A novel prostate cell type-specific gene signature to interrogate prostate tumor differentiation status and monitor therapeutic response (running title: Phenotypic classification of prostate tumors)

In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumElow). LumElow tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC). Using discriminant function analysis, we generate a predictive 10-gene classifier for clinical implementation. This mini-classifier predicted with high accuracy the luminal status in both primary tumors and CRPCs. Immunohistochemistry for COL4A1, a low- luminal marker, sustained the association of attenuated luminal phenotype with metastatic disease. We found also an association of LumE score with tumor phenotype in genetically engineered mouse models (GEMMs) of prostate cancer. Notably, the metagene approach led to the discovery of drugs that could revert the low luminal status in prostate cell lines and mouse models. This study describes a novel tool to dissect the intrinsic heterogeneity of prostate tumors and provide predictive information on clinical outcome and treatment response in experimental and clinical samples

Transcriptional Reprogramming and Novel Therapeutic Approaches for Targeting Prostate Cancer Stem Cells

Prostate cancer is the most common malignancy in men and the second cause of cancer-related deaths in western countries. Despite the progress in the treatment of localized prostate cancer, there is still lack of effective therapies for the advanced forms of the disease. Most patients with advanced prostate cancer become resistant to androgen deprivation therapy (ADT), which remains the main therapeutic option in this setting, and progress to lethal metastatic castration-resistant prostate cancer (mCRPC). Current therapies for prostate cancer preferentially target proliferating, partially differentiated, and AR-dependent cancer cells that constitute the bulk of the tumor mass. However, the subpopulation of tumor-initiating or tumor-propagating stem-like cancer cells is virtually resistant to the standard treatments causing tumor relapse at the primary or metastatic sites. Understanding the pathways controlling the establishment, expansion and maintenance of the cancer stem cell (CSC) subpopulation is an important step toward the development of more effective treatment for prostate cancer, which might enable ablation or exhaustion of CSCs and prevent treatment resistance and disease recurrence. In this review, we focus on the impact of transcriptional regulators on phenotypic reprogramming of prostate CSCs and provide examples supporting the possibility of inhibiting maintenance and expansion of the CSC pool in human prostate cancer along with the currently available methodological approaches. Transcription factors are key elements for instructing specific transcriptional programs and inducing CSC-associated phenotypic changes implicated in disease progression and treatment resistance. Recent studies have shown that interfering with these processes causes exhaustion of CSCs with loss of self-renewal and tumorigenic capability in prostate cancer models. Targeting key transcriptional regulators in prostate CSCs is a valid therapeutic strategy waiting to be tested in clinical trials

On the inadequacy of environment impact assessments for projects in Bhagwan Mahavir Wildlife Sanctuary and National Park of Goa, India : a peer review

The Environment Impact Assessment (EIA) is a regulatory framework adopted since 1994 in India to evaluate the impact and mitigation measures of projects, however, even after 25 years of adoption, EIAs continue to be of inferior quality with respect to biodiversity documentation and assessment of impacts and their mitigation measures. This questions the credibility of the exercise, as deficient EIAs are habitually used as a basis for project clearances in ecologically sensitive and irreplaceable regions. The authors reiterate this point by analysing impact assessment documents for three projects: the doubling of the National Highway-4A, doubling of the railway-line from Castlerock to Kulem, and laying of a 400-kV transmission line through the Bhagwan Mahavir Wildlife Sanctuary and National Park in the state of Goa. Two of these projects were recently granted ‘Wildlife Clearance’ during a virtual meeting of the Standing Committee of the National Board of Wildlife (NBWL) without a thorough assessment of the project impacts. Assessment reports for the road and railway expansion were found to be deficient on multiple fronts regarding biodiversity assessment and projected impacts, whereas no impact assessment report was available in the public domain for the 400-kV transmission line project. This paper highlights the biodiversity significance of this protected area complex in the Western Ghats, and highlights the lacunae in biodiversity documentation and inadequacy of mitigation measures in assessment documents for all three diversion projects. The EIA process needs to improve substantially if India is to protect its natural resources and adhere to environmental protection policies and regulations nationally and globally

Metabolomics in oncology

Abstract Background Oncogenic transformation alters intracellular metabolism and contributes to the growth of malignant cells. Metabolomics, or the study of small molecules, can reveal insight about cancer progression that other biomarker studies cannot. Number of metabolites involved in this process have been in spotlight for cancer detection, monitoring, and therapy. Recent Findings In this review, the “Metabolomics” is defined in terms of current technology having both clinical and translational applications. Researchers have shown metabolomics can be used to discern metabolic indicators non‐invasively using different analytical methods like positron emission tomography, magnetic resonance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically feasible way to track changes in tumor metabolism and gauge treatment response across time. Recent studies have shown metabolomics can also predict individual metabolic changes in response to cancer treatment, measure medication efficacy, and monitor drug resistance. Its significance in cancer development and treatment is summarized in this review. Conclusion Although in infancy, metabolomics can be used to identify treatment options and/or predict responsiveness to cancer treatments. Technical challenges like database management, cost and methodical knowhow still persist. Overcoming these challenges in near further can help in designing new treatment régimes with increased sensitivity and specificity

Targeting neovascularization and respiration of tumor grafts grown on chick embryo chorioallantoic membranes

