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Discovery of novel anticancer agents is of crucial importance to expand the therapeutic options for cancer patients. In this study, a series of 49 5-oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine analogs, containing different pyridine alkyl carboxylates at C3 and various aliphatic, aromatic, and heteroaromatic substitutions at the C4 position of the central core, were synthesized. The target compounds were tested for antiproliferative effect against three human cancer cell lines including MOLT-4 (acute lymphoblastic leukemia), K562 (chronic myelogenous leukemia), and MCF-7 (breast adenocarcinoma) by MTT assay, and the effect of the most potent derivatives on cell cycle was evaluated by RNase/propidium iodide (PI) flow cytometric assay. Generally, 5-oxo-hexahydroquinoline derivatives (E series) possessed superior antiproliferative activities compared to their 5-oxo-tetrahydrocyclopentapyridine counterparts (F series). 5-Oxo-hexahydroquinoline compounds bearing 2-pyridyl propyl carboxylate (group D) and 3-pyridyl propyl carboxylate (group E) were better antiproliferative agents than those bearing other pyridyl alkyl carboxylates. Five best compounds with IC50 values in the range of 9.5-22.9 µM against MOLT-4 cells were selected for cell-cycle analysis, which revealed that derivatives D5, E3, and E5 with 2,3-dichlorophenyl, 3-nitrophenyl, and 2-nitrophenyl substitutions at C4 position, respectively, may induce apoptosis in MOLT-4 cells. Molecular docking analysis, which was employed to make some predictions on the interaction of the most active derivatives with the binding site of Bcl-2 and Bcl-xL proteins, suggested that the compounds may be well accommodated within the binding sites of these anti-apoptotic proteins via hydrogen-bonding and hydrophobic interactions. The findings of this study present 5-oxo-hexahydroquinoline derivatives as antiproliferative agents with potential apoptosis-inducing ability in cancer cells.

Brain cancers pose a novel set of difficulties due to the limited accessibility of human brain tumor tissue. For this reason, clinical decision-making relies heavily on MR imaging interpretation, yet the mapping between MRI features and underlying biology remains ambiguous. Standard tissue sampling fails to capture the full heterogeneity of the disease. Biopsies are required to obtain a pathological diagnosis and are predominantly taken from the tumor core, which often has different traits to the surrounding invasive tumor that typically leads to recurrent disease. One approach to solving this issue is to characterize the spatial heterogeneity of molecular, genetic, and cellular features of glioma through the intraoperative collection of multiple image-localized biopsy samples paired with multi-parametric MRIs. We have adopted this approach and are currently actively enrolling patients for our ‘Image-Based Mapping of Brain Tumors’ study. Patients are eligible for this research study (IRB #16-002424) if they are 18 years or older and undergoing surgical intervention for a brain lesion. Once identified, candidate patients receive dynamic susceptibility contrast (DSC) perfusion MRI and diffusion tensor imaging (DTI), in addition to standard sequences (T1, T1Gd, T2, T2-FLAIR) at their presurgical scan. During surgery, sample locations are tracked using neuronavigation and genetic aberrations are later quantified through whole-exome and RNA sequencing. The collected specimens from this NCI-funded research study will be primarily used to generate regional maps of the spatial distribution of tumor cell density and/or treatment-related key genetic marker status across tumors, within clinically feasible time frames, to identify biopsy and/or treatment targets based on insight from the entire tumor makeup regional histologic and genetic makeup. This type of methodology, when delivered within clinically feasible time frames, has the potential to further inform medical decision-making by improving surgical intervention, radiation, and targeted drug therapy for patients with glioma. From October 1, 2017 to October 31, 2022, this study has enrolled 186 patients with 197 surgeries, of which 163 resulted in the successful collection of image-guided biopsy samples. A total of 995 biopsies have been collected of which 962 are image localized, with a mean of 5.90 image-localized samples per surgery.

Background and purpose: Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need. Experimental approach: A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs ( C1 - C10 ) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted. Results/Findings: Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one ( C2 ) was the most potent derivative amongst the series with an IC 50 value of 8.8 μM which was slightly more favorable to that of the reference kojic acid (IC 50 = 9.7 μM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. I n silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties. Conclusion and implications: Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.

