Comparative study between histological changes in placenta from pre-eclampsia cases and normal pregnancy with special reference to cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis

Background: Placenta is a vital organ and the most accurate record of the infant’s prenatal experience. Pregnancy complications like hypertension significantly affect the placenta. Thus there is a need for thorough examination of it. Therefore the present study is dedicated to see the histological changes in placenta of pre-eclampsia with special reference to cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis and compared it with that of normal placenta.Methods: Total 60 placentas were collected (30 from pre-eclampsia and 30 from normal pregnancy). Results were expressed in percentage after counting 100 villi. Data analysis has been done using Graphpad InStat 3 version and data is significant when p – value is <0.05.Results: Mean no. of cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis in normal placenta are 10.1±5.01, 2.26±1.56 and 2.84±1.4 respectively and those in pre-eclampsia placenta are 36.82±16.15, 28.16± 34.42 and 8.22±1.44 respectively which are highly significant ( p-value <0.001).Conclusions: There is significant increase in number of cytotrophoblastic cell hyperplasia, villous stromal fibrosis and areas fibrinoid necrosis in placenta from pre-eclampsia cases than that of normal placenta. These changes may be due to vascular insufficiency which is usually occurring in pre-eclampsia

Is breast cancer a result of epigenetic responses to traffic-related air pollution? A review of the latest evidence

Environmental toxicants can exert adverse health effects via epigenetic regulation. We conducted a review of studies assessing traffic-related air pollution (TRAP) exposure and breast cancer (BC) risk, and the evidence for epigenetic mediation. 14 epidemiological studies demonstrated associations between TRAP exposure and BC risk, in which a total of 26 comparisons were assessed. 11 of these comparisons reported a positive association; whereas 15 comparisons were negative. Five publications linked TRAP exposure to epigenetic alterations in genes that may be related to BC risk. One animal study provided evidence of TRAP-treatment inducing breast tumorigenesis. Associations between TRAP components polycyclic aromatic hydrocarbons (PAH) and nitrogen dioxide (NO2) and BC risk were more consistent. While evidence for epigenetic regulation remains limited, polycyclic aromatic hydrocarbons (PAH) and nitrogen dioxide (NO2) exposures may alter methylation of breast tumorigenic genes (e.g., EPHB2, LONP1). Future epigenomic studies with environmental measures are needed to interrogate the relationship between TRAP and BC risk

Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair

Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway

Identification of heparin-binding EGF-like growth factor (HB-EGF) as a biomarker for lysophosphatidic acid receptor type 1 (LPA1) activation in human breast and prostate cancers

Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA₁₋₆). LPA receptor type 1 (LPA₁) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA₁ is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA₁ is known to induce IL-6 and IL-8 secretion, as also do LPA₂ and LPA₃. In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA₁,₂,₆; MDA-MB-231: LPA1,2; MCF-7: LPA₂,₆). Among the set of genes upregulated by LPA only in LPA₁-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA₁-₃ antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA₁ (MDA-B02/LPA₁) and downregulated for LPA₁ (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA₁ and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA₁. We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA₁ activation state in patients receiving anti-LPA₁ therapies

Identification des gènes et des marqueurs biologiques impliqués dans la dissémination métastatique des cancers du sein sous la dépendance de l'acide lysophosphatidique et de son récepteur LPA1

Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA1-6). It has been demonstrated that blocking LPA1 activity in vivo inhibits breast cancer cell metastasis, however, activated genes involved in LPA-induced metastasis have not been defined yet. In addition most mammalian cells co-express multiple LPA receptors, resulting in the co-activation of multiple intracellular signaling pathways with potential redundant or opposite effects impairing the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. In the first part of this thesis I found that HB-EGF is a specific biomarker of LPA1 activity. HB-EGF upregulation was inhibited by LPA1-3 antagonists (Ki16425, Debio0719) and by stably silencing LPA1. Using a human xenograft prostate tumors mouse model with PC3 cells, we found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. In the second part of experimental work, we focused our attention on miRNAs that are master gene regulators. We carried out correlation studies in 1488 human primary breast tumors from publically available databases and found ZEB1 as the most correlated gene with LPAR1. The coefficient of correlation between ZEB1 and LPAR1 was higher in human basal tumors than in non basal tumors. In three different basal cell lines LPA up-regulated ZEB1 through an LPA1/Phosphatidylinositol-3-Kinase (Pi3K)/AKT-dependent pathway. Based on microarray and real-time PCR analyses we found that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/AKT/ZEB1-dependent mechanism. MirVana miR-21 inhibitor, silencing LPA1 or silencing ZEB1 totally blocked in vitro LPA-induced cell migration and invasion, and in vivo tumor cell bone colonization. In all cases, basal breast cancer cell functions were rescued with mirVana miR-21 mimic. All together our results identify HB-EGF as a new and relevant biomarker with potentially high value in quantifying LPA1 activation state in patients receiving anti-LPA1 therapiesL'acide lysophosphatique est un biolipide naturel actif capable de réguler diverses fonctions biologiques et d'agir en tant que facteur de croissance, via l'activation de six différents récepteurs de surfaces couplées aux protéines G (LPA1-6). Notre laboratoire a montré que le ciblage thérapeutique du récepteur LPA1 bloque de façon remarquable la dissémination métastatique des cellules de cancer du sein. Les mécanismes moléculaires et génétiques impliqués dans ce processus sont cependant encore inconnus. De plus, la plupart des cellules de mammifères co-expriment plusieurs formes de récepteurs du LPA. La réponse cellulaire est la résultante de l'activation de multiples voies de signalisation, parfois synergiques ou opposées, compromettant la validation chez le patient de l'efficacité des thérapies ciblant ces récepteurs. Au cours de cette thèse, nous avons dans un premier temps montré que HB-EGF est un marqueur spécifique de l'activité de LPA1. Le blocage pharmacologique de ce récepteur via des antagonistes des récepteurs LPA1-3 (Ki16425/Debio0719) ou l'invalidation de son expression par une technique d'ARN interférence entraine une inhibition de la surexpression en HB-EGF. Le ciblage thérapeutique de LPA1 via l'antagoniste Ki16425, dans notre modèle animal préclinique de xénogreffe de cancer de la prostate PC3, conduit également à une diminution de l'expression en ARNm de HB-EGF au niveau de la tumeur primaire et à une diminution des concentrations en HB-EGF humain circulants dans le sérum. Dans un deuxième temps, nous nous sommes intéressé au rôle des miRNAs, qui sont impliqués dans la régulation de l'expression de gènes. Grâce à l'analyse de 1488 patients atteins de cancers du sein référencés sur des bases de données publiques, nous avons pu établir une corrélation entre le gène LPA1 et le gène ZEB1. Nous avons également trouvé que le coefficient de corrélation entre ZEB1 et LPA1 était supérieur au niveau des tumeurs mammaires basale

