Possible protective effect of rosuvastatin in chemotherapy-induced cardiotoxicity in HER2 positive breast cancer patients: a randomized controlled trial.

Cardiotoxicity is a side effect of chemotherapy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients receiving both anthracyclines and trastuzumab. We looked for a possible protective effect of rosuvastatin against chemotherapy-induced cardiotoxicity. Methods: 50 newly diagnosed HER2 positive breast cancer patients were randomly allocated into two groups: 25patients in each. Group 1(control group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy. Group 2 (treatment group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy and 20 mg of oral rosuvastatin 24 h before the first cycle of chemotherapy and once daily for the rest of the follow-up period (6 months). Transthoracic echocardiography was done, and blood samples were collected for patients 24 h before the initiation of therapy, after 3 months and after 6 months to assess serum levels of high sensitivity cardiac troponin I (hs-cTnI), Myeloperoxidase (MPO), Interleukin-6 (IL-6) and Alanine aminotransferase (ALT). The study was retrospectively registered in Clinical Trials.gov in April 2022. Its ID is NCT05338723. Compared to control group, Rosuvastatin-treated group had a significantly lower decline in LVEF after 3 months and after 6 months. They had significantly lower Hs-cTnI and IL-6 after 3 months and after 6 months, and significantly lower MPO after 6 months. Four patients in control group experienced cardiotoxicity while no one in rosuvastatin-treated group. Rosuvastatin attenuated cardiotoxicity, so it is a promising protective agent against chemotherapy-induced cardiotoxicity.

Exploring the role of Müller cells-derived exosomes in diabetic retinopathy.

Exosomes are nanosized vesicles that have been reported as cargo-delivering vehicles between cells. Müller cells play a crucial role in the pathogenesis of diabetic retinopathy (DR). Activated Müller cells in the diabetic retina mediate disruption of barrier integrity and neovascularization. Endothelial cells constitute the inner blood-retinal barrier (BRB). Herein, we aim to evaluate the effect of Müller cell-derived exosomes on endothelial cell viability and barrier function under normal and hyperglycemic conditions. Müller cell-derived exosomes were isolated and characterized using Western blotting, nanoparticle tracking, and electron microscopy. The uptake of Müller cells-derived exosomes by the human retinal endothelial cells (HRECs) was monitored by labeling exosomes with PKH67. Endothelial cell vitality after treatment by exosomes under normo- and hypoglycemic conditions was checked by MTT assay and Western blot for apoptotic proteins. The barrier function of HRECs was evaluated by analysis of ZO-1 and transcellular electrical resistance (TER) using ECIS. Additionally, intracellular Ca+2 in HRECs was assessed by spectrofluorimetry. Analysis of the isolated exosomes showed a non-significant change in the number of exosomes isolated from both normal and hyperglycemic condition media, however, the average size of exosomes isolated from the hyperglycemic group showed a significant rise when compared to that of the normoglycemic group. Müller cells derived exosomes from hyperglycemic condition media markedly reduced HRECs cell count, increased caspase-3 and Annexin V, decreased ZO-1 levels and TER, and increased intracellular Ca+ when compared to other groups. However, treatment of HRECs under hyperglycemia with normo-glycemic Müller cells-derived exosomes significantly decreased cell death, preserved cellular integrity and barrier function, and reduced intracellular Ca+2. Collectively, Müller cell-derived exosomes play a remarkable role in the pathological changes associated with hyperglycemia-induced inner barrier dysfunction in DR. Further in vivo research will help in understanding the role of exosomes as therapeutic targets and/or delivery systems for DR.

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties.

Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.

The role of ANCA in the management of cocaine-induced midline destructive lesions or ENT pseudo-granulomatosis with polyangiitis: a London multicentre case series.

