Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity.

Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell's ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell's ability to drive disease recurrence

Neural stem cell properties of Müller glia in the mammalian retina: Regulation by Notch and Wnt signaling

AbstractThe retina in adult mammals, unlike those in lower vertebrates such as fish and amphibians, is not known to support neurogenesis. However, when injured, the adult mammalian retina displays neurogenic changes, raising the possibility that neurogenic potential may be evolutionarily conserved and could be exploited for regenerative therapy. Here, we show that Müller cells, when retrospectively enriched from the normal retina, like their radial glial counterparts in the central nervous system (CNS), display cardinal features of neural stem cells (NSCs), i.e., they self-renew and generate all three basic cell types of the CNS. In addition, they possess the potential to generate retinal neurons, both in vitro and in vivo. We also provide direct evidence, by transplanting prospectively enriched injury-activated Müller cells into normal eye, that Müller cells have neurogenic potential and can generate retinal neurons, confirming a hypothesis, first proposed in lower vertebrates. This potential is likely due to the NSC nature of Müller cells that remains dormant under the constraint of non-neurogenic environment of the adult normal retina. Additionally, we demonstrate that the mechanism of activating the dormant stem cell properties in Müller cells involves Wnt and Notch pathways. Together, these results identify Müller cells as latent NSCs in the mammalian retina and hence, may serve as a potential target for cellular manipulation for treating retinal degeneration

Multi-Criteria Hydro-Economic Decision Tool for Rejuvenating Community Irrigation Tanks in Rural India

Rising water scarcity in agriculture has been a major concern worldwide. As resource managers seek to address this issue, Integrated Water Resources Management (IWRM) has become a widely accepted sustainability paradigm. The purpose of this study is to evaluate restoration alternatives of irrigation tanks by applying multi-criteria and probabilistic benefit–cost analysis for a rural watershed in India. We incorporate the principles of local-IWRM, namely, hydrological balance, efficiency, equity, stakeholders’ involvement, and uncertainty. We use the mixed-method approach of data collection, including remotely sensed hydro-ecological data, walk-through field observations, focus groups, and household surveys. The study region produces a large percent of runoff water (i.e., about 67% of the total precipitation) which can be partially captured to sustain irrigation tanks. The majority of the tanks in the study area do possess moderate to high irrigation potential yet remain in poor conditions. A proposed lift irrigation scheme with a 75% or more increase in water availability could return from ₹ 1.23 to ₹ 1.73 on every Indian rupee (₹) invested, in addition to other socio-ecological benefits. The increase in water availability could lead to future crop area expansion, which comes with a high price tag. Therefore, using additional water on the existing crop area can be just as economically viable as water-induced crop expansion. A coordinated effort on the part of local agencies and water users is necessary for efficient and equitable use of incremental water that comes from any restoration efforts in the study area or elsewhere

Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity.

Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell's ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell's ability to drive disease recurrence

Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity.

Although chemotherapy is used to treat most advanced solid tumors, recurrent disease is still the major cause of cancer-related mortality. Cancer stem cells (CSCs) have been the focus of intense research in recent years because they provide a possible explanation for disease relapse. However, the precise role of CSCs in recurrent disease remains poorly understood and surprisingly little attention has been focused on studying the cells responsible for re-initiating tumor growth within the original host after chemotherapy treatment. We utilized both xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) to characterize the residual tumor cells that survive chemotherapy treatment and go on to cause tumor regrowth, which we refer to as tumor re-initiating cells (TRICs). We set out to determine whether TRICs display characteristics of CSCs, and whether assays used to define CSCs also provide an accurate readout of a cell's ability to cause tumor recurrence. We did not find consistent enrichment of CSC marker positive cells or enhanced tumor initiating potential in TRICs. However, TRICs from all models do appear to be in EMT, a state that has been linked to chemoresistance in numerous types of cancer. Thus, the standard CSC assays may not accurately reflect a cell's ability to drive disease recurrence

Tumor initiating potential of TRICs in transplantation assays.

<p>Tumor size >50 mm³ was considered as positive for tumor growth.</p

Effect of stroma on tumor-initiating potential of TRICs in transplantation assays.

<p>VT = Tumor cells from vehicle-treated mice, CT = Tumor cells from chemo-treated mice at regression, VS = Stromal cells from vehicle-treated mice, and CS = Stromal cells from chemo-treated mice at regression. Tumor size of >50 mm³ was considered as positive for tumor growth.</p

TRICs are in a state of EMT.

<p>(A) Expression of EMT markers and EMT-driving transcription factors in Calu3-GFP and H441-GFP tumor cells isolated from vehicle or chemo treated mice at tumor regression was assessed by qRT-PCR. (B–C) Proportions of E-Cadherin and Vimentin expressing tumor cells were determined by immunofluorescence analysis in B) Calu3-GFP and C) H441-GFP tumors. Sections were co-stained for GFP and E-Cadherin or GFP and Vimentin. Data are expressed as average+/−SEM. (D–E) Correlation between the time course of chemotherapy-induced cell death (D) and expression of EMT-drivers as determined by qRT-PCR (E) Presented expression levels are relative to time-matched vehicle-treated controls.</p

Increased Stromal Component in Residual Chemotherapy-Treated Tumors.

<p>A) Masson’s Trichrome staining of vehicle and regressed chemo-treated tumors showing a decrease in tumor cells (red) and an increase in collagen-containing stromal cells (blue) in residual tumors. B) FACS analysis of vehicle and regressed tumors showing a decreased tumor:stroma ratio in residual tumors.</p

Role of CTLA4 in the Proliferation and Survival of Chronic Lymphocytic Leukemia

<div><p>Earlier, we reported that CTLA4 expression is inversely correlated with CD38 expression in chronic lymphocytic leukemia (CLL) cells. However, the specific role of CTLA4 in CLL pathogenesis remains unknown. Therefore, to elucidate the possible role of CTLA4 in CLL pathogenesis, CTLA4 was down-regulated in primary CLL cells. We then evaluated proliferation/survival in these cells using MTT, ³H-thymidine uptake and Annexin-V apoptosis assays. We also measured expression levels of downstream molecules involved in B-cell proliferation/survival signaling including STAT1, NFATC2, c-Fos, c-Myc, and Bcl-2 using microarray, PCR, western blotting analyses, and a stromal cell culture system. CLL cells with CTLA4 down-regulation demonstrated a significant increase in proliferation and survival along with an increased expression of STAT1, STAT1 phosphorylation, NFATC2, c-Fos phosphorylation, c-Myc, Ki-67 and Bcl-2 molecules. In addition, compared to controls, the CTLA4-downregulated CLL cells showed a decreased frequency of apoptosis, which also correlated with increased expression of Bcl-2. Interestingly, CLL cells from lymph node and CLL cells co-cultured on stroma expressed lower levels of CTLA4 and higher levels of c-Fos, c-Myc, and Bcl-2 compared to CLL control cells. These results indicate that microenvironment-controlled-CTLA4 expression mediates proliferation/survival of CLL cells by regulating the expression/activation of STAT1, NFATC2, c-Fos, c-Myc, and/or Bcl-2.</p></div