P–624 Doxorubicin exposure detrimentally effects establishment of early ovarian reserve, ex-vivo mouse model

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Ozcan ◽  
M Woodman ◽  
J Chaqour ◽  
K Grive
Keyword(s):  
Mouse Model ◽  
Ovarian Reserve ◽  
Ex Vivo ◽  
Reproductive Age ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Phenotypic Change ◽  
Power Calculation ◽  
Treatment Level ◽  
Oocyte Number ◽  
The Impact

Abstract Study question Does exposure to chemotherapy agents used to treat cancer during pregnancy cause significant decrease in early establishment of the ovarian reserve? Summary answer Significant oocyte loss is noted following exposure of early mouse ovaries to doxorubicin. This apoptotic decline is not seen with cisplatin, docetaxel or paclitaxel exposure. What is known already Chemotherapy has been shown to adversely affect the ovarian reserve of pre-pubertal and reproductive age females. However, little is known regarding the effects in the next generation following treatment in pregnancy beyond observational population studies that examined rates of birth defects and developmental delays. Reproductive function in offspring develops over time and would be difficult to quantify in these short-term studies. An ex-vivo mouse ovary culture offers the ability to closely mimic maternal treatment level serum concentrations and directly evaluate the impact on oocyte number and cell death markers. Study design, size, duration In mice, the ovarian reserve is matured postnatally, mimicking the biologic second trimester activity of the human ovary. Wild-type C57bl/6 pups were collected on postnatal day 0. Ovaries were cultured in hanging well organ culture media with addition of DMSO or a chemotherapy agent. Immunofluorescence was used to quantify oocyte number and density. Power calculation showed a N of 11 per drug would be needed to demonstrate a decrease of ⅔ or more. Participants/materials, setting, methods: 83 ovaries were cultured, sectioned and analyzed in duplicate. Planned analysis at serum max and mid concentrations was performed at 48 hours and 5 days. Given clinically variation in concentrations of cisplatin, additional concentration samples were added. After noting the degradation following exposure to doxorubicin, additional samples at earlier time points of 12 and 24 hours of exposure were added for dynamic evaluation. Means were calculated and then compared using a 2-way ANOVA. Main results and the role of chance Doxorubicin exposure during establishment of the ovarian reserve resulted in a significant loss of oocyte number and density. At 12 hours a 22% decrease was noted; this increased to a loss of 91% of oocytes by 48 hours of exposure. The oocyte density fell from 693 oocytes/ mm² in the control to only 63 oocytes/ mm² in the serum max concentration (p = 0.003). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed early impact within the stroma by 12 hours with widespread apoptotic changes by 24 hours. Treatment with cisplatin resulted in a phenotypic change in the oocyte population with preservation of smaller, more peripheral cells. The average oocyte density remained similar to control even at the highest clinical concentrations, 536 oocytes/ mm² compared to 570 oocytes/ mm² (p = 0.772). Docetaxel and paclitaxel demonstrated an increase in oocyte number and density, though not enough to reach significance. The oocyte density 5 days following docetaxel exposure was 802 oocytes/ mm², a 41% increase (p = 0.12). The oocyte density 5 days following paclitaxel exposure was 780 oocytes/ mm², a 37% increase (p = 0.817). The drug exposure did impact stromal cells, as noted in TUNEL images. Limitations, reasons for caution This ex-vivo mouse model offers tight control of chemotherapy concentration, it does not account for filtration and modification by the placenta. Longer term cultures may also demonstrate that temporary arrest in small oocytes, such as those exposed to cisplatin, do not thrive and later progress to apoptosis. Wider implications of the findings: Doxorubicin is employed as the most common chemotherapy during pregnancy. Utilization may be to the serious detriment of the younger generation. If other alternatives are clinically effective they should be considered. No other models have explored the effect of fetal ovary exposure to chemotherapy on the establishment of ovarian reserve. Trial registration number Not applicable

Corticosteroids alter alveolar macrophage control of Lichtheimia corymbifera spores in an ex vivo mouse model

