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الملخص: أهداف البحث: يلعب هرمون الاستروجين دورا رئيسا في تطور أورام الثدي. وفقا لذلك، تُستخدم مثبطات الأروماتاز (مثل الليتروزول) على نطاق واسع في علاج سرطان الثدي عن طريق تثبيط إنزيم الأروماتاز الذي يحول الأندروجين إلى هرمون الاستروجين مما يؤدي إلى إنخفاض مستوى هرمون الاستروجين. وكذلك فإن هرمون الاستروجين له دور كبير في سلامة كتلة العظام، ويمنع هشاشه العظام لدى النساء. لذلك استخدام البايفوسفونيت (مثل حمض الزوليدرونيك) مع الليتروزول من أجل أن يقلل من هشاشة العظام لدى المرضي الذين يعالجون بمثبطات الأروماتاز. في هذه الدراسة، تم فحص التأثير المضاد للسرطان لكلا من الليتروزول وحمض الزوليدرونيك لعلاج سرطان الثدي البشري وتقليل حدوث هشاشة العظام. طرق البحث: تم استخدام كيمياء الخلايا المناعية والتقنيات المناعية لقياس مستوي البروتين في هذه الدراسة. النتائج: وجد أن الليتروزول ثبط النمو الخلوي بتركيز ٥٠٪ من الخلايا لـكل من الخلايا المدروسة عند تركيز ٧٠± ٠.٠٠١ و١٤٠±٠.٠٠١ نانومولار، على التوالي، في حين ثبط حمض الزوليدرونيك النمو الخلوي عند ٥٠± ٠.٠٠٥ و١٥٠ ± ٠.٠٠٤ ميكرومولار لخطوط الخلايا المدروسة، على التوالي. ومن المثير للاهتمام أن استخدام الليتروزول مع حمض الزوليدرونيك سويا قد خفف من التعبير البروتيني لبروتين تحويل الإشارة وتنشيط النسخ، بينما لوحظ زيادة ملحوظة في مستوي التعبير البروتيني للبروتين المسئول عن تنظيم انقسامات الخلايا المدروسة. بالإضافة إلى ذلك، لقد كان هناك زيادة ملحوظة في التواجد النووي لبروتين المسئول عن تنظيم انقسامات الخلايا بعد علاج الخلايا لمدة ٢٤ ساعة بالليتروزول مقارنة بالخلايا الضابطة. وعلى الجانب الاخر، كان هناك انخفاض في التواجد النووي لبروتين تحويل الإشارة وتنشيط النسخ الذي يمكن أن يكون هدفا جذابا يمكن استخدامه للعلاج وتثبيط انتشار وتطور سرطان الثدي. الاستنتاجات: يمكن استنتاج أن العلاج باستخدام كلا من الليتروزول وحمض الزوليدرونيك قد عزز من الموت المبرمج للخلايا السرطانية المستخدمة بجانب تثبيط نموها. بالإضافة إلى ذلك، قد يكون هذا المزيج مفيدا في علاج سرطان الثدي بجانب الحفاظ على سلامة العظام في حالة جيدة لدى النساء المصابات بسرطان الثدي. Abstract: Objectives: Oestrogen plays a key role in the development of breast malignancies. Therefore, aromatase inhibitors (e.g. letrozole [LTZ]) are widely used in the treatment of breast cancer. On the other hand, oestrogen is important to the integrity of bone mass. Research has shown that zoledronic acid (ZLA) may prevent osteoporosis. Therefore, the present research aims to investigate the effect of a combination of LTZ and ZLA in the treatment of breast cancer and in reducing osteoporosis in patients with breast cancer. Methods: We used immunocytochemistry and Western immunoblotting techniques in this study. Results: We observed that LTZ inhibited cellular growth of Michigan Cancer Foundation-7 (MCF-7) and T-47D at IC50 (70 ± 0.001) and (140 ± 0.004) nM, respectively, whereas ZLA inhibited cellular growth at IC50 (50 ± 0.005) μM and (150 ± 0.004) μM for MCF-7 and T-47D cell lines, respectively. Interestingly, the LTZ and ZLA combination down-regulated the protein expression of signal transducer and activator of transcription 3 (STAT3) and up-regulated BRCA1 protein expression in both cell lines. Moreover, a notable enhancement in the nuclear localisation of the BRCA1 protein was obtained after treatment of T-47D cells with LTZ for 24 h compared to the control cells. In contrast, there was a reduction in the nuclear localisation of STAT3 protein, which could be an attractive target for inhibition of breast cancer proliferation and progression. Conclusion: Our study has shown that a combination of LTZ and ZLA enhanced apoptosis and inhibited growth of both breast cancer cell lines. This combination can be used to maintain bone integrity in women with breast cancer.