Although antibiotics are among the most commonly used treatments of acne, there are refractory cases, or they can cause some complications. Recently, leukotriene B4 has been found to play a major role in inflammatory acne lesions. This double blind, randomized clinical trial was conducted on 108 patients with acne who needed systemic therapy and referred to dermatology clinics affiliated to Shiraz University of Medical Sciences. One group (53 patients) received 100 mg doxycycline daily plus placebo and the other group (55 patients) received 100 mg daily doxycycline plus 10 mg daily montelukast. Both groups also received topical benzoyl peroxide 5% every other night. The study period was 3 months and the patients were investigated by lesion count, investigator global assessment (IGA), global acne grading system (GAGS), and Cardiff acne disability index (CADI) scoring systems. Total lesion count, inflammatory lesion count, and non-inflammatory lesion count as well as IGA and GAGS decreased in both treatment groups. At the end of the study, however, the inflammatory lesion count and IGA score reduced more significantly in the montelukast group (p = 0.018 and 0.045, respectively). In addition, the two groups were significantly different with regard to the percentage of decrease in the total lesion count, inflammatory lesions, and IGA (p = 0.033, 0.003, and 0.044, respectively). Thus, montelukast can be used as an adjuvant therapy besides other treatments of acne, especially for inflammatory lesions.

Automatic brain tumor segmentation is particularly challenging on magnetic resonance imaging (MRI) with marked pathologies, such as brain tumors, which usually cause large displacement, abnormal appearance, and deformation of brain tissue. Despite an abundance of previous literature on learning-based methodologies for MRI segmentation, few works have focused on tackling MRI skull stripping of brain tumor patient data. This gap in literature can be associated with the lack of publicly available data (due to concerns about patient identification) and the labor-intensive nature of generating ground truth labels for model training. In this retrospective study, we assessed the performance of Dense-Vnet in skull stripping brain tumor patient MRI trained on our large multi-institutional brain tumor patient dataset. Our data included pretreatment MRI of 668 patients from our in-house institutional review board–approved multi-institutional brain tumor repository. Because of the absence of ground truth, we used imperfect automatically generated training labels using SPM12 software. We trained the network using common MRI sequences in oncology: T1-weighted with gadolinium contrast, T2-weighted fluid-attenuated inversion recovery, or both. We measured model performance against 30 independent brain tumor test cases with available manual brain masks. All images were harmonized for voxel spacing and volumetric dimensions before model training. Model training was performed using the modularly structured deep learning platform NiftyNet that is tailored toward simplifying medical image analysis. Our proposed approach showed the success of a weakly supervised deep learning approach in MRI brain extraction even in the presence of pathology. Our best model achieved an average Dice score, sensitivity, and specificity of, respectively, 94.5, 96.4, and 98.5% on the multi-institutional independent brain tumor test set. To further contextualize our results within existing literature on healthy brain segmentation, we tested the model against healthy subjects from the benchmark LBPA40 dataset. For this dataset, the model achieved an average Dice score, sensitivity, and specificity of 96.2, 96.6, and 99.2%, which are, although comparable to other publications, slightly lower than the performance of models trained on healthy patients. We associate this drop in performance with the use of brain tumor data for model training and its influence on brain appearance.

Background and purpose: The aim of this study was to evaluate the in vitro and in vivo anti- Toxoplasma gondii ( T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out. Experimental approach: A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z 3 and Z 4 in vitro , their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina ® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs. Findings / Results: Flow cytometry assay results indicated compounds Z 3 and Z 4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z 3 and Z 4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti- T. gondii activity through the inhibition of the ENR enzyme. Conclusion and implications: Compounds Z 3 and Z 4 are good leads in order to develop better anti- T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti- T. gondii impacts of 5-oxo-hexahydroquinoline compounds.

Background and Aims. Inflammation is strongly associated with the severity and mortality rate of SARS-CoV-2 disease (COVID-19). Dietary factors have a crucial role in preventing chronic and systemic inflammation. This study aimed to evaluate the association between energy-adjusted dietary inflammatory index (E-DII) scores and body composition parameters in COVID-19-infected patients compared to noninfected controls. Methods. A total of 133 COVID-19-infected patients and 322 noninfected controls were selected and enrolled from the Cohort Study of Employees of Shiraz University of Medical Sciences. E-DII score was calculated based on a validated food frequency questionnaire (FFQ) and body composition was measured using In-Body 770 equipment. Logistic regression models were utilized to estimate the odds ratio (OR). Results. In the control group, the mean E-DII score was significantly lower than the case group (−2.05 vs. −0.30, P ≤ 0.001 ), indicating that the diet of COVID-19-infected subjects was more proinflammatory than the controls. For every 1 unit increase in E-DII score, the odds of infection with COVID-19 was nearly triple (OR: 2.86, CI: 2.30, 3.35, P ≤ 0.001 ). Moreover, for each unit increase in body mass index (BMI), the odds of infection to COVID-19 increased by 7% (OR: 1.07, CI: 1.01, 1.13, P = 0.02). No significant difference was observed for other anthropometric parameters. Conclusion. The findings revealed that obese people and those consuming a more proinflammatory diet were more susceptible to coronavirus infection. Therefore, maintaining ideal body weight and consuming a more anti-inflammatory diet can decrease the probability of COVID-19 infection.

Novel phenanthro-triazine-3-thiol derivatives were designed as potential DNA intercalators and Bcl-2 inhibitors. After being synthesized, the compounds were evaluated for their cytotoxic activity against MOLT-4 (human acute lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma) cells by MTT assay. P1 (bearing hydrogen substitution) was the most potent derivative against MOLT-4 with an IC50 value of 7.1 ± 1.1 μM, whereas P11 (bearing phenyl substitution) demonstrated considerable cytotoxicity against MCF-7 with an IC50 value of 15.4 ± 2.9 μM. Compounds P7, P8, P14 and P15 exhibited moderate cytotoxic effects. Furthermore, to confirm the potential DNA intercalation and Bcl-2 inhibitory activities of phenanthro-triazine scaffolds, molecular docking analysis was performed. Molecular docking studies indicated that these compounds not only bind to DNA by intercalation mainly through stacking interactions but also are well accommodated in the active site of Bcl-2. Therefore, P1 and P11 having phenanthro-triazine-3-thiol scaffold could be presented as cytotoxic agents with dual DNA intercalation and Bcl-2 inhibitory activities.

INTRODUCTION Glioblastoma (GBM) is a diffusely invasive primary brain tumor with significant spread of tumor cells to the periphery of visible image abnormality. Enhancement of Gadolinium (Gd) contrast agent on magnetic resonance imaging (MRI) has historically been considered a confirmation of local breakdown of the blood brain barrier (BBB) and sufficient drug delivery to the bulk of tumors. In this work, we used GBM-derived xenograft (PDX) models to compare drug delivery in GBM brain for high and low BBB-permeable drugs. MATERIALS AND METHODS Five patient-derived orthotopic xenograft models from two GBM cell lines (GBM39 and GBM12) were co-dosed with erlotinib and osimertinib, two drugs with low and high BBB-permeability, respectively. T1Gd and T2-weighted MRIs were acquired from all animals prior to model sacrifice. Tumors were manually segmented on denoised and standardized MRIs and intensity patterns were captured using first and second order statistical features in the moving 3x3 kernel. We compared drug levels found in Matrix Assisted Laser Desorption Ionization (MALDI) in T1Gd enhancement, T2 enhancement, and normal brain. We also performed linear regression modeling to predict drug levels using MRI features. Model performance was measured using root mean squared error (RMSE). RESULTS Our analysis showed correlations between imaging features and MALDI drug levels. Osimertinib had a uniform distribution across the brain for all animals and all cell lines, consistent with our expectation for a high BBB-penetrant drug. Erlotinib showed the highest drug levels in T2 for GBM39 and in T1Gd for GBM12. Regression models showed promising results for predicting Erlotinib with a low RMSE of 0.037. CONCLUSION Our preliminary results suggest MRI can be predictive of drug levels for low-BBB penetrant drugs. Understanding the relationship between MRIs and drug distribution in diffuse tumors can be beneficial to developing effective treatment.

Cathepsin B, an abundant expressed cysteine peptidase, plays a key role in cancer cell proliferation, tumor metastasis, apoptosis, angiogenesis, invasion and migration. Therefore, development of cathepsin B inhibitors to treat cancer is of great significance. In this study, dihydronaphthalenone chalconoid derivatives containing different benzyliden moieties were synthesized via an efficient route in microwave condition that resulted in the desired compounds in high yields compared to acid- or base-catalyzed refluxing conditions. Cytotoxicity of the compounds was evaluated against K562, HT-29 and MCF-7 human cancer cell lines by MTT assay. P1, P3 and P9 (containing 4-OCH3, 3-NO2 and 4-CN moieties on phenyl ring, respectively) exhibited good cytotoxic activity with an IC50 range of 7.1-28.9 μM. Molecular docking analysis was carried out to investigate the possible interactions and binding modes of all compounds with cathepsin B. The most promising compounds, P1, P3 and P9 were well accommodated within the active site and had the least estimated free binding energies. It was concluded from both MTT assay and docking studies that some dihydronaphthalenone chalconoid derivatives could be suggested as effective cytotoxic agents and potential cathepsin B inhibitors

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 14 months. GBMs are challenging to treat due to their heterogeneous nature. It has also been seen that these tumors have sex differences in their cellular subtypes as well as imaging. Radiomics has the potential to provide a non-invasive, spatial understanding of genetic and epigenetic diversity in these complex tumors and to aid in treatment planning. We have an ongoing study to obtain image-localized biopsies from GBM patients, allowing us to complete radiomic analysis and make connections between immunohistochemistry (IHC) and magnetic resonance imaging (MRI) features. We sought to determine if the patterns on imaging were correlated with underlying tumor biology. We focused on immunohistochemistry (IHC) markers of key features of tumor biology including SOX2 for stem-like tumor cells, CD68 for immune response and Ki67 for proliferation kinetics. Our study included 38 patients with a total of 99 biopsies (bxs): 27 males with 77 bxs and 11 females with 22 bxs. Biopsies were sectioned and stained for the SOX2, CD68, and KI67 markers. We computed 18 first-order radiomic features at each biopsy location for patients’ multimodal MRIs: T1W, T1Gd, T2W, FLAIR, apparent diffusion coefficient, diffusion weighted imaging (DWI) and susceptibility weighted imaging. We then performed correlation analysis between each radiomic feature and marker abundance for each IHC stain. Overall, we found sex-distinct patterns connecting imaging with these IHC markers. For example, amongst female patients, DWI held more prominent correlations with SOX2 than in males. Whereas there were more correlations between CD68 IHC abundance and T1Gd imaging features in males compared to females. Taken together, the overall patterns connecting locoregional imaging features to these IHC markers showed sex-distinct patterns suggesting the potential for sex to be an important biological variable when interpreting the biology underlying imaging changes.

Brain tumor associated edema is a significant cause of patient morbidity and mortality often requiring continual treatment with differing levels of success across patients. Edema is a broad term that can indicate increased local water as well as diffusely infiltrating tumor cells. Edema is visualized as hyperintense regions on T2-weighted (T2W) magnetic resonance imaging (MRI) and is typically associated with blood-brain barrier (BBB) breakdown and tumor aggressiveness. Understanding the molecular mechanisms driving imaging patterns of “edema” could provide insights into clinical imaging interpretation. We have an ongoing image-guided biopsy study that allows us to link biopsy molecular markers with locoregional MRI patterns of edema. Further, we previously developed a physics-based method to estimate edema abundance (i.e., edema map) from T2W MRIs. Our goal was to identify connections between BBB-associated molecular factors and edema abundance in brain tumors. Our cohort included 38 patients (female: 15, male: 23) with 129 image-guided biopsies (female: 62, male: 67). We correlated image-localized edema map values with the mean transcriptional frequency for 57 genes related to BBB function. Additionally, we examined correlations separately according to patient reported sex (i.e., male and female) and imaging phenotype (i.e., ENH: enhancing and NE: non-enhancing). We utilized multiple comparisons corrections with a 5% false discovery rate to determine significance. For the overall cohort, we observed significant positive correlations for the HIF1A (p< 0.001) and SOX2 markers with edema. For NE samples, significant correlations included APOE (p=0.001), HIF1A (p< 0.001), PIK3CA (p< 0.001), PTCH1 (p< 0.001), and SOX2 (p< 0.001). Amongst female samples, a significant correlation with PTCH1 (p=0.002) was observed. There were no significant correlations noted for male and enhancing sub-cohorts. Significant correlations between molecular markers of BBB and edema map values could lead to clinical biomarkers for edema or tumor aggressiveness.