Comparative study between histological changes in placenta from pre-eclampsia cases and normal pregnancy with special reference to cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis

Background: Placenta is a vital organ and the most accurate record of the infant’s prenatal experience. Pregnancy complications like hypertension significantly affect the placenta. Thus there is a need for thorough examination of it. Therefore the present study is dedicated to see the histological changes in placenta of pre-eclampsia with special reference to cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis and compared it with that of normal placenta.Methods: Total 60 placentas were collected (30 from pre-eclampsia and 30 from normal pregnancy). Results were expressed in percentage after counting 100 villi. Data analysis has been done using Graphpad InStat 3 version and data is significant when p – value is &lt;0.05.Results: Mean no. of cytotrophoblastic cell hyperplasia, villous stromal fibrosis and fibrinoid necrosis in normal placenta are 10.1±5.01, 2.26±1.56 and 2.84±1.4 respectively and those in pre-eclampsia placenta are 36.82±16.15, 28.16± 34.42 and 8.22±1.44 respectively which are highly significant ( p-value &lt;0.001).Conclusions: There is significant increase in number of cytotrophoblastic cell hyperplasia, villous stromal fibrosis and areas fibrinoid necrosis in placenta from pre-eclampsia cases than that of normal placenta. These changes may be due to vascular insufficiency which is usually occurring in pre-eclampsia

Autotaxin-&#x3B2; interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis

International audienc

Laboratory Investigation to Assess Spontaneous Combustion/Fire During Extraction of Thick Coal Seam

Spontaneous combustion/fire and explosions occurring in the goaf area due to depillaring of thick coal seam (5–8 m) experiences significant loss to the mining industry. This ultimately causes destruction of natural resources and fatal accidents in India. Thus, it is threatening the safety of underground coal mines. This paper includes various laboratory studies to determine the cause of spontaneous combustion/fire during depillaring of panels in thick coal seams. The laboratory investigation comprises of proximate analysis, critical oxidation temperature study, differential scanning calorimetric analysis, fire ladder study, and goaf ignition temperature. The field investigation comprises of hygrometric survey to determine moisture loss and ventilation survey of the working seam to reveal that the goaf of the working panel is highly prone to spontaneous combustion/fire. The results of the above studies will help to develop suitable technique, i.e., partial stowing in goaf areas with the application of water mist spraying to prevent spontaneous combustion/fire during depillaring of thick coal seam. The above studies were carried out during depillaring panels (B2A and B2B) of a thick seam (5.4 m) at Khottadih Colliery, M/s Eastern Coalfields Limited of Raniganj coalfield of India

Pharmacological blockade of LPA₁<i>in vivo</i> inhibits HB-EGF secretion by human PC3 xenographs.

<p>PC3 tumor cells were injected subcutaneously in the right flank of male BALB/C nude mice. At day 35, post-tumor cell injection animals were randomized into two groups and treated with Ki16425 (25 mg/kg) or the vehicle for 5 d. (A) Representative photographs of primary tumors at day 40 (upper panels). Box plot represent tumor volumes (in mm³) (lower panels). Bar represents 10 mm. (B) <i>LPAR1</i>, <i>LPAR2</i> and <i>LPAR3</i> expressions were measured by real-time quantitative PCR and normalized to housekeeping <i>L32</i> gene values (Veh: Vehicle; Ki: Ki16425) (C) Box plot represents expression of HB-EGF mRNA expression detected by real-time quantitative PCR from total RNAs isolated from tumors of animals treated with vehicle or Ki16425. Values were normalized to housekeeping L32 gene. ¶: <i>p</i><0.05, using unpaired Student t-Test. (D) Box plot represents HB-EGF concentration detected by ELISA in the serum of animals treated with Ki16425 or vehicle. ¶: <i>p</i><0.05, using unpaired Student t-Test.</p