Early-stage cancer recognition could improve awareness and treatment strategies. Twenty four breast cancer affected individuals had their DNA isolated from malignant tissues and from blood. DNA was then amplified by RAPD with six different ten-mer primers. RAPD-PCR yields were electrophoresed on a 1 .5% agarose gel and visualized using ethidium-bromide staining. Only two out of the selected RAPD data have exhibited distinguishable polymorphic markers between cancerous and normal tissues. Enzyme-Linked Immunosorbent Assay (ELISA) was used for the determination plasma immunoglobulins (IgG, IgA and IgM) in patient samples preoperatively, postoperatively and after six cycles of chemotherapy treatment.

The onset of labour in rodents and in humans is associated with physiological inflammation which is manifested by infiltration of activated maternal peripheral leukocytes (mPLs) into uterine tissues. Here, we used flow cytometry to immunophenotype mPLs throughout gestation and labour, both term and preterm. Peripheral blood was collected from non‐pregnant women and pregnant women in the 1st, 2nd and 3rd trimesters. Samples were also collected from women in active labour at term (TL) or preterm (PTL) and compared with women term not‐in‐labour (TNIL) and preterm not‐in‐labour (PTNIL). Different leukocyte populations were identified by surface markers such as CD45, CD14, CD15, CD3, CD4, CD8, CD19 and CD56. Their activation status was measured by the expression levels of CD11b, CD44, CD55, CD181 and CD192 proteins. Of all circulating CD45+ leukocytes, we detected significant increases in CD15+ granulocytes (i) in pregnant women versus non‐pregnant; (ii) in TL women versus TNIL and versus pregnant women in the 1st/2nd/3rd trimester; (iii) in PTL women versus PTNIL. TL was characterized by (iv) increased expressions of CD11b, CD55 and CD192 on granulocytes; (v) increased mean fluorescent intensity (MFI) of CD55 and CD192 on monocytes; (vi) increased CD44 MFI on CD3+ lymphocytes as compared to late gestation. In summary, we have identified sub‐populations of mPLs that are specifically activated in association with gestation (granulocytes) or with the onset of labour (granulocytes, monocytes and lymphocytes). Additionally, beta regression analysis created a set of reference values to rank this association between immune markers of pregnancy and to identify activation status with potential prognostic and diagnostic capability.

Perinatal maternal smoking exposure (PMSE) is one of the major environmental risk factors encountered by the fetus. PMSE is usually associated with adverse pregnancy outcomes that may manifest at different stages of life. Nevertheless, fetal growth restriction is the most common smoking-induced side effect. PMSE induces changes in the maternal multiple organ systems. These alterations may affect placentation, which subsequently affects fetal growth. It is worthy to note, however, that the extent of maternal smoking-induced changes depends mainly on the maternal level of susceptibility. Hence, the perinatal pregnancy outcomes vary depending on the interaction between the triad: the maternal, fetal, and placental modifications, making it more complex. In this review, we try to unveil the effect of smoking-induced maternal changes on the maternal immune, endocrine, and metabolic pathways and their impact on fetal growth.