2020 ◽  
Author(s):  
Kévin Brunet ◽  
François Arrivé ◽  
Jean-Philippe Martellosio ◽  
Isabelle Lamarche ◽  
Sandrine Marchand ◽  
...  
Keyword(s):  
Mouse Model ◽  
Alveolar Macrophage ◽  
Oxidative Burst ◽  
Ex Vivo ◽  
Fungal Growth ◽  
Invasive Infection ◽  
Ex Vivo Model ◽  
Lichtheimia Corymbifera ◽  
The Impact

Abstract Alveolar macrophages (AM) are the first-line lung defense against Mucorales in pulmonary mucormycosis. Since corticosteroid use is a known risk factor for mucormycosis, the aim of this study was to describe the role of corticosteroids on AM capacities to control Lichtheimia corymbifera spore growth using a new ex vivo model. An in vivo mouse model was developed to determine the acetate cortisone dose able to trigger pulmonary invasive infection. Then, in the ex vivo model, male BALB/c mice were pretreated with the corticosteroid regimen triggering invasive infection, before AM collection through bronchoalveolar lavage. AMs from corticosteroid-treated mice and untreated control AMs were then exposed to L. corymbifera spores in vitro (ratio 1:5). AM control of fungal growth, adherence/phagocytosis, and oxidative burst were assessed using optical densities by spectrophotometer, flow cytometry, and 2', 7'-dichlorofluoresceine diacetate fluorescence, respectively. Cortisone acetate at 500 mg/kg, at D-3 and at D0, led to pulmonary invasive infection at D3. Co-incubated spores and AMs from corticosteroid-treated mice had significantly higher absorbance (fungal growth) than co-incubated spores and control AMs, at 24 h (P = .025), 36 h (P = .004), and 48 h (P = .001). Colocalization of spores with AMs from corticosteroid-treated mice was significantly lower than for control AMs (7.6 ± 1.9% vs 22.3 ± 5.8%; P = .003), reflecting spore adherence and phagocytosis inhibition. Finally, oxidative burst was significantly increased when control AMs were incubated with spores (P = 0.029), while corticosteroids hampered oxidative burst from treated AMs (P = 0.321). Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease in our ex vivo model. Lay Summary The aim of this study was to describe the impact of corticosteroids on alveolar macrophage (AM) capacities to control Mucorales growth in a new murine ex vivo model. Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease.

scholarly journals The effect of prophylactic bilateral salpingectomy on ovarian reserve in patients who underwent laparoscopic hysterectomy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shizhuo Wang ◽  
Jiahui Gu
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Reserve ◽  
Premenopausal Women ◽  
Laparoscopic Hysterectomy ◽  
Ovarian Tumors ◽  
Reproductive Age ◽  
Control Group ◽  
Significant Difference ◽  
Bilateral Salpingectomy ◽  
The Impact

Abstract Background Bilateral salpingectomy has been proposed to reduce the risk of ovarian cancer, but it is not clear whether the surgery affects ovarian reserve. This study compares the impact of laparoscopic hysterectomy for benign disease with or without prophylactic bilateral salpingectomy on ovarian reserve. Methods Records were reviewed for 373 premenopausal women who underwent laparoscopic hysterectomy with ovarian reserve for benign uterine diseases. The serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and three-dimensional antral follicle count (AFC) were assessed before surgery and 3 and 9 months postoperatively to evaluate ovarian reserve. Patients were divided into two groups according to whether they underwent prophylactic bilateral salpingectomy. The incidence of pelvic diseases was monitored until the ninth month after surgery. Results There was no significant difference between the two surgery groups in terms of baseline AMH, E2, FSH, LH, and AFC (all P > 0.05). There was no difference in potential bias factors, including patient age, operative time, and blood loss (all P > 0.05). There was also no significant difference between the two groups 3 months after surgery with respect to AMH (P = 0.763), E2 (P = 0.264), FSH (P = 0.478), LH (P = 0.07), and AFC (P = 0.061). Similarly, there were no differences between groups 9 months after surgery for AMH (P = 0.939), E2 (P = 0.137), FSH (P = 0.276), LH (P = 0.07) and AFC (P = 0.066). At 9 months after the operation, no patients had malignant ovarian tumors. The incidences of benign ovarian tumors in the salpingectomy group were 0 and 2.68 % at 3 and 9 months after surgery, respectively, and the corresponding values in the control group were 0 and 5.36 %. The incidences of pelvic inflammatory disease in the salpingectomy group were 10.72 and 8.04 % at 3 and 9 months after surgery, respectively, while corresponding values in the control group were 24.13 and 16.09 %. Conclusions Prophylactic bilateral salpingectomy did not damage the ovarian reserve of reproductive-age women who underwent laparoscopic hysterectomy. Prophylactic bilateral salpingectomy might be a good method to prevent the development of ovarian cancer. Larger clinical trials with longer follow-up times are needed to further evaluate the risks and benefits.

Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Nga Cao ◽  
Yung George Wong ◽  
Sarah Rosli ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Ex Vivo ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Diastolic Dysfunction ◽  
The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

scholarly journals Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Inès R. H. Ben-Nejma ◽  
Aneta J. Keliris ◽  
Jasmijn Daans ◽  
Peter Ponsaerts ◽  
Marleen Verhoye ◽  
...  
Keyword(s):  
Mouse Model ◽  
Postnatal Development ◽  
Amyloid Beta ◽  
Resting State ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Fold Increase ◽  
Brain Network ◽  
Resting State Networks ◽  
The Impact

AbstractAlzheimer’s disease (AD) is the most common form of dementia in the elderly. According to the amyloid hypothesis, the accumulation and deposition of amyloid-beta (Aβ) peptides play a key role in AD. Soluble Aβ (sAβ) oligomers were shown to be involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sAβ effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice. TG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3 m of age to suppress transgenic Aβ production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4 T MR-system starting from week 0 (3 m old mice) up to 28w post DOX treatment. Ex-vivo immunohistochemistry and ELISA analysis was performed to assess the development of amyloid pathology. Functional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment, particularly across regions of the default mode-like network, known to be affected in AD. Ex-vivo analyses performed at this time point confirmed a 20-fold increase in total sAβ levels preceding the apparition of Aβ plaques and inflammatory responses in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of Aβ plaques in the brain. By preventing developmental influence of APP and/or sAβ during brain postnatal development, we demonstrated FC abnormalities potentially driven by sAβ neurotoxicity on resting-state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD.

scholarly journals Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

2019 ◽  
Author(s):  
Inès R.H. Ben-Nejma ◽  
Aneta J. Keliris ◽  
Jasmijn Daans ◽  
Peter Ponsaerts ◽  
Marleen Verhoye ◽  
...  
Keyword(s):  
Mouse Model ◽  
Postnatal Development ◽  
Amyloid Beta ◽  
Resting State ◽  
Ex Vivo ◽  
Fold Increase ◽  
Brain Network ◽  
Resting State Networks ◽  
The Impact

ABSTRACTBackgroundAlzheimer’s disease (AD) is the most common form of dementia in the elderly population. Currently, no effective cure is available for AD. According to the amyloid hypothesis, the accumulation and deposition of the amyloid-beta (Aβ) peptides plays a key role in AD pathology. Soluble Aβ (sAβ) oligomers were shown to be synaptotoxic and involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sAβ effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice.MethodsTG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3m of age to suppress transgenic Aβ production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4T MR-system starting from week 0 (3m old mice) up to 28w post DOX treatment. Ex vivo immunohistochemistry and ELISA analysis (additional mice cohort) was performed to address the development of amyloid pathology.ResultsFunctional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment. This effect was observed particularly across regions of the default mode-like network, known to be affected in AD. Ex vivo analyses performed at this time point confirmed a 20-fold increase in total sAβ levels and the absence of Aβ plaques in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of Aβ plaques in the brain.ConclusionsBy preventing developmental influence of APP and/or sAβ during brain postnatal development, we demonstrated FC abnormalities driven by sAβ synaptotoxicity on resting state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD. Therefore, this inducible APP expression model used in combination with early non-invasive in vivo rsfMRI readout for sAβ synaptotoxicity sets the stage for future Aβ targeting preventative treatment studies.

scholarly journals The Impact of Endometriosis on Controlled Ovarian Stimulation Outcome

2021 ◽  
Author(s):  
Dragoș Albu ◽  
Alice Albu
Keyword(s):  
In Vitro Fertilization ◽  
Ovarian Reserve ◽  
Ovarian Stimulation ◽  
Predictive Value ◽  
Reproductive Age ◽  
Important Predictor ◽  
Controlled Ovarian Stimulation ◽  
Vitro Fertilization ◽  
The Impact

Endometriosis, a frequent condition in reproductive age women, is also associated with infertility by mechanisms incompletely clarified. The effectiveness of endometriosis treatment for infertility is debated, being possible that in vitro fertilization (IVF) offers a better alternative. The response to controlled ovarian stimulation (COS) is an important predictor of live birth, but it might be affected in endometriosis possibly through a decrease of ovarian reserve. Moreover, the predictive value of anti-mullerian hormone (AMH) for the response to COS could be altered by factors disrupting the AMH production in endometriosis. Therefore, we aim to review the literature regarding the response to COS and the AMH production and their predictive value for COS response in patients with endometriosis.

scholarly journals The effect of prophylactic bilateral salpingectomy on ovarian reserve in patients who underwent laparoscopic hysterectomy

2021 ◽  
Author(s):  
Shizhuo Wang ◽  
jiahui gu
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Reserve ◽  
Premenopausal Women ◽  
Laparoscopic Hysterectomy ◽  
Ovarian Tumors ◽  
Reproductive Age ◽  
Control Group ◽  
Significant Difference ◽  
Bilateral Salpingectomy ◽  
The Impact

Abstract Background Bilateral salpingectomy has been proposed to reduce the risk of ovarian cancer, but it is not clear whether the surgery affects ovarian reserve. This study compares the impact of laparoscopic hysterectomy for benign disease with or without prophylactic bilateral salpingectomy on ovarian reserve. Methods Records were reviewed for 373 premenopausal women who underwent laparoscopic hysterectomy with ovarian reserve for benign uterine diseases. The serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and three-dimensional antral follicle count (AFC) were assessed before surgery and 3 and 9 months postoperatively to evaluate ovarian reserve. Patients were divided into two groups according to whether they underwent prophylactic bilateral salpingectomy. The incidence of pelvic diseases was monitored until the ninth month after surgery. Results There was no significant difference between the two surgery groups in terms of baseline AMH, E2, FSH, LH, and AFC (all P > 0.05). There was no difference in potential bias factors, including patient age, operative time, and blood loss (all P > 0.05). There was also no significant difference between the two groups 3 months after surgery with respect to AMH (P = 0.763), E2 (P = 0.264), FSH (P = 0.478), LH (P = 0.07), and AFC (P = 0.061). Similarly, there were no differences between groups 9 months after surgery for AMH (P = 0.939), E2 (P = 0.137), FSH (P = 0.276), LH (P = 0.07) and AFC (P = 0.066). At 9 months after the operation, no patients had malignant ovarian tumors. The incidences of benign ovarian tumors in the salpingectomy group were 0% and 2.68% at 3 and 9 months after surgery, respectively, and the corresponding values in the control group were 0% and 5.36%. The incidences of pelvic inflammatory disease in the salpingectomy group were 10.72% and 8.04% at 3 and 9 months after surgery, respectively, while corresponding values in the control group were 24.13% and 16.09%. Conclusion Prophylactic bilateral salpingectomy did not damage the ovarian reserve of reproductive-age women who underwent laparoscopic hysterectomy. Prophylactic bilateral salpingectomy might be a good method to prevent the development of ovarian cancer. Larger clinical trials with longer follow-up times are needed to further evaluate the risks and benefits.

scholarly journals Association between thyroid autoimmunity and ovarian reserve in women with hypothyroidism

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Felipe A. Morales-Martínez ◽  
Luis H. Sordia-Hernández ◽  
Martha Merino Ruiz ◽  
Selene Garcia-Luna ◽  
Otto H. Valdés-Martínez ◽  
...  
Keyword(s):  
Ovarian Reserve ◽  
Ovarian Function ◽  
Thyroid Autoimmunity ◽  
Antral Follicle ◽  
Serum Levels ◽  
Antral Follicle Count ◽  
Reproductive Age ◽  
Autoimmune Hypothyroidism ◽  
Thyroid Hormone Concentration ◽  
The Impact