Since growing tumors stimulate angiogenesis, via vascular endothelial growth factor (VEGF), angiogenesis inhibitors (AIs, blockers of the VEGF signaling pathway) have been introduced to cancer therapy. However, AIs often yielded only modest and short-lived gains in cancer patients and more invasive tumor phenotypes in animal models. Combining anti-VEGF strategies with lactate uptake blockers may boost both efficacy and safety of AIs. We assessed this hypothesis by using the ex ovo chorioallantoic membrane (CAM) assay. We show that AI-based monotherapy (Avastin$^{®}$, AVA) increases tumor hypoxia in human CAM cancer cell xenografts and cell spread in human as well as canine CAM cancer cell xenografts. In contrast, combining AVA treatment with lactate importer MCT1 inhibitors (α-cyano-4-hydroxycinnamic acid (CHC) or AZD3965 (AZD)) reduced both tumor growth and cell dissemination of human and canine explants. Moreover, combining AVA+AZD diminished blood perfusion and tumor hypoxia in human explants. Thus, the ex ovo CAM assay as an easy, fast and cheap experimental setup is useful for pre-clinical cancer research. Moreover, as an animal-free experimental setup the CAM assay can reduce the high number of laboratory animals used in pre-clinical cancer research

The Advancement of Herbal-Based Nanomedicine for Hair

Polymer, lipid, and natural protein-based hair care nanocarriers are in preclinical testing. Nanomedicine has enhanced therapeutic efficacy and decreased side effects. This review examines herbal nanomedicine for hair care. We also reviewed the hair cycle, its morphology, and the mechanisms of herbal-based medicine that regulate the hair cycle to treat hair loss. Nano-formulations have better solubility, permeability, therapeutic efficacy, and prolonged distribution than standard herbal medicines. This review also discussed the nanotechnology barrier and nano formulations for hair loss and growth and includes a recent herbal nanomedicine study. Researchers interested in using herbs to treat hair problems and clinically translating hair care products may find the results presented significant

Targeting neovascularization and respiration of tumor grafts grown on chick embryo chorioallantoic membranes.

Since growing tumors stimulate angiogenesis, via vascular endothelial growth factor (VEGF), angiogenesis inhibitors (AIs, blockers of the VEGF signaling pathway) have been introduced to cancer therapy. However, AIs often yielded only modest and short-lived gains in cancer patients and more invasive tumor phenotypes in animal models. Combining anti-VEGF strategies with lactate uptake blockers may boost both efficacy and safety of AIs. We assessed this hypothesis by using the ex ovo chorioallantoic membrane (CAM) assay. We show that AI-based monotherapy (Avastin®, AVA) increases tumor hypoxia in human CAM cancer cell xenografts and cell spread in human as well as canine CAM cancer cell xenografts. In contrast, combining AVA treatment with lactate importer MCT1 inhibitors (α-cyano-4-hydroxycinnamic acid (CHC) or AZD3965 (AZD)) reduced both tumor growth and cell dissemination of human and canine explants. Moreover, combining AVA+AZD diminished blood perfusion and tumor hypoxia in human explants. Thus, the ex ovo CAM assay as an easy, fast and cheap experimental setup is useful for pre-clinical cancer research. Moreover, as an animal-free experimental setup the CAM assay can reduce the high number of laboratory animals used in pre-clinical cancer research

Interaction of HIF and USF signaling pathways at human genes flanked by hypoxia-response elements and E-box palindromes

Rampant activity of the hypoxia-inducible factor (HIF)-1 in cancer is frequently associated with the malignant progression into a harder-to-treat, increasingly aggressive phenotype. Clearly, anti-HIF strategies in cancer cells are of considerable clinical interest. One way to fine-tune, or inhibit, HIF's transcriptional outflow independently of hydroxylase activities could be through competing transcription factors. A CACGTG-binding activity in human hepatoma cells was previously found to restrict HIF's access to hypoxia response cis-elements (HRE) in a Daphnia globin gene promoter construct (phb2). The CACGTG factor, and its impact on hypoxia-responsive human genes, was analyzed in this study by genome-wide computational scans as well as gene-specific quantitative PCR, reporter and DNA-binding assays in hepatoma (Hep3B), cervical carcinoma (HeLa), and breast carcinoma (MCF7) cells. Among six basic helix-loop-helix transcription factors known to target CACGTG palindromes, we identified upstream stimulatory factor (USF)-1/2 as predominant phb2 CACGTG constituents in Hep3B, HeLa, and MCF7 cells. Human genes with adjacent or overlapping HRE and CACGTG motifs included with lactate dehydrogenase A (LDHA) and Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3) hypoxia-induced HIF-1 targets. Parallel recruitment of HIF-1α and USF1/2a to the respective promoter chromatin was verified for all cell lines investigated. Mutual complementing (LDHA) or moderating (BNIP3) cross-talk was seen upon overexpression or silencing of HIF-1α and USF1/2a. Distinct (LDHA) or overlapping (BNIP3) promoter-binding sites for HIF-1 and USFs were subsequently characterized. We propose that, depending on abundance or activity of its protein constituents, O(2)-independent USF signaling can function to fine-tune or interfere with HIF-mediated transcription in cancer cells. Mol Cancer Res; 1-17. ©2011 AACR