Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.

When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half (P = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. SIGNIFICANCE: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2327/F1.large.jpg.

Intravaginal Delivery of Polyphenon 60 and Curcumin Nanoemulsion Gel.

Polyphenon 60 (P60) and curcumin (CUR) were loaded in a single nanoemulsion system and their combined antibacterial action was studied against uropathogenic Escherichia coli. To enhance availability at target organs and to inhibit enzymatic degradation in gastro intestinal tract, vaginal route of administration was explored. P60 + CUR nanoemulsion (NE) was formulated by ultra-sonication and optimized using Box-Behnken design. Optimized NE showed Z-average of 211.2 nm, polydispersity index of 0.343, and zeta potential of -32.7 mV. Optimized P60+ CUR NE was characterized by stability testing and transmission electron microscopy, and it was observed that NE was stable at 4°C for 30 days and monodisperse in nature with particle size of 195-205 nm. P60+ CUR NE was further formulated as gel and characterized by viscosity, growth curve analysis, and in vitro permeation studies. In vitro drug permeation studies in simulated vaginal media showed maximum permeation (84 ± 0.21%) of curcumin within 5 h and (91 ± 0.16%) of P60 within 8 h. Both the drugs maintained sustained permeation for 12 h. To investigate the transport via intravaginal route, gamma scintigraphy and biodistribution study of P60 + CUR NBG was performed on Sprague-Dawley rats using 99mtechnetium pertechnetate for radiolabeling to P60 molecule. Following intravaginal administration, P60 + CUR NBG dispersed in the kidney and urinary bladder with (3.07 ± 0.15) and (3.35 ± 0.45) percentage per gram after 3 h for P60 and CUR, respectively, and remained active for 12 h. Scintigraphy images suggested that the P60 + CUR NBG given by intravaginal route led to effective distribution of actives in urinary tract, and this observation was in agreement with the biodistribution results.

Induced lexico-syntactic patterns improve information extraction from online medical forums.

OBJECTIVE: To reliably extract two entity types, symptoms and conditions (SCs), and drugs and treatments (DTs), from patient-authored text (PAT) by learning lexico-syntactic patterns from data annotated with seed dictionaries. BACKGROUND AND SIGNIFICANCE: Despite the increasing quantity of PAT (eg, online discussion threads), tools for identifying medical entities in PAT are limited. When applied to PAT, existing tools either fail to identify specific entity types or perform poorly. Identification of SC and DT terms in PAT would enable exploration of efficacy and side effects for not only pharmaceutical drugs, but also for home remedies and components of daily care. MATERIALS AND METHODS: We use SC and DT term dictionaries compiled from online sources to label several discussion forums from MedHelp (http://www.medhelp.org). We then iteratively induce lexico-syntactic patterns corresponding strongly to each entity type to extract new SC and DT terms. RESULTS: Our system is able to extract symptom descriptions and treatments absent from our original dictionaries, such as 'LADA', 'stabbing pain', and 'cinnamon pills'. Our system extracts DT terms with 58-70% F1 score and SC terms with 66-76% F1 score on two forums from MedHelp. We show improvements over MetaMap, OBA, a conditional random field-based classifier, and a previous pattern learning approach. CONCLUSIONS: Our entity extractor based on lexico-syntactic patterns is a successful and preferable technique for identifying specific entity types in PAT. To the best of our knowledge, this is the first paper to extract SC and DT entities from PAT. We exhibit learning of informal terms often used in PAT but missing from typical dictionaries.

Green tea extract: possible mechanism and antibacterial activity on skin pathogens.

Camellia sinensis (tea) is known for its therapeutic properties (anti-inflammatory, anti-microbial, anti-tumour, anti-oxidative and anti-ageing). Although, anti-microbial properties of green tea have been studied, its role against bacterial strains related to skin infections and mechanism of action is not well understood. We focussed on exploring anti-microbial activity and the basic mechanism of aqueous green tea leaf extract on selected bacterial strains. Staphylococcus epidermidis, Micrococcus luteus, Brevibacterium linens, Pseudomonas fluorescens and Bacillus subtilis were found to be sensitive to green tea extract via disc diffusion assay (zone of inhibition ≥7 mm). Minimal inhibitory concentration (MIC) was determined via nitro blue tetrazolium (NBT) assay (0.156-0.313 mg/ml). Moreover, the aqueous extract was found to be not toxic to the Vero cell-line up to a concentration of 500 µg/ml. The effect of aqueous extract on adhesion of different bacteria to Vero cells indicated that it inhibits the adhesion at its MIC value.