Monoamine Oxidase (MAO) as a Potential Target for Anticancer Drug Design and Development.

Monoamine oxidases (MAOs) are oxidative enzymes that catalyze the conversion of biogenic amines into their corresponding aldehydes and ketones through oxidative deamination. Owing to the crucial role of MAOs in maintaining functional levels of neurotransmitters, the implications of its distorted activity have been associated with numerous neurological diseases. Recently, an unanticipated role of MAOs in tumor progression and metastasis has been reported. The chemical inhibition of MAOs might be a valuable therapeutic approach for cancer treatment. In this review, we reported computational approaches exploited in the design and development of selective MAO inhibitors accompanied by their biological activities. Additionally, we generated a pharmacophore model for MAO-A active inhibitors to identify the structural motifs to invoke an activity.

Inverse Filtering for Frequency Identification of Bridges Using Smartphones in Passing Vehicles: Fundamental Developments and Laboratory Verifications.

This paper puts forward a novel methodology of employing inverse filtering technique to extract bridge features from acceleration signals recorded on passing vehicles using smartphones. Since the vibration of a vehicle moving on a bridge will be affected by various features related to the vehicle, such as suspension and speed, this study focuses on filtering out these effects to extract bridge frequencies. Hence, an inverse filter is designed by employing the spectrum of vibration data of the vehicle when moving off the bridge to form a filter that will remove the car-related frequency content. Later, when the same car is moving on the bridge, this filter is applied to the spectrum of recorded data to suppress the car-related frequencies and amplify the bridge-related frequencies. The effectiveness of the proposed methodology is evaluated with experiments using a custom-built robot car as the vehicle moving over a lab-scale simply supported bridge. Nine combinations of speed and suspension stiffness of the car have been considered to investigate the robustness of the proposed methodology against car features. The results demonstrate that the inverse filtering method offers significant promise for identifying the fundamental frequency of the bridge. Since this approach considers each data source separately and designs a unique filter for each data collection device within each car, it is robust against device and car features.

New phenolic Mannich bases with piperazines and their bioactivities.

In this study, new Mannich bases, 2-(4-hydroxy-3-methoxy-5-((substitutedpiperazin-1-yl)methyl)benzylidene)-2,3-dihydro-1H-inden-1-one (1, 2, 4, 5, 8), 2-(3-((substituted)piperazin-1-yl)methyl)-4-hydroxy-5-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one (3, 6, 7) were synthesized with the reaction of vanilin derived chalcone compound (2-(4-hydroxy-3-methoxybenzylidene)indan-1-one), paraformaldehyde and suitable amine in 1:1.2:1 mol ratios. Amine part was changed as N-methylpiperazine (1), N-phenylpiperazine (2), N-benzylpiperazine (3), 1-(2-methoxyphenyl)piperazine (4), 1-(3-methoxyphenyl)piperazine (5), 1-(2-fluorophenyl)piperazine (6), 1-(4-fluorophenyl)piperazine (7), and 1-(3-trifluoromethyl)phenyl piperazine (8). Compounds were evaluated in terms of cytotoxic/anticancer and CA inhibitory effects. According to the results obtained, the compounds 2 and 8 had the highest potency selectivity expression (PSE) values (60.6 and 19.2, respectively). On the other hand, the compounds 3 (Ki = 209.6 ±â€¯70.2 pM) and 5 (Ki = 342.66 ±â€¯63.72 pM) had the lowest Ki values in CA inhibition experiments towards hCA I and hCA II, respectively. In conclusion, the compounds 2 (with cytotoxic/anticancer activity), 3 (with hCA I inhibiting activity) and 5 (with hCA II inhibiting activity) can be leading compounds of the study for further designs and evaluations.

Oxidative stress before and after surgery in benign prostatic hyperplasia patients.

The aim was to assess oxidative stress in benign prostatic hyperplasia patients and also to evaluate the effect of operation in late (60 days) post-operative period. This study was conducted with 16 patients with benign prostatic hyperplasia and 16 healthy subjects. Serum malondialdehyde, blood 8-hydroxy-2'-deoxyguanosine/deoxyguanosine, erythrocyte superoxide dismutase, serum total coenzyme Q10 and coenzyme Q10 levels were measured. Independent samples t test was used to analyse the differences between control group and patients, while paired t test was used to analyse the differences between pre-operative and post-operative periods. Malondialdehyde and total coenzyme Q10 levels were lower in patients, while 8-hydroxy-2'-deoxyguanosine/deoxyguanosine level was increased. However, superoxide dismutase activity and coenzyme Q10 levels did not differ. After 60 days of operation, 8-hydroxy-2'-deoxyguanosine/deoxyguanosine and superoxide dismutase activity decreased, while total coenzyme Q10 level increased. However, malondialdehyde and coenzyme Q10 levels were not affected. The international prostate symptom scores of the patients were also decreased after the operation. The results suggest that blood 8-hydroxy-2'-deoxyguanosine/deoxyguanosine level may reflect the oxidative stress better than the malondialdehyde level, and surgical operation attenuates the oxidative stress in late post-operative period in benign prostatic hyperplasia patients.

Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes.

In this study, new dibenzensulfonamides, 7-9, having the chemical structure 4,4'-(5'-chloro-3'-methyl-5-aryl-3,4-dihydro-1'H,H-[3,4'-bipyrazole]-1',2-diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7-9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7-28.1 nM and 4.5-9.3 nM, respectively.

Curcumin analogue 1,5-bis(4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)penta-1,4-dien-3-one mediates growth arrest and apoptosis by targeting the PI3K/AKT/mTOR and PKC-theta signaling pathways in human breast carcinoma cells.

Recent developments in the literature have demonstrated that curcumin exhibit antioxidant properties supporting its anti-inflammatory, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Despite the valuable findings of curcumin against different cancer cells, the clinical use of curcumin in cancer treatment is limited due to its extremely low aqueous solubility and instability, which lead to poor in vivo bioavailability and limited therapeutic effects. We therefore focused in the present study to evaluate the anti-tumor potential of curcumin analogues on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as their effects on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of curcumin analogue J1 in these cancer cell lines were determined to be 5 ng/ml and 10 ng/ml, in MDA-MB-231 and MCF-7 cells respectively. Interestingly, at these concentrations, the J1 did not affect the viability of non-tumorigenic normal breast epithelial cells MCF-10. Furthermore, we found that J1 strongly induced growth arrest of these cancer cells by modulating the mitochondrial membrane potentials without significant effect on normal MCF-10 cells using JC-1 staining and flow cytometry analysis. Using annexin-V/PI double staining assay followed by flow cytometry analysis, we found that J1 robustly enhanced the induction of apoptosis by increasing the activity of caspases in MDA-MB-231 and MCF-7 cancer cells. In addition, treatment of breast cancer cells with J1 revealed that, in contrast to the expression of cyclin B1, this curcumin analogue vigorously decreased the expression of cyclin A, CDK2 and cyclin E and subsequently sensitized tumor cells to cell cycle arrest. Most importantly, the phosphorylation of AKT, mTOR and PKC-theta in J1-treated cancer cells was markedly decreased and hence affecting the survival of these cancer cells. Most interestingly, J1-treated cancer cells exhibited a significant inhibition in the activation of RhoA followed by reduction in actin polymerization and cytoskeletal rearrangement in response to CXCL12. Our data reveal the therapeutic potential of the curcumin analogue J1 and the underlying mechanisms to fight breast cancer cells.

Microwave-assisted synthesis and bioevaluation of new sulfonamides.

In this study, 4-[5-(4-hydroxyphenyl)-3-aryl-4,5-dihydro-1H-pyrazol-1-yl]benzenesulfonamide derivatives (8-14) were synthesized for the first time by microwave irradiation and their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS. Cytotoxic activities and inhibitory effects on carbonic anhydrase I and II isoenzymes of the compounds were investigated. The compounds 9 (PSE = 4.2), 12 (PSE = 4.1) and 13 (PSE = 3.9) with the highest potency selectivity expression (PSE) values in cytotoxicity experiments and the compounds 13 (Ki = 3.73 ± 0.91 nM toward hCA I) and 14 (Ki = 3.85 ± 0.57 nM toward hCA II) with the lowest Ki values in CA inhibition studies can be considered as leader compounds for further studies.

Protective effect of Naringin on experimental hindlimb ischemia/reperfusion injury in rats.

This study was designed to investigate the antioxidant effects of Naringin, in ischemia/reperfusion (I/R)-induced skeletal muscle injury in rats. The rats were randomly allocated into three groups including control, I/R and I/R + Naringin groups. Muscle tissues of I/R groups revealed significantly higher antioxidant enzyme activities, and increased levels of malondialdehyde, as specific a marker of the lipid peroxidation and tissue damage, compared to the control group (p < 0.05). Levels of these parameters in muscle revealed significant reductions in the I/R + Naringin group compared to the I/R group (p < 0.05). Histopathological examination of ischemia muscles in the I/R group showed significant degeneration and inflammation compared to the control group, whereas ischemic muscles of Naringin-administered group showed significant reduction in degeneration and inflammation compared to the I/R group (p < 0.05). We suggest that the protective effect of Naringin may reduce the I/R injury in cases of extremity injuries with acute vascular complications, extremity surgery with prolonged tourniquet application.

Which prosthesis is more resistant to vascular graft infection: polytetrafluoroethylene or Omniflow II biosynthetic grafts?

PURPOSE: The aim of this study was to determine whether polytetrafluoroethylene grafts or Omniflow II biosynthetic grafts are more resistant to infection caused by Staphylococcus aureus. METHODS: Sixty rats were divided into six groups. In Groups 1A, 1B and 1C, a polytetrafluoroethylene graft was implanted in each rat, and, in Groups 2A, 2B and 2C, a biosynthetic graft was implanted in each rat. Staphylococcus aureus was inoculated into Groups 1B, 1C, 2B and 2C, and the rats in Groups 1C and 2C were treated with teicoplanin. One week later, the rats were euthanized, the grafts were removed and a microbiological count was performed. A histopathological examination was subsequently carried out, and the C-reactive protein, prealbumin and leukocyte levels were investigated. RESULTS: There were no significant differences in the C-reactive protein, prealbumin and leukocyte levels. The differences in the results of the microbiological evaluations between the groups were significant. The quantitative culture results showed no bacterial growth in Groups 1A, 1C and 2A. The number of bacteria in Group 1B was statistically lower than that in Group 2B. When the groups receiving treatment were compared, Group 2C had bacterial growth, whereas Group 1C did not. The histopathological examinations showed similar results. CONCLUSIONS: Omniflow II grafts are more susceptible to infection than polytetrafluoroethylene grafts.

Efficacy of linezolid, teicoplanin, and vancomycin in prevention of an experimental polytetrafluoroethylene graft infection model caused by methicillin-resistant Staphylococcus aureus.

BACKGROUND: The aim of this study was to evaluate the effectiveness of linezolid, teicoplanin, and vancomycin in prevention of prosthetic vascular graft infections in a vascular graft infection model. MATERIAL AND METHODS: Fifty rats were divided into 5 groups. A polytetrafluoroethylene graft was implanted on the back of each rat. Methicillin-resistant Staphylococcus aureus (MRSA) strain was inoculated into all rats except Group 1. Group 2 was not given any treatment, Group 3 received linezolid, Group 4 received vancomycin, and Group 5 received teicoplanin. The grafts were removed for microbiological and histological examinations on the 7th day. In addition, C-reactive protein and prealbumin levels and leukocyte counts in obtained blood specimens were determined. RESULTS: Group 1 did not have infection. Group 2 had bacteria 5.7 × 10(4) CFU/cm(2). Group 3 and Group 4 had less bacterial growth. Group 5 had no bacterial growth. The number of bacteria was significantly higher in Group 2 than in the other experimental groups and the control group (p<0.001). Although there was no bacterial growth in Group 5, it did not significantly differ from Group 3 and Group 4. Group 2 had a significantly higher CRP level and leukocyte count and a significantly lower prealbumin level than the other groups. CONCLUSIONS: Linezolid, teicoplanin, and vancomycin are effective in prevention of prosthetic vascular graft infections.

Cytoreductive surgery (SRC) and hyperthermic intraperitoneal chemotherapy (HIPEC) for treatment of peritoneal carcinomatosis: Our initial experience and technical details.

OBJECTIVE: The aim of this study is to present our initial experience in peritoneal carcinomatosis treatment and the technical details of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the light of current literature. MATERIAL AND METHODS: Data of 27 consecutive patients who were treated with CRS and HIPEC for peritoneal carcinomatosis in Medical Park Samsun Hospital, between November 2012 and September 2014 were retrospectively reviewed. Treatment indication and management were evaluated at the multidisciplinary oncology council. All patients underwent CRS and HIPEC with the aim of complete cytoreduction. Patients with unresectable disease and/or palliative surgery were excluded from analysis. Perioperative complications were classified according to Clavien-Dindo classification, and HIPEC-related side effects were identified using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) criteria. Demographic, clinical and histopathological data of the patients were analyzed. RESULTS: The mean age was 54 (32-72). Nineteen patients were female. The origin of peritoneal carcinomatosis was colorectal cancer in 12 patients, ovarian cancer in 12 patients, gastric cancer in 2 patients and pseudomyxoma peritonei in 1 patient. The mean Peritoneal Carcinomatosis Index was 12 (3-32), with a mean operative time of 420 (300-660) minutes. Perioperative morbidity, HIPEC-related toxicity and perioperative mortality were observed in eight (30%), one (3.7%) and four patients (14.8%), respectively. During a mean follow up of 13 (1-22) months, overall and disease-free survival rates were 95.8% and 82.6%, respectively. Two patients with colorectal cancer (after 9 and 12 months) and one patient with ovarian cancer (after 11 months) had intra-abdominal recurrence. One patient with ovarian cancer had liver metastases 13 months after surgery, and underwent resection of segments 6-7. The remaining patients are being followed-up without any recurrence. CONCLUSION: Cytoreductive surgery and HIPEC have favorable results in the treatment of patients with peritoneal carcinomatosis. Compatible with the literature, surgical outcomes of the presented series are encouraging for this treatment modality that have been recently popularized in our country. Careful perioperative evaluation, proper patient selection and multidisciplinary approach are essential for success in curative treatment of peritoneal carcinomatosis.

Increased susceptibility to apoptosis and growth arrest of human breast cancer cells treated by a snake venom-loaded silica nanoparticles.

BACKGROUND: The development of effective treatments against metastatic cancers, including breast cancer, is among the most important challenges in current experimental and clinical cancer research. We recently demonstrated that Walterinnesia aegyptia venom (WEV), either alone or in combination with silica nanoparticles (WEV+NP), resulted in the growth arrest and apoptosis of different cancer cell lines. AIMS: In the present study, we evaluated the impact of WEV alone and WEV+NP on human breast cancer cells isolated from cancer biopsies. METHODS: The potential effects of WEV alone and WEV+NP on the proliferation, induction of apoptosis and generation of free radicals in breast cancer cells isolated from 80 patients clinically diagnosed with breast cancer were evaluated by flow cytometry and ELISA. RESULTS: WEV alone and WEV+NP inhibited the proliferation, altered the cell cycle and enhanced the induction of apoptosis of the breast cancer cells by increasing the activities of caspase-3, caspase-8 and caspase-9. In addition, the combination of WEV and NP robustly sensitized the breast cancer cells to growth arrest and apoptosis by increasing the generation of free radicals, including reactive oxygen species (ROS), hydroperoxide and nitric oxide. The combination of WEV with NP significantly enhanced the anti-tumor effect of WEV in breast cancer cells. CONCLUSION: Our data indicate the therapeutic potential of the nanoparticle-sustained delivery of snake venom for the treatment of breast cancer.

Synthesis of new N,N'-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against human hepatoma and breast cancer cells.

N,N'-Bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides were synthesized by the reaction of 2 mols of 1-aryl-3-(piperidine-1-yl)-1-propanone hydrochlorides with 1 mol of hydrazine hydrate. Aryl part was C6H5 (P1), 4-CH3C6H4 (P2), 4-CH3OC6H4 (P3), 4-HOC6H4 (P4), 4-ClC6H4 (P5), 3-CH3OC6H4 (P6), 4-FC6H4 (P7) and 4-BrC6H4 (P8). Except P1, all compounds were reported for the first time. The chemical structures were confirmed by UV, (1)H NMR, (13)C NMR and HRMS spectra. P1, P2, P7 and P8 against human hepatoma (Huh7) cells and P1, P2, P4, P5, P6, P7 and P8 against breast cancer (T47D) cells have shown cytotoxicity. P1, P2 and P7 had more potent cytotoxicity against Huh7 cells than the reference compound 5-FU, whereas only P2 was more potent than the 5-FU against T47D cells. Representative compound P7 inhibited the mitochondrial respiration at 144, 264 and 424 µM concentrations dose-dependantly in liver homogenates. The results suggest that P1, P2, P7 and P8 may serve as model compounds for further synthetic studies.

[Distribution of blaOXA genes in Acinetobacter baumannii strains: a multicenter study]. / Acinetobacter baumannii Izolatlarinda blaOXA Genlerinin Dagilimi: Çok Merkezli Bir Çalisma.

Acinetobacter baumannii is the most important agent of nosocomial infections within the Acinetobacter genus. This gram-negative coccobacillus is intrinsically resistant to many antibiotics used in antimicrobial therapy, and capable of developing resistance including carbapenems. The objective of this study was to develop a multiplex real time polymerase chain reaction (qPCR) kit for OXA subgroups in A.baumannii, and to investigate the distribution of OXA subgroups in A.baumannii strains isolated from geographically different regions of Turkey. A total of 834 A.baumannii clinical isolates collected from different state and university medical centers in 13 provinces (Afyonkarahisar, Ankara, Bolu, Elazig, Erzurum, Isparta, Istanbul, Kahramanmaras, Konya, Sakarya, Van) between 2008-2011, were included in the study. The isolates were identified by conventional methods and automated systems [Vitek2 (bioMerieux, ABD) and Phoenix (BD Diagnostic, MD)]. The susceptibility profiles of the isolates were studied with automated systems and standard disc diffusion method. All samples were subjected to qPCR to detect blaOXA-51-like, blaOXA-23-like and blaOXA-58-like genes. A conventional PCR method was also used to detect blaOXA-24-like gene. The resistance rates observed during the study period were as follows: 96.8% for amoxicillin-clavulanate, 86.8% for ciprofloxacin, 74.7% for gentamicin, 71.7% for amikacin, 73.5% for cefaperozone-sulbactam, 72.1% for imipenem and 73% for meropenem. Six hundred and two (72.2 %) isolates were resistant to both imipenem and meropenem. Colistin was found to be the most effective antibiotic against A.baumannii isolates with 100% susceptibility rate. All isolates were positive for blaOXA-51-like, however blaOXA-24-like gene could not be demonstrated in any isolate. Total positivity rates of blaOXA-23-like and blaOXA-58-like genes were found as 53.7% and 12.5%, respectively, while these rates were 74.4% and 17.3% in carbapenem-resistant isolates, respectively. Twenty-five isolates were positive for both blaOXA-23-like and blaOXA-58-like genes. All of the carbapenem-resistant isolates have OXA type genes with the exception of blaOXA-24-like gene. The positivity rates for blaOXA-23-like and blaOXA-58-like genes varied for each center. In addition, there was a decrease in the frequency of blaOXA-58-like gene, however both blaOXA-23-like gene and carbapenem resistance rates increased during the study period. In conclusion, high rates of resistance to carbapenems were also remarkable but A.baumannii strains keep on sensitivity to colistin. Both blaOXA-23-like and blaOXA-58-like genes were shown to be widespread in carbapenem-resistant A.baumannii clinical isolates. However, blaOXA-23-like gene positive strains were increased throughout the study. Currently, multiplex qPCR is the best way for rapid diagnosis of resistant bacteria for prevention of hospital-acquired infections. The multiplex qPCR kit developed in this study could be useful for rapid diagnosis and identify the frequencies of blaOXA-23-like, blaOXA-51-like and blaOXA-58-like genes in carbapenem-resistant A.baumannii clinical isolates.

Short-term tourism alters abundance, size, and composition of microplastics on sandy beaches.

Microplastics have become a global threat to sandy beach ecosystems. To efficiently manage this threat, potential sources of microplastics should be deeply understood, which requires direct evidence as this is always a challenging task. Previous studies have reported various sources; however, the topic still needs attention to identify other potential sources of microplastics on sandy shores. Therefore, the abundance, size, color, shape, and polymer type of microplastics on nine sandy shores of the Turkish Coast of the Black Sea were examined before and after the regular tourism season to understand whether short-term tourism might be an important source. A total of 3402 microplastic items from 270 sand samples were obtained and examined. Both the abundance and the average size of the microplastics increased after the tourism season associated with the potential number of visitors and beach cleaning efforts. Further, the color, shape, and polymer type of microplastics varied between sampling times. Beach cleaning seemed to be an efficient way to minimize the adverse effect of short-term tourism influence. This study clearly identifies short-term tourism as an important source of microplastics on sandy shores and beach cleaning as an important tool to minimize microplastic abundance. The results of this study are important insights into current literature by identifying another source of microplastics on sandy shores, which should be useful for the potential management actions to reduce the harm of these global pollutants.

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design.

A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medicinal/pharmaceutical chemistry.

Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries.

According to population-based studies, lung cancer is the prominent reason for cancer-related mortality worldwide in males and is also rising in females at an alarming rate. Sorafenib (SOR), which is approved for the treatment of hepatocellular carcinoma and renal cell carcinoma, is a multitargeted protein kinase inhibitor. Additionally, SOR is the subject of interest for preclinical and clinical trials in lung cancer. This study was designed to assess in vivo the possible effects of sorafenib (SOR) in diethylnitrosamine (DEN)-induced lung carcinogenesis and examine its probable mechanisms of action. A total of 30 adult male rats were divided into three groups (1) control, (2) DEN, and (3) DEN + SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum and lung tissue samples were analyzed to determine SRY-box transcription factor 2 (SOX-2) levels. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels were measured in lung tissue supernatants. Lung sections were analyzed for cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) histopathologically. In addition, cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) were analyzed by immunohistochemistry and immunofluorescence methods, respectively. SOR reduced the level of SOX-2 that maintenance of cancer stemness and tumorigenicity, and TNF-α and IL-1ß levels. Histopathological analysis demonstrated widespread inflammatory cell infiltration, disorganized alveolar structure, hyperemia in the vessels, and thickened alveolar walls in DEN-induced rats. The damage was markedly reduced upon SOR treatment. Further, immunohistochemical and immunofluorescence analysis also revealed increased expression of COX-2 and JNK expression in DEN-intoxicated rats. However, SOR treatment alleviated the expression of these inflammatory markers in DEN-induced lung carcinogenesis. These findings suggested that SOR inhibits DEN-induced lung precancerous lesions through decreased inflammation with concomitant in reduced SOX-2 levels, which enables the maintenance of cancer stem cell properties.

Use of measured accelerations from a passenger rail car to evaluate ride quality and track roughness - A case study.

Increasing traffic and speeds on passenger rail lines, and a short season for maintenance work, have motivated the industry to find new methods to assess the condition of existing infrastructure and determine where upgrades are required. In this study, acceleration data from the car body and axle boxes of a revenue car over 92 km of a Canadian passenger rail route in Ontario were collected for two purposes: first, to apply weighted filtering method according to ISO 2631-1997 standard as a technique to determine the locations which highly impact the ride quality and to investigate the effect of type of track features and speed on the ride quality; second, a new analytical method called the envelope of acceleration was applied to use the recorded accelerations to evaluate the alignment and surface roughness along the track. Since the alignment and surface roughness values are always positive and are calculated over a specified length (e.g. 9.5 m, 18.9 m, 38 m) an envelope technique was employed which uses spline interpolations over local maxima of the absolute magnitude of accelerations at every separated n samples corresponding to best fit with track roughness. The regression analysis between the envelope of accelerations and alignment and surface roughness presented a meaningful correlation and showed the applied method is a promising analytical technique to indicate rough sections of the track. The limitations to the application of envelope of acceleration are also discussed.

Diffusion-Weighted Imaging of Brain Metastasis: Correlation of MRI Parameters with Histologic Type.

AIM: To compare the diffusion properties of brain metastases as imaging biomarkers in various types of tumours, to determine their histology and origin. MATERIAL AND METHODS: Magnetic Resonance Imaging (MRI) and diffusion-weighted imaging (DWI) were used to retrospectively study the data of 143 patients suffering from brain metastases. Four categories of primary tumours with metastases to the brain were included: lung carcinoma (n=102, 71.3%); breast carcinoma (n=27, 18.8%); colon carcinoma (n=8, 5.6%); and others (n=6, 4.2%). The Apparent Diffusion Coefficient (ADCmin ) values, as well as the normalised ADC ratio (nADC), were determined. The lesions on the DWI were categorised as follows: type 1, with negative findings on DWI; type 2, which were isointense with the normal cortical grey matter; type 3, which were hyperintense compared to the normal cortical grey matter. RESULTS: The diffusion type, mean ADCmin, and mean nADC showed statistically significant differences in different types of metastases. In the subgroup analysis, it was found that type 3 was the diffusion type found most extensively in the brain metastases of small cell carcinoma (SCLC) (n=52, 65.8%, p < 0.000). Furthermore, the mean ADCmin and nADC values were the least for the brain metastases of the SCLC (552.0 ± 134.2 and nADC = 0.8 ± 0.1, p < 0.000, respectively). The value of the mean ADCmin was low in the human epidermal growth factor receptor 2 (HER-2) negative groups than in the HER-2 positive groups at 786.8 ± 299.1 vs 844.8 ± 141.3 (p < 0.006). CONCLUSION: Our findings indicated that there is a correlation between diffusion parameters as imaging biomarkers of the solid component of brain metastases of primary tumours and the tumour histology.

The design and cytotoxic evaluation of some 1-aryl-3-isopropylamino-1-propanone hydrochlorides towards human Huh-7 hepatoma cells.

A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated.