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- Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells. [Journal Article]
- Biomed Res Int 2014.:612823.
High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.
- Recombinant Lysostaphin Protects Mice from Methicillin-Resistant Staphylococcus aureus Pneumonia. [Journal Article]
- Biomed Res Int 2014.:602185.
The advent of methicillin-resistant Staphylococcus aureus (MRSA) and the frequent and excessive abuse of ventilators have made MRSA pneumonia an inordinate threat to human health. Appropriate antibacterial therapies are crucial, including the use of lysostaphin as an alternative to antibiotics. To explore the potential use of lysostaphin as a therapeutic agent for MRSA pneumonia, mice were intranasally infected with MRSA and then treated with recombinant lysostaphin (rLys; 45 mg/kg in the high-dose group and 1 mg/kg in the low-dose group) (0.33 mg/mL, 15 mg/mL), vancomycin (120 mg/kg) (40 mg/mL), or phosphate-buffered saline (PBS, negative control) 4 h after infection. Therapeutic efficacy was assessed by mouse survival, lung histopathology, bacterial density in the lungs, bodyweight, lung weight, temperature, white blood cells counts, lymphocytes counts, granulocytes counts, and monocytes counts. The mice treated with rLys showed lower mortality, less lung parenchymal damage, and lower bacterial density at metastatic tissue sites than mice treated with PBS or vancomycin. The overall mortality was 100%, 60%, 40%, and 60% for the control, vancomycin, high-dose rLys, and low-dose rLys groups, respectively. These findings indicate that, as a therapeutic agent for MRSA pneumonia, lysostaphin exerts profound protective effects in mice against the morbidity and mortality associated with S. aureus pneumonia.
- Effects of Crude Extracts from Medicinal Herbs Rhazya stricta and Zingiber officinale on Growth and Proliferation of Human Brain Cancer Cell Line In Vitro. [Journal Article]
- Biomed Res Int 2014.:260210.
Hitherto, limited clinical impact has been achieved in the treatment of glioblastoma (GBMs). Although phytochemicals found in medicinal herbs can provide mankind with new therapeutic remedies, single agent intervention has failed to bring the expected outcome in clinical trials. Therefore, combinations of several agents at once are gaining increasing attractiveness. In the present study, we investigated the effects of crude alkaloid (CAERS) and flavonoid (CFEZO) extracts prepared from medicinal herbs, Rhazya stricta and Zingiber officinale, respectively, on the growth of human GBM cell line, U251. R. stricta and Z. officinale are traditionally used in folkloric medicine and have antioxidant, anticarcinogenic, and free radical scavenging properties. Combination of CAERS and CFEZO treatments synergistically suppressed proliferation and colony formation and effectively induced morphological and biochemical features of apoptosis in U251 cells. Apoptosis induction was mediated by release of mitochondrial cytochrome c, increased Bax : Bcl-2 ratio, enhanced activities of caspase-3 and -9, and PARP-1 cleavage. CAERS and CFEZO treatments decreased expression levels of nuclear NF-κBp65, survivin, XIAP, and cyclin D1 and increased expression level of p53, p21, and Noxa. These results suggest that combination of CAERS and CFEZO provides a useful foundation for studying and developing novel chemotherapeutic agents for the treatment of GBM.
- Tolvaptan. [Journal Article]
- South Asian J Cancer 2014 Jul; 3(3):182-4.
Hyponatremia is a common and often under-recogonised clinical problem in oncologic practice. The recogonition of the cause of hyponatremia and initiation of appropriate and timely intervention can prevent morbidity and improve treatment tolerance. This drug review aims at discussing the currently approved oral vaptanagent Tolvaptan. Vaptans including Tolvaptan act as "aquaretic" agents cousing excretion of water while retaining the sodium. Administration of this agent for prescribed periods result in improvement of serum sodium levels. The drug can be used in many clinical situations resulting in hyponatremia including congestive heart failure, cirrhosis and syndrome of inappropriate ADH secretion (SIADH) including SIADH related to malignancies.
- Comparative analysis of Salmonella susceptibility and tolerance to the biocide chlorhexidine identifies a complex cellular defense network. [Journal Article]
- Front Microbiol 2014.:373.
