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1.
Sci Rep ; 14(1): 9106, 2024 04 20.
Article in English | MEDLINE | ID: mdl-38643226

ABSTRACT

Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit biofilm formation of Gram positive bacterium (Staphylococcus aureus), Gram negative bacterium (Escherichia coli) as well as the methicillin-resistant S. aureus (MRSA) has been previously described. In the present work, new hybrid coumarin-heterocycles have been synthesized via the reaction of coumarin-6-sulfonyl chloride and 6-aminocoumarin with different small heterocycle moieties. The biological efficacy of the new compounds was evaluated towards their ability to inhibit biofilm formation and their anti-inflammatory properties. The antimicrobial activities of the newly synthesized compounds were tested against Gram positive bacterium (S. aureus ATCC 6538), Gram negative bacterium (E. coli ATCC 25922), yeast (Candida albicans ATCC 10231) and the fungus (Aspergillus niger NRRL-A326). Compounds 4d, 4e, 4f, 6a and 9 showed significant MIC and MBC values against S. aureus, E. coli, C. albicans, and methicillin-resistant S. aureus (MRSA) with especial incidence on compound 9 which surpasses all the other compounds giving MIC and MBC values of (4.88 and 9.76 µg/mL for S. aureus), (78.13 and 312.5 µg/mL for E. coli), (9.77 and 78.13 µg/mL for C. albicans), and (39.06 and 76.7 µg/mL for MRSA), respectively. With reference to the antibiofilm activity, compound 9 exhibited potent antibiofilm activity with IC50 of 60, 133.32, and 19.67 µg/mL against S. aureus, E. coli, and MRSA, (respectively) considering the reference drug (neomycin). Out of all studied compounds, the anti-inflammatory results indicated that compound 4d effectively inhibited nitric oxide production in lipopolysaccharide-(LPS-) stimulated RAW264.7 macrophage cells, giving NO% inhibition of 70% compared to Sulindac (55.2%).


Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Staphylococcus aureus , Escherichia coli , Gram-Positive Bacteria , Gram-Negative Bacteria , Coumarins/pharmacology , Inflammation/drug therapy , Biofilms , Anti-Inflammatory Agents/pharmacology , Microbial Sensitivity Tests
2.
Clin Pharmacol Ther ; 115(5): 1007-1014, 2024 May.
Article in English | MEDLINE | ID: mdl-38073049

ABSTRACT

A model-based meta-analysis (MBMA) was conducted to compare the efficacy of bimekizumab with other psoriatic arthritis (PsA) treatment regimens using ≥ 20%/50%/70% improvements in American College of Rheumatology (ACR) criteria (ACR20/50/70) for patients with PsA. Forty-nine trials of 16 drugs were identified in the literature, comprising 21,340 patients. Trial-level covariates, including prior biologic use, concomitant methotrexate use, time since diagnosis, trial completion year, and active comparator were considered for exploratory models. The final model was selected using leave-one-out cross-validation (LOO CV) to assess predictive performance based on prespecified criteria. LOO CV was conducted for 15 trials; the final model demonstrated that 91.5% (952/1,040) of the observed treatment differences, and 96.1% of the observed ACR20/50/70 response rates were within the 95% prediction interval (PI). Median ACR50 response rates (95% PI) at week 16 in biologic-naïve patients were predicted to be 44% (40-49%) for bimekizumab 160 mg, among the highest of all treatments analyzed. Response rates for secukinumab 150 mg and risankizumab 150 mg were 28% (25-32%) and 27% (24-31%), respectively. The MBMA was also used to predict the probability of success (PoS) of potential head-to-head trials using ACR50 response as the end point with varying sample sizes: vs. secukinumab 150 mg, the PoS for bimekizumab 160 mg was 62% (N = 200) and 90% (N = 400). Versus risankizumab 150 mg, the PoS for bimekizumab 160 mg was 68% (N = 200) and 94% (N = 400). In summary, a predictive MBMA described ACR20/50/70 outcomes in PsA, allowing accurate and precise treatment comparisons and robust PoS calculations.