OBJECTIVE: In this multicentric study involving three London hospitals, we compared ANCA-positive and ANCA-negative cocaine-induced midline destructive lesions (CIMDL) patients to assess how presence of antineutrophil cytoplasmic antibodies (ANCA) may correlate with disease severity. Our secondary aims are to better classify etiology centered around ANCA positivity and, consequently, better disease management. METHODS: A retrospective review was performed to identify patients with CIMDL seen between January 2019 and December 2022. Population data including age, sex, presentation, endoscopic findings, duration of cocaine use and active use of cocaine, type of treatment, laboratory (including ANCA serology), radiological, and histological findings were collected. RESULTS: Forty CIMDL patients (25 male, median age of 42 years) were identified. The majority of them (72.5%) presented with either a septal perforation, a saddle nose deformity (22.5%), and/or a palatal fistula (20.0%). ANCA was positive in 71.1% of cases (66.7% p-ANCA). No statistically significant differences in the general characteristics, type of treatment, laboratory results, radiological or histological findings were observed when comparing ANCA-positive and ANCA-negative CIMDL patients or when comparing p-ANCA and c-ANCA patients. Similarly, no statistically significant difference was obtained when comparing the pattern of distribution of lesions between the two groups. CONCLUSIONS: A large percentage of CIMDL patients showed positive ANCA test (71.1%) and in the majority of the cases a p-ANCA pattern specifically targeting PR3 (p-ANCA, PR3 + MPO-). However, ANCA positivity or presence of a specific ANCA pattern was not associated with more severe presentation or more aggressive disease. Given its similarities to granulomatosis with polyangiitis (GPA), we recommend the use of the term "cocaine-induced ENT pseudo-GPA" instead of CIMDL. LEVEL OF EVIDENCE: IV Laryngoscope, 2023.

Clarifying solvent effect during photocatalytic glycerol conversion on TiO2/GQD as selective photocatalyst.

Nowadays, dealing with the growing chemical and energy demands is important without compromising the environment. So, this work studies photocatalytic glycerol conversion (as biomass derivativ feedstock) into value-added products using an eco-friendly synthesized catalyst. Graphene quantum dots (GQDs) were prepared from available/cheap precursors like glucose via the hydrothermal method and used as a support for TiO2. TiO2/GQDs were characterized via different analytical techniques, revealing very small particle sizes of ~ 3-6 nm with a large surface area of ~ 253 m2/g and a band gap of ~ 2.6 eV. The prepared photocatalyst shows good efficiency during photocatalytic glycerol conversion to dihydroxyacetone (DHA). Different reaction conditions were tested: reaction time, catalyst amount, presence of oxidant (H2O2), and biphasic media (aqueous/organic phases). Comparing a monophasic (H2O) photoreactor with a biphasic reactor containing 90% organic phase (ethyl acetate) and 10% aqueous phase (H2O and/or H2O2) indicates that the presence of H2O2 increases glycerol conversion and liquid selectivity to reach 57% and 91%, respectively after 120 min. However, it still suffers a low DHA/GA ratio (2.7). On the other hand, using a biphasic reactor in the presence of an H2O2 oxidant increases the DHA/GA ratio to ~ 6.6, which was not reached in previous research. The formation of H2O/H2O2 as micro-reactors dispersed in the ethyl acetate phase increased the average light intensity effect of the glycerol/photocatalyst system in the micro-reactors. Unlike previous work, this work presents a facile way to prepare eco-friendly/cheap (noble metal free) photocatalysts for glycerol conversion to ultrapure DHA using a biphasic photoreactor.

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Visible light photoreforming of greenhouse gases by nano Cu-Al LDH intercalated with urea-derived anions.

The accumulation of anthropogenic greenhouse gases (GHGs) in the atmosphere causes global warming. Global efforts are carried out to prevent temperature overshooting and limit the increase in the Earth's surface temperature to 1.5 °C. Carbon dioxide and methane are the largest contributors to global warming. We have synthesized copper-aluminium layered double hydroxide (Cu-Al LDH) catalysts by urea hydrolysis under microwave (MW) irradiation. The effect of MW power, urea concentration, and MII/MIII ratios was studied. The physicochemical properties of the prepared LDH catalysts were characterized by several analysis techniques. The results confirmed the formation of the layered structure with the intercalation of urea-derived anions. The urea-derived anions enhanced the optical and photocatalytic properties of the nano Cu-Al LDH in the visible-light region. The photocatalytic activity of the prepared Cu-Al LDH catalysts was tested for greenhouse gas conversion (CH4, CO2, and H2O) under visible light. The dynamic gas mixture flow can pass through the reactor at room temperature under atmospheric pressure. The results show a high conversion percentage for both CO2 and CH4. The highest converted amounts were 7.48 and 1.02 mmol mL-1 g-1 for CH4 and CO2, respectively, under the reaction conditions. The main product was formaldehyde with high selectivity (>99%). The results also show the stability of the catalysts over several cycles. The current work represents a green chemistry approach for efficient photocatalyst synthesis, visible light utilization, and GHGs' conversion into a valuable product.

Effect of preharvest conditions on cut-flower quality.

The cut flower industry has a global reach as flowers are often produced in countries around the equator and transported by plane or ship (reefer) mostly to the global north. Vase-life issues are often regarded as linked to only postharvest conditions while cultivation factors are just as important. Here, we review the main causes for quality reduction in cut flowers with the emphasis on the importance of preharvest conditions. Cut flower quality is characterised by a wide range of features, such as flower number, size, shape, colour (patterns), fragrance, uniformity of blooming, leaf and stem colour, plant shape and developmental stage, and absence of pests and diseases. Postharvest performance involves improving and preserving most of these characteristics for as long as possible. The main causes for cut flower quality loss are reduced water balance or carbohydrate availability, senescence and pest and diseases. Although there is a clear role for genotype, cultivation conditions are just as important to improve vase life. The role of growth conditions has been shown to be essential; irrigation, air humidity, and light quantity and quality can be used to increase quality. For example, xylem architecture is affected by the irrigation scheme, and the relative humidity in the greenhouse affects stomatal function. Both features determine the water balance of the flowering stem. Light quality and period drives photosynthesis, which is directly responsible for accumulation of carbohydrates. The carbohydrate status is important for respiration, and many senescence related processes. High carbohydrates can lead to sugar loss into the vase water, leading to bacterial growth and potential xylem blockage. Finally, inferior hygiene during cultivation and temperature and humidity control during postharvest can lead to pathogen contamination. At the end of the review, we will discuss the future outlook focussing on new phenotyping tools necessary to quantify the complex interactions between cultivation factors and postharvest performance of cut flowers.

Indole-Based Compounds as Potential Drug Candidates for SARS-CoV-2.

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

Can coenzyme Q10 alleviate the toxic effect of fenofibrate on skeletal muscle?

Fenofibrate (FEN) is an antilipidemic drug that increases the activity of the lipoprotein lipase enzyme, thus enhancing lipolysis; however, it may cause myopathy and rhabdomyolysis in humans. Coenzyme Q10 (CoQ10) is an endogenously synthesized compound that is found in most living cells and plays an important role in cellular metabolism. It acts as the electron carrier in the mitochondrial respiratory chain. This study aimed to elucidate FEN-induced skeletal muscle changes in rats and to evaluate CoQ10 efficacy in preventing or alleviating these changes. Forty adult male rats were divided equally into four groups: the negative control group that received saline, the positive control group that received CoQ10, the FEN-treated group that received FEN, and the FEN + CoQ10 group that received both FEN followed by CoQ10 daily for 4 weeks. Animals were sacrificed and blood samples were collected to assess creatine kinase (CK). Soleus muscle samples were taken and processed for light and electron microscopic studies. This study showed that FEN increased CK levels and induced inflammatory cellular infiltration and disorganization of muscular architecture with lost striations. FEN increased the percentage of degenerated collagen fibers and immune expression of caspase-3. Ultrastructurally, FEN caused degeneration of myofibrils with distorted cell organelles. Treatment with CoQ10 could markedly ameliorate these FEN-induced structural changes and mostly regain the normal architecture of muscle fibers due to its antifibrotic and antiapoptotic effects. In conclusion, treatment with CoQ10 improved muscular structure by suppressing oxidative stress, attenuating inflammation, and inhibiting apoptosis.

Insights of different analytical approaches for estimation of budesonide as COVID-19 replication inhibitor in its novel combinations: green assessment with AGREE and GAPI approaches.

Simple, direct, rapid, and sensitive HPLC and spectrophotometric methods were established for simultaneous estimation of a novel combination of budesonide and azelastine (BUD/AZL) in their laboratory-prepared mixture and dosage form according to the medicinally recommended ratio 1:4.28. Budesonide is an important inhalation corticosteroid that plays a vital role in the inhibition of COVID-19 replication and cytokine production. The first chromatographic method was created for the simultaneous estimation of BUD epimers in the presence of AZL with excellent efficiency in a relatively short chromatographic run (< 9 min). The separation of BUD epimers with AZL was carried out on a C18 column using acetonitrile: phosphate buffer of pH 3.5 adjusted by 0.2 M orthophosphoric acid (40:60, v/v) as a mobile phase, UV detection at 230 nm and a flow rate of regulated at 2 mL/min. Besides, three spectrophotometric methods were applied for the simultaneous determination of the provided mixture adopting zero order, first order derivative, and ratio first derivative approaches. The Zero-order spectrophotometry was used for the determination of AZL in presence of BUD, where BUD shows no absorbance at 290 nm. The first derivative amplitude at 265 nm (1D265) (zero-crossing of AZL) and the ratio of first derivative amplitudes at 270 nm (1DD270) using 10.0 µg mL-1 AZL as divisor was chosen for the simultaneous determination of BUD in the presence of AZL in the binary mixture. The proposed methods were found to be rectilinear in the concentration range of (0.4-40.0 µg mL-1) and (0.05-40.0 µg mL-1) for BUD and AZL, respectively in the HPLC method. Whereas the concentration range for AZL in the zero-order method was (1.0-35.0 µg mL-1) and for BUD in the first derivative and ratio derivative method was (6.0-20.0 µg mL-1). Validation of the suggested approaches according to the ICH criteria was performed. Furthermore, to ensure the proposed approaches' greenness, The AGREE and GAPI metrics were utilized, and the afforded results revealed an excellent greenness of the proposed approaches.

Fast-track pathway for early diagnosis and management of giant cell arteritis: the combined role of vascular ultrasonography and [18F]-fluorodeoxyglucose PET-computed tomography imaging.

Giant cell arteritis (GCA) is a medical emergency, which can lead to irreversible blindness and other ischaemic vascular events if left untreated. Prompt access to specialist assessment, diagnostics in the form of a fast-track pathway (FTP) and access to appropriate treatment are key factors in preventing morbidity associated with this disease. Recent developments in vascular imaging prompted review of our management of GCA patients. Here, we present the newly implemented FTP in GCA at the University College London Hospital, with added vascular imaging in the form of temporal artery ultrasound (TAUS) and [18F]-fluorodeoxyglucose PET-computed tomography ( 18 F-FDG PET-CT) with temporal artery biopsy. The initial pilot data on the FTP showed a significant negative predictive value of the combined TAUS and 18 F-FDG PET-CT, and the vast majority of cases positive on imaging were confirmed by biopsy. Through the new FTP in GCA, the diagnosis was completed within 48-72 h, compared with the conventional pathway time of up to 2-3 weeks awaiting biopsy results. Prompt and accurate diagnosis of GCA enables commencement of corticosteroid (prednisolone) treatment in the appropriate patient population while avoiding unnecessary steroid exposure and toxicity in GCA-negative patients.

Synthesis and bio-properties of 4-piperidone containing compounds as curcumin mimics.

The broad spectrum of curcumin's beneficial properties has encouraged medicinal researchers to investigate its therapeutic efficacy against diverse diseases. The clinical potential of curcumin is, however limited due to its poor pharmacodynamic/pharmacokinetic properties (such as low solubility, pH instability, poor absorption in circulation, rapid elimination from the body and photochemical degradation). 3,5-Bis(ylidene)-4-piperidone scaffolds are considered a curcumin mimic that exhibit diverse bio-properties. The current review provides a brief overview of these mimics and highlights biological activities relevant to drug development.

KRAS G12C-Mutant Non-Small-Cell Lung Adenocarcinoma: First Documented Report in the Arabian Gulf.

We report the first documented case series of two lung adenocarcinoma patients demonstrating Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations by reverse transcription-polymerase chain reaction techniques from Saudi Arabia. Both patients were males aged 64 and 76 years. The first had a heavy smoking history, while the second did not report any history of smoking. The tumor subtype was identified to be non-mucinous lung adenocarcinoma in both cases. The younger patient presented with generalized lymphadenopathy and a right-sided lung mass lesion, while the older patient exhibited stage III-A left lung adenocarcinoma that required rapid response. An initial examination of the first case showed a right-sided mediastinal shift, bilateral neck lymphadenopathy, and poorly differentiated neoplasm from a right supraclavicular core biopsy, leading to treatment with palliatives along with regular checkups. The second case was afebrile after being confirmed to be vitally stable and laboratory testing (Neutr 100). Further studies, specifically on large numbers of patients from the Arabian Gulf, are needed to confirm significant differences between the national and international populations. Additionally, future studies should investigate more differences in the differentiation of KRAS-mutant lung adenocarcinoma between patients from the Arabian Gulf and others.

Estrogen-Related Receptors Gene Expression and Copy Number Alteration Association With the Clinicopathologic Characteristics of Breast Cancer.

Purpose: It has been suggested that dysregulation of transcription factors expression or activity plays significant roles in breast cancer (BC) severity and poor prognosis. Therefore, our study aims to thoroughly evaluate the estrogen-related receptor isoforms (ESRRs) expression and copy number alteration (CNA) status and their association with clinicopathologic characteristics in BC. Methods: A METABRIC dataset consist of 2509 BC patients' samples was obtained from the cBioPortal public domain. The gene expression, putative CNA, and relevant tumor information of ESRRs were retrieved. ESRRs messenger RNA (mRNA) expression in BC cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE). Association and correlation analysis of ESRRs expression with BC clinicopathologic characteristics and molecular subtype were performed. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of ESRRs expression on patient survival. Results: ESRRα expression correlated negatively with patients' age and overall survival, whereas positively correlated with tumor size, the number of positive lymph nodes, and Nottingham prognostic index (NPI). Conversely, ESRRγ expression was positively correlated with patients' age and negatively correlated with NPI. ESRRα and ESRRγ expression were significantly associated with tumor grade, expression of hormone receptors, human epidermal growth factor receptor 2 (HER2), and molecular subtype, whereas ESRRß was only associated with tumor stage. A significant and distinct association of each of ESRRs CNA with various clinicopathologic and prognostic factors was also observed. Kaplan-Meier survival analysis demonstrated no significant difference for survival curves among BC patients with high or low expression of ESRRα, ß, or γ. On stratification, high ESRRα expression significantly reduced survival among premenopausal patients, patients with grade I/II, and early-stage disease. In BC cell lines, only ESRRα expression was significantly higher in HER2-positive cells. No significant association was observed between ESRRß expression and any of the clinicopathologic characteristics examined. Conclusions: In this clinical dataset, ESRRα and ESRRγ mRNA expression and CNA show a significant correlation and association with distinct clinicopathologic and prognostic parameters known to influence treatment outcomes; however, ESRRß failed to show a robust role in BC pathogenesis. ESRRα and ESRRγ can be employed as therapeutic targets in BC-targeted therapy. However, the role of ESRRß in BC pathogenesis remains unclear.

Development of three ecological spectroscopic methods for analysis of betrixaban either alone or in mixture with lercanidipine: greenness assessment.

Three eco-friendly spectrophotometric methods were developed for determination of the novel anticoagulant drug, betrixaban (BTX). The first method (method A) was based on direct analysis of BTX at 229.4 nm on the zero-order spectrum using methanol as the optimum solvent. While the second method (method B) was based on measuring difference absorption value (ΔA) of BTX at 335 nm, which was obtained from pH-induced spectral difference (difference spectra of BTX in 0.1 M NaOH versus 0.1 M HCl). The third method (method C) was based on measurement of the first-derivative amplitudes of BTX and its co-administered Ca channel blocker lercanidipine (LER) at 304 and 229 nm for simultaneous assay of BTX and LER, respectively. All methods were linear over concentration ranges of 1.0-20.0 and 8.0-80.0 µg ml-1 for BTX in methods A and B, respectively, and of 1.0-20.0 and 1.0-25.0 µg ml-1 for BTX and LER, respectively, in method C. The three methods were fully validated and assessed for greenness by three metrics: analytical eco-scale, green analytical procedure index and Analytical GREEnness metrics. The results indicated the validity and greenness of the proposed methods. Moreover, the methods were applied to assay the studied analytes in their dosage forms with high percentage of recovery and low percentage of relative s.d. values.

Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.

Targeted therapy is a hallmark of cancer treatment that has changed the landscape of cancer management and enabled a personalized treatment approach. Nevertheless, the development of cancer resistance is a major challenge that is currently threatening the effective utilization of targeted therapies. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and tumorigenic potential. MET is a well-known driver of cancer resistance. A growing body of evidence revealed a major role of MET in mediating acquired resistance to several classes of targeted therapies. Deregulations of MET commonly associated with the development of cancer resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways. Small-molecule tyrosine kinase inhibitors of MET are currently approved for the treatment of different solid cancers. This review summarizes the current evidence regarding MET-mediated cancer resistance toward targeted therapies. The molecular mechanisms associated with resistance are described along with findings from preclinical and clinical studies on using MET inhibitors to restore the anticancer activity of targeted therapies for the treatment of solid tumors.

Quantitative proton nuclear magnetic resonance method for simultaneous analysis of fluticasone propionate and azelastine hydrochloride in nasal spray formulation.

A facile, rapid, accurate and selective quantitative proton nuclear magnetic resonance (1H-qNMR) method was developed for the simultaneous determination of fluticasone propionate (FLP) and azelastine hydrochloride (AZH) in pharmaceutical nasal spray for the first time. The 1H-qNMR analysis of the studied analytes was performed using inositol as the internal standard and dimethyl sulfoxide-d6 (DMSO-d6) as the solvent. The quantitative selective proton signal of FLP was doublet of doublet at 6.290, 6.294, 6.316 and 6.319 ppm, while that of AZH was doublet at 8.292 and 8.310 ppm. The internal standard (inositol) produced a doublet signal at 3.70 and 3.71 ppm. The method was rectilinear over the concentration ranges of 0.25-20.0 and 0.2-15.0 mg ml-1 for FLP and AZH, respectively. No labelling or pretreatment steps were required for NMR analysis of the studied analytes. The proposed 1H-qNMR method was validated efficiently according to the International Council on Harmonisation guidelines in terms of linearity, limit of detection, limit of quantification, accuracy, precision, specificity and stability. Moreover, the method was applied to assay the analytes in their combined nasal spray formulation. The results ensured the linearity (r 2 > 0.999), precision (% RSD < 1.5), stability, specificity and selectivity of the developed method.

Optimization and Validation of a Facile RP-HPLC Method for Determination of Betrixaban and Lercanidipine in Pharmaceutical and Biological Matrices.

A simple, accurate, rapid and sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) method was established for determination of a novel non-vitamin K antagonist oral anticoagulant drug, betrixaban, and its co-administered calcium-channel blocker drug, lercanidipine, in pharmaceutical formulations and biological fluids. The proposed HPLC method was the first chromatographic method applied to estimate this mixture in a short chromatographic run (<6 min), high resolution between betrixaban/lercanidipine (Rs = 7.12) and acceptable values of limit of detection (LOD), limit of quantification (LOQ) and percentage of relative standard deviation (%RSD). The chromatographic separation was performed on a cyano column using a mobile phase composed of acetonitrile:methanol:water (35:35:30, v/v/v) containing 0.2% orthophosphoric acid adjusted to pH 3.2 by triethylamine, programmed with a flow rate of 1 mL/min with UV detection at 240 nm. The proposed method showed linearity over the concentration ranges of (0.20-20.0 µg/mL) and (0.25-25.0 µg/mL) for betrixaban and lercanidipine, respectively. All validation parameters met the acceptance criteria according to ICH guidelines in terms of linearity, LOD, LOQ, accuracy, precision, robustness, specificity and system suitability. The method was applied to assay the studied analytes in their pharmaceutical formulations with high % recovery (98-102%) and low %RSD (<1.5). Furthermore, the proposed method was successfully applied for the determination of betrixaban in spiked human plasma.

Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor.

Hormone-dependent breast cancer is the most abundant molecular subtype of the disease. Despite the availability of endocrine treatments, the use of these drugs is limited by their serious adverse reactions and development of acquired resistance often mediated by growth factor receptors. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and mediating resistance to targeted therapies. Crizotinib is a small-molecule tyrosine kinase inhibitor of MET. In this study, the anticancer effects of combined crizotinib and endocrine drugs were investigated in breast cancer cells in vitro along with the molecular mechanisms associated with these effects. Results showed that crizotinib inhibited growth of MCF7 and T-47D breast cancer cells in a dose-dependent manner with IC50 values of 2.88 µM and 0.93 µM, respectively. Combined treatment of crizotinib and 4-hydroxytamoxifen resulted in synergistic growth inhibition of MCF7 and T-47D cells with combination index values of 0.39 and 0.8, respectively. The combined treatment significantly suppressed migration and colony formation of MCF7 and T-47D cells. Immunofluorescence showed a significant reduction of the expression of the nuclear protein Ki-67 with the combination of crizotinib and 4-hydroxytamoxifen in both cell lines. Western blotting indicated that the combination treatment reduced the levels of active and total MET, estrogen receptor α (ERα), total and active levels of AKT, ERK, c-SRC, NFĸB p65, GSK-3ß, and the anti-apoptotic BCL-2 protein. Findings from this study suggest a potential role of MET inhibitors in breast cancer treatment as monotherapy or combination with endocrine drugs.