB, compared to general Swedish population. Close interaction between hematologists and gynecologists is necessary in order to prevent limitations and improve quality of life in women with vWD. Study II investigated the incidence of PPH in women with vWD, its correlation with i) type of vWD ii) levels of vWF and FVIII iii) treatment options. 34 women (59 deliveries) occurred in 14 different clinics (years 1995-2012) were included in the study. The incidence of primary PPH, severe primary PPH and secondary PPH was 44%, 20% and 12%, respectively, which is greater than in general population. Women with type 3 vWD was at greater risk of experiencing severe primary PPH, compared to other types. Another risk factors were instrumental assisted delivery and undiagnosed vWD at the time of delivery. FVIII levels during late pregnancy was inversely correlated to blood loss during delivery. Therefore, in order to decrease morbidity, we should identify women with yet unknown vWD more actively, probably through providing them with the validated self-administered blood questionnaires in the antenatal settings. Once being diagnosed, vWD require comprehended approach, so that PPH could be prevented. Study III assessed the changes in hemostatic variables in women with vWD during a regular menstrual cycle and compared them with healthy controls. 12 vWD affected females (NOT pregnant/breastfeeding/on hormonal treatment) were compared with 102 healthy controls, matched for age and BMI. In women with vWD, thrombin generation profiles were altered, with prolonged lag-time, time to peak and decreased peak thrombin concentration, compared to controls. AT was also higher in the study group, which may potentially contribute to the excessive bleeding in this cohort. Within the vWD group, FVIII and FX were significantly lower during the luteal phase, than in follicular phase. The decrease in procoagulant agents prior to menstruation may predispose women with vWD to the development of HMB. Therefore, altered thrombin generation dynamics, together with increased AT and decline in FVIII and FX prior to menstruation, can potentially play role in the excessive blood loss during menstruation in women with vWD. Study IV explored how do inflammatory and endothelial markers change during the menstrual cycle in women with vWD. 12 vWD affected females (NOT pregnant/breastfeeding) were compared with 102 healthy controls, matched for age and BMI. Within the study group (vWD), endostatin levels were higher during the follicular phase, than in luteal phase. Since endostatin inhibits angiogenesis and coagulation, its rise during early follicular phase (which corresponds to menstrual phase of the uterine cycle) may affect the hemostasis within the uterine cavity and therefore contribute to the development of HMB. Women with vWD were different from healthy controls in terms of balance between pro- and anti-angiogenic markers, with sICAM-1 and IL-6 being higher in women with vWD, compared to controls, while sVCAM-1, cathepsin S and sPselectin were lower. The pattern was constant across the menstrual cycle. Hypothetically, this imbalance could lead to the formation of angiodysplasia - common complication of vWD. The above statement, however, requires verification in larger well-designed studies. In conclusion; this thesis reports, that the current approaches are still insufficient in terms of preventing common vWD complications - HMB and PPH. It emphasizes the importance of early diagnosis, providing to the patients the reliable information on drugs, proactive management and close collaboration between hematologists and ob&gyn specialists. Furthermore, the thesis provides additional knowledge on how do coagulation and inflammatory systems change in response to the sex steroids fluctuations during the menstrual cycle. It reaffirms intimate interactions between coagulation and inflammatory systems. Our work suggests, that multiple factors with versatile effects, rather than simple decrease in vWF, are responsible for the development of HMB in women with vWD.
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| 6. |
- Razumova, Zoia, et al.
(författare)
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Cadmium intake as a prognostic factor in endometrial cancer : a Swedish cohort-based study
- 2022
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Ingår i: Nutrition and Cancer. - Stockholm : Karolinska Institutet, Dept of Women's and Children's Health. - 0163-5581 .- 1532-7914.
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Tidskriftsartikel (refereegranskat)abstract
- Metalloendocrinology is a new interdisciplinary field, which was established due to the importance of connections between inorganic chemicals and hormonal mechanisms. The role of cadmium in hormone-related tumors is an excellent example of this connection, as cadmium mimics estrogen in the human body. Since endometrial cancer (EC) is hormonerelated, it is well-suited for assessing the estrogenic effects of cadmium. Therefore, the present study aims to explore the role of dietary cadmium intake in the progression-free survival (PFS) and overall survival (OS) in women with EC. Dietary cadmium intake was estimated based on a large cohort of Swedish women (n ¼ 416) with EC. Median dietary cadmium intake was then analyzed in relation to different tumor characteristics and clinical outcomes. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Median daily dietary cadmium intake in the cohort was 13.1 lg (interquartile range 25%-75%¼6.4). High dietary cadmium intake (lg/day) was associated with significantly decreased OS in the study cohort (HR ¼ 0.956, 95% CI ¼ 0.914- 1.001, p ¼ 0.05). Dietary cadmium intake was not associated with PFS (HR ¼ 0.975, 95% CI ¼ 0.924-1.028, p ¼ 0.348). Therefore, our results indicate that high dietary cadmium intake could be associated with poor outcome in women with EC.
