What do we really know about vital pulp therapy?

DESIGN: Retrospective cohort study using STROBE cohort reporting guidelines. COHORT SELECTION: Patients from Mehr Dental Clinic in Tehran, Iran, who received different types of vital pulp therapy (VPT) by a single endodontist, due to carious pulpal exposure, between April 2011 and October 2022. These were: Full Pulpotomy (FP), Miniature Pulpotomy (MP) and Direct Pulp Capping (DPC). Data were accessed via the dental clinic's electronic database. Patients were deemed eligible if they had pulpal exposure due to caries, but not trauma. Pre-operative, immediate post-operative and at least one follow-up radiograph at a minimum 3-month interval were required. Demographic, diagnostic, and procedural data as well as informed consent were also required. Teeth with probing depths greater than 4 mm or pulpal necrosis were excluded. DATA ANALYSIS: Patient, tooth and treatment factors were statistically analysed for an outcome of success or failure using a Cox proportional hazards model. Kaplan/Meier curves were used to establish the mean survival times. The Log-rank test was used to compare survival across the three treatment groups. The Omnibus test of model and the -2 log likelihood ratio (-2LL) were used to assess sensitivity and model fitness. Statistical analyses were determined using the IBM SPSS Statistics for Windows Version 21.0, with P value set at <0.05. RESULTS: 1257 VPTs from 1149 patients had complete data and were used in the analysis. 802 cases were excluded due to no follow up radiograph. The VPT cases were divided into FP (n = 272), MP (n = 217) and DPC (n = 768). The average follow up was 42.21 months, with an overall 116-month survival rate of 99.1% and success rate of 91.6%. FP had a mean survival time of 99.43 months; for MP it was 104.26 months; for DPC it was 102.27 months. There were no significant differences between these groups (P = 0.363). There were statistically significant correlations between symptomatic Irreversible Periodontitis (IP), radiographic signs of Apical Periodontitis (AP), restoration type, restoration surfaces and the outcome of VPT. CONCLUSIONS: This is one of the largest cohort studies of its kind, with over 1250 cases of various VPT techniques in 10 years. There was deviation from gold standard practice, with lack of rubber dam. A lack of haemostasis after 2 min could be construed as bacterially infected pulpal tissue and require further resection of pulp. Yet, these approaches still resulted in successful outcomes. Another interesting finding was that symptomatic IP with associated AP was treated with VPT, with a 78% success rate. Considering this study and other emerging evidence in the literature, application of VPT as an alternative to conventional Root Canal Treatment could be adopted in general practice, depending on the skills and knowledge of the practitioner and patient preferences.

Artificial intelligence and dental panoramic radiographs: where are we now?

DATA SOURCES: Bielefeld Academic Search Engine (BASE), Google Scholar Association for Computing Machinery: Guide to Computing Literature (ACM) and National Library of Medicine: PubMed databases were searched for systematic reviews. STUDY SELECTION: This study addressed a structured PICO question (Population, Intervention, Comparison, Outcome). Population was panoramic radiographs in human subjects. Intervention was use of artificial intelligence (AI) diagnostics, compared to human-only diagnosis. Quantitative or qualitative AI efficiency was the outcome. Systematic reviews were considered if they stated 'systematic review' in their title or abstract, were published in English and were not bound by a certain time frame. No supplemental primary studies were included. Screening and removal of duplicates were performed using the Rayyan tool. DATA EXTRACTION AND SYNTHESIS: Data were extracted from each systematic review by two authors, with a third author having the deciding vote in cases of inconsistency. Cohen's Kappa co-efficient was used to measure reliability between authors, resulting in almost perfect agreement. The risk of bias was accounted for using the ROBIS method which resulted in one paper being rejected, so only 11 included in results. Data were then grouped into seven domains which were detected by AI: teeth identification and numbering, detection of periapical lesions, periodontal bone loss, osteoporosis, maxillary sinusitis, dental caries, and other tasks. The effectiveness of the AI systems was assessed by various outcome metrics - accuracy, sensitivity, specificity, and precision being the most common variables. RESULTS: Results of this overview show a significant increase in accuracy of AI in analysing OPTs between 1988-2023. Latest AI models are most accurate in teeth identification and numbering (93.67%) whilst caries detection and osteoporosis showed 91.5% and 89.29% accuracy, respectively. Accurate results were also observed for the detection of maxillary sinusitis and periodontal bone loss. However, given the heterogeneity of source studies used in these systematic reviews, results should be interpreted with caution. CONCLUSIONS: With improving AI technology, its use in dental radiology can be increasingly effective in supporting dentists in the detection of different pathologies. This overview has shown that systematic reviews of AI can quickly become outdated and that results of any systematic review should be treated with caution as this field advances. As such, regular updating and ongoing research is required.

