Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies

BACKGROUND: The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1α stability is controlled by O(2)-sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L-PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development. METHODS AND FINDINGS: Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1α levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA FIH knockdown experiments in trophoblastic JEG-3 cells. E-PE tissues had markedly diminished HIF-1α hydroxylation at proline residues 402 and 564 as assessed with monoclonal antibodies raised against hydroxylated HIF-1α P402 or P564, suggesting regulation by PHD2 and not PHD3. Culturing villous explants under varying oxygen tensions revealed that E-PE, but not L-PE, placentae were unable to regulate HIF-1α levels because PHD2, FIH and SIAHs did not sense a hypoxic environment. CONCLUSION: Disruption of oxygen sensing in E-PE vs. L-PE and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O(2)-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity

Rock-uplift history of the Central Pontides from river-profile inversions and implications for development of the North Anatolian Fault

Major strike-slip fault systems on Earth, like the North Anatolian Fault (NAF), play an important role in accommodating plate motion, but surprisingly little is known about how such structures evolve through space and time. Along the central sector of the NAF in the Central Pontides, transpression and crustal thickening along the northward restraining bend of the fault are thought to have generated rock-uplift rates of 0.2-0.3 km/Myr since at least 400 ka based on Quaternary marine and river terraces, while data from low-temperature thermochronology suggest that an enhanced exhumation phase occurred within the last 11 Myr. However, the precise onset of this faster uplift phase, which likely reflects deformation associated with the development of the central sector of the NAF, is poorly constrained. Here we define the spatiotemporal pattern of rock-uplift rates within the Central Pontides over the last -10 Myr by performing linear inversions of 19 river profiles that drain the northern margin of the Central Pontides, from the Sinop Range to the Black Sea. We use 21 new 10Be-derived basin-average denudation rates to calibrate an erodibility parameter, which we use to convert our & chi;-transformed river profiles into rock-uplift histories. Our results document an increase in rock-uplift rates after 10 Ma, with peak rates of -0.15-0.25 km/Myr occurring between 4 and 2 Ma. Moreover, the spatiotemporal pattern of uplift suggests that faster rock uplift started in the eastern part of the Sinop Range and migrated westward over a period of ca. 2 to 2.5 Myr, which we relate to the westward propagation of the NAF through this sector at a rate of 74 & PLUSMN; 13 km/Myr. In the context of previously published constraints on the westward propagation of the NAF starting in eastern Turkey at -12 Ma, our results suggest differences in fault-propagation rates that coincide with differences in the orientation of the NAF relative to plate -convergence velocity vectors. Fault segments with higher obliquity appear to have propagated at rates up to 2-fold slower than those oriented more parallel to the plate-convergence vector. & COPY; 2023 Elsevier B.V. All rights reserved

Transient response to changes in uplift rates in the northern Atlas-Meseta system (Morocco)

International audienceTransient topography represents an opportunity for extracting information on the combined effect of tectonics, mantle-driven processes, lithology and climate across different temporal and spatial scales. The geomorphic signature of transient conditions can be used to unravel landscape evolution, especially in areas devoid of stratigraphic constraints. The topography of the Western Moroccan Meseta domain (WMM) is characterized by elevated non-lithological knickpoints, that delimit an uplifted relict landscape, implying a transient response to a change in uplift rate that occurred during the Cenozoic. Here, we determine denudation rates of selected watersheds and bedrock outcrops from cosmogenic nuclides and perform stream profile, regional and basin-scale geomorphic analysis. Denudation rates of the relict and the rejuvenated landscape range from 15 to 20 m/Myr and from 30 to 40 m/Myr, respectively. Rock uplift rates from river-profile inversions are 10-25 m/Myr from 45 to 22 Ma and 30-55 m/Myr from 22 to 10 Ma. Despite the different time scales, the inverted rates are consistent with 10Be averaged denudation rates (15-20 and 30-40 m/Myr) and river incision values from Pleistocene lava flows (<10 and ~50 m/Myr) for the rejuvenated and relict regions of the WMM. These results agree with geological data and indicate that the observed ~400 m of surface uplift in the WMM started to develop possibly during the early Miocene (first phase). Given the wavelength of the topographic swell forming the topography of the WMM, uplift is here interpreted to reflect localized crustal thickening through magma addition or lithospheric thinning through mantle delamination. More recently, the occurrence of late Miocene marine sediments at ~1200 m of elevation indicates that the adjacent Folded Middle Atlas during the last 5-7 Ma experienced surface uplift at ~170-220 m/Myr. Considering the cumulative amount of surface uplift that varies eastward from 400 to 800 and 1200 m from the Meseta to the Tabular and the Folded Middle Atlas, as well as the spatio-temporal pattern of alkaline volcanism (middle Miocene and Pliocene to Present), we suggest that the most recent episode (second phase) of surface uplift was induced by a larger-scale process that most likely included upwelling of asthenospheric mantle and to a lesser extent crustal shortening in the Folded Middle Atlas