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| 7. |
- Razumova, Zoia, et al.
(författare)
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The Prognostic Role of LRIG Proteins in Endometrial Cancer
- 2021
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Ingår i: Cancers. - Stockholm : MDPI. - 2072-6694. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women’s and Children’s Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression-free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1-, LRIG2- and LRIG3-positive cells. A statistically significant association was observed between having a high number of LRIG3-positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958–0.996, p = 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09–0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.
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| 8. |
- Wersäll, Ofra Castro, et al.
(författare)
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PGC1α and VDAC1 expression in endometrial cancer
- 2021
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Ingår i: Molecular and clinical oncology. - : Spandidos Publications. - 2049-9450 .- 2049-9469. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer (EC) is one of the ten most common gynecological cancers. As in most cancers, EC tumour progression involves alterations in cellular metabolism and can be associated with, for instance, altered levels of glycolytic enzymes. Mitochondrial functions and proteins are known to serve key roles in tumour metabolism and progression. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α) is a major regulator of mitochondrial biogenesis and function, albeit of varying prognostic value in different cancers. The voltage-dependent anion channel type 1 (VDAC1) regulates apoptosis as well as metabolite import and export over the mitochondrial outer membrane, and is often used for comparative quantification of mitochondrial content. Using immunohistochemistry, the present study examined protein expression levels of PGC1α and VDAC1 in tumour and paired benign tissue samples from 148 patients with EC, in order to examine associations with clinical data, such as stage and grade, Ki-67, p53 status, clinical resistance and overall survival. The expression levels of both PGC1α and VDAC1, as well as a PGC1α downstream effector, were significantly lower in tumor tissues than in benign tissues, suggesting altered mitochondrial function in EC. However, Kaplan-Meier, log rank and Spearman's rank correlation tests revealed that their expression was not correlated with survival and clinical data. Therefore, PGC1α and VDAC1 are not of major prognostic value in EC.
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| 9. |
- Wersäll, Ofra Castro, et al.
(författare)
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Which dietary and everyday life habits affect endometrial cancer recurrence? The machine gives the answer
- 2020
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 30:Suppl. 4, s. A32-A33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Background: The increased life expectancy and westernization of the lifestyle are considered the major contributors to a sustainable rise in endometrial cancer (EC) rates. The factors predicting EC recurrence include patient age and tumour characteristics, such as type, differentiation, and depth of invasion. At the same time, recent studies testify the impact of meal and exercises on the course of various diseases. What are the food preferences and activities that could influence the ultimate risk of EC relapse and death?Methodology: The study included 481 women who previously underwent a hysterectomy due to EC at Karolinska University Hospital. The participants filled an extensive questionnaire on their dietary habits and everyday routines. Related clinical data was obtained through the National e-health system. It resulted in a large dataset with more than 180 variables, which was processed using the Random Survival Forest (RSF) approach. The latter is applied to a right-censored data and uses a collection of decision trees to rank the variables by their importance for the occurrence of an event. The top-ranked variables were further investigated with the Cox proportional hazards model. Analyzes were performed using the RandomForestSRC package for Python.Results: The consumption of the fried potatoes significantly increased the risk of EC relapse and death [HR=8.62 (2.22–33.56), p=0.002; HR=6.00 (1.06–34.01), p=0.043, respectively), the latter persisted after adjustment for body mass index, age and smoking status. Besides, each additional serving of sweetened soda drinks increased the risk of death [3.262 (1.834–5.800), p=0.0001]. In contrast, physical activity was beneficial with each additional Metabolic Equivalent per day decreasing the risk of death by 7.3% [HR=0.927 (0.892–0.964), p< 0.0001).Conclusion: We hypothesise that the fried potatoes’ detrimental effect may be related to the acrylamide, which is formed in starch-rich foods under high-temperature conditions. It acts as a carcinogen and endocrine disruptor, causing the endometrial hyperplasia and EC in animal studies. Sweetened beverages cause a rise in insulin, which in turn inhibits sex-hormone binding protein. This results in higher levels of circulating free oestrogens. Also, insulin has mitogenic and anti-apoptotic properties, further inducing the endometrium proliferation. The favorable influence of regular physical activity on EC relapse and death is in accordance with previous studies, including recent meta-analysis.Therefore, we encourage women treated for EC to consider reducing sweetened beverages and fried potatoes consumption and increasing physical activity.
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