Elevated KDM4D Expression in Pterygium: Impact and Potential Inhibition by Lycium Barbarum Polysaccharide.

Purpose: This study aimed to explore the effects of elevated KDM4D expression and potential therapeutic effects of Lycium barbarum polysaccharide (LBP) on pterygium. Methods: The expression levels of KDM4D in the primary pterygium (n = 29) and normal conjunctiva (n = 14) were detected by immunohistochemistry. The effects of KDM4D on pterygium fibroblasts were detected by the CCK-8 assay, liquid chromatography-mass spectrometry assay, flow cytometry, and scratch wound healing assay. The relative expression of KDM4D in pterygium fibroblasts stimulated by interleukin (IL)-1ß, IL-6, IL-8, and LBP was detected by quantitative real-time PCR and Western blot. The effects of LBP on pterygium fibroblasts were detected using flow cytometry and scratch wound healing assays. Results: The expression level of KDM4D in pterygium was higher than that in normal conjunctiva. KDM4D increased the cell viability of pterygium fibroblasts. The differentially expressed genes identified in the LM-MS assay enriched in "actin filament organization" and "apoptosis." KDM4D promoted migration and inhibited apoptosis of pterygium fibroblasts in vitro. Inflammatory cytokines, including IL-1ß, IL-6, and IL-8, enhanced the expression of KDM4D in pterygium fibroblasts. LBP inhibited the expression of KDM4D in pterygium fibroblasts and decreased their cell viability. Moreover, LBP attenuated the KDM4D effects on migration and apoptosis of pterygium fibroblasts. Conclusions: Elevated KDM4D expression is a risk factor for pterygium formation. LBP inhibits the expression of KDM4D in pterygium fibroblasts and may be a potential drug for delaying pterygium development.

Effects of repeated low-level red-light therapy on macular retinal thickness and microvascular system in children with myopia.

OBJECTIVE: The objective of the study was to use optical coherence tomography angiography (OCTA) to analyze the effects of repeated low-level red-light (LLLT) therapy on macular retinal thickness and the microvascular system in children with myopia to evaluate the safety of this therapy. METHODS: This prospective study included 40 school-age children with myopia (80 eyes), aged 7-14 years, who received therapy using a LLLT instrument. At baseline and therapy for 1 month, 3 months, 6 months, all children underwent comprehensive ophthalmological examinations, including slit-lamp examination, uncorrected visual acuity, best-corrected visual acuity, spherical equivalent degree, axial length, and OCTA. The vessel densities of the superficial retinal capillary plexus, macular inner retinal thickness, and full-layer retinal thickness were measured. RESULTS: The macular inner retinal thickness increased at 1 month and remained unchanged thereafter, It differed significantly in nine areas at 1, 3, and 6 months compared to the thicknesses before therapy (P < 0.05); however, we observed no significant differences between the different time points (P > 0.05). The macular full-layer retinal thickness increased at 1 month and remained unchanged thereafter; the changes showed significant differences at 1 month and 3 months compared to before therapy, for the inner nasal region (P < 0.05). The other eight areas showed significant differences at 1, 3, and 6 months compared with before therapy (P < 0.05); however, no significant difference was observed between the different time points after therapy (P > 0.05). The vessel density of the superficial retinal capillary plexus did not differ significantly among the four groups (P > 0.05). CONCLUSIONS: LLLT therapy was safe. The school-aged children exhibited macular thickening after LLLT therapy, which had no significant effect on macular microcirculation.

LC-MS/MS based untargeted lipidomics uncovers lipid signatures of late-onset preeclampsia.

