REGULATION OF CANCER METASTASIS BY PROTEIN KINASE D1: A GLOBAL REGULATORY CASCADE

Protein Kinase D1 (PKD1) is a serine threonine kinase which is downregulated in Prostate, Breast and Colon Cancer. It functions as a tumor suppressor in different cancer cells. Downregulation of PKD1 is known to be associated with aggressiveness of the cancer. PKD1 is known to regulate many key oncogenic signaling pathways such as E-cadherin, β-catenin and Androgen Receptor signaling pathways. Aberrant expression of these oncogenic pathways leads to transformation of cells from normal to malignant phenotype, thereby leading to increased proliferation, growth and metastasis to distant organs of these cancer cells. Literature evidence also points to the fact that E-cadherin β-catenin and PKD1 play a role in regulation of epithelial mesenchymal transition (EMT). To fully understand how PKD1 regulates β-catenin signaling, we investigated the effect of PKD1 overexpression on β-catenin signaling in colon cancer cells. We observed that PKD1 overexpression is responsible for inhibition of cell proliferation and colony formation ability of different colon cancer cell lines. Moreover, nuclear PKD1 overexpression leads to inhibition of β-catenin transcription activity in colon cancer cells. Further evaluation in in vivo mouse model showed that PKD1 is responsible for inhibition of colon cancer tumor growth in xenograft mouse model. This paved way for us to look for the effect of PKD1 on other downstream targets of β-catenin pathway which regulate EMT process in cancer cells such as Metastasis associated Protein 1. Metastasis associated Protein 1 (MTA1) is a nucleosome remodeling and histone deacetylase protein (NuRD) which is overexpressed in all the cancers. MTA1 is an initiator of epithelial and mesenchymal transition and is responsible for cancer cells metastasizing to different organs of the body. Expression of MTA1 directly correlates with the aggressiveness of the cancer. MTA1 is known to regulate β-catenin and Androgen Receptor signaling pathways leading to cancer cells acquiring metastatic capabilities. Therefore, in our study we evaluated the inverse correlation between MTA1 and PKD1 in different cancer cells. To investigate the cellular effect of PKD1 in prostate and colon cancer, stable PKD1 overexpressing prostate (C4-2) and colon cancer cells (SW480) were utilized. PKD1 overexpression inhibited MTA1 expression in prostate and colon cancer cells. PKD1 interacts, phosphorylate, translocate and degrades MTA1. Kinase domain and N terminal domain of PKD1 play a significant role in MTA1 interaction and phosphorylation. Phosphorylation of MTA1 leads to nuclear export via golgi and trans-golgi network to lysosome. Bryostatin-1 is a macrocyclic lactone which modulates PKD1 activity. Bryostatin-1 was used to activate PKD1 expression in C4-2 cells and MTA1 translocation was then tracked. This translocation of MTA1 to lysosome is a ubiquitin dependent phenomenon leading protein degradation. PKD1 overexpression leads to inhibition of tumor growth and bone metastasis leading to inhibition of osteoblast to osteoclast formation as determined by RANK expression. PTEN Knockout and TRAMP mouse model also show inverse correlation between PKD1 and MTA1 expression in prostate tissues at different weeks. Human tissue microarray of prostate, colon and breast cancer (MTA1 is overexpressed and PKD1 is downregulated in breast cancer, therefore, we tested our hypothesis in breast cancer as well) showed inverse correlation between PKD1 and MTA1 in different grade tumor tissue signifying clinical relevance of this correlation. For proof of concept of our hypothesis we used ormeloxifene because Bryostatin-1 has mild toxicity issue. Ormeloxifene is a novel modulator of PKD1 activity and it targets rapidly dividing cells Further, we investigated the effect of ormeloxifene on activation of PKD1 leading to inhibition of cancer metastasis. We observed specific activation of PKD1 expression of ormeloxifene which inhibited MTA1 expression leading to inhibition of tumor growth in xenograft mouse. We further evaluated the efficacy of ormeloxifene to inhibit metastatic prostate cancer cells (PC3 and DU145). Ormeloxifene showed excellent anti-cancer efficacy against prostate cancer as it inhibited cell proliferation, invasion and migration of metastatic prostate cancer cells. Moreoever, ormeloxifene induced cell cycle arrest at G0/G1 phase by regulating key cell cycle regulatory proteins. It also inhibited metastasis of prostate cancer leading to inhibition of key metastatic markers involved to epithelial mesenchymal transition. Ormeloxifene also showed excellent in vivo efficacy against metastatic prostate cancer cells. Therefore, ormeloxifene could be a potential therapeutic modality for metastatic cancers as it targets EMT signaling. To conclude, we for the very first time have elucidated a novel regulatory mechanism of PKD1 mediated regulation of MTA1 that plays an important role in cancer progression and metastasis. For cancer cells to metastasize PKD1 expression is suppressed with subsequent increased expression of MTA1. We elucidated that repression of MTA1 with subsequent activation of MTA1 leads to attenuation of cancer metastasis. Moreover, therapeutic modality that targets this novel regulatory pathway leading to activation of PKD1 and inhibition of MTA1 is an ideal candidate for treatment of advanced stage metastatic cancers