Multi-drug resistance (MDR) in cancer cells is often associated with overexpression of P-glycoprotein (P-gp or ABCB1 or MDR1); therefore, modulators of this transporter might be helpful in overcoming MDR. In this study, 16 novel unsymmetrical dihydropyridine (DHP) derivatives bearing 2-pyridyl methyl carboxylate at C3and a nitroimidazole or nitrophenyl ring at C4positions of the DHP ring were synthesized. Their cytotoxicity was tested against four human cancer cells by MTT assay. The reversal capacity of MDR was examined in P-gp overexpressing cells (MES-SA/DX5) by measuring the alteration of doxorubicin’s IC50and performing flow cytometric determination of intracellular rhodamine 123 accumulation. The calcium channel blocking (CCB) activity, as a side effect of DHPs, was tested on the ileum of a guinea pig. Molecular docking was performed to explain the binding mode of compounds. Two derivatives, 4a and 4c, containing 4-nitrophenyl at C4and possessing methyl (4a) and iso-propyl (4c) carboxylates at the C5position of DHP core demonstrated superior cytotoxic and MDR reversal activities and lower CCB effect. Docking analysis confirmed the importance of the 4-nitrophenyl ring for P-gp inhibitory activity. Some of the synthesized DHP derivatives with considerable MDR reversal capacity could be promising compounds for further discovery of useful agents for management of drug resistant cancer.

Methotrexate (MTX) is a folate antagonist drug used for several diseases, such as cancers, various malignancies, rheumatoid arthritis (RA) and inflammatory bowel disease. Due to its structural features, including the presence of two carboxylic acid groups and its low native fluorescence, there are some challenges to develop analytical methods for its determination. MTX is metabolized to 7-hydroxymethotrexate (7-OH-MTX), 2,4-diamino-N10-methylpteroic acid (DAMPA), and the active MTX polyglutamates (MTXPGs) in the liver, intestine, and red blood cells (RBCs), respectively. Additionally, the drug has a narrow therapeutic range; hence, its therapeutic drug monitoring (TDM) is necessary to regulate the pharmacokinetics of the drug and to decrease the risk of toxicity. Due to environmental toxicity of MTX; its sensitive, fast and low cost determination in workplace environments is of great interest. A large number of methodologies including high performance liquid chromatography equipped with UV–visible, fluorescence, or electrochemical detection, liquid chromatography-mass spectroscopy, capillary electrophoresis, UV–visible spectrophotometry, and electrochemical methods have been developed for the quantitation of MTX and its metabolites in pharmaceutical, biological, and environmental samples. This paper will attempt to review several published methodologies and the instrumental conditions, which have been applied to measure MTX and its metabolites within the last decade., Graphical abstract Image 1, Highlights • Several analytical methods have been applied to determine MTX and its metabolites. • LC-MS and HPLC are the most frequently used techniques for MTX analysis. • There are some challenges to develop analytical methods for MTX determination. • Nanomaterial optical sensors-based methods might lead us to a new horizon.

A novel series of phthalimide-1,2,3-trizole hybrids linked to benzyl ring containing different substituents were synthesized and evaluated for their tyrosinase inhibitory activity (inhibitory activity and inhibition kinetic). It was found that compounds 2-((1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione (6m) and 2-((1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione (6k), exhibited the best tyrosinase inhibitory activity, with IC50 values of 26.20 ± 1.55 and 26.55 ± 2.31 μM, respectively. The inhibition kinetic analysis of 6m indicated that the compound inhibited tyrosinase in a competitive manner. Moreover, molecular docking analysis was performed to study the interactions and binding modes of the tested compounds. Docking results confirmed that the active inhibitors well accumulated in the mushroom tyrosinase active site.