Background In the last two decades, the consumption of drugs of abuse among women of childbearing age has experienced a significant increase and results from analyses of surveys concerning maternal intake of psychoactive prescription drugs during pregnancy indicate that the rates of intake are increasing each year. Analyses of biological matrices such as maternal hair and neonatal meconium have recently been used for assessment of gestational consumption and consequent prenatal exposure to drugs of abuse in high-risk groups of women. Methods Maternal hair and neonatal meconium were analyzed by validated chromatographic-mass spectrometric methodologies to disclose the gestational use of drugs of abuse and psychoactive prescription drugs and consequent prenatal exposure in a cohort of 513 mother-newborn dyads at the Sant Joan de Deu Barcelona Hospital, Spain, during 2012-2013. Results A total of 3.9% women reported drugs of abuse or prescription psychoactive drug consumption at any time during pregnancy. The prevalence of gestational consumption and the consequent prenatal exposure to drugs of abuse (e.g. cannabis, cocaine and MDMA) was 1.2% in maternal hair and 0.4% in meconium; and of psychoactive prescription drugs (e.g. venlafaxine, citalopram, fluoxetine, clomipramine), was 1.7% in maternal hair and 1.2% in meconium. The prevalence of drugs of abuse and prescription psychoactive drug consumption was lower in our specific cohort of Spanish pregnant women than in other cohorts such as those from U.S. or Denmark. Conclusion Analysis of materno-fetal matrices provides a viable alternative to study prenatal exposure to these substances and develop specific social and health intervention recommendations.

BACKGROUND: Maternal smoking during pregnancy has repeatedly been associated with decreased sperm counts in sons. Nevertheless, our team recently detected a lower total sperm count in the sons of smoking fathers as compared to sons of non-smoking fathers. Since paternal and maternal tobacco smoking often coincide, it is difficult to discriminate whether effects are mediated paternally or maternally when using questionnaire- or register-based studies. Therefore, getting an objective measure of the maternal nicotine exposure level during pregnancy might help disentangling the impact of paternally and maternally derived exposure. OBJECTIVES: Our aim was to study how paternal smoking at the time of the pregnancy was associated with semen quality in the sons after adjusting for the maternal levels of nicotine exposure during pregnancy. METHODS: We recruited 104 men (17-20 years old) from the general Swedish population. The participants answered a questionnaire about paternal smoking. Associations between smoking and semen volume, total sperm count, sperm concentration, morphology and motility were adjusted for levels of the nicotine metabolite cotinine in stored maternal serum samples obtained from rubella screening between the 6th and 35th week of pregnancy. We additionally adjusted for the estimated socioeconomic status. RESULTS: After adjusting for the maternal cotinine, the men of smoking fathers had 41% lower sperm concentration and 51% lower total sperm count than the men of non-smoking fathers (p = 0.02 and 0.003, respectively). This was robust to the additional adjustment. CONCLUSIONS: Our results suggest a negative association between paternal smoking and sperm counts in the sons, independent of the level maternal nicotine exposure during the pregnancy. (Less)

Background: Prenatal heavy metals exposure has shown a negative impact on birth weight. However, their influence on different clinical forms of fetal smallness was never assessed. Objectives: To investigate whether there is a differential association between heavy metals exposure and fetal smallness subclassification into intrauterine growth restriction (IUGR) and small-for-gestational age (SGA). Method: In this prospective case-control study, we included 178 mother–infant pairs; 96 of appropriate for gestational age (AGA) and 82 of small fetuses diagnosed in third trimester. The small ones were further subclassified into IUGR, n = 49 and SGA, n = 33. Cadmium (Cd), mercury (Hg), lead (Pb), arsenic (As) and zinc (Zn) levels were measured in the maternal and cord serum, and in the placentas of the three groups. Results: Maternal serum level of Cd (p

This study aimed to objectively verify smoking and drinking behavior during pregnancy and to disclose self-misreporting through maternal hair analysis. A total of 153 women attending a university hospital in Barcelona (Spain) were selected and interviewed after delivery, on their smoking and drinking habits during pregnancy. A 9-cm hair strand was collected and analyzed by liquid chromatography tandem mass spectrometry for the presence of nicotine (NIC) and ethyl glucuronide (EtG) as biomarkers of tobacco and alcohol consumption, respectively. Concentrations of EtG