Memory deficits in a juvenile rat model of type 1 diabetes are due to excess 11ß-HSD1 activity, which is upregulated by high glucose concentrations rather than insulin deficiency.

AIMS/HYPOTHESIS: Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared. Variations in glucose levels together with relative insulin deficiency in treated type 1 diabetes have been reported to impact brain function indirectly through dysregulation of the hypothalamus-pituitary-adrenal axis. We have recently shown that enhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion but also on glucocorticoid tissue concentrations, which is linked to 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. Hypothalamus-pituitary-adrenal axis dysfunction and memory alteration were further dissected in a juvenile rat model of diabetes showing that excess 11ß-HSD1 activity within the hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11ß-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11ß-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11ß-HSD1 activity is due to an increase in brain glucose concentrations and/or a decrease in insulin signalling. METHODS: Diabetes was induced in juvenile rats by daily i.p. injection of streptozotocin for 2 consecutive days. Inhibition of 11ß-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after which hippocampal-dependent object location memory was assessed. Hippocampal 11ß-HSD1 activity was estimated by the ratio of corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11ß-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11ß-HSD1 was further examined in vivo using virally mediated knockdown of insulin receptor expression specifically in the hippocampus. RESULTS: Our data show that inhibiting 11ß-HSD1 activity prevents hippocampal-related memory deficits in diabetic juvenile rats. A significant increase (53.0±9.9%) in hippocampal 11ß-HSD1 activity was found in hippocampal slices incubated in high glucose conditions (13.9 mmol/l) vs normal glucose conditions (2.8 mmol/l) without insulin. However, 11ß-HSD1 activity was not affected by variations in insulin concentration either in the hippocampal slices or after a decrease in hippocampal insulin receptor expression. CONCLUSIONS/INTERPRETATION: Together, these data demonstrate that an increase in 11ß-HSD1 activity contributes to memory deficits observed in juvenile diabetic rats and that an excess of hippocampal 11ß-HSD1 activity stems from high glucose levels rather than insulin deficiency. 11ß-HSD1 might be a therapeutic target for treating cognitive impairments associated with diabetes.

Three-photon absorption spectra of zinc blende semiconductors: theory and experiment: erratum.

We provide a correction to the spectral dependence of the three-photon absorption in zinc-blende semiconductors using Kane's 4-band model in Opt. Lett.33, 2626 (2008).OPLEDP0146-959210.1364/OL.33.002626.

A Novel Robotic Endoscopic Device Used for Operative Hysteroscopy.

To trial the use of a novel endoscopic robot that functions using concentric tube robots, enabling 2-handed surgery in small spaces, in a bioengineering laboratory. This was a feasibility study of the endoscopic robot for hysteroscopic applications, including removal of a simulated endometrial polyp. The endoscopic robot was successfully used to resect a simulated endometrial polyp from a porcine uterine tissue model in a fluid environment. The potential advantages of this platform to the surgeon may include improved exposure, finer dissection capability, and use of a 2-handed surgical technique. Further study regarding the safe, efficient, and cost-effective use of the endoscopic robot in gynecology is needed.

11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis.

A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11ßHSD1). Although 11ßHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11ßHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast-specific, Hsd11b1fl/fl /Pdgfrb-cre) 11ßHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11ßHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11ßHSD1 inhibitor [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1-/- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION: 11ßHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11ßHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181).

Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11ß-HSD1 Inhibitors.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11ß-HSD1. In continuation of our efforts to discover potent and selective 11ß-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11ß-HSD1, although with low selectivity over the isoenzyme 11ß-HSD2, and poor microsomal stability.

The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis.

A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.

Elevated hepatic 11ß-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia.

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11ß-Hydroxysteroid dehydrogenase type 1 (11ßHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11ßHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11ßHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11ßHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11ßHSD1(-/-) mice and rats treated with a specific 11ßHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11ßHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11ßHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment.

Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal neuroinflammatory changes after TBI in an AD model, the APP/PS1 knock-in (KI) mouse. Discrete temporal aspects of astrocyte, cytokine, and chemokine responses in the injured KI mice were delayed compared with the injured wild-type mice, with a peak neuroinflammatory response in the injured KI mice occurring at 7 d after injury. The neuroinflammatory responses were more persistent in the injured KI mice, leading to a chronic neuroinflammation. At late time points after injury, KI mice exhibited a significant impairment in radial arm water maze performance compared with sham KI mice or injured wild-type mice. Intervention with a small-molecule experimental therapeutic (MW151) that selectively attenuates proinflammatory cytokine production yielded improved cognitive behavior outcomes, consistent with a link between neuroinflammatory responses and altered risk for AD-associated pathology changes with head injury.

Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic.

BACKGROUND: Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test dose dependence of MW151 to suppress the target mechanism (proinflammatory cytokine up-regulation), and explore the therapeutic window for MW151 efficacy. METHODS: We examined suppression of the acute cytokine surge when MW151 was administered at different times post-injury and the dose-dependence of cytokine suppression. We also tested a more prolonged treatment with MW151 over the first 7 days post-injury and measured the effects on cognitive impairment and glial activation. RESULTS: MW151 administered up to 6 h post-injury suppressed the acute cytokine surge, in a dose-dependent manner. Administration of MW151 over the first 7 days post-injury rescues the CHI-induced cognitive impairment and reduces glial activation in the focus area of the CHI. CONCLUSIONS: Our results identify a clinically relevant time window post-CHI during which MW151 effectively restores cytokine production back towards normal, with a resultant attenuation of downstream cognitive impairment.

Novel 11ß-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold.

The adamantane scaffold is found in several marketed drugs and in many investigational 11ß-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11ß-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11ß-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.

Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11ß-HSD1 inhibitors.

The structural and physicochemical properties of the adamantane nucleus account for its use as a chemical scaffold in multiple drugs. In the last years, we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As adamantane is a common structural feature in several 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11ß-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11ß-HSD1 inhibitory activity. Molecular modeling studies support the binding of the compounds to the active site of the enzyme. However, a fine tuning of the hydrophobicity of the size-expanded nucleus may be beneficial for the inhibitory potency.

5α-Tetrahydrocorticosterone: A topical anti-inflammatory glucocorticoid with an improved therapeutic index in a murine model of dermatitis.

BACKGROUND AND PURPOSE: Glucocorticoids are powerful anti-inflammatory drugs, but are associated with many side-effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α-Tetrahydrocorticosterone (5αTHB) is a potential selective anti-inflammatory with reduced metabolic effects. Here, the efficacy and side-effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis. EXPERIMENTAL APPROACH: Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side-effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non-irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration. KEY RESULTS: 5αTHB suppressed ear swelling in mice, with ED50 similar to hydrocortisone (23 µg vs. 13 µg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED50 ). 5αTHB was rapidly cleared from the systemic circulation. CONCLUSIONS AND IMPLICATIONS: Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin.

Mass spectrometry imaging for dissecting steroid intracrinology within target tissues.

Steroid concentrations within tissues are modulated by intracellular enzymes. Such "steroid intracrinology" influences hormone-dependent cancers and obesity and provides targets for pharmacological inhibition. However, no high resolution methods exist to quantify steroids within target tissues. We developed mass spectrometry imaging (MSI), combining matrix assisted laser desorption ionization with on-tissue derivatization with Girard T and Fourier transform ion cyclotron resonance mass spectrometry, to quantify substrate and product (11-dehydrocorticosterone and corticosterone) of the glucocorticoid-amplifying enzyme 11ß-HSD1. Regional steroid distribution was imaged at 150-200 µm resolution in rat adrenal gland and mouse brain sections and confirmed with collision induced dissociation/liquid extraction surface analysis. In brains of mice with 11ß-HSD1 deficiency or inhibition, MSI quantified changes in subregional corticosterone/11-dehydrocorticosterone ratio, distribution of inhibitor, and accumulation of the alternative 11ß-HSD1 substrate, 7-ketocholesterol. MSI data correlated well with LC-MS/MS in whole brain homogenates. MSI with derivatization is a powerful new tool to investigate steroid biology within tissues.

Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain.