International audience; Multidrug resistance (MDR) in cancer cells is often associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). Modulators of these transporters might be helpful in overcoming MDR. Moreover, exploiting collateral sensitivity (CS) could be another approach for efficient treatment of cancer. Twelve novel 5-oxo-hexahydroquinoline derivatives bearing different aromatic substitutions at C 4 , while having 2-pyridyl alkyl carboxylate substituents at the C 3 were synthesized and evaluated for MDR reversal activity by flow cytometric determination of rhodamine 123, calcein and mitoxantrone accumulations in P-gp, MRP1 and BCRP-overexpressing cell lines, respectively. Furthermore, to confirm the P-gp inhibitory activity, the effect of compounds on the reduction of doxorubicin's IC 50 of drug-resistant human uterine sarcoma cell line, MES-SA/DX5, was evaluated. Compounds D6, D5 and D3 (bearing 3-chlorophenyl, 2,3-dichlorophenyl and 4-chlorophenyl substituents at C 4 position of 5-oxo-hexahydroquinoline core) were the most potent P-gp, MRP1 and BCRP inhibitors, respectively, causing significant MDR reversal at concentrations of 1-10 μM. Additionally, D4 (containing 3-flourophenyl) was the most effective MRP1-dependent CS inducing agent. Overall, chlorine containing compounds D6, C4 and D3 were capable of significant inhibition of all 3 important efflux pumps in cancer cells. Moreover, D6 also induced CS triggered by reducing glutathione efflux. In conclusion, some of the 5-oxo-hexahydroquinoline derivatives are effective efflux pump inhibitors capable of simultaneously blocking 3 important ABC transporters involved in MDR, and represent promising agents to overcome MDR in cancer cells.

Glioblastoma (GBM) is a devastating primary brain tumor known for its heterogeneity with a median survival of 15 months. Clinical imaging remains the primary modality to assess brain tumor response, but it is nearly impossible to distinguish between tumor growth and treatment response. Ki67 is a marker of active cell proliferation that shows inter- and intra-patient heterogeneity and should change under many therapies. In this work, we assessed the utility of a semi-supervised deep learning approach for regionally predicting high-vs-low Ki67 in GBM patients based on MRI. We used both labeled and unlabeled datasets to train the model. Labeled data included 114 MRI-localized biopsies from 43 unique GBM patients with available immunohistochemistry Ki67 labels. Unlabeled data included nine repeat routine pretreatment paired scans of newly-diagnosed GBM patients acquired within three days. Data augmentation techniques were utilized to enhance the size of our data and increase generalizability. Data was split between training, validation, and testing sets using 65-15-20 percent ratios. Model inputs were 16x16x3 patches around biopsies on T1Gd and T2 MRIs for labeled data, and around randomly selected patches inside the T2 abnormal region for unlabeled data. The network was a 4-conv layered VGG-inspired architecture. Training objective was accurate prediction of Ki67 in labeled patches and consistency in predictions across repeat unlabeled patches. We measured final model accuracy on held-out test samples. Our promising preliminary results suggest potential for deep learning in deconvolving the spatial heterogeneity of proliferative GBM subpopulations. If successful, this model can provide a non-invasive readout of cell proliferation and reveal the effectiveness of a given cytotoxic therapy dynamically during the patient's routine follow up. Further, the spatial resolution of our approach provides insights into the intra-tumoral heterogeneity of response which can be related to heterogeneity in localization of therapies (e.g. radiation therapy, drug dose heterogeneity).

Background: Soy has several beneficial effects on cardiovascular disease (CVD); however, results of clinical trial studies are equivocal. Thus, the present study sought to discern the efficacy of soy intake on blood pressure. Methods: The search process was conducted in PubMed, Scopus, Web of Science, and Cochrane Library, to ascertain studies investigating the efficacy of soy intake on blood pressure in adults, published up to June 2020. A random-effects model was applied to pool mean difference and 95 % confidence interval (CI). Begg’s and Egger’s methods were conducted to assess publication bias. Results: Pooled effects from 17 effect sizes revealed a significant improvement in systolic blood pressure (SBP) (−1.70; −3.34 to −0.06 mmHg; I2 = 45.4 %) and diastolic blood pressure (DBP) (−1.27; −2.36 to −0.19 mmHg, I2 = 43.9 %) following soy consumption, in comparison with controls. Subgroup analysis demonstrated a reduction in both SBP and DBP in younger participants with lower baseline DBP and intervention durations of

