Spinal infections are challenging to diagnose and represent a life-threatening medical condition. Diagnosis is often delayed because of nonspecific accompanying symptoms. The role of interventional ...neuroradiology in spinal infection is double: diagnostic and therapeutic, consisting substantially of 2 main procedures, represented by spine biopsies and positioning of percutaneous drainage, which represent a minimally invasive, faster and more cost-effective alternative to open surgery procedures. This article will focus on the available state-of-the-art techniques to perform discovertebral image-guided biopsies in case of suspected infections and on image-guided placement of percutaneous drainage to treat infectious collections of the spine and paravertebral structures.
Thrombosis of celiacomesenteric trunk:Report of a case Lovisetto, Federico; Finocchiaro De Lorenzi, Gianbattista; Stancampiano, Piera ...
World journal of gastroenterology : WJG,
08/2012, Letnik:
18, Številka:
29
Journal Article
Odprti dostop
Here we present the case of a 79-year-old woman who complained of acute abdominal pain,vomiting and diarrhoea.Laboratory exams demonstrated a severe metabolic imbalance.Abdominal X-rays showed bowel ...overdistension and pneumatosis of the stomach wall.Abdominal tomography revealed infarction of the stomach,duodenum and small bowel due to thrombosis of the celiacomesenteric trunk.Exploratory laparotomy revealed ischemia of the liver,spleen infarction and necrosis of the gastro-intestinal tube(from the stomach up to the first third of the transverse colon).No further surgical procedures were performed.The patient died the following day.To our knowledge,this is the first reported case about severe gastro-intestinal ischemia due to thrombosis of the celiacomesenteric trunk,a rare anatomic variation of the gastrointestinal vascularisation.
The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as ...Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1
-inden-1-one (
), which in the
isomeric form (and about tenfold less in the UV-B photo-induced isomer
) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs
-
with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable
geometric isomer, along with the
mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75%
), was investigated for the inhibition of human ChEs and MAOs. The pure
-isomer of the N-benzyl(ethyl)amino analog
achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC
s 39 and 355 nM, respectively), whereas photoisomerization to the
isomer (75%
in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different
/
selectivity of
toward the two target enzymes.
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that ...targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
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•CBL0137 inhibits DIPG tumor growth and restores H3K27me3 through FACT inhibition•Co-administration of CBL0137 and panobinostat enhances survival in DIPG xenografts•CBL0137 and panobinostat synergistically inhibit the Rb/E2F1 pathway and restore H3K27me3
Ehteda et al. find that the histone chaperon FACT is an oncogenic target in diffuse intrinsic pontine glioma. Pharmacological inhibition of FACT with CBL0137 reverses the effect of H3K27M. Co-administration of CBL0137 and panobinostat significantly prolongs survival in two aggressive DIPG in vivo models.
The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one target-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as ...Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b–h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (ICsub.50s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.
Abstract Advanced chronic kidney disease (CKD) is associated with poor outcomes in patients undergoing surgical aortic valve replacement while its prognostic role in transcatheter aortic valve ...implantation (TAVI) remains unclear. This study aimed to investigate outcomes in patients with advanced CKD undergoing TAVI. 1904 consecutive patients undergoing balloon-expandable TAVI in 33 centers between 2007-2012 were enrolled in the I talian T ranscatheter Balloon- E xpandable Valve Implantation R egistry (ITER). Advanced CKD was defined according to estimated glomerular filtration rate (eGFR): 15-29 mL/min/1.73m2 stage 4 (S4), <15 mL/min/1.73m2 stage 5 (S5). Edwards Sapien or Sapien-XT prosthesis were used. Primary end-point was all-cause mortality during follow-up. Secondary end-points were 30-days and FU major-adverse-cardiac-events (MACE), defined with VARC-2 criteria. 421 patients were staged S5 (n=74) or S4 (n=347). S5 patients were younger, had more frequently porcelain aorta and lower incidence of previous stroke. Peri-procedural and 30-days outcomes were similar in S5 and S4 patients. During a 670 (±466) days of FU, S5 patients suffered higher mortality rates (69% vs. 39%, p<0.01) and cardiac death (19% vs. 9%, p=0.02) compared to S4. Male sex (HR 1.6, 95%CI 1.2-2.2), LVEF<30% (HR 2.3, 95% CI: 1.3-4), atrial fibrillation (HR 1.4, 95%CI:1.0-1.9) and S5 CKD (HR 1.5, 95%CI: 1.0-2.1) were independent predictors of death. In conclusion, TAVI in pre-dialytic or dialytic patients (i.e. S5) is independently associated with poor outcomes with more than double risk of death compared to patients with stage 4 renal function. Conversely, in severe CKD (i.e. S4) a rigorous risk stratification is required to avoid the risk of futility risk.
Alzheimer’s disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, ...acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation. Herein, we describe the design, synthesis, and pharmacological effects in vitro and in vivo of dual-acting compounds that inhibit AChE and butyrylcholinesterase (BChE) and target CB2R. Within the investigated series, compound 4g proved to be the most promising. It achieved IC50 values in the low micromolar to submicromolar range against both human cholinesterase isoforms while antagonizing CB2R with K i of 31 nM. Interestingly, 4g showed neuroprotective effects on the SH-SY5Y cell line thanks to its ability to prevent oxidative stress-induced cell toxicity and reverse scopolamine-induced amnesia in the Y-maze forced alternation test in vivo.
Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) ...structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anticancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 °C at 5 μM, while three other candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed antiproliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.
Abstract
DIPG is an aggressive and incurable childhood brain tumour for which new treatments are needed. A high throughput drug screen of 3500 pharmaceutical compounds identified anti-malarials, ...including quinacrine as having potent activity against DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is a novel anti-cancer compound which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier and has recently completed Phase I testing in adult patients. CBL0137 induced apoptosis in DIPG neurospheres and had profound cytotoxic activity against a panel of DIPG cultures. In a DIPG orthotopic model, treatment with CBL0137 significantly improved survival. We found that treatment with CBL0137 up-regulated TP53 and increased histone H3.3 acetylation and tri-methylation in DIPG cells. We therefore examined the interaction between CBL0137 and the histone deacetylase (HDAC) inhibitor panobinostat. In vitro experiments showed that the two agents had profound synergistic activity against DIPG neurospheres in clonogenic assays and enhanced caspase activation and apoptosis. The FACT subunit SSRP1 was found to directly interact with H3.3K27M and treatment with CBL0137 targeted this epigenetic defect, restoring histone H3.3 trimethylation and leading to tumor cell death. Transcriptomic analysis and immunoblotting indicated that combination treatment activated signalling pathways controlled by Retinoblastoma (RB)/E2F1 and subsequently increased phosphorylation and enzymatic activity of enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged survival in two independent orthotopic models of DIPG, while histological analysis showed restoration of H3K27me3 and decreased Ki67 positive cells. In addition to panobinostat, CBL0137 has been found to combine synergistically in vitro and in vivo with PARP and BET inhibitors. Given these promising results, a paediatric trial of CBL0137 will open through the Children’s Oncology Group with an expansion cohort for DIPG patients.
Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumour for which new treatments are needed. A high throughput drug screen of 3500 pharmaceutical ...compounds identified anti-malarials, including quinacrine as having potent activity against DIPG neurospheres. CBL0137, a compound modelled on quinacrine, is an anti-cancer compound which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. CBL0137 effectively crosses the blood-brain barrier and is currently in Phase I trials in adult cancer. CBL0137 induced apoptosis in DIPG neurospheres in vitro and had profound cytotoxic activity against a panel of DIPG cultures. In a DIPG orthotopic model, treatment with CBL0137 significantly improved survival. We found that treatment with CBL0137 up-regulated TP53 and increased histone H3.3 acetylation and tri-methylation in DIPG cells. We therefore examined the interaction between CBL0137 and the HDAC inhibitor, panobinostat. In vitro experiments showed that the two agents had profound synergistic activity against DIPG neurospheres in clonogenic assays and enhanced apoptosis. Transcriptomic analysis and immunoblotting indicated that combination treatment activated signalling pathways controlled by Retinoblastoma (RB)/E2F1 and subsequently increased phosphorylation and enzymatic activity of enhancer of zeste homolog 2 (EZH2). Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of two orthotopic models of DIPG, while histological analysis showed increased H3K27me3 and decreased Ki67 positive cells. Given these promising results, a paediatric trial of CBL0137 is planned to open through the Children’s Oncology Group with an expansion cohort for DIPG patients.