Subject(s)
Antibodies, Monoclonal, Humanized , Antirheumatic Agents , Arthritis, Psoriatic , Biological Products , Rheumatology , Humans , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/drug therapy , Arthritis, Psoriatic/chemically induced , Antirheumatic Agents/therapeutic use , Biological Products/therapeutic use , Treatment Outcome
3.
Naunyn Schmiedebergs Arch Pharmacol ; 397(3): 1817-1828, 2024 03.
Article in English | MEDLINE | ID: mdl-37750935

ABSTRACT

Antihypertensive medications have been associated with a reduction in hemoglobin (Hb) levels, leading to clinically significant anemia. We aimed to provide valuable insights into the impact of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on hematological parameters by measuring the levels of erythropoietin (EPO), ferritin, and complete blood count (CBC) in individuals with type 2 diabetes mellitus (T2DM), particularly considering the duration of the antihypertensives use. In addition to comparing their effects on blood pressure, glycemic status, and renal function, a retrospective cohort study was conducted at the consultation unit of Alsalam Teaching Hospital, Mosul, Nineveh Province, between October 2022 and February 2023. A total of 160 participants were enrolled after being fully examined by the consultants to detect their eligibility for inclusion in the study and to rule out any abnormality. They consisted of 40 healthy controls, 30 T2DM patients (T2DM group), 30 T2DM patients with newly diagnosed hypertension (HT) (T2DM+HT group), 30 type 2 diabetic-hypertensives on ARBs (T2DM+HT+ARBs group), and 30 type 2 diabetic-hypertensives on CCBs (T2DM+HT+CCBs group). Five milliliters of blood was drawn from a vein and divided into two parts. Two milliliters was transferred into an anticoagulant tube for the measurement of HbA1c and complete blood picture. Serum was obtained from the remaining blood and used for assessment of ferritin, EPO, FSG, creatinine, urea, and uric acid. Significantly reduced FSG and HbA1c levels were observed in T2DM+HT+CCBs and T2DM+HT+ARBs groups vs T2DM+HT group (p < 0.05). The T2DM+HT+CCBs group had statistically higher urea levels than the T2DM group (p < 0.05). Both CCBs and ARBs use resulted in reduced creatinine clearance (CrCl). T2DM+HT+CCBs group exhibited slightly higher uric acid levels compared to controls (p < 0.05). Prolonged use of CCBs and ARBs led to disturbances in hematological parameters, with CCBs users showing the lowest levels of hemoglobin (Hb), RBCs, and hematocrit (Hct) among the groups. ARBs users displayed the lowest values of EPO and ferritin compared to other patient groups, along with reduced levels of Hb, RBCs, and Hct, albeit slightly higher than CCBs users. Our study highlights the importance of a balanced approach in prescribing ARBs and CCBs to patients with T2DM, given their potential to induce blood abnormalities, particularly with prolonged usage.


Subject(s)
Diabetes Mellitus, Type 2 , Hypertension , Humans , Calcium Channel Blockers/therapeutic use , Diabetes Mellitus, Type 2/complications , Angiotensin Receptor Antagonists/therapeutic use , Glycated Hemoglobin , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Creatinine , Retrospective Studies , Uric Acid , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Hemoglobins , Urea , Ferritins/therapeutic use
4.
ACS Nano ; 17(22): 22642-22655, 2023 Nov 28.
Article in English | MEDLINE | ID: mdl-37963265

ABSTRACT

Upconversion of near-infrared light into the visible has achieved limited success in applications due to the difficulty of creating solid-state films with high external quantum efficiency (EQE). Recent developments have expanded the range of relevant materials for solid-state triplet-triplet annihilation upconversion through the use of a charge-transfer state sensitization process. Here, we report the single-step solution-processed deposition of a bulk heterojunction upconversion film using organic semiconductors. The use of a bulk heterojunction thin film enables a high contact area between sensitizer and annihilator materials in this interface-triplet-generation mechanism and allows for a facile single-step deposition process. Demonstrations of multiple deposition and patterning methods on glass and flexible substrates show the promise of this materials system for solid-state upconversion applications.

5.
Egypt J Immunol ; 30(1): 105-115, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36592386

ABSTRACT

Rheumatoid arthritis (RA) is a chronic autoimmune disease with multiple morbidity burdens. Early diagnosis of RA is the main key in management and prevention of disease complications. Much research nowadays is looking for a serological marker with high accuracy in diagnosis of early RA cases. Our aim in this study was to evaluate the role of anti-mutated citrullinated vimentin (anti-MCV) antibodies in the early diagnosis of RA. In addition to compare its diagnostic sensitivity and specificity with anti-cyclic citrullinated peptide antibodies (anti-CCP) and RF antibodies in early versus established RA patients. This prospective cross-sectional study included 80 participants: 40 RA patients (20 early RA patients and 20 established RA patients), 20 patients with other rheumatic diseases (as a disease control group), and 20 apparently healthy participants as normal controls. All participants underwent history taking, clinical examination (general, articular assessment and calculation of disease activity score (DAS28-ESR)) for RA patients, radiological and laboratory investigations (RF, anti-CCP2 and anti-MCV antibodies measurements by ELISA technique). The results showed that the mean values of anti-CCP2 and anti-MCV were significantly increased in RA cases compared to the control groups (p=0.00 and p=0.01, respectively). Anti-MCV had sensitivity and specificity of 63% and 83%, respectively for diagnosing of early RA at area under curve of 0.80 compared to sensitivity and specificity 37% and 100%, respectively for anti-CCP2. Also, both (anti-CCP2 and anti-MCV) had positive significant correlations with ESR (p < 0.001 and p=0.02, respectively), CRP (p=0.01 and p=0.02, respectively) and DAS 28 (p < 0.001 for both). In conclusion, our data indicated that anti-MCV antibodies may represent a valuable marker for diagnosis of early RA cases.


Subject(s)
Arthritis, Rheumatoid , Autoantibodies , Humans , Vimentin , Cross-Sectional Studies , Prospective Studies , Arthritis, Rheumatoid/diagnosis , Anti-Citrullinated Protein Antibodies , Peptides, Cyclic , Biomarkers
6.
J Ayub Med Coll Abbottabad ; 35(Suppl 1)(4): S785-S792, 2023.
Article in English | MEDLINE | ID: mdl-38406910

ABSTRACT

Antihypertensive medications known as angiotensin receptor blockers (ARBs) have become increasingly popular for treating conditions beyond hypertension. The reason for this widespread use is mainly due to its reno-protective and cardioprotective properties in patients with congestive heart failure and diabetes mellitus. There have been conflicting studies on the relationship between ARBs and haematological abnormalities. Using the supplied search terms, we carried out a thorough search for relevant papers written in English and published before January 2024. All of the studies that met the selection criteria were searched for on PubMed, Cochrane Library, and Google Scholar. Based on the examined data from the searched literature, it has been demonstrated that angiotensin II is essential for the stimulation of erythropoiesis and inhibition of it by drugs such as ARBs can lower haematocrit levels, leading to anaemia. Accordingly, dose reduction or stopping the administration of ARBs could be a choice to correct anaemia. However, such a decision is based on the clinical situation and the requirements for other management options.


Subject(s)
Anemia , Hypertension , Humans , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Antihypertensive Agents/therapeutic use , Anemia/drug therapy
7.
J Am Chem Soc ; 144(34): 15862-15870, 2022 Aug 31.
Article in English | MEDLINE | ID: mdl-35977424

ABSTRACT

Metal-halide perovskite nanocrystals have demonstrated excellent optoelectronic properties for light-emitting applications. Isovalent doping with various metals (M2+) can be used to tailor and enhance their light emission. Although crucial to maximize performance, an understanding of the universal working mechanism for such doping is still missing. Here, we directly compare the optical properties of nanocrystals containing the most commonly employed dopants, fabricated under identical synthesis conditions. We show for the first time unambiguously, and supported by first-principles calculations and molecular orbital theory, that element-unspecific symmetry-breaking rather than element-specific electronic effects dominate these properties under device-relevant conditions. The impact of most dopants on the perovskite electronic structure is predominantly based on local lattice periodicity breaking and resulting charge carrier localization, leading to enhanced radiative recombination, while dopant-specific hybridization effects play a secondary role. Our results suggest specific guidelines for selecting a dopant to maximize the performance of perovskite emitters in the desired optoelectronic devices.

8.
Matter ; 4(10): 3074-3077, 2021 Oct 06.
Article in English | MEDLINE | ID: mdl-34632371

ABSTRACT

The COVID-19 pandemic continues to impact nearly every aspect of our lives, including academic research. In this Matter of Opinion, we reflect on hosting both in-person and virtual undergraduate students during these challenging times.

9.
Target Oncol ; 16(3): 339-355, 2021 05.
Article in English | MEDLINE | ID: mdl-33939068

ABSTRACT

BACKGROUND: Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs. OBJECTIVE: To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies. PATIENTS AND METHODS: In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition. RESULTS: Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients. CONCLUSIONS: The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02143466; 21 May 2014.


For patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors, like osimertinib, are the standard treatment. However, for most patients, these treatments eventually stop working, as tumors develop resistance to them. Early studies suggest that combining osimertinib with savolitinib can overcome this resistance. We report Part C of the four-part TATTON study, in which two groups of Japanese adult patients received treatment. One group received savolitinib 400 mg once daily, then 600 mg. The other group received osimertinib 80 mg with savolitinib 300/400/600 mg once daily. The main objective of the study was to determine the maximum dose of savolitinib that patients could receive (maximum tolerated dose) and to monitor the safety of the combination. Overall, 17 patients received savolitinib alone and 12 received the combination. The maximum tolerated dose of savolitinib was found to be 400 mg once daily in both groups of patients. The data demonstrated that savolitinib had acceptable safety outcomes either alone, or in combination with osimertinib.


Subject(s)
Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pyrazines/therapeutic use , Triazines/therapeutic use , Acrylamides/pharmacology , Aged , Aniline Compounds/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Japan , Lung Neoplasms/pathology , Male , Middle Aged , Pyrazines/pharmacology , Triazines/pharmacology
10.
AAPS J ; 23(3): 46, 2021 03 17.
Article in English | MEDLINE | ID: mdl-33733338

ABSTRACT

Savolitinib is an oral, potent, and highly selective MET-tyrosine kinase inhibitor under investigation in various tumor types. A thorough QT study evaluated effects on QT interval after a 600-mg single savolitinib dose in healthy subjects. We report exposure-response (E-R) modeling from this study to characterize the effects of savolitinib and its metabolites, M2 and M3, on QTc changes. In a novel application, in vitro potencies against hERG current provided mechanistic support to model the metabolites' effects. The hERG IC50 estimates (95% CI) were 25.8 (22.2-29.9) and 22.6 (14.7-34.6) µM for parent and M2, respectively. The E-R was described by both linear and Emax models, with exposure captured by an active moiety that consisted of savolitinib and M2 concentrations, weighted by the hERG IC50 ratio (1.14). The maximal increase in ΔΔQTcF and EC50 estimates (95% CI) was 18.5 (9.2-27.7) ms and 5709 (2889-8529) nM, respectively. Ignoring M2 contribution resulted in under prediction of QTcF prolongation in the hypothetical case of inhibited M2 clearance; at 300 mg Cmax, the mean (90% CI) of ∆∆QTcF was 9.0 (5.7-12.6) and 5.9 (2.9-8.9) ms using the hERG-informed and parent-only linear models, respectively. Simulations in normal setting confirmed modest QTcF prolongation with 600 mg, but not 300 mg. Using the linear model, the mean (90% CI) maximum ΔΔQTcF were 12.3 (8.6-16.2) and 5.5 (2.6-8.5) ms for 600 and 300 mg, respectively. Further clinical studies will monitor cardiac safety to assess the clinical significance of QT-interval prolongation with savolitinib.


Subject(s)
Long QT Syndrome/chemically induced , Models, Biological , Protein Kinase Inhibitors/adverse effects , Pyrazines/adverse effects , Triazines/adverse effects , Double-Blind Method , Electrocardiography , Healthy Volunteers , Heart Rate/drug effects , Humans , Inhibitory Concentration 50 , Long QT Syndrome/diagnosis , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Triazines/administration & dosage , Triazines/pharmacokinetics
11.
Clin Pharmacol Drug Dev ; 10(5): 521-534, 2021 05.
Article in English | MEDLINE | ID: mdl-33400845

ABSTRACT

Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, bioavailable, selective MET-tyrosine kinase inhibitor. This randomized, double-blind, 3-way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placebo-evaluated effects on the QT interval after a single savolitinib dose. Healthy non-Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time-matched, placebo-adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula (ΔΔQTcF). Secondary end points included 12-lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600-mg dose, the highest least-squares mean ΔΔQTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2-sided 90% confidence interval for ΔΔQTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3-6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive ΔΔQTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of adverse events. In this thorough QT/QTc study, QTcF prolongation was observed with a single savolitinib 600-mg dose. ECG monitoring will be implemented in ongoing and future studies of savolitinib to assess the clinical relevance of the observed QT changes from this study.


Subject(s)
Long QT Syndrome/chemically induced , Protein Kinase Inhibitors/adverse effects , Pyrazines/adverse effects , Triazines/adverse effects , Adult , Cross-Over Studies , Double-Blind Method , Electrocardiography , Female , Humans , Male , Middle Aged , Moxifloxacin/adverse effects , Protein Kinase Inhibitors/administration & dosage , Pyrazines/administration & dosage , Triazines/administration & dosage
12.
Invest New Drugs ; 39(2): 477-487, 2021 04.
Article in English | MEDLINE | ID: mdl-33052556

ABSTRACT

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Gefitinib/therapeutic use , Lung Neoplasms/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/therapeutic use , Triazines/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Dose-Response Relationship, Drug , ErbB Receptors/genetics , Female , Gefitinib/administration & dosage , Gefitinib/adverse effects , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Proto-Oncogene Proteins c-met/biosynthesis , Pyrazines/administration & dosage , Pyrazines/adverse effects , Triazines/administration & dosage , Triazines/adverse effects
13.
Br J Pharmacol ; 178(3): 600-613, 2021 02.
Article in English | MEDLINE | ID: mdl-33125717

ABSTRACT

BACKGROUND AND PURPOSE: Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly MET receptor TK inhibitor. This series of studies aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to link inhibition of MET phosphorylation (pMET) by savolitinib with anti-tumour activity. EXPERIMENTAL APPROACH: Cell line-derived xenograft (CDX) experiments using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells were conducted in athymic nude mice using a variety of doses and schedules of savolitinib. Tumour pMET changes and growth inhibition were calculated after 28 days. Population PK/PD techniques were used to construct a PK/PD model for savolitinib. KEY RESULTS: Savolitinib showed dose- and dose frequency-dependent anti-tumour activity in the CDX models, with more frequent, lower dosing schedules (e.g., twice daily) being more effective than intermittent, higher dosing schedules (e.g., 4 days on/3 days off or 2 days on/5 days off). There was a clear exposure-response relationship, with maximal suppression of pMET of >90%. Data from additional CDX and patient-derived xenograft (PDX) models overlapped, allowing calculation of a single EC50 of 0.38 ng·ml-1 . Tumour growth modelling demonstrated that prolonged, high levels of pMET inhibition (>90%) were required for tumour stasis and regression in the models. CONCLUSION AND IMPLICATIONS: High and persistent levels of MET inhibition by savolitinib were needed for optimal monotherapy anti-tumour activity in preclinical models. The modelling framework developed here can be used to translate tumour growth inhibition from the mouse to human and thus guide choice of clinical dose and schedule.


Subject(s)
Antineoplastic Agents , Proto-Oncogene Proteins c-met , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Mice , Mice, Nude , Protein Kinase Inhibitors/pharmacology , Pyrazines , Triazines , Xenograft Model Antitumor Assays
14.
Egypt J Immunol ; 27(1): 97-107, 2020 Jan.
Article in English | MEDLINE | ID: mdl-33180392

ABSTRACT

Lupus nephritis (LN) is a common major organ manifestation and main cause of morbidity and mortality of the disease. We aimed to determine the level of serum and urinary monocyte chemoattractant protein-1(sMCP-1 and uMCP-1) in systemic lupus erythematosus (SLE) patients with and without LN and analyze their association with different clinical and serologic parameters of disease activity. We enrolled 60 female patients with SLE (32 with LN and 28 without LN) and 20 controls.MCP-1 and anti-dsDNA were measured by ELISA. There was statistically significant increase in serum and urinary MCP-1 in all SLE patients (mean=711.59, 676.68 pg/ml respectively) as compared to the control group (mean= 635.70, 632.40 pg/ml respectively), P=0.034, 0.020 respectively. Among patients with LN there was statistically significant increase in sMCP-1 (mean=723.58) compared to the control group (P=0.038, and in uMCP-1 (mean=699.08) compared to patients without LN (mean=651.07) and control group (mean=632.40), P=0.007, 0.002 respectively. Urinary, but not serum MCP-1, positively correlated with 24 hour proteinuria, anti-dsDNA, renal SLEDAI ,biopsy activity index (r=0.362, P=0.004; r=0.303, P=0.019; r= 0.267, P=0.039; r=0.353, P=0.047 respectively) and negatively correlated with serum albumin (r=-0.329, P=0.010).There was statistically significant increase in uMCP-1 and anti-dsDNA in patients with poor response compared to patients with good response to immunosuppressant therapy (P= 0.025; P=0.034 respectively). In conclusion, uMCP-1 is associated with LN and disease activity and may be used as a useful tool for diagnosis and follow up.


Subject(s)
Chemokine CCL2/blood , Chemokine CCL2/urine , Lupus Erythematosus, Systemic , Lupus Nephritis , Biomarkers/blood , Biomarkers/urine , Case-Control Studies , Female , Humans , Lupus Nephritis/diagnosis , Severity of Illness Index
15.
Int J Rheum Dis ; 23(9): 1226-1232, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32783391

ABSTRACT

Disturbances in autophagy are known to be implicated in autoimmune disorders. Many studies have connected polymorphisms in autophagy-related gene 5 (ATG-5) to systemic lupus erythematosus (SLE). Our aim was the determination of the expression level of ATG-5, Beclin-1 and microtubule-associated protein-light chain 3 (LC-3) in Egyptian SLE patients to investigate the impact of disturbances in autophagy genes on the incidence and progression of the disease. Also, we investigated the incidence of single nucleotide polymorphism (SNP) rs573775 in ATG-5 gene among Egyptian SLE patients. Our results showed that the mean levels of Beclin-1, LC-3 and interleukin (IL)-10 transcripts were significantly higher in SLE patients compared to healthy controls. The previous transcripts were positively correlated with SLE Disease Activity Index (SLEDAI). Beclin-1 and LC-3 transcripts were negatively correlated to complement component 3 (C3) levels. Only LC-3 transcripts were negatively correlated to complement component 4 (C4). The rs573775 SNP of ATG-5 with the variant allele was significantly associated with disease susceptibility, conferring a higher risk of SLE development. This variant allele was more prevalent in patients below 30 years, patients with anemia and in patients with anti-double-stranded DNA (dsDNA), confirming the essential role of ATG-5 polymorphism in the susceptibility of Egyptian patients to SLE.


Subject(s)
Autophagy-Related Protein 5/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide , Adult , Autophagy-Related Protein 5/blood , Beclin-1/blood , Beclin-1/genetics , Biomarkers/blood , Case-Control Studies , Complement C3/analysis , Complement C4/analysis , Egypt , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Interleukin-10/blood , Interleukin-10/genetics , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/diagnosis , Male , Microtubule-Associated Proteins/blood , Microtubule-Associated Proteins/genetics , Phenotype , RNA, Messenger/blood , RNA, Messenger/genetics , Risk Assessment , Risk Factors
16.
J Phys Chem A ; 124(23): 4855-4860, 2020 Jun 11.
Article in English | MEDLINE | ID: mdl-32396362

ABSTRACT

Single-particle spectroscopy has demonstrated great potential for analyzing the microscopic behavior of various nanoparticles (NPs). However, high-resolution optical imaging of these materials at the nanoscale is still very challenging. Here, we present an experimental setup that combines high sensitivity of time-correlated single-photon counting (TCSPC) techniques with atomic force microscopy (AFM). This system enables single-photon detection with a time resolution of 120 ps and a spatial resolution of 5 nm. We utilize the setup to investigate the photoluminescence (PL) characteristics of both zero-dimensional (0D) and three-dimensional (3D) perovskite nanocrystals and establish a correlation between the particles' sizes, their PL blinking, and the lifetime behavior. Our system demonstrates an unprecedented level of information, opening the door to understanding the morphology-luminescence correlation of various nanosystems.

17.
J Chem Phys ; 152(2): 020902, 2020 Jan 14.
Article in English | MEDLINE | ID: mdl-31941323

ABSTRACT

The luminescence and charge transport properties of inorganic CsPbX3 perovskite nanocrystals (NCs) make them attractive candidates for various optoelectronic applications, such as lasing, X-ray imaging, light communication, and light-emitting diodes (LEDs). However, to realize cutting-edge device performance, high-quality NCs with high photoluminescence quantum yields (PLQYs) are essential. Therefore, substantial efforts and progress have been made to attain superior design/engineering and optimization of the inorganic NCs with a focus on surface quality, reduced nonradiative charge carrier recombination centers, and improved colloidal stabilities. Metal-ion doping has been proven to have a robust influence on the electronic band structure, PL behavior, and charge carrier recombination dynamics. Thus, in this perspective, we summarize the recent progress of the significant impact of metal cation doping on the optical properties, including the PL enhancement of CsPbCl3, CsPbBr3, and CsPbI3 perovskite NCs. Moreover, we shed light on the mechanism behind such improved properties. We conclude by recommending possible aspects and strategies to be further explored and considered for better utilization of these doped NCs in thin-film optoelectronic and energy conversion devices.

18.
Arab J Gastroenterol ; 20(2): 86-90, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31182342

ABSTRACT

BACKGROUND AND STUDY AIMS: pancreatic cysts are commonly found lesions and proper diagnosis is very important for planning further management. The study aims to evaluate the role of cyst fluid amylase and tumour markers as cancer antigen (CA 19-9) and carcinoembryonic antigen (CEA) in addition to mucin stain in diagnosing pancreatic cysts and differentiating malignant from benign lesions. PATIENTS AND METHODS: This prospective study was conducted on 184 patients diagnosed to have pancreatic cystic lesions from January 2013 to January 2018. Fluid analysis for CA 19-9, CEA, amylase, mucin stain and cytopathology were done. We compared these data with the final diagnosis based on histopathology after surgical resection, positive cytopathology and long period of follow up of the patients for at least 18 months. RESULTS: The highest AUC was that of cystic CEA with cut-off value of 160 ng/ml; it had a sensitivity of 60.4% and a specificity of 85%. The best cut-off value for cystic CA 19-9 was 1318 U/ml with a sensitivity of 64.1% and a specificity of 68.1%. The cut-off value of cyst amylase level was 5500 U/L, with 84.2% sensitivity and 37.1% specificity. The sensitivity of mucin stain in detecting mucinous cystic neoplasm was 85.45%, specificity was 86.05% with accuracy 85.87%. CONCLUSION: Cyst fluid analysis by investigating amylase, mucin, CA 19-9, CEA and EUS examination improves the diagnosis of different pancreatic cysts.


Subject(s)
Pancreatic Cyst/diagnosis , Pancreatic Cyst/metabolism , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/metabolism , Adolescent , Adult , Aged , Amylases/metabolism , CA-19-9 Antigen/metabolism , Carcinoembryonic Antigen/metabolism , Child , Diagnosis, Differential , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Female , Humans , Male , Middle Aged , Mucins/metabolism , Pancreatic Cyst/pathology , Pancreatic Neoplasms/pathology , Prospective Studies , ROC Curve , Young Adult
19.
RSC Adv ; 9(39): 22389-22400, 2019 Jul 17.
Article in English | MEDLINE | ID: mdl-35519441

ABSTRACT

Electrodeposition of silver, tin and their alloys from different aqueous electrolytes suffer from various environmental issues and deposits are affected by H2 evolution and metal oxide formation. In this work, these metals and their alloys are electrodeposited by cyclic voltammetry utilizing ionic liquids based on C5H14ClNO (choline chloride) that permits deposit properties control. Both Ag and Sn concentrations in the ionic liquid were varied from 0.01 to 0.15 mol L-1. Methionine effect on the reduction potential of Sn and Ag was studied. Different techniques were applied to explore the structures, morphologies, and electrochemical (EC) activities of the deposits. A single Ag3Sn phase with orthorhombic packed structure was observed for all alloys, whereas the preferred growth orientation was varied from (202) to (112) depending on Ag%. Also, the dislocation density is decreased by increasing Ag content. EDX spectra showed only Ag and Sn signals indicating the high purity of the Sn-Ag alloys. The deposit from Sn-rich liquid showed rougher and larger agglomerates at the surface than that formed from the Ag-rich liquids with or without methionine. The electrochemical activities of the deposits toward the H2 evolution reaction (HER) were investigated through electrochemical polarization (ECP) measurements and EC impedance spectroscopies (EISs). The Sn-Ag alloys possess higher performance, as a catalyst for HER using alkaline solution, than Ag or Sn electrodes. The highest rate of HER was recorded for Sn-35% Ag and Sn-97% Ag deposits, which correlated strongly to the microstructure and surface morphology. The ECP results were confirmed by EIS investigations. The measured impedance values are close-fitting to a hypothetical model for the electrode/electrolyte interface.

20.
Pak J Biol Sci ; 22(12): 614-622, 2019 Jan.
Article in English | MEDLINE | ID: mdl-31930861

ABSTRACT

BACKGROUND AND OBJECTIVE: Potato is one of the world's leading vegetable crops. Potato viral diseases cause adversely effects on the agricultural sector. Recently there is a growing interest to control plant viruses using spices and herbs (including curcumin). Poor solubility of curcumin in water limited its applications. Therefore, the main objective of the present study was to evaluate the effect of antiviral activity of curcumin-milk proteins nanoparticles against potato virus Y (PVY). MATERIALS AND METHODS: Curcumin-milk proteins nanoparticles were prepared via ionic gelation method. The antiviral activity of the resultant nanoparticles against PVY was evaluated at different concentrations (500, 1000 and 1500 mg/100 mL). Chlorophyll content as well as the activity of peroxidase (POX) and polyphenol oxidase (PPO) was examined. RESULTS: Curcumin-milk proteins nanoparticles showed inhibitory effect on PVY in a concentration dependent manner. CONCLUSION: Curcumin-milk proteins nanoparticles displayed a successful tool to control the PVY under green house conditions.


Subject(s)
Antiviral Agents/administration & dosage , Curcumin/administration & dosage , Milk Proteins/administration & dosage , Potyvirus/drug effects , Catechol Oxidase/metabolism , Chitosan/administration & dosage , Chlorophyll/metabolism , Nanogels/administration & dosage , Nanoparticles/administration & dosage , Peroxidase/metabolism , Plant Diseases/prevention & control , Plant Diseases/virology , Plant Immunity , Potyvirus/pathogenicity , Solanum tuberosum/growth & development , Solanum tuberosum/metabolism , Solanum tuberosum/virology
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