Quality Assurance and Quality Control Correlations for the Dynamic Cone Penetrometer

The Dynamic Cone Penetrometer (DCP) is a device that is used for the estimation of in situ compaction quality of constructed subgrades and embankments. It is a relatively inexpensive, light-weight and easy to use device that measures the dynamic penetration resistance of the compacted soil, from which an estimate of soil strength and stiffness characteristics can be made. Owing to its ease of use, many DOTs in the U.S. have employed the DCP in their compaction quality control procedures, and over the past few decades, extensive research has been carried out on the development of correlations between the results of the DCP test and the results of strength and stiffness tests performed on compacted soils (e.g., California bearing ratio, and resilient modulus). The objectives of this research are to refine DCP-based quality assurance and quality control correlations for compaction quality control developed by previous research studies carried out at Purdue for the Indiana Department of Transportation, especially focusing on i) grouping of the soils based on their mechanical response to the DCP loading, and ii) limiting the in situ moisture range of the soils used for development of correlations within -2% of the optimum moisture content of the tested soil. The factors outlined above are studied, and in particular, soil grouping is examined critically. The AASHTO (`A-based\u27) classification employed previously for classification of soils is replaced by a new classification criteria specifically developed for the DCP test. Soils are grouped into one of the two categories of coarse-grained or fine-grained soils on the basis of the size of the dominant particle in the soil. The criteria developed for the classification of soil into one of these two categories is based on index properties of the soil, such as the standard Proctor maximum dry density, optimum moisture content, plasticity index (PI) and fines content (percentage passing 0.075 mm sieve size). For the purpose of refinement of the QA/QC correlations, extensive field and laboratory tests (more than 750 DCP tests) were carried out on soils found in Indiana to add to the existing database of DCP test results. The database was then statistically analyzed for extraction of the representative DCP test value (number of DCP blows required for a specific depth of penetration into the compacted soil) for different types of soil. Results show that the DCP test results for fine-grained soils have a good correlation with the PI, which is indicative of the clay content of the soil, while the DCP test results for coarse-grained soils have good correlations with the optimum moisture content of the soil, which is indicative of the targeted in situ density of the soil. Furthermore, a statistical analysis of the distribution of DCP blow counts in the field revealed that the mean of a minimum of 7 closely spaced tests is required to get a representative blow count of the compacted soil at a given location. More targeted testing is needed to assess the frequency of DCP testing required for larger areas

A novel approach for direct estimation of fresh groundwater discharge to an estuary

This paper is not subject to U.S. copyright. The definitive version was published in Geophysical Research Letters 38 (2011): L11402, doi:10.1029/2011GL047718.Coastal groundwater discharge is an important source of freshwater and nutrients to coastal and estuarine systems. Directly quantifying the spatially integrated discharge of fresh groundwater over a coastline is difficult due to spatial variability and limited observational methods. In this study, I applied a novel approach to estimate net freshwater discharge from a groundwater-fed tidal creek over a spring-neap cycle, with high temporal resolution. Acoustic velocity instruments measured tidal water fluxes while other sensors measured vertical and lateral salinity to estimate cross-sectionally averaged salinity. These measurements were used in a time-dependent version of Knudsen's salt balance calculation to estimate the fresh groundwater contribution to the tidal creek. The time-series of fresh groundwater discharge shows the dependence of fresh groundwater discharge on tidal pumping, and the large difference between monthly mean discharge and instantaneous discharge over shorter timescales. The approach developed here can be implemented over timescales from days to years, in any size estuary with dominant groundwater inputs and well-defined cross-sections. The approach also directly links delivery of groundwater from the watershed with fluxes to the coastal environment.Funding was provided by the USGS Coastal and Marine Geology Program

