Modelling the pH dependent retention and competitive adsorption of charged and ionizable solutes in mixed-mode and reversed-phase liquid chromatography.

This study investigated the influence of pH on the retention of solutes using a mixed-mode column with carboxyl (-COOH) groups acting as weak cation exchanger bonded to the terminal of C18 ligands (C18-WCX column) and a traditional reversed-phase C18 column. First, a model based on electrostatic theory was derived and successfully used to predict the retention of charged solutes (charged, and ionizable) as a function of mobile phase pH on a C18-WCX column. While the Horváth model predicts the pH-dependent retention of ionizable solutes in reversed-phase liquid chromatography (RPLC) solely based on solute ionization, the developed model incorporates the concept of surface potential generated on the surface of the stationary phase and its variation with pH. To comprehensively understand the adsorption process, adsorption isotherms for these solutes were individually acquired on the C18-WCX and reversed-phase C18 columns. The adsorption isotherms followed the Langmuir model for the uncharged solute and the electrostatically modified Langmuir model for charged solutes. The elution profiles for the single components were calculated from these isotherms using the equilibrium dispersion column model and were found to be in close agreement with the experimental elution profiles. To enable modelling of two-component cases involving charged solute(s), a competitive adsorption isotherm model based on electrostatic theory was derived. This model was later successfully used to calculate the elution profiles of two components for scenarios involving (a) a C18 Column: two charged solutes, (b) a C18 Column: one charged and one uncharged solute, and (c) a C18-WCX Column: two charged solutes. The strong alignment between the experimental and calculated elution profiles in all three scenarios validated the developed competitive adsorption model.

Biodegradation of PHB/PBAT films and isolation of novel PBAT biodegraders from soil microbiomes.

Polyhydroxyalkanoates (PHAs) are important candidates for replacing petroleum-based plastics. This transition is urgent for the development of a biobased economy and to protect human health and natural ecosystems. PHAs are biobased and biodegradable polyesters that when blended with other polymers, such as poly(butylene adipate-co-terephthalate) (PBAT), acquire remarkable improvements in their properties, which allow them to comply with the requirements of packaging applications. However, the biodegradation of such blends should be tested to evaluate the impact of those polymers in the environment. For instance, PBAT is a compostable aliphatic-aromatic copolyester, and its biodegradation in natural environments, such as soil, is poorly studied. In this work, we evaluated the biodegradation of a bilayer film composed of PHB and PBAT, by a soil microbiome. The bilayer film reached 47 ± 1 % mineralization in 180 days and PHB was no longer detected after this period. The increased crystallinity of the PBAT residue was a clear sign of biodegradation, indicating that the amorphous regions were preferentially biodegraded. Seven microorganisms were isolated, from which 4 were closely related to microorganisms already known as PHB degraders, but the other 3 species, closely related to Streptomyces coelicoflavus, Clonostachys rosea and Aspergillus insuetus, were found for the first time as PHB degraders. Most remarkably, two fungi closely related to Purpureocillium lilacinum and Aspergillus pseudodeflectus (99.83 % and 100 % identity by ITS sequencing) were isolated and identified as PBAT degraders. This is very interesting due to the rarity of isolating PBAT-degrading microorganisms. These results show that the bilayer film can be biodegraded in soil, at mesophilic temperatures, showing its potential to replace synthetic plastics in food packaging.

Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth.

We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 µM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.

Early pharmacological profiling of isatin derivatives as potent and selective cytotoxic agents.

Isatin derivatives have attracted a lot of interest for their potential in the development of new anticancer drugs. A library of 38 isatin derivatives, created through an Ugi four-component reaction, underwent an initial screening in a panel of six human solid tumor cell lines. The four most active derivatives were then selected for further testing. These compounds showed selectivity towards the non-small cell lung cancer (NSCLC) cell line SW1573, whilst NSCLC A549 cells were barely affected. The combination of phenotypic assays, including wound healing, clonogenic and continuous live cell imaging provided a deeper understanding of the compounds' mode of action. In particular, the latter demonstrated that isatin derivatives were able to induce necroptosis in SW1573 cells. The kinetics of cell death showed that necroptosis appeared after 2.5 h of exposure, which could be delayed to 7 h when co-treated with necrostatin-1. Interaction between the isatin derivatives and the KRAS G12C protein variant was discarded after in silico studies. Further studies are warranted to identify the cellular target responsible for the observed selectivity among cell lines.

Estimating how contouring differences affect normal tissue complication probability modelling.

Background and purpose: Normal tissue complication probability (NTCP) models are developed from large retrospective datasets where automatic contouring is often used to contour the organs at risk. This study proposes a methodology to estimate how discrepancies between two sets of contours are reflected on NTCP model performance. We apply this methodology to heart contours within a dataset of non-small cell lung cancer (NSCLC) patients. Materials and methods: One of the contour sets is designated the ground truth and a dosimetric parameter derived from it is used to simulate outcomes via a predefined NTCP relationship. For each simulated outcome, the selected dosimetric parameters associated with each contour set are individually used to fit a toxicity model and their performance is compared. Our dataset comprised 605 stage IIA-IIIB NSCLC patients. Manual, deep learning, and atlas-based heart contours were available. Results: How contour differences were reflected in NTCP model performance depended on the slope of the predefined model, the dosimetric parameter utilized, and the size of the cohort. The impact of contour differences on NTCP model performance increased with steeper NTCP curves. In our dataset, parameters on the low range of the dose-volume histogram were more robust to contour differences. Conclusions: Our methodology can be used to estimate whether a given contouring model is fit for NTCP model development. For the heart in comparable datasets, average Dice should be at least as high as between our manual and deep learning contours for shallow NTCP relationships (88.5 ± 4.5 %) and higher for steep relationships.

Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors.

The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1-4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor-enzyme interactions.

Melanoma in situ of the penis: A very rare entity with an even rarer presentation.

Penile melanoma in situ is a very rare malignant neoplasm. Surgical treatment is the standard approach, although there are no recommendations regarding the extent and best technique. A 28-year-old male presented with a dark-brown macule on the glans, whose biopsy revealed melanoma in situ. A local excision followed by a partial resurfacing was performed, with follow-up revealing no sign of recurrence and good quality of life. Melanoma is a very dangerous tumor due to its metastization potential. The main challenge is early diagnosis. Surgical treatment is the best approach, although it is difficult to balance resection and organ preservation.

Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.

The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH2 groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC50 = 9.7 nM and 11 nM) and BuChE (IC50 = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI50 > 100 µM), or to have weak antiproliferative properties (GI50 = 84-97 µM) against a panel of human cancer cells.

Comparing human to electronic observers to monitor hand hygiene compliance in an intensive care unit.

Objective: We sought to determine whether an electronic hand hygiene (HH) system could monitor HH compliance at similar rates to direct human observation. Methods: This 4-year proof-of-concept study was conducted in an intensive care unit (ICU) of a private tertiary-care hospital in São Paulo, Brazil, where electronic HH systems were installed in 2 rooms. HH compliance was reported respectively using direct observation and electronic counter devices with an infrared system for detecting HH opportunities. Results: In phase 1, HH compliance by human observers was 56.3% (564 of 1,001 opportunities), while HH compliance detected by the electronic observer was 51.0% (515 of 1,010 opportunities). In phase 2, human observers registered 484 HH opportunities with a HH compliance rate of 64.7% (313 of 484) versus 70.6% (346 of 490) simultaneously detected by the electronic system. In addition, an enhanced HH electronic system monitored activity 24 hours per day and HH compliance without the presence of a human observer was 40.3% (10,642 of 26,421 opportunities), providing evidence for the Hawthorne effect. Conclusions: The electronic HH monitoring system had good correlation with human HH observation, but compliance was remarkably lower when human observers were not present due to the Hawthorne effect (25%-30% absolute difference). Electronic monitoring systems can replace direct observation and can markedly reduce the Hawthorne effect.

Lactate dehydrogenase A inhibitors with a 2,8-dioxabicyclo[3.3.1]nonane scaffold: A contribution to molecular therapies for primary hyperoxalurias.

Human lactate dehydrogenase A (hLDHA) is one of the main enzymes involved in the pathway of oxalate synthesis in human liver and seems to contribute to the pathogenesis of disorders with endogenous oxalate overproduction, such as primary hyperoxaluria (PH), a rare life-threatening genetic disease. Recent published results on the knockdown of LDHA gene expression as a safe strategy to ameliorate oxalate build-up in PH patients are encouraging for an approach of hLDHA inhibition by small molecules as a potential pharmacological treatment. Thus, we now report on the synthesis and hLDHA inhibitory activity of a new family of compounds with 2,8-dioxabicyclo[3.3.1]nonane core (23-42), a series of twenty analogues to A-type proanthocyanidin natural products. Nine of them (25-27, 29-34) have shown IC50 values in the range of 8.7-26.7 µM, based on a UV spectrophotometric assay, where the hLDHA inhibition is measured according to the decrease in absorbance of the cofactor ß-NADH (340 nm). Compounds 25, 29, and 31 were the most active hLDHA inhibitors. In addition, the inhibitory activities of those nine compounds against the hLDHB isoform were also evaluated, finding that all of them were more selective inhibitors of hLDHA versus hLDHB. Among them, compounds 32 and 34 showed the highest selectivity. Moreover, the most active hLDHA inhibitors (25, 29, 31) were evaluated for their ability to decrease the oxalate production by hyperoxaluric mouse hepatocytes (PH1, PH2 and PH3) in vitro, and the relative oxalate output at 24 h was 16% and 19 % for compounds 25 and 31, respectively, in Hoga1-/- mouse primary hepatocyte cells (a model for PH3). These values improve those of the reference compound used (stiripentol). Compounds 25 and 31 have in common the presence of two hydroxyl groups at rings B and D and an electron-withdrawing group (NO2 or Br) at ring A, pointing to the structural features to be taken into account in future structural optimization.

A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE).

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.

Prostate resection weight matters in severely obstructed men undergoing transurethral resection of the prostate.