Lichen planus is considered a chronic inflammatory disease which affects different sites, such as the skin, mucous membranes, hair, and nails. Based on the evidence, a complex cytokine network plays a crucial role in lichen planus pathogenesis. The study was aimed at assessing the serum IL-23 levels in the patients with cutaneous and oral lichen planus compared to healthy controls. Method. The study included 30 cutaneous lichen planus patients, 20 oral lichen planus patients, and 33 control subjects. Five milliliters of peripheral blood was obtained from each patient, and the serum was separated. IL-23 levels were determined using the ELISA kit, and the data were analyzed using the Mann–Whitney test. Results. IL-23 levels in the patient serum with oral lichen planus ( P value ≤ 0.001) were significantly higher than in controls. Furthermore, there were significant differences in IL-23 serum levels in the patients with cutaneous lichen planus compared to the healthy controls ( P value ≤ 0.001). Moreover, IL-23 serum levels were statistically different between patients with cutaneous lichen planus and patients with oral lichen planus ( P value ≤ 0.001). Based on the mean concentration of interleukin-23, IL-23 levels were higher in the patients with oral lichen planus than in the patients with cutaneous lichen planus. Conclusions. Elevated serum IL-23 levels in the patients with oral lichen planus may indicate that IL-23 plays a crucial role in the pathogenesis of oral lichen planus. However, more research is needed with a larger sample size.

Purpose: Deep learning (DL) algorithms have shown promising results for brain tumor segmentation in MRI. However, validation is required prior to routine clinical use. We report the first randomized and blinded comparison of DL and trained technician segmentations. Approach: We compiled a multi-institutional database of 741 pretreatment MRI exams. Each contained a postcontrast T1-weighted exam, a T2-weighted fluid-attenuated inversion recovery exam, and at least one technician-derived tumor segmentation. The database included 729 unique patients (470 males and 259 females). Of these exams, 641 were used for training the DL system, and 100 were reserved for testing. We developed a platform to enable qualitative, blinded, controlled assessment of lesion segmentations made by technicians and the DL method. On this platform, 20 neuroradiologists performed 400 side-by-side comparisons of segmentations on 100 test cases. They scored each segmentation between 0 (poor) and 10 (perfect). Agreement between segmentations from technicians and the DL method was also evaluated quantitatively using the Dice coefficient, which produces values between 0 (no overlap) and 1 (perfect overlap). Results: The neuroradiologists gave technician and DL segmentations mean scores of 6.97 and 7.31, respectively (p

In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a-d and 8a-h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl-triazole moiety were found to be the most potent tyrosinase inhibitors with IC50 values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC50 values in the range of 29.9-324.9 μM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC50 values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 μM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of -8.55 and -8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme-inhibitor complexes.

Objective To evaluate whether the use of a computer-aided diagnosis–contrast-enhanced spectral mammography (CAD-CESM) tool can further increase the diagnostic performance of CESM compared with that of experienced radiologists. Materials and methods This IRB-approved retrospective study analyzed 50 lesions described on CESM from August 2014 to December 2015. Histopathologic analyses, used as the criterion standard, revealed 24 benign and 26 malignant lesions. An expert breast radiologist manually outlined lesion boundaries on the different views. A set of morphologic and textural features were then extracted from the low-energy and recombined images. Machine-learning algorithms with feature selection were used along with statistical analysis to reduce, select, and combine features. Selected features were then used to construct a predictive model using a support vector machine (SVM) classification method in a leave-one-out–cross-validation approach. The classification performance was compared against the diagnostic predictions of 2 breast radiologists with access to the same CESM cases. Results Based on the SVM classification, CAD-CESM correctly identified 45 of 50 lesions in the cohort, resulting in an overall accuracy of 90%. The detection rate for the malignant group was 88% (3 false-negative cases) and 92% for the benign group (2 false-positive cases). Compared with the model, radiologist 1 had an overall accuracy of 78% and a detection rate of 92% (2 false-negative cases) for the malignant group and 62% (10 false-positive cases) for the benign group. Radiologist 2 had an overall accuracy of 86% and a detection rate of 100% for the malignant group and 71% (8 false-positive cases) for the benign group. Conclusions The results of our feasibility study suggest that a CAD-CESM tool can provide complementary information to radiologists, mainly by reducing the number of false-positive findings.