Objective To determine the proportion of patients diagnosed with cervical cancer or cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3) despite testing negative for HPV. Methods A prospective study was conducted at a university hospital in Barcelona, Spain, between March 2003 and January 2015 among women with abnormal cytology results according to the Bethesda classification system. All participants underwent HPV testing, cytology, and colposcopy. Results Among 1376 participants, 609 (44.3%) were diagnosed with CIN 2/3. Of these women, 74 (12.2%) tested negative for HPV. Among 479 women with colposcopy-guided biopsy sampling showing CIN 2/3, cone biopsy results that were negative for CIN 2/3 were more frequent among patients with negative HPV testing (13/61 [21.3%]) than among those with positive HPV tests (58/418 [13.9%]; P=0.03). Additionally, among 59 patients diagnosed with cervical cancer, 9 (15.3%) tested negative for HPV. Conclusion The HPV test was negative for 12% and 15% of patients diagnosed with biopsy-proven CIN 2/3 and cervical cancer, respectively.

EG-VEGF is an angiogenic factor that we identified as a new placental growth factor during human pregnancy. EG-VEGF is also expressed in the mouse fetal membrane (FM) by the end of gestation, suggesting a local role for this protein in the mechanism of parturition. However, injection of EG-VEGF to gravid mice did not induce labor, suggesting a different role for EG-VEGF in parturition. Here, we searched for its role in the FM in relation to human parturition. Human pregnant sera and total FM, chorion, and amnion were collected during the second and third trimesters from preterm no labor, term no labor, and term labor patients. Primary human chorion trophoblast and FM explants cultures were also used. We demonstrate that circulating EG-VEGF increased toward term and significantly decreased at the time of labor. EG-VEGF production was higher in the FM compared to placentas matched for gestational age. Within the FM, the chorion was the main source of EG-VEGF. EG-VEGF receptors, PROKR1 and PROKR2, were differentially expressed within the FM with increased expression toward term and an abrupt decrease with the onset of labor. In chorion trophoblast and FM explants collected from nonlaboring patients, EG-VEGF decreased metalloproteinase-2 and -9 activities and increased PGDH (prostaglandin-metabolizing enzyme) expression. Altogether these data demonstrate that EG-VEGF is a new cytokine that acts locally to ensure FM protection in late pregnancy. Its fine contribution to the initiation of human labor is exhibited by the abrupt decrease in its levels as well as a reduction in its receptors.

Background. The cause of secondary amenorrhea in the following case cannot be explained by traditional etiologies. We therefore questioned whether long-term methotrexate treatment played a role as an endometrial inhibitor.Case. A 44-year-old G4P2, with a 5-year history of rheumatoid arthritis, presented with a 2-year history of secondary amenorrhea. The patient took methotrexate since diagnosis. Her FSH, estrogen, prolactin, TSH and T4 levels were normal, her B-HCG was negative, her BMI was 22 and she had no history of Asherman's syndrome.Conclusion. There is no information, based on our search, on whether long-term methotrexate treatment has an effect on the menstrual cycle. This case highlights the need for the elucidation of the effects of long-term methotrexate treatment on the menstrual cycle in patients with rheumatoid arthritis.

Maternal exposure to tobacco and alcohol is a known cause, among others, for fetal growth restriction (FGR). Clinically, FGR can be subclassified into two forms: intrauterine growth restriction (IUGR) and small for gestational age (SGA), based on the severity of the growth retardation, and abnormal uterine artery Doppler or cerebro-placental ratio. This study aimed at investigating any differential correlation between maternal exposures to these toxins with the two clinical forms of FGR. Therefore, a case-control study was conducted in Barcelona, Spain. Sixty-four FGR subjects, who were further subclassified into IUGR (n = 36) and SGA (n = 28), and 89 subjects matched appropriate-for-gestational age (AGA), were included. The levels of nicotine (NIC) and ethyl glucuronide (EtG), biomarkers of tobacco and alcohol exposure, respectively, were assessed in the maternal hair in the third trimester. Our analysis showed 65% of the pregnant women consumed alcohol, 25% smoked, and 19% did both. The odds ratios (ORs) of IUGR were 21 times versus 14 times for being SGA with maternal heavy smoking, while with alcohol consumption the ORs for IUGR were 22 times versus 37 times for the SGA group. The differential correlations between these toxins with the two subtypes of FGR suggest different mechanisms influencing fetal weight. Our alarming data of alcohol consumption during pregnancy should be considered for further confirmation among Spanish women.