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DiFranza J.R.,University of Massachusetts Medical School | Wellman R.J.,Fitchburg State College | Mermelstein R.,University of Illinois at Chicago | Pbert L.,University of Massachusetts Medical School | And 12 more authors.
Current Pediatric Reviews

Addicted smokers experience nicotine withdrawal anytime they go too long without smoking. Withdrawal presents as a continuum of symptoms of escalating severity described by smokers as "wanting," then "craving," and eventually "needing" to smoke. These may be followed by irritability, impatience, moodiness, difficulty concentrating, restlessness, and sleep disturbances. This spectrum of intensifying withdrawal symptoms creates a compulsion to smoke that makes quitting difficult. The compulsion to smoke is the core feature of nicotine addiction accounting for its clinical course, physiological characteristics, prognosis, and behavioral manifestations. A compulsion can develop quickly, having been experienced by one third of youth who have smoked only 3 or 4 cigarettes. Its physiologic basis is evident in neurophysiological measures and its recurrence after each cigarette at a characteristic interval. At first, a single cigarette can keep withdrawal at bay for weeks, but as addiction progresses, cigarettes must be smoked at progressively shorter intervals to suppress withdrawal symptoms. The physiologic need to repeatedly self-administer nicotine at shorter intervals explains a full spectrum of addictive symptoms ranging from the prodromal symptom of wanting, to chain smoking. The early process of nicotine addiction is recognized if a person experiences regular wanting for a cigarette. When symptoms include craving or needing, the now addicted patient is experiencing a compulsion to smoke. This simple diagnostic approach covers the full spectrum of addiction in smokers of all ages and levels of tobacco use, and is more valid than a clinical diagnosis based on the current Diagnostic and Statistical Manual criteria. © 2011 Bentham Science Publishers Ltd. Source

Telang N.,Cancer Prevention Research Program | Katdare M.,Hampton University
Oncology Letters

Clinical breast cancer progresses via a multi-step carcinogenic process wherein genetic, molecular, endocrine and dietary factors play significant roles in the pathogenesis, prevention and therapy of the disease. Preclinical cell culture models, expressing clinically relevant genetic and endocrine defects and exhibiting quantifiable cancer risk, may provide facile, clinically translatable approaches to identify molecular targets and susceptible mechanistic pathways for the efficacy of novel interventional approaches. This review summarizes laboratory investigations focused on i) developing murine and human mammary tissue-derived cell culture models; ii) optimizing mechanism-based quantitative endpoint biomarker assays specific for carcinogenic risk and preventive/therapeutic efficacy; and iii) providing quantifiable proof-of-principle evidence for validation of the present cell culture approaches, capable of prioritizing efficacious lead compounds for subsequent in vivo animal studies and clinical trials for the prevention/therapy of breast cancer. Epithelial cell culture models are developed and characterized where the carcinogenic process is initiated by the targeted expression of clinically relevant oncogenes. The cell culture systems from mouse mammary tissue are in vitro approaches that complement the Ras and Myc transgenic mouse models. The human mammary tissue-derived systems are in vitro models for chemoendocrine, therapy-resistant, clinical, pre-invasive ER -/PR -/HER-2 + comedo ductal carcinoma in situ, ER +/PR + chemoendocrine therapy-responsive breast cancer and ER -/PR -/HER-2 - triple-negative chemoendocrine, therapy-resistant breast cancer. The oncogene-initiated phenotypes exhibit loss of homeostatic growth control, downregulation of cell apoptosis and gain of carcinogenic risk in vitro, as well as transplantable tumor development in vivo. Numerous mechanistically distinct, synthetic pharmacological agents, as well as naturally occurring dietary compounds, re-establish homeostatic growth control via cell cycle arrest and/or induction of cell apoptosis, downregulate oncogene-mediated cell signaling pathways, modulate the expression of numerous cell cycle regulatory and apoptosis-specific proteins and reduce carcinogenic risk in pre-neoplastic and carcinoma-derived cell culture models. These data validate the present cell culture approaches as novel, mechanism-based screens to evaluate and prioritize promising lead compounds for the prevention/therapy of clinical breast cancer. Source

Telang N.T.,Cancer Prevention Research Program | Li G.,Foundation Medicine | Sepkovic D.W.,David and Alice Jurist Institute for Research | Bradlow H.L.,David and Alice Jurist Institute for Research | And 2 more authors.
Molecular Medicine Reports

Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER +) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER + clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17β-estradiol (E 2) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E 2) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E 2, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E 2- stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E 2 metabolite 2-hydoxyestrone (2-OHE 1), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE 1) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E 3). These alterations led to a 14.5-fold increase in the 2-OHE 1:16α- OHE 1, and a 3.3-fold increase in the E 3:16α-OHE 1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER + clinical breast cancer. Source

Telang N.,Cancer Prevention Research Program | Katdare M.,Hampton University
Oncology Reports

Genetically engineered mice with targeted alterations in clinically relevant oncogenes, tumor suppressor genes or DNA mismatch repair genes provide unique predictive animal models for human carcinogenesis, and cancer prevention/ therapy. However, some of the genetically engineered mouse models lack target organ specificity for colon carcinogenesis. We have established, characterized and validated stable epithelial cell lines from 'normal' and 'genetically' predisposed target organs that offer innovative and mechanistic approaches, complementing in vivo studies on existing animal models for clinical breast and colon cancer. Epithelial cell lines with up-regulated Ras or myc oncogene, mutated Apc tumor suppressor gene and Mlh1 DNA mismatch repair gene provide facile experimental systems for organ site carcinogenesis and cancer prevention. Altered expression of cancer specific biomarkers and their modulation by several synthetic pharmacological agents such as retinoids, selective estrogen receptor modulators, non-steroidal anti-inflammatory drugs and specific enzyme inhibitors have been reported from our laboratory. Oncogene expressing MMEC-Ras and MMEC-myc mammary epithelial cells, Apc mutant 850 Min COL and 1638N COL, and DNA mismatch repair/Ape mutant Mlh 1/1638N COL colon epithelial cells exhibit aberrant cell cycle progression, down-regulated apoptosis and enhanced carcinogenic risk in vitro and tumor formation in vivo. We have reported that relative to the parental 'normal' non-neoplastic cells, genetically 'altered' pre-neoplastic cells exhibit enhanced sensitivity for growth arrest by multiple mechanistically distinct pharmacological agents. Comparative experiments on isogenic 'normal' and genetically 'altered' target cell lines facilitate cancer selective efficacy and identification of susceptible mechanistic pathways. Treatment of these genetically 'altered' pre-neoplastic cells with low dose combination of mechanistically distinct pharmacological agents as well as naturally occurring phytochemicals induce cytostatic growth arrest, alter cell cycle progression and reduce carcinogenic risk The availability of validated technology for model development, and for mechanism based biomarker assays now establishes a novel platform to rapidly test carcinogenicity and preventive/therapeutic efficacy of novel pharmacological agents as well as naturally occurring phytochemicals. Thus, these data permit rational prioritization of efficacious lead compounds for preclinical testing and future clinical trials for prevention/ therapy of breast and colon cancer. Source

Telang N.,Cancer Prevention Research Program | Li G.,Foundation Medicine | Sepkovic D.,Hackensack University Medical Center | Bradlow H.L.,Hackensack University Medical Center | And 2 more authors.
Nutrition and Cancer

Chemo-endocrine therapy for estrogen receptor positive (ER+) breast cancer exhibits acquired tumor resistance. Herbal medicines provide integrative support for breast cancer patients. Present study compared the efficacy of aqueous extracts from Lycium barbarum bark (LBB) and Lycium barbarum fruit (LBF) on ER+ MCF-7 cells. Cellular growth and 17ß-estradiol (E2) metabolism quantified the efficacy. MCF-7 cells maintained in serum depleted medium+ E2 exhibited increased anchorage-dependent and anchorage-independent growth. LBB exhibited greater potency than LBF (95% reduction in IC50). LBB produced a 6.8-fold increase, 40% decrease, and a 3.7-fold increase in 2-hydroxyestrone (2-OHE 1), 16α-hydroxyestrone (16α-OHE1), and estriol (E3) formation. The corresponding values for LBF were 3.9, 33, and 10.5. LBB produced a16.3-fold and a twofold increase in 2-OHE 1:16α-OHE1 and E3:16α-OHE 1 ratios, whereas LBF produced a sixfold and a 2.9-fold increase. The efficacy of LBB is due to increased 2-OHE1 formation, whereas that of LBF is due to accelerated conversion of 16α-OHE1 to E 3. Specific growth inhibitory profiles of LBB and LBF may be due to their distinct chemical composition and their complementary actions on E 2 metabolism. This study validates a mechanistic approach to identify efficacious herbal extracts for clinical ER+ breast cancer. © 2014 Copyright Taylor and Francis Group, LLC. Source

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