Abstract Background The ovarian function and therefore the ovarian reserve may be compromised by the pathogenesis of autoimmune diseases of which, Hashimoto’s thyroiditis (HT) is the most common in women of reproductive age. Furthermore, a prolonged reduction in thyroid hormone concentration results in a broad spectrum of reproductive alteration. Previous reports in the literature have been controversial regarding the impact of hypothyroidism and alterations in the ovarian reserve. Thus, this prospective and comparative study aimed to evaluate the association of hypothyroidism with low ovarian reserve. Materials and Methods A subset of 27 patients with primary autoimmune hypothyroidism were compared to healthy women. The ovarian reserve was assessed through the anti-Mullerian hormone (AMH) and the antral follicle count (AFC). Results Overall, the two groups did not display significant differences in length of their menstrual cycles neither in the AMH serum levels nor the AFC. Conclusions No significant alteration was found in the ovarian reserve of women with HT.

scholarly journals THE SPECIFICITY OF THE OVARIAN RESERVE OF WOMEN WITH CHRONIC SALPINGOOPHORITIS

2018 ◽  
Vol 25 (6) ◽  
pp. 119-126
Author(s):  
V. A. Novikova ◽  
F. R. Autleva ◽  
A. A. Sorochenko ◽  
D. I. Fayzullina ◽  
E. V. Nurgalieva
Keyword(s):  
Ovarian Reserve ◽  
Reproductive Period ◽  
Main Group ◽  
Reproductive Age ◽  
Control Group ◽  
Regression Equations ◽  
Women Of Reproductive Age ◽  
Antral Follicles ◽  
Preconception Consultation ◽  
The Impact

Aim. The research was conducted for the assessment of the impact of chronic salpingoophoritis on the ovarian reserve of women in various phases of reproductive age.Materials and methods. A prospective, controlled and open cohort study was performed in 2013-2018 (n=202). The main group consisted of women with chronic salpingoophoritis (ChrSO) who applied for preconception consultation (n=138). In accordance with the reproductive age phase, the main group was divided into subgroups: the early reproductive age period (ERP, n=44), the peak reproductive age period (PRP, n=56), the late reproductive period (LRP, n=38). The control group consisted of conditionally healthy women of reproductive age (n=64). The ovarian reserve (OR) was estimated on the basis of the serum level of antimullerian hormone (AMH), inhibin B, estradiol, follicle stimulating hormone (FSH), an ultrasoundbased assessment of the number of antral follicles (AF), and the ovarian volume. Results. The age of women ranged from 18 to 40 years. Based on the discriminant analysis, it was found that the main indicators determining the specificity of the OR in ChrSO, depending on the phase of reproductive age, are the number of antral follicles, estradiol level and AMH (Wilks’ lambda = 0.35503, p<0.0001). The specificity of the OR of women with ChrSO (difference from the control group), regardless of the phase of reproductive age, initially and when evaluated after 6 months, is determined by the number of AF and the level of estradiol and AMH; the number of AF and AMH is determined with a similar estimate after 12 months. The specificity of the OR in ChrSO, which is dependent on the reproductive age phase, has been proved through the analysis with the neural networks training(the proportion of correct answers is more than 80%). The linear relationships were established between the values of each OR parameter in women with ChrSO. Initially, when estimating after 6 and 12 months, linear regression equations were calculated, allowing the values of individual OR parameters to be calculated over 6 and 12 months.Conclusion. Chronic salpingoophoritis (ChrSO) is associated with a decrease in ovarian reserve in women of reproductive age. The effect of ChrSO on some parameters of the ovarian reserve depends on the age phase of the reproductive period, which increases with time (after 6, 12 months). The presence of ChrSO in women planning future pregnancies requires preventive and therapeutic measures aimed at preserving the ovarian reserve and the preferred implementation of fertility in early reproductive age before the ovarian reserve starts to decline.