INTRODUCTION: Mutations in proteolipid protein (PLP), the most abundant myelin protein in the CNS, cause the X-linked dysmyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2). Point mutations, deletion, and duplication of the PLP1 gene cause PMD/SPG2 with varying clinical presentation. Deletion of an intronic splicing enhancer (ISEdel) within intron 3 of the PLP1 gene is associated with a mild form of PMD. Clinical and preclinical studies have indicated that mutations in myelin proteins, including PLP, can induce neuroinflammation, but the temporal and spatial onset of the reactive glia response in a clinically relevant mild form of PMD has not been defined. METHODS: A PLP-ISEdel knockin mouse was used to examine the behavioral and neuroinflammatory consequences of a deletion within intron 3 of the PLP gene, at two time points (two and four months old) early in the pathological progression. Mice were characterized functionally using the open field task, elevated plus maze, and nesting behavior. Quantitative neuropathological analysis was for markers of astrocytes (GFAP), microglia (IBA1, CD68, MHCII) and axons (APP). The Aperio ScanScope was used to generate a digital, high magnification photomicrograph of entire brain sections. These digital slides were used to quantify the immunohistochemical staining in ten different brain regions to assess the regional heterogeneity in the reactive astrocyte and microglial response. RESULTS: The PLP-ISEdel mice exhibited behavioral deficits in the open field and nesting behavior at two months, which did not worsen by four months of age. A marker of axonal injury (APP) increased from two months to four months of age. Striking was the robust reactive astrocyte and microglia response which was also progressive. In the two-month-old mice, the astrocyte and microglia reactivity was most apparent in white matter rich regions of the brain. By four months of age the gliosis had become widespread and included both white as well as gray matter regions of the brain. CONCLUSIONS: Our results indicate, along with other preclinical models of PMD, that an early reactive glia response occurs following mutations in the PLP gene, which may represent a potentially clinically relevant, oligodendrocyte-independent therapeutic target for PMD.

Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 µM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11ß-HSD1. In this model, compound 1 binds into the catalytic site of 11ß-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).

Two-photon absorption spectra of a near-infrared 2-azaazulene polymethine dye: solvation and ground-state symmetry breaking.

Polymethine dyes (PDs) with absorption bands in the near-infrared region undergo symmetry breaking in polar solvents. To investigate how symmetry breaking affects nonlinear optical responses of PDs, an extensive and challenging experimental characterization of a cationic 2-azaazulene polymethine dye, including linear absorption, fluorescence, two-photon absorption and excited-state absorption, has been performed in two solvents with different polarity. Based on this extensive set of experimental data, a three-electronic-state model, accounting for the coupling of electronic degrees of freedom to molecular vibrations and polar solvation, has been reliably parameterized and validated for this dye, fully rationalizing optical spectra in terms of spectral position, intensities and bandshapes. In low-polarity solvents where the dye is mainly in its symmetric form, a nominally forbidden two-photon absorption band is observed, due to a vibronic activation mechanism. Inhomogeneous broadening plays a major role in polar solvents: absorption spectra represent the weighted sum of contributions from states with a variable amount of symmetry breaking, leading to a complex evolution of linear and nonlinear optical spectra with solvent polarity. In more polar solvents, the dominant role of the asymmetric form leads to the activation of two-photon absorption as a result of the symmetry lowering. The subtle interplay between the two mechanisms for two-photon absorption activation, vibronic coupling and polar solvation, can be fully accounted for within the proposed microscopic model allowing a detailed interpretation of the optical spectra of PDs.

Enhanced intersystem crossing rate in polymethine-like molecules: sulfur-containing squaraines versus oxygen-containing analogues.

Two different approaches to increase intersystem crossing rates in polymethine-like molecules are presented: traditional heavy-atom substitution and molecular levels engineering. Linear and nonlinear optical properties of a series of polymethine dyes with Br- and Se-atom substitution, and a series of new squaraine molecules, where one or two oxygen atoms in a squaraine bridge are replaced with sulfur atoms, are investigated. A consequence of the oxygen-to-sulfur substitution in squaraines is the inversion of their lowest-lying ππ* and nπ* states leading to a significant reduction of singlet-triplet energy difference and opening of an additional intersystem channel of relaxation. Experimental studies show that triplet quantum yields for polymethine dyes with heavy-atom substitutions are small (not more than 10%), while for sulfur-containing squaraines these values reach almost unity. Linear spectroscopic characterization includes absorption, fluorescence, quantum yield, anisotropy, and singlet oxygen generation measurements. Nonlinear characterization, performed by picosecond and femtosecond laser systems (pump-probe and Z-scan measurements), includes measurements of the triplet quantum yields, excited state absorption, two-photon absorption, and singlet and triplet state lifetimes. Experimental results are in agreement with density functional theory calculations allowing determination of the energy positions, spin-orbital coupling, and electronic configurations of the lowest electronic transitions.

11ß-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis.

Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11ß-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11ß-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11ß-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11ß-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.