BACKGROUND AND PURPOSE: Because sinonasal inverted papilloma can harbor squamous cell carcinoma, differentiating these tumors is relevant. The objectives of this study were to determine whether MR imaging–based texture analysis can accurately classify cases of noncoexistent squamous cell carcinoma and inverted papilloma and to compare this classification performance with neuroradiologists9 review. MATERIALS AND METHODS: Adult patients who had inverted papilloma or squamous cell carcinoma resected were eligible (coexistent inverted papilloma and squamous cell carcinoma were excluded). Inclusion required tumor size of >1.5 cm and preoperative MR imaging with axial T1, axial T2, and axial T1 postcontrast sequences. Five well-established texture analysis algorithms were applied to an ROI from the largest tumor cross-section. For a training dataset, machine-learning algorithms were used to identify the most accurate model, and performance was also evaluated in a validation dataset. On the basis of 3 separate blinded reviews of the ROI, isolated tumor, and entire images, 2 neuroradiologists predicted tumor type in consensus. RESULTS: The inverted papilloma (n = 24) and squamous cell carcinoma (n = 22) cohorts were matched for age and sex, while squamous cell carcinoma tumor volume was larger (P = .001). The best classification model achieved similar accuracies for training (17 squamous cell carcinomas, 16 inverted papillomas) and validation (7 squamous cell carcinomas, 6 inverted papillomas) datasets of 90.9% and 84.6%, respectively (P = .537). For the combined training and validation cohorts, the machine-learning accuracy (89.1%) was better than that of the neuroradiologists9 ROI review (56.5%, P = .0004) but not significantly different from the neuroradiologists9 review of the tumors (73.9%, P = .060) or entire images (87.0%, P = .748). CONCLUSIONS: MR imaging–based texture analysis has the potential to differentiate squamous cell carcinoma from inverted papilloma and may, in the future, provide incremental information to the neuroradiologist.

Omolbanin Shahraki,1,2 Najmeh Edraki,1 Mehdi Khoshneviszadeh,1,2 Farshid Zargari,1 Sara Ranjbar,1,2 Luciano Saso,3 Omidreza Firuzi,1 Ramin Miri1 1Medicinal and Natural Products Chemistry Research Center, 2Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 3Department of Physiology and Pharmacology “Vittorio Ersparmer”, Sapienza University of Rome, Rome, Italy Abstract: Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells’ sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal. Keywords: cancer, P-glycoprotein, multidrug resistance, 1,4-dihydropyridine, molecular dynamics simulation

P-glycoprotein (P-gp) is a transmembrane efflux pump that has been associated with ineffective cancer chemotherapy and multidrug resistance (MDR). Chemical inhibitors of P-gp could have potential cancer therapeutic applications by preventing or reversing MDR. To exploit this, we designed twenty-five tetrahydroquinolinone analogs bearing pyridyl methyl carboxylate at C3 and different substituents at C4 as MDR reversal agents. The inhibitory effects of the synthesized compounds against P-gp were assessed by flow cytometric determination of rhodamine 123 accumulation in P-gp over-expressing MES-SA/DX5 cells. Fluorescence imaging of intracellular rhodamine 123 accumulation in MES-SA/DX5 cells was also performed. Furthermore, the effect of active derivatives on the reduction of doxorubicin's IC50 in MES-SA/DX5 cells was evaluated using MTT assay. Molecular docking was used to confirm the binding mode of some of the synthesized compounds. Five compounds in group A, bearing a 2-pyridyl methyl ester substituent at the C3 position, significantly increased rhodamine accumulation at 25 μM comparable to verapamil, a well-established P-gp inhibitor, while only 2 compounds in group B bearing 3-pyridyl methyl ester at the same position had this effect. This study shows that tetrahydroquinolinones containing methyl pyridine esters could represent an attractive scaffold for the discovery of P-gp inhibitors as MDR reversal agents in cancer cells.