OBJECTIVES: Transurethral resection of the prostate (TURP) remains one of the goldstandard surgical treatments for benign prostatic hyperplasia/lower urinary tract symptoms. The usefulness of a complete adenoma resection is questionable, with studies reporting no impact of the amount of resected tissue on surgical outcomes, irrespective of prostate volume. The aim of this study was to assess whether in less obstructed patients a less extensive TURP may be considered. MATERIALS AND METHODS: Retrospective analysis of 185 men undergoing TURP in one university hospital. Retrieved data included pre-operative prostate volume and Qmax, as well as resected prostate weight and post-operative Qmax. Patients were divided in two groups according to pre-operative Qmax < 10mL/s and ≥ 10 mL/s. RESULTS: A correlation was found between absolute resected prostate weight and post-operative Qmax in the group of patients with pre-operative Qmax < 10 mL/s (r2 = 0.038, p = 0.032), independently of the pre-operative prostate volume. This association was neither observed in the group of patients with pre-operative Qmax ≥ 10 mL/s (r2 = -0.033, p = 0.796) nor in whole population analysis (r2 = 0.019, p = 0.064). Likewise, in the group of patients with pre-operative Qmax < 10 mL/s, the improvement in Qmax was correlated with absolute resected weight and percentage of prostate resected weight (r2 = 0.036, p = 0.037 and r2 = 0.040, p = 0.029, respectively). None of these correlations was found in the group of patients with pre-operative Qmax ≥ 10 mL/s (r2 = 0.009, p = 0.463 and r2 = -0.018, p = 0.294, respectively). CONCLUSIONS: Patients with pre-operative Qmax ≥ 10 mL/s may do well with less profound prostate resections, whereas patients with lower pre-operative Qmax seem to benefit from a complete adenoma resection.

Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease.

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data.

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations.

(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.

New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production.

The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether, this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.

A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors.

Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.

Translation and validation of the Portuguese version of the International Consultation on Incontinence Questionnaire (ICIQ) Bladder Diary.

INTRODUCTION AND HYPOTHESIS: The International Consultation on Incontinence Questionnaire (ICIQ) Bladder Diary (BD) is a standardized and validated diary, developed in the English language, designed to assess lower urinary tract symptoms (LUTS) in men and women. This study reports the translation, cross-cultural adaptation and validation process of this diary to the Portuguese language. METHODS: After translation and back-translation of the ICIQ-BD to Portuguese, 140 urologic patients were asked to fill in this 3-day diary as well as the Overactive Bladder questionnaire Short Form (OABqSF) and a questionnaire evaluating the difficulties in filling out the ICIQ-BD. A subset of 60 patients filled out a second diary with/without LUTS treatment in between (30 patients in each group). In addition, content validity, internal consistency, criterion and construct validity were tested. RESULTS: The Portuguese version of the ICIQ-BD showed adequate internal consistency (Cronbach's alpha of 0.78), and patients reported few difficulties in filling out this tool, answering most commonly 1 on a 1-6 scale of difficulty. Excellent test-retest reliability and responsiveness of the diary were observed when comparing the first diary to a second completed 2-6 weeks later. Criterion validity was also confirmed, given the good correlation with the OABqSF (Pearson's 0.386-0.447). Finally, construct validity was established through statistically significant concordance between data obtained in the BD with generally accepted theories. CONCLUSION: The present version of the ICIQ-BD is the first bladder diary successfully validated in the Portuguese language. It is a suitable and standardized tool for scientific research and diagnostic assessment of LUTS in adult men and women.

Mitochondria, energy, and metabolism in neuronal health and disease.

Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates aging and neurodegeneration with anomalous neuronal metabolism as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress, and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted.

2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Deep learning model for automatic contouring of cardiovascular substructures on radiotherapy planning CT images: Dosimetric validation and reader study based clinical acceptability testing.

BACKGROUND AND PURPOSE: Large radiotherapy (RT) planning imaging datasets with consistently contoured cardiovascular structures are essential for robust cardiac radiotoxicity research in thoracic cancers. This study aims to develop and validate a highly accurate automatic contouring model for the heart, cardiac chambers, and great vessels for RT planning computed tomography (CT) images that can be used for dose-volume parameter estimation. MATERIALS AND METHODS: A neural network model was trained using a dataset of 127 expertly contoured planning CT images from RT treatment of locally advanced non-small-cell lung cancer (NSCLC) patients. Evaluation of geometric accuracy and quality of dosimetric parameter estimation was performed on 50 independent scans with contrast and without contrast enhancement. The model was further evaluated regarding the clinical acceptability of the contours in 99 scans randomly sampled from the RTOG-0617 dataset by three experienced radiation oncologists. RESULTS: Median surface dice at 3 mm tolerance for all dedicated thoracic structures was 90% in the test set. Median absolute difference between mean dose computed with model contours and expert contours was 0.45 Gy averaged over all structures. The mean clinical acceptability rate by majority vote in the RTOG-0617 scans was 91%. CONCLUSION: This model can be used to contour the heart, cardiac chambers, and great vessels in large datasets of RT planning thoracic CT images accurately, quickly, and consistently. Additionally, the model can be used as a time-saving tool for contouring in clinic practice.