Cancer Stem Cells in Recurrent and Drug-Resistant Lung Cancers

With a 5-year survival rate of less than 20%, lung cancer is a leading cause of cancer-related deaths worldwide. Considering the treatments currently in place, this statistic is frankly shocking. A possible explanation for the disconnect between sophisticated treatments and the survival rate can be found in the Cancer Stem Cell (CSC) hypothesis. The CSC hypothesis suggests the idea of a subpopulation of tumor cells with the abilities of self-renewal, cancer initiation, and further maintenance of tumors. Lung CSCs have been associated with resistance to radiation and chemotherapeutic treatments. CSCs have also been implicated in recurrent cancers; if the CSCs are not completely killed off after treatment, the cancer tends to reemerge. Extensive investigation of CSCs to determine their responsibility in recurrent and drug-resistant cancers heavily relied on the use of specific markers present in CSCs, including CD133, ALDH, ABCG2, and Nanog. Yet another method that results in increased resistance to treatment is epithelial mesenchymal transition, or EMT. Through this process, epithelial cells lose the epithelial phenotype and gain mesenchymal properties. One of these properties is increased drug- resistance, rendering EMT culpable – at least in part – for drug-resistance in cancer cells . Furthermore, since miRNA-based therapies are coming to light, various miRNAs will be discussed in terms of their relationship to chemoresistance as well as CSCs in general. Finally, a discussion of the natural and synthetic anti-cancer compounds curcumin, CDF, and BR-DIM will ensue

Up-Regulation of Sonic Hedgehog Contributes to TGF-β1-Induced Epithelial to Mesenchymal Transition in NSCLC Cells

BACKGROUND:Lung cancer, especially non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the United States. The aggressiveness of NSCLC has been shown to be associated with the acquisition of epithelial-to-mesenchymal transition (EMT). The acquisition of EMT phenotype induced by TGF-β1in several cancer cells has been implicated in tumor aggressiveness and resistance to conventional therapeutics; however, the molecular mechanism of EMT and tumor aggressiveness in NSCLC remains unknown. METHODOLOGY/PRINCIPAL FINDINGS:In this study we found for the first time that the induction of EMT by chronic exposure of A549 NSCLC cells to TGF-β1 (A549-M cells) led to the up-regulation of sonic hedgehog (Shh) both at the mRNA and protein levels causing activation of hedgehog signaling. These results were also reproduced in another NSCLC cell line (H2030). Induction of EMT was found to be consistent with aggressive characteristics such as increased clonogenic growth, cell motility and invasion. The aggressiveness of these cells was attenuated by the treatment of A549-M cells with pharmacological inhibitors of Hh signaling in addition to Shh knock-down by siRNA. The inhibition of Hh signaling by pharmacological inhibitors led to the reversal of EMT phenotype as confirmed by the reduction of mesenchymal markers such as ZEB1 and Fibronectin, and induction of epithelial marker E-cadherin. In addition, knock-down of Shh by siRNA significantly attenuated EMT induction by TGF-β1. CONCLUSIONS/SIGNIFICANCE:Our results show for the first time the transcriptional up-regulation of Shh by TGF-β1, which is mechanistically associated with TGF-β1 induced EMT phenotype and aggressive behavior of NSCLC cells. Thus the inhibitors of Shh signaling could be useful for the reversal of EMT phenotype, which would inhibit the metastatic potential of NSCLC cells and also make these tumors more sensitive to conventional therapeutics

Association between Preparatory Knee Muscle Activation and Knee Valgus Angle during Single Leg Cross Drop Landing Following Anterior Cruciate Ligament Reconstruction

Background: Knee valgus angle seems to be a key factor in both primary– and second–ACL injury risk models. The control of the alignment of the lower limb during dynamic movements depends on the neural activation of the muscles crossing the knee joint prior to the occurrence of stressful events. The current study examined the relationship between the preparatory knee muscle activity and knee valgus angle. Methods: Twenty-eight ACL reconstructed (ACLR) athletes were asked to perform three trials of a single-leg cross drop landing (SCD). Lower extremity kinematics and surface EMG were recorded. Initial contact knee valgus angle and EMG from 100 ms prior to ground contact were used in the data analyses. Results: Preparatory activation medial and lateral hamstring muscles were found to be negatively correlated with knee valgus angle at initial contact (P<0.05). However, the preparatory activity of vastus medialis and vastus lateralis muscles was not associated with initial contact knee valgus angle (P>0.05). Conclusion: The preparatory activity of the knee muscles is linked to knee valgus angle at initial contact, and it may indicate a potential target of second ACL injury prevention programs

Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB

<p>Abstract</p> <p>Background</p> <p>Platinum-resistance (PR) continues to be a major problem in the management of epithelial ovarian cancer (EOC). Response to various chemotherapeutic agents is poor in patients deemed PR. Genistein, a soy isoflavone has been shown to enhance the effect of chemotherapy in prostate and pancreatic cancer cells <it>in vitro </it>and <it>in vivo </it>by reversing chemo-resistance phenotype. The goal of this study was to investigate the effects of combination therapy with genistein and cisplatin as well as other cytotoxic conventional chemotherapeutic agents in platinum-sensitive (PS) and resistant EOC cells.</p> <p>Methods</p> <p>The PS human ovarian cancer cell line A2780 and its PR clone C200 cells were pretreated with genistein, followed by the combination of genistein and either cisplatin, taxotere or gemcitabine. Cell survival and apoptosis was assessed by MTT and histone-DNA ELISA. Electrophoretic mobility shift assay (EMSA) was used to evaluate NF-κB DNA binding activity. Western blot analysis was performed with antibodies to Bcl-2, Bcl-xL, survivin, c-IAP and PARP.</p> <p>Results</p> <p>Reduction in cell viability, and corresponding induction of apoptosis was observed with genistein pretreatment followed by combination treatment with each of the drugs in both cell lines. The PS cell line was pretreated for 24 hours; in contrast, the PR cell line required 48 hours pretreatment to achieve a response. The anti-apoptotic genes c-IAP1, Bcl-2, Bcl-xL, survivin and NF-κB DNA binding activity were all found to be down-regulated in the combination groups.</p> <p>Conclusion</p> <p>This study convincingly demonstrated that the current strategy can be translated in a pre-clinical animal model, and thus it should stimulate future clinical trial for the treatment of drug-resistant ovarian cancer.</p

Mood booster / Abdul Jalil Mohammad Ali...[et al.]

Everyday life can no longer be imagined without fragrances and scented products. Humans have tempted to have perfumes or fragrances, which emulates nature's pleasant smells. Perfumes today are being made and used in different ways than in previous centuries. Perfumes are being manufactured more and more frequently with synthetic chemicals rather than natural oils. Less concentrated forms of perfume are also becoming increasingly popular. Combined, these factors decrease the cost of the scents, encouraging more widespread and frequent, often daily use. Using perfumes to heal, make people feel good and improve relationships between the sexes are the new frontiers being explored by the industry. The sense of smell is considered a right brain activity which rules emotions, memory, and creativity. The smelling oils and fragrances to cure physical and emotional problems is called aromatherapy can help to balance hormonal and body energy. The theory behind aromatherapy states that using essential oils helps bolster the immune system when inhaled or applied topically. Smelling sweet smells also affects one's mood and can be used as a form of psychotherapy. Thus, a new technology must be applied to make home fragrance a much more efficient use by having as many type of perfume you can store and at the same time you can mix it up to decide which smell suits the environment. Therefore, our company, MEWANGI Enterprise has introduced a product which is Mood Booster which the fragrance can be controlled by the tip of our finger

Activated K-ras and INK4a/Arf Deficiency Cooperate During the Development of Pancreatic Cancer by Activation of Notch and NF-κB Signaling Pathways

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, suggesting that novel strategies for the prevention and treatment of PDAC are urgently needed. K-ras mutations are observed in >90% of pancreatic cancer, suggesting its role in the initiation and early developmental stages of PDAC. In order to gain mechanistic insight as to the role of mutated K-ras, several mouse models have been developed by targeting a conditionally mutated K-ras(G12D) for recapitulating PDAC. A significant co-operativity has been shown in tumor development and metastasis in a compound mouse model with activated K-ras and Ink4a/Arf deficiency. However, the molecular mechanism(s) by which K-ras and Ink4a/Arf deficiency contribute to PDAC has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS:To assess the molecular mechanism(s) that are involved in the development of PDAC in the compound transgenic mice with activated K-ras and Ink4a/Arf deficiency, we used multiple methods, such as Real-time RT-PCR, western blotting assay, immunohistochemistry, MTT assay, invasion, EMSA and ELISA. We found that the deletion of Ink4a/Arf in K-ras(G12D) expressing mice leads to PDAC, which is in part mediated through the activation of Notch and NF-κB signaling pathways. Moreover, we found down-regulation of miR-200 family, which could also play important roles in tumor development and progression of PDAC in the compound transgenic mice. CONCLUSIONS/SIGNIFICANCE:Our results suggest that the activation of Notch and NF-κB together with the loss of miR-200 family is mechanistically linked with the development and progression of PDAC in the compound K-ras(G12D) and Ink4a/Arf deficient transgenic mice

Loss of Let-7 Up-Regulates EZH2 in Prostate Cancer Consistent with the Acquisition of Cancer Stem Cell Signatures That Are Attenuated by BR-DIM

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3′UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3′-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact