Effectiveness of Genicular Artery Embolization for Reducing Synovitis As Assessed by Contrast-Enhanced MR Imaging in Knee Osteoarthritis: A Pilot Study.

PURPOSE: To investigate the impact of Genicular Artery Embolization (GAE) on synovitis in knee osteoarthritis (OA) and assess its predictive role in pain response. MATERIALS AND METHODS: A single-center retrospective analysis was conducted on 35 contrast-enhanced MRI results from 33 patients treated with GAE for knee OA between December 2022 and March 2023. Assessments pre-procedure and at the 3-month post-embolization mark utilized a semi-quantitative scoring system for synovitis, referencing Guermazi et al.'s criteria from the MOST study. This included 11 knee points for comprehensive synovitis severity and distribution analysis, alongside evaluating the procedure's impact on pain and function through WOMAC and VAS scores. RESULTS: The study comprised 24 females (72.7%) and 9 males (27.3%), with a mean age of 59.1 years. Significant synovitis reduction was noted post-GAE, particularly in parapatellar and periligamentous areas. Synovial contrast scores significantly decreased from 5.1±2 to 2.9±2 at 3 months (p < 0.001), with a moderate negative correlation between synovial scores and pain levels (p = 0.005). CONCLUSION: GAE significantly reduces synovitis in knee OA, evidenced by CE-MRI score changes. The correlation between pre-procedural synovial contrast scores and pain relief post-procedure, while promising, requires careful interpretation due to the complex factors affecting pain in knee OA.

Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies.

Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 µM to 0.662 ± 0.042 µM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 µM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 µM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 µM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 µM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 µM and 158.49 ± 2.73 µM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.

Peripheral (E)-2-[(4-hydroxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one)]-coordinated phthalocyanines with improved enzyme inhibition properties and photophysicochemical behaviors.

In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of 1O2 production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (ΦΔ) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (α-Gly) enzymes. Ki values are in the range of 2.60 ± 9.87 to 11.53 ± 6.92 µM, 3.35 ± 0.53 to 15.47 ± 1.20 µM, and 28.60 ± 4.82 to 40.58 ± 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of α-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.

The Effect of "Proanthocyanidin" on Ischemia-Reperfusion Injury in Skeletal Muscles of Rats.

Background and Objectives: Lower limb skeletal muscle ischemia-reperfusion (IR) injury is associated with increased morbidity and mortality, and it is common in several clinical situations such as aortic aneurysms repairment, peripheral arterial surgery, vascular injury repairment, and shock. Although it is generally accepted that oxidative stress mediators have a significant role in IR injury, its precise mechanism is still unknown. Anecdotally, it is sustained not only by structural and functional changes in the organ it affects but also by damage to distant organs. The purpose of this report is to illustrate the effect of proanthocyanidin on IR injury. Materials and Methods: In our study, 18 male Wistar albino rats were used. The subjects were divided into three groups containing six mice each (control, C; ischemia-reperfusion, IR; ischemia-reperfusion and proanthocyanidin; IR-PRO). Intraperitoneal proanthocyanidin was given to the IR and proanthocyanidin groups 30 min before laparotomy, and 1 h ischemia led to these two groups. After one hour, reperfusion started. Muscle atrophy-hypertrophy, muscle degeneration-congestion, fragmentation-hyalinization, muscle oval-central nucleus ratio, leukocyte cell infiltration, catalase enzyme activity, and TBARS were all examined in lower-limb muscle samples after one hour of reperfusion. Results: When skeletal muscle samples were evaluated histopathologically, it was discovered that muscle atrophy-hypertrophy, muscle degeneration-congestion, fragmentation-hyalinization, and leukocyte cell infiltration with oval-central nucleus standardization were significantly higher in the IR group than in the C and IR-P groups. Oval-central nucleus standardization was significantly higher in the IR and IR-PRO groups than in the control group. TBARS levels were significantly higher in the IR group than in the control and IR-PRO groups, while catalase enzyme activity was found to be significantly lower in the IR group than in the control and IR-PRO groups. Conclusions: As a consequence of our research, we discovered that proanthocyanidins administered before IR have a protective impact on skeletal muscle in rats. Further research in this area is required.

The Effect of Cerium Oxide (CeO2) on Ischemia-Reperfusion Injury in Skeletal Muscle in Mice with Streptozocin-Induced Diabetes.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, in temporary clamping of the aorta in aortic surgery, or following acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress such as DM. Cerium oxide (CeO2) nanoparticles mimic antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n = 6), diabetes group (group D, n = 8), diabetes-CeO2 (group DCO, n = 8), diabetes-ischemia/reperfusion (group DIR, n = 8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n = 8). The DCO and DIRCO groups were given doses of CeO2 of 0.5 mg/kg intraperitoneally 30 min before the IR procedure. A 120 min ischemia-120 min reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p = 0.047 and p = 0.022, respectively). In group DIRCO, total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p < 0.001). The oxidative stress index (OSI) was found to be significantly lower in group DIR compared with group DCO (p < 0.001). Paraoxanase (PON) enzyme activity was found to be significantly increased in group DIR compared with group DCO (p < 0.001). The disorganization and degeneration score for muscle cells, inflammatory cell infiltration score, and total injury score in group DIRCO were found to be significantly lower than in group DIR (p = 0.002, p = 0.034, and p = 0.001, respectively). Conclusions: Our results confirm that CeO2, with its antioxidative properties, reduces skeletal muscle damage in lower extremity IRI in diabetic mice.

Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase.

A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) inhibitors of human α-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2­iodophenyl (7f, KI of 105.00 nM and SI of 2.98) and 2­naphthyl (7h, KI of 32.11 nM and SI of 3.48) analogues (over off-target hCA I) and phenyl (7a, KI of 50.13 nM and SI of 2.74) and 2,6­dimethylphenyl (7d, KI of 50.60 nM and SI of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (KI of 18.29 nM) compared with the reference drug acetazolamide (AAZ, KI of 437.20 nM), and analogue 7h showed higher potency (KI of 9.22 nM) than AAZ (KI of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC50 values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 µM. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn2+ ion. At the same time, the tail extension engages in various hydrophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids.

Effects of cerium oxide (CeO2) on liver tissue in liver ischemia-reperfusion injury in rats undergoing desflurane anesthesia.

INTRODUCTION: During liver surgery and transplantation, periods of partial or total vascular occlusion are inevitable and result in ischemia-reperfusion injury (IRI). Nanomedicine uses the latest technology, which has emerged with interdisciplinary effects, such as biomedical sciences, physics, and engineering, to protect and improve human health. Interdisciplinary research has brought along the introduction of antioxidant nanoparticles as potential therapeutics. The goal of this study was to investigate the effects of cerium oxide (CeO2) administration and desflurane anesthesia on liver tissue in liver IR injury. MATERIAL AND METHODS: Thirty rats were randomly divided into five groups: control (C), ischemia-reperfusion (IR), IR-desflurane (IRD), cerium oxide-ischemia reperfusion (CeO2-IR), and cerium oxide-ischemia reperfusion-desflurane (CeO2-IRD). In the IR, IRD, and CeO2-IRD groups, hepatic ischemia was induced after the porta hepatis was clamped for 120 min, followed by 120 min of reperfusion. Intraperitoneal 0.5 mg/kg CeO2 was administered to the CeO2 groups 30 min before ischemia. Desflurane (6%) was administered to the IRD and CeO2-IRD groups during IR. All groups were sacrificed under anesthesia. Liver tissue samples were examined under a light microscope by staining with hematoxylin-eosin (H&E). Malondialdehyde (MDA) levels, catalase (CAT), glutathione-s-transferase (GST), and arylesterase (ARE) enzyme activities were measured in the tissue samples. RESULTS: The IR group had considerably more hydropic degeneration, sinusoidal dilatation, and parenchymal mononuclear cell infiltration than the IRD, CeO2-IR, and CeO2-IRD groups. Catalase and GST enzyme activity were significantly higher in the CeO2-IR group than in the IR group. The MDA levels were found to be significantly lower in the IRD, CeO2-IR, and CeO2-IRD groups than in the IR group. CONCLUSION: Intraperitoneal CeO2 with desflurane reduced oxidative stress and corrected liver damage.

N-substituted phthalazine sulfonamide derivatives as non-classical aldose reductase inhibitors.

Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo-keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N-substituted phthalazine sulfonamide derivatives 5a-l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4-(6-nitro-1,4-dioxo-1,2,3,4-tetrahydrophthalazine-2-carbonyl)benzenesulfonamide (5e) and 1,4-dioxo-3-(4-sulfamoylbenzoyl)-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI  = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a-l) with the target enzyme AR. According to ADME-Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug-like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif.

The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and hCAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and hCAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N-substituted sulfonyl amide derivatives (6a-j) were determined to be highly potent inhibitors for AChE and hCAs (KIs are in the range of 23.11-52.49 nM, 18.66-59.62 nM, and 9.33-120.80 nM for AChE, hCA I, and hCA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a, 6d, and 6h, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and hCAIs. The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs.

T3 versus T4a staging challenges in deeply invasive colonic adenocarcinomas and correlation with clinical outcomes.

Despite the latest 8th edition American Joint Committee on Cancer Staging Manual guidelines, disagreement still exists among pathologists regarding staging deeply invasive colonic adenocarcinomas ≤1 mm to the serosal surface. In this retrospective study, 151 untreated colonic adenocarcinomas staged initially as either pT3 or pT4a and with available 5-year follow-up data were retrieved and re-categorized: Group 1 (38 cases): pT4a with tumor at the serosa; Group 2 (49 cases): tumor ≤1 mm from the serosa, with intervening reactive fibrosis (40/49) or inflammation (9/49); Group 3 (64 cases): pT3 tumor >1 mm from the serosa. Clinical outcomes were analyzed. Groups 1 and 2 tumors showed significantly lower 5-year recurrence-free survival and lower overall survival rates (log-rank p < 0.001 for both), when compared with Group 3 tumors. Even after adjusting for adjuvant therapy and nodal metastases, the proportional hazards ratios for the risk of death (p < 0.001) and risk of recurrence (p = 0.005) showed significantly higher risk in Groups 1 and 2 compared with Group 3. The synchronous nodal (p = 0.012) and metachronous distant metastases (p = 0.004) were also significantly more in Groups 1 and 2 versus Group 3. Colonic adenocarcinomas ≤1 mm from the serosal surface behaved more akin to "bona fide" pT4a tumors at the serosal surface in our study with regards to clinical outcomes. We recommend these tumors be staged as pT4a rather than pT3, as supported by outcome data in our study. We hope this will also ensure reproducibility and consistency in staging these tumors across institutions.

Evaluation of Diarrhea in Patients with COVID-19.

BACKGROUND/AIMS: The COVID-19 disease, which was declared epidemic by the WHO, is a global emergency public health problem. Patients with extrapulmonary symptoms are the group of patients who should be considered for person-to-person transmission in the community. In our study, it was aimed to investigate the characteristics of patients with COVID-19-related diarrhea symptoms. MATERIALS AND METHODS: The study was conducted retrospectively in CO-VID-19 rtRT-PCR-positive patients in 5 medical centers. Three or more loose/liquid stools per day or increased number of defecations compared to normal defecation were defined as diarrhea. The patients were analyzed in 2 groups as those with and without diarrhea. RESULTS: One thousand eighty-six patients were included in the study. Seventy-eight (7.2%) of the patients had diarrhea. Diarrhea was watery in 54 (69.2%) patients while with blood and mucus in 18 (23.1%) patients. Diarrhea continued for an average of 5.2 ± 1.6 (2-11) days. The clinical and laboratory findings of patients with diarrhea were more serious than those without diarrhea. Diarrhea is more common in the elderly and people with comorbid disease, and patients with diarrhea had higher CMI score and CRP and higher complaints of fever, cough, shortness of breath, myalgia, and fatigue. CONCLUSIONS: The presence of diarrhea should indicate a suspected COVID-19 infection and suggest testing for early diagnosis of the disease. It should be kept in mind that the course of the disease may be more severe in these patients, and precautions should also be taken in terms of fecal transmission during discharge.

Appendiceal inflammation in colectomy is independently correlated with early pouchitis following ileal pouch anal anastomosis in ulcerative colitis and indeterminate colitis.

BACKGROUND: Appendiceal inflammation in colectomy is one of the histologic predictors of pouchitis in ulcerative colitis (UC) following ileal pouch anal anastomosis (IPAA). Fecal calprotectin level has been shown to increase 2 months prior to the onset of pouchitis. We evaluated whether inflammation and calprotectin expression in appendiceal specimens correlate with early-onset pouchitis in UC and indeterminate colitis (IC). MATERIALS AND METHODS: IPAA (2000-2018) cases with appendix blocks available in colectomy specimens were identified (n = 93, 90 UC, 3 IC). Histologic features thought to predict pouchitis were evaluated. The degree of appendiceal inflammation was scored. Calprotectin immunostain was performed on the appendix blocks and the extent of mucosal staining was quantified. Electronic medical records were reviewed for demographics, smoking history, clinical pouchitis, time of onset of pouchitis, and clinical and endoscopic components of the Pouchitis Disease Activity Index (PDAI) score. Follow-up pouch biopsies were reviewed and scored to generate histologic PDAI score, when available. RESULTS: Among the patients with clinical pouchitis (n = 73), moderate to severe appendiceal inflammation independently correlated with earlier pouchitis compared to no/mild inflammation (median time to pouchitis 12.0 vs. 23.8, log rank p = 0.016). Calprotectin staining correlated with inflammatory scores of the appendix (Spearman's rho, r = 0.630, p < 0.001) but not with early pouchitis (p > 0.05). CONCLUSIONS: The presence of moderate to severe appendiceal inflammation at the time of colectomy was associated with a shorter time to pouchitis following IPAA. Calprotectin immunostain may be used to demonstrate the presence of inflammation in the appendix but its role in predicting early pouchitis remains limited.

Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for AD treatment. In this direction, the improvement of new multitarget drugs, which can simultaneously modulate several mechanisms or targets included in the AD pathway, may be a potent strategy to treat AD. In light of these data for understanding and developing AD-related multitarget AChE and hCAs inhibitors, in this study, novel methylene-aminobenzoic acid and tetrahydroisoquinolynyl-benzoic acid derivatives (4a-g and 6a-g) were designed. The synthesized analogs were experimentally validated for their effects by in vitro and direct enzymatic tests. Also, the compounds were subjected to in silico monitoring with Schrödinger Suite software to assign binding affinities of potential derivatives based on Glide XP scoring, molecular mechanics-generalized Born surface area computing, and validation by molecular docking. The results revealed that 6c (1,3-dimethyldihydropyrimidine-2,4-(1H,3H)-dione-substituted, KI  value of 33.00 ± 0.29 nM), 6e (cyclohexanone-substituted, KI  value of 18.78 ± 0.09 nM), and 6f (2,2-dimethyl-1,3-dioxan-4-one-substituted, KI  value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.

Synthesis of new series of thiazol-(2(3H)-ylideneamino)benzenesulfonamide derivatives as carbonic anhydrase inhibitors.

Human carbonic anhydrase I and II isoenzymes (hCA I and II) are important metabolic enzymes. In this study, a new series of thiazol-(2(3H)-ylideneamino)benzenesulfonamide derivatives were synthesized and also some inhibition parameters including IC50 (hydratese) and inhibition constant values (Ki , esterase) were determined. All studied compounds exhibited potent inhibition against these enzymes. They inhibited carbonic anhydrases (CAs) with the IC50 values of 113 to 395.8 nM (Ki = 77.38-319.59 nM) for hCA I and 91.9 to 516 nM (Ki = 62.79-425.89 nM) for hCA II. Among the compounds, 5c was found to be the most active one (Ki : 77.38 nM) for hCA I and 5g was found for hCA II with the value of 62.79 nM.

Frequency of Plexiform Fibromyxoma relative to gastrointestinal stromal tumor: A single center study.

Plexiform Fibromyxoma (PF) is an exceedingly rare mesenchymal tumor of the gastric antrum that was first described in 2007. PF is a close mimic of gastrointestinal stromal tumor (GIST) clinically and histopathologically, but the frequency of PF relative to GIST is unknown. Moreover, although likely benign, long-term follow-up of PF is limited due to its recent description and rarity. PF has not been reported in distal jejunum. 118 primary GISTs that were surgically resected at our center (2000-2019) were retrieved. The patients' age, gender, clinical presentation, tumor location, size and number, and the presence or absence of metastasis, were documented. Risk of progressive disease was assessed according to the published GIST risk stratification model. Two unique cases of PF were compared. One gastric PF has been followed-up for 8 years, and the other occurred in the distal jejunum. In the latter, the PF diagnosis was rendered after the case was re-reviewed for the study. Clinical presentation resembled GIST in both PF cases. 14% of GISTs showed high risk features or were clinically malignant, whereas the PF patient with 8-year follow-up was free of disease. Based on this study, PF may be under-recognized, with 1 to 2% (1.7%) of GIST-like tumors possibly representing PF. PF may involve variable segments of intestine similar to GIST. Given the remarkable clinical and histopathologic overlap with GIST but differing outcomes, awareness and cognizance of this rare entity, plexiform fibromyxoma, is required for proper patient care.

Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors.

In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the KI values in the low nanomolar range (KI = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino)vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression. Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

Synthesis of carbazole bearing pyridopyrimidine-substituted sulfonamide derivatives and studies their carbonic anhydrase enzyme activity.

The synthesis of carbazole containing pyridopyrimidine-substituted sulfonamide derivatives (3a-i) and their inhibitory effects on human carbonic anhydrase (hCA) I and II were studied. Spectral data and elemental analysis confirmed the structures of the compounds synthesized. The results show that all the synthesized compounds inhibited the CA I and II activities. Among them, 3a was found to be the most active ( K i : 14 µM) for hCA I and 3f ( K i : 126 µM) for hCA II.

Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors.

The synthesis, characterization and biological evaluation of a series of novel N-substituted phthalazine sulfonamide (5a-l) are disclosed. Phthalazines which are nitrogen-containing heterocyclic compounds are biologically preferential scaffolds, endowed with versatile pharmacological activity, such as anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant, antihypertensive, antibacterial, anti-cancer action. The compounds were investigated for the inhibition against the cytosolic hCA I, II and AChE. Most screened sulfonamides showed high potency in inhibiting hCA II, widely involved in glaucoma, epilepsy, edema, and other pathologies (Kis in the ranging from 6.32 ±â€¯0.06 to 128.93 ±â€¯23.11 nM). hCA I was inhibited with Kis in the range of 6.80 ±â€¯0.10-85.91 ±â€¯7.57 nM, whereas AChE in the range of 60.79 ±â€¯3.51-249.55 ±â€¯7.89 nM. ADME prediction study of the designed N-substituted phthalazine sulfonamides showed that they are not only with carbonic anhydrase and acetylcholinesterase inhibitory activities but also with appropriate pharmacokinetic, physicochemical parameters and drug-likeness properties. Also, in silico docking studies were investigated the binding modes of selected compounds, to hCA I, II, and AChE.

Evaluation of flexural strength and surface properties of prepolymerized CAD/CAM PMMA-based polymers used for digital 3D complete dentures.

PURPOSE: The objectives of this in vitro study were to evaluate the flexural strength (FS), surface roughness (Ra), and hydrophobicity of polymethylmethacrylate (PMMA)-based computer-aided design/computer-aided manufacturing (CAD/CAM) polymers and to compare the properties of different CAD/CAM PMMA-based polymers with conventional heat-polymerized PMMA following thermal cycling. MATERIALS AND METHODS: Twenty rectangular-shaped specimens (64 × 10 × 3.3 mm) were fabricated from three CAD/CAM PMMA-based polymers (M-PM Disc [M], AvaDent Puck Disc [A], and Pink CAD/CAM Disc Polident [P], and one conventional heat-polymerized PMMA (Promolux [C]), according to ISO 20795-1:2013 standards. The specimens were divided into two subgroups (n = 10), a control and a thermocycled group. The specimens in the thermocycled group were subjected to 5000 thermal cycling procedures (5 to 55°C; 30 s dwell times). The Ra value was measured using a profilometer. Contact angle (CA) was assessed using the sessile drop method to evaluate surface hydrophobicity. In addition, the FS of the specimens was tested in a universal testing machine at a crosshead speed of 1.0 mm/min. Surface texture of the materials was assessed using scanning electron microscope (SEM). The data were analyzed using two-way analysis of variance (ANOVA), followed by Tukey's HSD post-hoc test (α < 0.05). RESULTS: CAD/CAM PMMA-based polymers showed significantly higher FS than conventional heat-polymerized PMMA for each group (P < 0.001). CAD/CAM PMMA-based polymer [P] showed the highest FS, whereas conventional PMMA [C] showed the lowest FS before and after thermal cycling (P < 0.001). There were no significant differences among the Ra values of the tested denture base polymers in the control group (P > 0.05). In the thermocycled group, the lowest Ra value was observed for CAD/CAM PMMA-based polymer [M] (P < 0.001), whereas CAD/CAM PMMA-based polymers [A] and [P], and conventional PMMA [C] had similar Ra values (P > 0.05). Conventional PMMA [C] had a significantly lower CA and consequently lower hydrophobicity compared to the CAD/CAM polymers in the control group (P < 0.001). In the thermocycled group, CAD/CAM PMMA-based polymer [A] and conventional PMMA [C] had significantly higher CA, and consequently higher hydrophobicity when compared to CAD/CAM polymers [M] and [P] (P < 0.001). However, no significant differences were found among the other materials (P > 0.05). CONCLUSIONS: The FS and hydrophobicity of the CAD/CAM PMMA-based polymers were higher than the conventional heat-polymerized PMMA, whereas the CAD/CAM PMMA-based polymers had similar Ra values to the conventional PMMA. Thermocycling had a significant effect on FS and hydrophobicity except for the Ra of denture base materials.