Glycolipid-peptide conjugate vaccines elicit CD8+ T-cell responses and prevent breast cancer metastasis.

Objectives: Metastasis is the principal cause of breast cancer mortality. Vaccines targeting breast cancer antigens have yet to demonstrate clinical efficacy, and there remains an unmet need for safe and effective treatment to reduce the risk of metastasis, particularly for people with triple-negative breast cancer (TNBC). Certain glycolipids can act as vaccine adjuvants by specifically stimulating natural killer T (NKT) cells to provide a universal form of T-cell help. Methods: We designed and made a series of conjugate vaccines comprising a prodrug of the NKT cell-activating glycolipid α-galactosylceramide covalently linked to tumor-expressed peptides, and assessed these using E0771- and 4T1-based breast cancer models in vivo. We employed peptides from the model antigen ovalbumin and from clinically relevant breast cancer antigens HER2 and NY-ESO-1. Results: Glycolipid-peptide conjugate vaccines that activate NKT cells led to antigen-presenting cell activation, induced inflammatory cytokines, and, compared with peptide alone or admixed peptide and α-galactosylceramide, specifically enhanced CD8+ T-cell responses against tumor-associated peptides. Primary tumor growth was delayed by vaccination in all tumor models. Using 4T1-based cell lines expressing HER2 or NY-ESO-1, a single administration of the relevant conjugate vaccine prevented tumor colonisation of the lung following intravenous inoculation of tumor cells or spontaneous metastasis from breast, respectively. Conclusion: Glycolipid-peptide conjugate vaccines that activate NKT cells prevent lung metastasis in breast cancer models and warrant investigation as adjuvant therapies for high-risk breast cancer.

Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration.

BACKGROUND: A major challenge for any glaucoma implant is their ability to provide long-term intraocular pressure lowering efficacy. The formation of a low-permeability fibrous capsule around the device often leads to obstructed drainage channels, which may impair the drainage function of devices. These foreign body-related limitations point to the need to develop biologically inert biomaterials to improve performance in reaching long-term intraocular pressure reduction. The aim of this study was to evaluate in vivo (in rabbits) the ocular biocompatibility and tissue integration of a novel suprachoroidal microinvasive glaucoma implant, MINIject™ (iSTAR Medical, Wavre, Belgium). RESULTS: In two rabbit studies, no biocompatibility issue was induced by the suprachoroidal, ab-externo implantation of the MINIject™ device. Clinical evaluation throughout the 6 post-operative months between the sham and test groups were similar, suggesting most reactions were related to the ab-externo surgical technique used for rabbits, rather than the implant material itself. Histological analysis of ocular tissues at post-operative months 1, 3 and 6 revealed that the implant was well-tolerated and induced only minimal fibroplasia and thus minimal encapsulation around the implant. The microporous structure of the device became rapidly colonized by cells, mostly by macrophages through cell migration, which do not, by their nature, impede the flow of aqueous humor through the device. Time-course analysis showed that once established, pore colonization was stable over time. No fibrosis nor dense connective tissue development were observed within any implant at any time point. The presence of pore colonization may be the process by which encapsulation around the implant is minimized, thus preserving the permeability of the surrounding tissues. No degradation nor structural changes of the implant occurred during the course of both studies. CONCLUSIONS: The novel MINIject™ microinvasive glaucoma implant was well-tolerated in ocular tissues of rabbits, with observance of biointegration, and no biocompatibility issues. Minimal fibrous encapsulation and stable cellular pore colonization provided evidence of preserved drainage properties over time, suggesting that the implant may produce a long-term ability to enhance aqueous outflow.

The Intervening Roles of Psychological Inflexibility and Functional Impairment in the Relation between Cancer-related Pain and Psychological Distress.

BACKGROUND: Psychological distress is a significant problem among patients with a diagnosis of cancer and is associated with elevated risk for mortality; however, not all patients with a diagnosis of cancer experience significant psychological distress. Cancer-related pain has been associated with greater psychological distress among patients with a cancer diagnosis (current or previous). The current study aimed to examine potential theoretical mechanisms (i.e., cognitive fusion, experiential avoidance, and functional impairment) as proposed by the psychological flexibility model, for the association between cancer-related pain and psychological distress. We hypothesized that cancer-related pain would be indirectly positively associated with psychological distress among patients with a cancer diagnosis (current or previous) through psychological inflexibility (i.e., cognitive fusion and experiential avoidance) related to pain and functional impairment, in serial. METHOD: Sixty-one adult outpatients diagnosed with cancer completed self-report assessments of cancer-related pain, psychological inflexibility related to pain, pain-related functional impairment, and psychological distress. RESULTS: Cancer-related pain was positively associated with psychological distress indirectly through greater pain-related psychological inflexibility (i.e., cognitive fusion and experiential avoidance) and functional impairment, in serial. Alternative models were explored but unsupported. CONCLUSION: Consistent with the psychological flexibility model, psychological inflexibility and functional impairment may be potential mechanisms underlying the association between cancer-related pain and psychological distress among patients with a cancer diagnosis (current or previous).

The importance of contractile reserve in predicting exercise tolerance in asymptomatic patients with severe aortic stenosis.

BACKGROUND: Mortality dramatically rises with the onset of symptoms in patients with severe aortic stenosis (AS). Surgery is indicated when symptoms become apparent or when there is ventricular decompensation. Cardiopulmonary exercise testing (CPET) in combination with exercise echocardiography can unmask symptoms and provides valuable information regarding contractile reserve. The aim of the present study was to determine the prevalence of reduced exercise tolerance and the parameters predicting adverse cardiovascular events. METHODS: Thirty-two patients with asymptomatic severe AS were included in this study. Patients were followed up as part of an enhanced surveillance clinic. RESULTS: Age was 69 ± 15.7 years, 75% of patients were male. Patients had a raised NT-ProBNP of 301 pg/mL. VO2peak was 19.5 ± 6.2 mL/kg/min. Forty-one percent of patients had a reduced %VO2peak and this predicted unplanned cardiac hospitalisation (P = 0.005). Exercise systolic longitudinal velocity (S') and age were the strongest independent predictors for VO2peak (R 2 = 0.76; P < 0.0001). Exercise S' was the strongest independent predictor for NT-ProBNP (R 2 = 0.48; P = 0.001). CONCLUSION: A large proportion of patients had a lower than predicted VO2peak. The major determinant of exercise and NT-ProBNP is the ability of the left ventricle (LV) to augment S' on exercise rather than the severity of aortic valve obstruction or resting structural remodelling of the LV. Reduced exercise tolerance and more adverse remodelling, rather than valve obstruction predicted unplanned hospitalisation. This study demonstrates that for those patients, in whom a watchful waiting is an agreed strategy, a detailed assessment should be undertaken including CPET, exercise echocardiography and biomarkers to ensure those with exercise limitation and risk of decompensation are detected early and treated appropriately.

Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: synthesis, biological evaluation and molecular modelling.

A novel series of TGX-221 analogues was prepared and tested for their potency against the p110α, p110ß, and p110δ isoforms of the PI3K enzyme, and in two cellular assays. The biological results were interpreted in terms of a p110ß comparative model, in order to account for their selectivity towards this isoform. A CH2NH type linker is proposed to allow binding into the specificity pocket proposed to accommodate the high p110ß-selectivity of TGX-221, although there was limited steric tolerance for substituents on the pendant ring with the 2-position most favourable for substitution.

Fragmentation of the quinoxaline N-oxide bond to the ˙OH radical upon one-electron bioreduction.

The ˙OH radical is released from 3-trifluoromethyl-quinoxaline 1,4-dioxides upon one-electron reduction by cytochrome P450 oxidoreductase. This process effectively competes with back oxidation of the intermediate radical anion by oxygen and underlies the increased aerobic cytotoxicity of such compounds compared to that seen for the related clinical bioreductive benzotriazine drug, tirapazamine.

Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors.

We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.

Evaluation of a crystalline nanosuspension: polymorphism, process induced transformation and in vivo studies.

The aim of this work was to evaluate a crystalline nanosuspension of an investigational anticancer compound, SN 30191. Solid forms of SN 30191 were prepared and characterized by thermal analysis, infrared spectroscopy, ¹³C CP/MAS SSNMR spectroscopy, SEM and powder XRD. Wet milling was performed using a high pressure homogenizer and process induced transformations were studied as a function of time and pressure using infrared spectroscopy. Dose-toxicity and pharmacokinetics (PK) of the nanocrystal formulation were evaluated in mice after intravenous administration. SN 30191 was found to exist in two polymorphic forms (I and II) and a hydrate with an equilibrium solubility < 0.1 µg/ml (pH 1.3-11.0, 37 °C). Wet milling resulted in solid state transformation as a function of pressure. Form II was found to transform into form I at intermediate pressures. A further increase in pressure resulted in formation of a hydrate. The final nanosuspension consisted of SN 30191 as a hydrate. The dose-toxicity studies revealed higher tolerance (~4 times) for the nanosuspension (10 mg/kg) when compared with a solution formulation (2.5 mg/kg). Compared with solution formulation, the nanosuspension allowed the delivery of a higher dose and rendered possible the performance of PK and tissue distribution studies in animals.

Morphologic assessment of patent ductus arteriosus in adults using retrospectively ECG-gated multidetector CT.

OBJECTIVE: Noninvasive imaging of a persistently patent ductus arteriosus in adults remains a challenge. Bearing in mind the excellent spatial resolution provided by multidetector CT (MDCT), we postulated that MDCT might be used to evaluate this anatomic defect. We sought to show that MDCT can depict in detail patent ductus arteriosus in adults and allow determination of the size of the duct, degree of calcification, and morphologic classification. CONCLUSION: MDCT represents a novel method of noninvasively assessing patent ductus arteriosus in adults that provides detailed anatomic information. Comparison with invasive angiographic findings is needed to validate the technique of sizing of ducts using MDCT.

Calcified patent ductus arteriosus diagnosed following aortic valve replacement.

A 71-year-old woman underwent aortic valve replacement for severe, symptomatic aortic stenosis. The left ventricle filled rapidly when the left ventricular vent was switched off and postoperatively she was slow to recover with bilateral pleural effusions. These findings prompted early reinvestigation, initially with echocardiography and subsequently with multi-detector row computed tomography. Using a retrospectively electrocardiographic-gated acquisition, adapted from a noninvasive coronary angiography protocol, a calcified, persistently patent ductus arteriosus was identified as the cause for her perioperative and postoperative condition. The defect has since been closed successfully using a transcatheter technique.

Quadricuspid aortic valves.

Quadricuspid aortic valves (QAV) are a rare but well recognized cause of significant aortic regurgitation. The first case was found reported in 1862. Since then there have been 110 reported cases of QAV and we report 4 more. Previously, these were diagnosed at the time of surgery or postmortem examination. With advances in echocardiography, including harmonic imaging, and also the advent of transesophageal echocardiography, more cases are being diagnosed prior to surgery. We describe four more cases, three diagnosed preoperatively and one at the time of surgery, and then review the previously reported cases. Of the 114 cases reported, 46 had the aortic valve replaced, most commonly in the 5th and 6th decade of life. Hurwitz and Roberts classified quadricuspid valves according to the size of the leaflets. It has previously been believed that QAVs with four equal sized leaflets were less likely to develop significant aortic regurgitation; however, on review of the available cases, this would not appear to be the case. The preoperative diagnosis of QAVs is important as they can be associated with abnormally placed coronary ostium. Of the 114 cases reported, there are 10 reports of abnormally placed ostia. There has been at least one reported case of death occurring because of obstruction of an abnormally placed right coronary ostium by a prosthetic aortic valve.