Environmental Geology of Lake and Porter Counties, Indiana - An Aid to Planning

Indiana Geological Survey Special Report 11; Indiana Geological Survey Environmental Study 8Lake and Porter Counties are subdivided into three physiographically and geologically distinct regions: (1) the Calumet Lacustrine Plain, (2) the ValparaisoMorainal Area, and (3) the Kankakee Outwash and Lacustrine Plain. The surficial deposits of these regions, which range in thickness from 40 feet near the Kankakee River to more than 250 feet near Valparaiso, Ind,. Are the products, either directly or indirectly, of the Wisconsinan Age of glaciation. The Calumet lake plain is characterized by low-lying complexly intermixed clay, sand, and silt deposits, mostly of glacial Lake Chicago origin , The Valparaiso Moraine forms high ground in the two counties and is composed of clay-rich to fine sandy till. Sand and fine gravel deposits constitute the bulk of the Kankakee Outwash and Lacustrine Plain, this area being the low-lying outwash and flood plain for the glacially derived rivers as well as for the present Kankakee River. The two-county area has an abundance of geologic and geologically related resources; some of the most important are: (1) groundwater of the Kankakee Outwash and Lacustrine Plain and Valparaiso Morainal Area, (2) sand deposits of glacial Lake Chicago and of recent origin, (3) rich soils developed on the Valparaiso Moraine and Kankakee outwash plain, and (4) surface water in the form of streams, rivers, and small lakes. Some of these resources have already been damaged during the course of man’s habitation and use, but all can, with proper understanding of the problems and the willingness to act, be saved from further unnecessary degradation. Certain kinds of land use, which are partly dependent on the local geology, are potential sources of difficulty. These include (1) siting and use of sanitary landfills, (2) placement of septic systems, sewage lagoons, and industrial holding ponds, (3) management of flood plains, (4) development of the Lake Michigan shoreline, (5) construction of all kinds in areas where little is known about the engineering and hydrologic properties of the materials, (6) disposal of industrial wastes by deep well injection methods, and (7) development of groundwater supplies without sufficient hydrologic and geologic data. The environmental problems of Lake and Porter Counties, are related to geology, are as varied and complex as the materials themselves. Specific questions related to a given problem are best answered by the competent consultant equipped to do so. This report, though intended to supply valuable geologic information on a variety of land use related subjects, should not replace onsite evaluation of the salient parameters involved with each problem that potentially arises whenever man uses earth materials or otherwise disturbs or rearranges the natural earth condition.Indiana Department of Natural Resource

The scaffolding protein NHERF1 sensitizes EGFR-dependent tumor growth, motility and invadopodia function to gefitinib treatment in breast cancer cells.

Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress EGFR but are resistant to Tyrosine Kinase Inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the down-regulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB-231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1-EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs

Involvement of nuclear NHERF1 in colorectal cancer progression.

NHERF1 (Na+/H+ exchanger regulatory factor 1) is expressed in the luminal membrane of many epithelia, and associated with proteins involved in tumor progression. Alterations of NHERF1 expression in different sites of metastatic colorectal cancer (mCRC) suggest a dynamic role of this protein in colon carcinogenesis. We focused on the observation of the altered expression of NHERF1 from non-neoplastic tissues to metastatic sites by immunohistochemistry. Moreover, we studied, by immunofluorescence, the colocalization between NHERF1 and the epidermal growth factor receptor (EGFR), whose overexpression is implicated in CRC progression. NHERF1 showed a different localization and expression in the examined sites. The distant non-neoplastic tissues showed NHERF1 mostly expressed at the apical membrane, while in surrounding non-neoplastic tissue decreased the apical membrane and increased cytoplasmic immunoreactivity. In adenomas a shift from apical membrane to cytoplasmic localization and nuclear expression were observed. Cytoplasmic staining in the tumor, and metastatic sites was stronger than surrounding non-neoplastic tissue. Furthermore, nuclear NHERF1 expression was noted in 80% of all samples and surprisingly, it appeared already in adenoma lesions, suggesting that NHERF1 represents an early marker of pre-morphological triggering of colorectal carcinogenesis. Then, in few tumors a positive direct correlation between membrane NHERF1 and EGFR expression was evidenced by their colocalization. Nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, may contribute to the onset of malignant phenotype. Specifically, we hypothesize the direct involvement of nuclear NHERF1 in both carcinogenesis and progression and its role as a potential colorectal cancer marke

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology.

Tissue acidosis plays a pivotal role in tumor progression: in particular, interstitial acidosis promotes tumor cell invasion, and is a major contributor to the dysregulation of tumor immunity and tumor stromal cells. The cell membrane and integral membrane proteins commonly act as important sensors and transducers of altered pH. Cell adhesion molecules and cation channels are prominent membrane proteins, the majority of which is regulated by protons. The pathophysiological consequences of proton-sensitive ion channel function in cancer, however, are scarcely considered in the literature. Thus, the main focus of this review is to highlight possible events in tumor progression and tumor immunity where the pH sensitivity of cation channels could be of great importance

Proton dynamics in cancer

Cancer remains a leading cause of death in the world today. Despite decades of research to identify novel therapeutic approaches, durable regressions of metastatic disease are still scanty and survival benefits often negligible. While the current strategy is mostly converging on target-therapies aimed at selectively affecting altered molecular pathways in tumor cells, evidences are in parallel pointing to cell metabolism as a potential Achilles' heel of cancer, to be disrupted for achieving therapeutic benefit. Critical differences in the metabolism of tumor versus normal cells, which include abnormal glycolysis, high lactic acid production, protons accumulation and reversed intra-extracellular pH gradients, make tumor site a hostile microenvironment where only cancer cells can proliferate and survive. Inhibiting these pathways by blocking proton pumps and transporters may deprive cancer cells of a key mechanism of detoxification and thus represent a novel strategy for a pleiotropic and multifaceted suppression of cancer cell growth