Role of STAT3 and Th17 Cells in Cutaneous T Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 66-66
Author(s):  
Swati Goel ◽  
Laura K Fogli ◽  
Mark Sundrud ◽  
Stefano Casola ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Th17 Cells ◽  
Ex Vivo ◽  
Hdac Inhibitors ◽  
Ifn Γ ◽  
Th17 Differentiation ◽  
And Control ◽  
The Impact

Abstract Abstract 66 Background Cutaneous T cell Lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas characterized by skin-homing malignant T cells. The etiology of CTCL remains enigmatic, but constitutive Signal Transducer and Activator of Transcription 3 (STAT3) activity is characteristic of this malignancy. CTCL cell lines undergo growth arrest and apoptosis following inhibition of STAT3 signaling, suggesting that STAT3 may be a pro-survival factor in these cells. STAT3 phosphorylation is also required for the initiation and maintenance of the Th17 differentiation program, a recently identified subset of CD4+ T helper cells, implicated in a number of chronic inflammatory conditions including rheumatoid arthritis and psoriasis. Furthermore, we know that Histone Deacetylase inhibitors (HDACi) namely Vorinostat and Romidepsin are very active agents for treatment of CTCL but their mechanism of action is still to be elucidated. Our goal is to probe the contribution of Th17 mediated inflammation in CTCL and to examine whether HDAC inhibitors work by modulating Th17 inflammation in the context of this malignancy. Methods Using conditional gene targeting approach we have generated a transgenic 100% penetrant mouse model of CTCL wherein expression of a hyper-active STAT3 mutant protein (STAT3C) selectively in T lymphocytes results in skin pathology highly reminiscent of this human malignancy. To have a better understanding of the contribution of STAT3 in CD4 T cell differentiation program and CTCL, we used lymphocytes and splenocytes from 8 weeks old STAT3Cstopfl/fl (without CD4Cre, thus no pathology) and control YFPstopfl/fl (Yellow Fluorescent Protein floxed) mice (Figure 1a). We isolated naïve CD4 cells using Dynabeads and treated these CD4 cells with a transducible Cre enzyme (Tat-Cre) to delete the upstream stop cassette ex-vivo. These cells were then plated with stimulating α CD3/CD28 antibodies in various cytokine cocktails as shown in Figure 1b. These cells were harvested after 84 hours and stimulated with PMA/Inomycin for 4 hours for flowcytometric analysis. We are now using this in-vitro approach as well as our mouse model and primary tissue samples from CTCL patients to explore the impact of HDAC inhibitors on Th17/Treg balance. Results Upon Tat-Cre treatment we were able to analyze GFP+ (and therefore STAT3C expressing) vs. GFP- (control) T cells in the same differentiation conditions. Hyperactive STAT3C mutant protein favored TH17 differentiation as GFP Positive cells had significantly augmented IL17A production (Figure 1b). On the other hand, STAT3C expressing GFP positive cells in Th0 and Th1 differentiation conditions had less IFN-γ production compared to the GFP negative cells and control YFP fractions. Even the GFP negative fraction of STAT3C had less IFN-γ and more IL17A production than the control YFP fractions due to the cytokine milieu created by STAT3C expressing cells present in the same well. Conclusions: These results highlight an intriguing possibility that STAT3 dependent Th17 cells play a role in CTCL pathogenesis. Using our newly developed mouse model and CTCL patients' blood and skin samples (IRB approved), we are trying to distinguish whether Th17 cells are instigators of chronic inflammation that contributes to the malignant transformation of T cells or that Th17 cells may actually be the cells of origin in this malignancy. Our ongoing experiments also include the effects of HDACi on this ex-vivo CD4 T cell differentiation. In addition, we are studying the hallmarks of Th17 differentiation namely IL-17A, IL-22 and pSTAT3 positivity in the skin biopsy and blood samples of CTCL patients before and after treatment with HDACi. These experiments will help us determine the impact of HDAC inhibition on STAT3 activity and Th17 differentiation and have a better understanding of their mechanism of action in CTCL. Our hope is that our study will guide us to comprehend the contribution of chronic inflammation in carcinogenesis and potentially identify novel treatment targets and strategies in the field of hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

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