Number of metastatic sentinel nodes as predictor of axillary involvement in patients with breast cancer

I.F. 3.132 Background and objectives. More than half of patients with positive sentinel node (SN) have no metastases in non-sentinel nodes (NSNs) on axillary lymph node dissection (ALND). The aim of this study was to investigate factors predictive of NSNs involvement, in order to identify patients with metastatic disease confined to the SN which might avoid ALND. Methods. ALND was performed in 167 patients with metastatic SN. Axillary NSNs status was correlated with the size of SN metastases, the size of the primary tumor and the occurrence of lymphovascular invasion. In 72 cases, the radiotracer (Tc-99m albumin colloid) marked multiple ( in most cases 2 or 3) nodes. In this group, NSNs status was correlated with the number of metastatic radioactive nodes ( 1 or > 1), and with the above mentioned histopathologic factors. Results. NSNs metastases were found in 57/167 cases (34.1%), the rate increasing proportionate to the size of both SN metastases ( p< 0.0001) and primary tumor ( p = 0.0075), while no significant correlation was found for lymphovascular invasion ( p = 0.1769). At univariate and multivariate analysis of findings from the 72 cases with multiple probe-detected hot nodes, positivity in more than one hot node was the strongest predictor of NSN involvement ( p = 0.0019). Conclusions. The identification and excision of multiple hot nodes can be useful in the prediction of NSNs involvement in patients with metastatic SN

Effect of periodontal therapy on the course of cyclosporin-induced gingival overgrowth: role of ABCB1 and PAI-1 gene polymorphisms.

OBJECTIVES: Etiological periodontal therapy is effective in reducing cyclosporin A-induced gingival overgrowth, but a high variability among subjects has been observed. This study aimed to evaluate the role of polymorphisms in PAI-1 and A BCB1 genes on the course of this side effect following periodontal therapy. METHOD AND MATERIALS: Forty-five transplant patients were subjected to nonsurgical periodontal therapy and evaluated for hypertrophy index, probing depths, bleeding, and plaque scores at baseline, and after 3 and 6 months. A BCB1 (C3435T and G2677T) and PAI-1 (4G/5G) polymorphisms were studied with polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction respectively. RESULTS: All the monitored periodontal indexes decreased significantly during the six months. Modeling of hypertrophy index by linearmixed- effect models (allowing non-normal distribution of the outcome variable hypertrophy index) resulted in the selection as the most significant model, of the one comprising the independent variables: time, C 3435T genotype, and their interaction term. This model indicated that C 3435T-mutated patients had significantly higher baseline hypertrophy index values (90% Markov chain Monte C arlo empirical confidence intervals: 5.08, 30.00). The decrease in hypertrophy index values over time showed a trend toward being faster in mutated than nonmutated patients (interaction time: C 3435T nonmutated, 90% Markov chain Monte C arlo empirical confidence interval: -11.08, -0.40). When hypertrophy index values were normalized, the significance and trend were lost. No effect of the A BCB1 G2677T and PAI-1 4G/5G polymorphisms was observed. CONCLUSION: These preliminary results suggest that C 3435T polymorphism is a genetic factor that could influence the course of cyclosporin A-induced gingival overgrowth in transplant patients subjected to periodontal therapy

Sentinel lymph node biopsy in breast cancer: the GIVOM experience in Veneto, Italy

IF 0,49

New insights into osteogenic and chondrogenic differentiation of human bone marrow mesenchymal stem cells and their potential clinical applications for bone regeneration in pediatric orthopaedics

Human mesenchymal stem cells (hMSCs) are pluripotent adult stem cells capable of being differentiated into osteoblasts, adipocytes, and chondrocytes.The osteogenic differentiation of hMSCs is regulated either by systemic hormones or by local growth factors able to induce specific intracellular signal pathways that modify the expression and activity of several transcription factors. Runt-related transcription factor 2 (Runx2) and Wnt signaling-related molecules are the major factors critically involved in the osteogenic differentiation process by hMSCs, and SRY-related high-mobility-group (HMG) box transcription factor 9 (SOX9) is involved in the chondrogenic one. hMSCs have generated a great interest in the field of regenerative medicine, particularly in bone regeneration. In this paper, we focused our attention on the molecular mechanisms involved in osteogenic and chondrogenic differentiation of hMSC, and the potential clinical use of hMSCs in osteoarticular pediatric disease characterized by fracture nonunion and pseudarthrosis