Exploring positive women\u27s lives in Namakkal District, India

This report describes an initiative that was undertaken to document the experiences of HIV-positive ever-married women in Namakkal district, Tamil Nadu, India. The initiative sought to explore the circumstances in which women learned about their HIV status; their feelings on finding out they were HIV-positive; the nature of husband–wife relationships prior to and following disclosure of women’s HIV status; the extent of support or discrimination that women experienced from family members, friends, and neighbors; treatment-seeking behaviors; and women’s perspectives about ways in which the multiple needs of HIV-infected women can be met. Drawing on the testimonies of these women gathered by trained investigators who were themselves HIV-positive, the report attempts to bring faces and voices to the reality of the HIV epidemic, particularly among married women. Findings show that women living with HIV face multiple vulnerabilities, ranging from physical and mental ill-health to concerns about financial security, family and peer support, and securing the future of their children. The findings call, correspondingly, for multiple efforts that address HIV-positive women’s health and well-being as well as empower them to lead their lives with confidence and dignity

Quantifying the residence time and flushing characteristics of a shallow, back-barrier estuary : application of hydrodynamic and particle tracking models

This paper is not subject to U.S. copyright. The definitive version was published in Estuaries and Coasts 38 (2015): 1719-1734, doi:10.1007/s12237-014-9885-3.Estuarine residence time is a major driver of eutrophication and water quality. Barnegat Bay-Little Egg Harbor (BB-LEH), New Jersey, is a lagoonal back-barrier estuary that is subject to anthropogenic pressures including nutrient loading, eutrophication, and subsequent declines in water quality. A combination of hydrodynamic and particle tracking modeling was used to identify the mechanisms controlling flushing, residence time, and spatial variability of particle retention. The models demonstrated a pronounced northward subtidal flow from Little Egg Inlet in the south to Pt. Pleasant Canal in the north due to frictional effects in the inlets, leading to better flushing of the southern half of the estuary and particle retention in the northern estuary. Mean residence time for BB-LEH was 13 days but spatial variability was between ∼0 and 30 days depending on the initial particle location. Mean residence time with tidal forcing alone was 24 days (spatial variability between ∼0 and 50 days); the tides were relatively inefficient in flushing the northern end of the Bay. Scenarios with successive exclusion of physical processes from the models revealed that meteorological and remote offshore forcing were stronger drivers of exchange than riverine inflow. Investigations of water quality and eutrophication should take into account spatial variability in hydrodynamics and residence time in order to better quantify the roles of nutrient loading, production, and flushing.Funding was provided by the New Jersey Department of Environmental Protection and the Coastal and Marine Geology Program of the U.S. Geological Survey

Use of intracervical Foley catheter for pre-induction cervical ripening in women planned for vaginal birth after previous caesarean section

Background: Vaginal birth after previous caesarean section is challenging for obstetricians due to increased risk of uterine rupture. Common methods for labour induction in post caesarean pregnancies are membrane sweeping, balloon catheters, prostaglandins (PGE2), and oxytocin. As currently available data is limited, the evidence of safest method of induction is lacking. The present study aimed to assess the effectiveness of intra-cervical Foley catheter for pre-induction cervical ripening in women planned for vaginal birth after caesarean section.Methods: This prospective cross-sectional study included 24 pregnant women with a history of previous caesarean section, admitted for induction of labour. Induction was performed in patients with unfavourable modified Bishop Score by intra-cervical Foley catheter. The change in modified Bishop Score, oxytocin requirement, induction-delivery interval, mode of delivery, maternal complications and neonatal outcome were observed.Results: There was significant improvement in modified BS noted at the end of trans-cervical Foley catheter induction and this improvement in mean of modified BS was observed to be statistically significant (p<0.0001). The vaginal delivery rate was 29.2% while 70.8% of patients underwent caesarean section. No significant maternal or foetal complications were observed with Foley catheter induction except for one case of vaginal bleeding. There was no case of intrapartum or postpartum maternal infection.Conclusions: Foley catheter may be a cheap and effective method for pre-induction cervical ripening and induction of labour in patients with previous caesarean section

