SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.

Intraocular pressure-lowering effects of imidazo[1,2-a]- and pyrimido[1,2-a]benzimidazole compounds in rats with dexamethasone-induced ocular hypertension.

Ocular hypertension is believed to be involved in the etiology of primary open-angle glaucoma. Although many pharmaceutical agents have been shown to be effective for the reduction of intraocular pressure (IOP), a significant opportunity to improve glaucoma treatments remains. Thus, the aims of the present study were: (1) to evaluate the IOP-lowering effect of four compounds RU-551, RU-555, RU-839 (pyrimido[1,2-a]benzimidazole), and RU-615 (imidazo[1,2-a]benzimidazole) on steroid-induced ocular hypertension in rats after single drop and chronic applications; and (2) to test in silico and in vitro conventional rho-associated kinase (ROCK) inhibitory activity of the selected compound. This study demonstrated that RU-551, RU-555, RU-839, and RU-615 significantly reduced IOP in Sprague Dawley rats with dexamethasone (DEXA) induced ocular hypertension after single drop administration (0.1%), however RU-615 showed the best IOP lowering effect as indicated by maximum IOP reduction of 22.32% from baseline. Repeated dose topical application of RU-615 caused sustained reduction of IOP from baseline throughout the 3 weeks of treatment with maximum IOP reduction of 30.31% on day 15. This study also showed that the steroid-induced increase in IOP is associated with increased retinal oxidative stress and significant retinal ganglion cells (RGCs) loss. Prolonged treatment with RU-615 over 3 weeks results in normalization of IOP in DEXA-treated rats with partial restoration of retinal antioxidant status (catalase, glutathione and superoxide dismutase) and subsequent protective effect against RGC loss. Thus, IOP lowering activity of RU-615 together with antioxidant properties might be the factors that contribute to prevention of further RGC loss. In vitro part of this study explored the ROCK inhibitory activity of RU-615 using dexamethasone-treated human trabecular meshwork cells as a possible mechanism of action of its IOP lowering activity. However, this study didn't show conventional ROCK inhibition by RU-615 which was later confirmed by in silico consensus prediction. Therefore, in the future studies it is important to identify the upstream target receptors for RU-615 and then delineate the involved intracellular signalling pathways which are likely to be other than ROCK inhibition.

Relationship between intraocular pressure lowering effect and chemical structure of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives.

This article contains data that relate to the study carried out in the work of Marcus et al. (2018) [1]. Data represent an information about pharmacophore analysis of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives and results of construction of the relationship between intraocular pressure (IOP) lowering activity and hypotensive activity of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives using a multilayer perceptron artificial neural network. In particular, they include the ones listed in this article: 1) table of all pharmacophores of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole derivatives that showed IOP lowering activity; 2) table of all pharmacophores of the compounds that showed absence of IOP lowering activity; 3) table of initial data for artificial neural network analysis of relationship between IOP activity and hypotensive activity of this chemical series; 4) graphical representation of the best neural network model of this dependence; 5) original txt-file of results of pharmacophore analysis; 6) xls-file of initial data for neural network modeling; 7) original stw-file of results of neural network modeling; 8) original xml-file of the best neural network model of dependence between IOP lowering activity and hypotensive activity of these azole derivatives. The data may be useful for researchers interested in designing new drug substances and will contribute to understanding of the mechanisms of IOP lowering activity.

Data on the effects of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds on intraocular pressure of ocular normotensive rats.

This data is to document the intraocular pressure (IOP) lowering activity of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds in ocular normotensive rats. Effects of single drop application of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds on IOP in ocular normotensive rats are presented at 3 different concentrations (0.1%, 0.2% and 0.4%). Time course of changes in IOP is presented over 6 h period post-instillation. The IOP lowering activities of test compounds were determined by assessing maximum decrease in IOP from baseline and corresponding control, duration of IOP lowering and area under curve (AUC) of time versus response curve. Data shown here may serve as benchmarks for other researchers studying IOP-lowering effect of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds and would be useful in determining therapeutic potential of these test compounds as IOP lowering agents.

Intraocular pressure lowering effect and structure-activity relationship of imidazo[1,2-a]benzimidazole and pyrimido[1,2-a]benzimidazole compounds in ocular normotensive rats: Insight on possible link with hypotensive activity.

In an effort to find new ocular hypotensive drug candidates, a total of 27 condensed benzimidazoles based compounds were screened. This study was done in normotensive rats and rebound tonometry was used to estimate IOP. All compounds were topically applied as a single drop, unilaterally, at 3 different concentrations (0.1%, 0.2% and 0.4%). The contralateral eye was instilled with vehicle and served as control. The IOP reduction was measured up to 6h. It was observed that with a single topical instillation, compounds RU 551, RU 555, RU839 (pyrimido[1,2-a]benzimidazole derivatives), and RU 615 (imidazo[1,2-a]benzimidazole derivative) showed significant IOP lowering activities in ocular normotensive rats. All other compounds showed none, weak and inconsistent IOP lowering effect. The relationship between ability of IOP lowering and hypotensive activities was studied. According to the pharmacophore analysis, the class of pyrimido[1,2-a]benzimidazole is more promising than the class of imidazo[1,2-a]benzimidazole as a source of compounds with high IOP lowering activity. Pharmacophore analysis also showed that the critical features of high IOP lowering activity are methoxyphenyl and [phenyl]alkyl fragments, and non-conjugated six-membered heterocyclic ring.

Predictive factors for successful colonic stenting in acute large-bowel obstruction: a 15-year cohort analysis.

BACKGROUND: Colonic stenting has failed to show an improvement in mortality rates in comparison with emergency surgery for acute large-bowel obstruction. However, it remains unclear which patients are more likely to benefit from this procedure. OBJECTIVE: The aim of this study is to identify factors that may be predictive of successful outcome of colonic stenting in acute large-bowel obstruction. DESIGN: All patients undergoing colonic stenting for acute large-bowel obstruction between 1999 and 2013 were studied. The demographics and characteristics of the obstructing lesion were analyzed. SETTINGS: This investigation was conducted at a district general hospital. PATIENTS: A total of 126 (76 men; median age, 76 y; range, 42-94 y) with acute large-bowel obstruction were included in the analysis. INTERVENTION: The insertion of a self-expanding metal stent was attempted for each patient to relieve the obstruction. MAIN OUTCOME MEASURES: The primary outcomes measured were technical success in the deployment of the stent, clinical decompression, and perforation rates. RESULTS: Technical deployment of the stent was accomplished in 108 of 126 (86%) patients; however, only 89 (70%) achieved clinical decompression. Successful deployment and clinical decompression was associated with colorectal cancer (p = 0.03), shorter strictures (p = 0.01), and wider angulation distal to the obstruction (p = 0.049). Perforation was associated with longer strictures (p = 0.03). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSION: Colonic stenting in acute large-bowel obstruction is more likely to be successful in shorter, malignant strictures with less angulation distal to the obstruction. Longer benign strictures are less likely to be successful and may be associated with an increased risk of perforation.

Inhibition of hepatitis C viral RNA-dependent RNA polymerase by α-P-boranophosphate nucleotides: exploring a potential strategy for mechanism-based HCV drug design.

Improved treatments for chronic HCV infections remain a challenge, and new chemical strategies are needed to expand the current paradigm. The HCV RNA polymerase (RdR(P)) has been a target for antiviral development. For the first time we show that the boranophosphate (BP) modification increases the substrate efficiency of ATP analogs into HCV NS5BΔ55 RdRP-catalyzed RNA. Boranophosphate nucleotides contain a borane (BH3) group substituted for a non-bridging phosphoryl oxygen of a normal phosphate group, resulting in a class of modified isoelectronic DNA and RNA mimics capable of modulating the reading and writing of genetic information. We determine that HCV NS5BΔ55, being a stereospecific enzyme, incorporates the Rp isomer of both ATPαB and the two boranophosphate analogs: 2'-O-methyladenosine 5'-(α-P-borano) triphosphate (2'-OMe ATPαB, 5a) and 3'-deoxyadenosine 5'-(α-P-borano) triphosphate (3'-dATPαB, 5b). The R(p) diastereomer of ATPαB (6), having no ribose modifications, was found to be a slightly better substrate than natural ATP, showing a 42% decrease in the apparent Michaelis-Menten constant (K(m)). The IC50 of both 2'-O-Me and 3'-deoxy ATP was decreased with the boranophosphate modification up to 16-fold. This "borano effect" was further confirmed by determining the steady-state inhibitory constant (K(i)), showing a comparable potency shift (21-fold). These experiments also indicate that the boranophosphate analogs 5a and 5b inhibit HCV NS5B through a competitive mode of inhibition. This evidence, together with previous crystal structure data, further supports the idea that HCV NS5B (in a similar manner to HIV-1 RT) discriminates against the 3'-deoxy modification via lost interactions between the 3'-OH on the ribose and the active site residues, or lost intramolecular hydrogen bonding interactions between the 3'-OH and the pyrophosphate leaving group during phosphoryl transfer. To our knowledge, these data represent the first time a phosphate modified NTP has been studied as a substrate for HCV NS5B RdRP.

Access to the superficial femoral artery in the presence of a "hostile groin": a prospective study.

PURPOSE: Lower limb angioplasty is commonly performed via antegrade common femoral artery (CFA) puncture, followed by selective superficial femoral artery (SFA) catheterization. Arterial access can be complicated by a "hostile groin" (scarring, obesity, or previous failed CFA puncture). We prospectively investigated color duplex ultrasound (CDU)-guided SFA access for radiological interventions. METHODS: Antegrade CDU-guided CFA and SFA puncture were compared in 30 patients requiring intervention for severe leg ischemia who had hostile groins. Demographics, screen time, radiation dose, intervention, and complications were prospectively recorded. RESULTS: Treatment in 30 patients involved 44 angioplasties (40 transluminal, 4 subintimal) and 2 diagnostic angiograms. Fifteen of these patients had CDU-guided CFA punctures; in 8 of these patients CDU-guided CFA puncture "failed" (i.e., there was failure to pass a guidewire or catheter into the CFA or SFA), necessitating immediate direct CDU-guided SFA puncture. Overall, the mean screen time and radiation dosage, via direct CDU-guided SFA puncture in 30 patients, was 4.8 min and 464 Gy cm(2) respectively. With CDU-guided CFA puncture, mean screen time (10 min), radiation dose (2023 Gy cm(2)), and complications (13%) were greater when compared with the SFA puncture results overall and in the same patients at subsequent similar procedures (2.7 min, 379 Gy cm(2) (p < 0.05), no complications in this subgroup). Five complications occurred: 2 each at CFA and SFA entry sites, and 1 angioplasty embolus. CONCLUSIONS: The CDU-guided SFA puncture technique was both more effective than CDU-guided CFA access in patients with scarred groins, obesity, or failed CFA punctures and safer, with reduced screen times, radiation doses, and complications.