Chlorhexidine is one of the most widely used biocides in health and agricultural settings as well as in the modern food industry. It is a cationic biocide of the biguanide class. Details of its mechanism of action are largely unknown. The frequent use of chlorhexidine has been questioned recently, amidst concerns that an overuse of this compound may select for bacteria displaying an altered susceptibility to antimicrobials, including clinically important anti-bacterial agents. We generated a Salmonella enterica serovar Typhimurium isolate (ST24(CHX)) that exhibited a high-level tolerant phenotype to chlorhexidine, following several rounds of in vitro selection, using sub-lethal concentrations of the biocide. This mutant showed altered suceptibility to a panel of clinically important antimicrobial compounds. Here we describe a genomic, transcriptomic, proteomic, and phenotypic analysis of the chlorhexidine tolerant S. Typhimurium compared with its isogenic sensitive progenitor. Results from this study describe a chlorhexidine defense network that functions in both the reference chlorhexidine sensitive isolate and the tolerant mutant. The defense network involved multiple cell targets including those associated with the synthesis and modification of the cell wall, the SOS response, virulence, and a shift in cellular metabolism toward anoxic pathways, some of which were regulated by CreB and Fur. In addition, results indicated that chlorhexidine tolerance was associated with more extensive modifications of the same cellular processes involved in this proposed network, as well as a divergent defense response involving the up-regulation of additional targets such as the flagellar apparatus and an altered cellular phosphate metabolism. These data show that sub-lethal concentrations of chlorhexidine induce distinct changes in exposed Salmonella, and our findings provide insights into the mechanisms of action and tolerance to this biocidal agent.
- The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress. [Journal Article]
- Front Aging Neurosci 2014.:191.
Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.
- Labor Induction with 50 μg Vaginal Misoprostol: Can We Reduce Induction-Delivery Intervals Safely? [Journal Article]
- J Obstet Gynaecol India 2014 Aug; 64(4):270-3.
To compare the efficacy and safety profile of two methods of labor induction i.e., intracervical dinoprostone gel (0.5 mg 8 h) and misoprostol (50 μg 4 h) for induction of labor in women with a poor Bishop's score.Observational study.January 1st, 2009 to December 31st, 2010.A total of 329 women with unfavorable cervices induced at or near term.Two cervical ripening agent study arms were used: dinoprostone gel (193 women) and misoprostol (137 women).Induction to delivery interval, cesarean section, incidence of meconium stained liquor, FHR pattern, incidence of uterine hyperstimulation, and neonatal outcomes.The induction to delivery interval was significantly shorter in the misoprostol group as compared to the dinoprostone group (p < 0.001). There was no difference in cesarean section rates between the two groups (dinoprostone gel 43 %; misoprostol 33 %; p = 0.144). The incidence of non-reassuring fetal heart rate pattern, meconium stained liquor, and uterine hyperstimulation were equivalent in both the groups (p = 0.529; 0.733; and 0.321, respectively). The neonatal outcomes in both the groups were comparable in terms of Apgar scores at birth (p = 0.160) and NICU admissions (p = 0.951).Labor induction in women with unfavorable cervices results in high caesarean section rates. However, the use of misoprostol significantly reduces the induction to delivery interval, without adversely affecting the caesarean section rates and neonatal outcomes. Hence it may become a cost-effective alternative to dinoprostone gel in resource-poor settings like India.
- AXL mediates resistance to cetuximab therapy. [JOURNAL ARTICLE]
- Cancer Res 2014 Aug 18.
The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical problem. In this study we show that overexpression of the oncogenic receptor kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft assays, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL targeting drugs to treat cetuximab-resistant cancers.
- Ceftaroline-Fosamil Efficacy against Methicillin-Resistant Staphylococcus aureus Rabbit Prosthetic Joint Infection. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Aug 18.
Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F) demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in difficult-to-treat MRSA endocarditis and acute osteomyelitis rabbit models. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using an MRSA knee PJI in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone or combined with rifampin (RIF) were compared. After partial knee replacement with a silicone implant fitting into the tibial intramedullary canal, 5 × 10(7) MRSA CFU (MICs 0.38, 0.006 and 1 mg/liter for CPT, RIF and VAN, respectively) were injected into the knees. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg i.m.), VAN (60 mg/kg i.m.), CPT-F+RIF (10 mg/kg i.m.) or VAN+RIF starting 7 days post-inoculation and lasting 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although in vivo mean log10 CFU/g of CPT- (3.0 ± 0.9, n = 12) or VAN-treated crushed bones (3.5 ± 1.1, n = 12) were significantly lower than controls (5.6 ± 1.1, n = 14) (P < 0.001), neither fully sterilized bones (3/12 for each). Means (log10 CFU/g) in combination with RIF were 1.9 ± 0.5 (12/14 sterile) for CPT-F and 1.9 ± 0.5 (12/14 sterile) for VAN. In this MRSA-PJI model, CPT-F and VAN efficacies did not differ, and ceftaroline appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.
- Validation of a model to predict the risk of nephrotoxicity in patients receiving colistin. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Aug 18.
Despite concerns of nephrotoxicity, colistin often remains the only effective agent for multidrug-resistant gram-negative infections. Published studies have reported a wide range of nephrotoxicity risk factors. To assess the clinical utility of various models, we compared their performance in predicting risk of nephrotoxicity. We identified a model demonstrating reasonable overall risk assessment with observed/expected ratio of 1.29 (95% CI, 0.68-1.90) and positive predictive value of 87.5% for identifying patients at high risk of developing nephrotoxicity.