Application of Neural Networks for Avalanche Forecasting

Application of neural networks is investigated for the prediction of avalanches on Chowkibal-Tangdhar road axis in Jammu and Kashmir. The networks are developed and trained monthwiseusing the past snow and weather parameters recorded at the Stage-II Observatory on the axisto generate an assessment of avalanche and non-avalanche activities. Two approaches havebeen considered for training the network. In the first approach, only avalanche activities observedin the axis were taken for training, and in the second approach, along with the observed activities,the opinion of expert forecasters were also considered. The performance of the networks variesfrom 67 to 82 per cent for correct predictions. Winter data for 2001-2002 has been used to validatethe network performance

Relationship of body mass index with bone mineral density in postmenopausal women: an Indian perspective

Background: Osteoporosis is a common health problem that affects postmenopausal females, leading to increased susceptibility to fractures. Body mass index (BMI) has been shown to be an important predictor of bone mineral density (BMD) with increased body weight correlating with positive influence on bone metabolism. Low BMI predisposes postmenopausal females to rapid bone loss and low bone mass, crucial in the pathogenesis of osteoporosis. However, a specific BMI value chart to accurately predict osteoporosis remains to be fully established. The present study aimed to investigate the relationship of BMI and BMD in postmenopausal Indian females.Methods: 90 healthy postmenopausal females with 1-5 years of menopause were enrolled in the study. Subjects were categorized according to their BMI into normal, overweight and obese. BMD was assessed using dual energy X-ray absorptiometry (DEXA) scan at L1-L4 vertebrae and femoral neck and expressed as T-scores. Quantitative variables were compared using ANOVA/Kruskal Wallis Test.Results: Bone mineral density was significantly higher in the obese group as compared to normal BMI group at both lumbar spine (p=0.001) and femoral neck (p=0.001). BMD at lumbar spine was lower than that at femoral neck across all the three groups of BMI.Conclusions: BMI and body weight are important factors affecting BMD. Postmenopausal females with low BMI are more likely to have osteopenia and osteoporosis and are thus at an increased risk of pathological fractures. Routine BMD monitoring in postmenopausal females with low BMI may be necessary to initiate early clinical interventions for osteoporosis

Sediment dynamics of a divergent bay-marsh complex

Author Posting. © Springer Nature , 2020. This article is posted here by permission of Springer Nature for personal use, not for redistribution. The definitive version was published in Nowacki, D. J., & Ganju, N. K. Sediment dynamics of a divergent bay-marsh complex. Estuaries and Coasts, (2020), doi:10.1007/s12237-020-00855-5.Bay–marsh systems, composed of an embayment surrounded by fringing marsh incised by tidal channels, are widely distributed coastal environments. External sediment availability, marsh-edge erosion, and sea-level rise acting on such bay–marsh complexes may drive diverse sediment-flux regimes. These factors reinforce the ephemeral and dynamic nature of fringing marshes: material released by marsh-edge erosion becomes part of a bay–marsh exchange that fuels the geomorphic evolution of the coupled system. The dynamics of this sediment exchange determine the balance among seaward export, deposition on the embayment seabed, flux into tidal channels, and import to the marsh platform. In this work, we investigate the sediment dynamics of a transgressive bay–marsh complex and link them to larger-scale considerations of its geomorphic trajectory. Grand Bay, Alabama/Mississippi, is a shallow microtidal embayment surrounded by salt marshes with lateral erosion rates of up to 5 m year−1. We collected 6 months of oceanographic data at four moorings within Grand Bay and its tidal channels to assess hydrographic conditions and net sediment-flux patterns and augmented the observations with numerical modeling. The observations imply a divergent sedimentary system in which a majority of the suspended sediment is exported seaward, while a smaller fraction is imported landward via tidal channels, assisting in vertical marsh-plain accumulation, maintenance of channel and intertidal-flat morphologies, and landward transgression. These results describe a dynamic system that is responsive to episodic atmospheric forcing in the absence of a strong tidal signal and the presence of severe lateral marsh loss.We thank the staff of the Grand Bay NERR for their role in facilitating fieldwork within Grand Bay. Jonathan Pitchford, also of the Grand Bay NERR, provided the SET data. Giulio Mariotti and an anonymous reviewer are acknowledged for their helpful comments