The mechanisms underlying late-onset preeclampsia (LOPE) remain unknown. Metabolic disturbances have been implicated as a primary factor in LOPE development. Lipids have been shown to have great clinical value in recent years. This study aimed to use lipidomics to provide evidence for the etiology and potential therapeutic approaches for LOPE. Twenty patients with LOPE and 20 healthy controls were enrolled in this study. Placental lipidomic data were acquired using liquid chromatographymass spectrometry (LC-MS/MS), and the data were analyzed by weighted gene correlation network analysis (WGCNA) and statistical methods. Of 1508 identified lipids, 226 were differentially expressed between the LOPE and control groups. In the LOPE group, the abundance of most unsaturated triglycerides (TG) increased, whereas that of other lipids, including phosphatidylcholine (PC), sphingomyelin, and phosphatidylserine (PS) increased. The WGCNA implied that the correlation network module of lipids was highly related to clinical traits. Pathway analysis revealed that these dysregulated lipids are closely related to glycerophospholipid metabolism. Lipidomics may help identify the pathogenesis underlying placental dysfunction in LOPE patients and provide potential therapeutic targets in the future.

The effect of a chrysanthemum water extract in protecting the retina of mice from light damage.

BACKGROUND: Oxidative stress can induce age-related diseases. Age-related retinal diseases, such as age-related macular degeneration (AMD), are difficult to cure owing to their complicated mechanisms. Although anti-neovascular therapeutics are used to treat wet AMD, vision cannot always be completely restored, and disease progression cannot always be inhibited. Therefore, determining a method to prevent or slow retinal damage is important. This study aimed to investigate the protective effect of a chrysanthemum water extract rich in flavone on the oxidatively stressed retina of mice. METHODS: Light damage was induced to establish oxidative stress mouse models. For in vitro experiments, ARPE-19 cells were cultured and divided into four groups: control, light-damaged, and low- and high-dose chrysanthemum extract. No treatment was administered in the control group. The light-damaged and low- and high-dose chrysanthemum extract groups were exposed to a similar white light level. The chrysanthemum extract was added at a low dose of 0.4 mg/mL or a high dose of 1.0 mg/mL before cell exposure to 2500-lx white light. Reactive oxygen species (ROS) level and cellular viability were measured using MTT and immunofluorescence staining. For in vivo experiments, C57BL/6 J mice were divided into the same four groups. Low- (0.23 g/kg/day) and high-dose (0.38 g/kg/day) chrysanthemum extracts were continuously intragastrically administered for 8 weeks before mouse exposure to 10,000-lx white light. Retinal function was evaluated using electroretinography. In vivo optical coherence tomography and in vitro haematoxylin and eosin staining were performed to observe the pathological retinal changes in each group after light damage. Fluorescein fundus angiography of the arteriovenous vessel was performed, and the findings were analysed using the AngioTool software. TUNEL immunofluorescence staining was used to assess isolated retinal apoptosis. RESULTS: In vitro, increased ROS production and decreased ARPE-19 cell viability were found in the light-damaged group. Improved ARPE-19 cell viability and reduced ROS levels were observed in the chrysanthemum extract treatment groups. In vivo, dysfunctional retinas and abnormal retinal structures were found in the light-damaged group, as well as increased apoptosis in the retinal ganglion cells (RGCs) and inner and outer nuclear layers. The apoptosis rate in the same layers was lower in the chrysanthemum extract treatment groups than in the light-damaged group. The production of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), increased in the treatment groups. NF-κB in the nucleus and TNF-α were more highly expressed in the light-damaged group than in the low- and high-dose chrysanthemum extract groups. CONCLUSIONS: Light damage-induced retinal oxidative stress can lead to ROS accumulation in the retinal tissues. Herein, RGC and photoreceptor layer apoptosis was triggered, and NF-κB in the nucleus and TNF-α were highly expressed in the light-damaged group. Preventive chrysanthemum extract administration decreased ROS production by increasing SOD, CAT, and GSH-Px activities and reversing the negative changes, demonstrating a potential protective effect on the retina.

Iron supplementation and iron-fortified foods: a review.

About one-third of the world population is suffering from iron deficiency. Delivery of iron through diet is a practical, economical, and sustainable approach. Clinical studies have shown that the consumption of iron-fortified foods is one of the most effective methods for the prevention of iron deficiency. However, supplementing iron through diet can cause undesirable side-effects. Thus, it is essential to develop new iron-rich ingredients, iron-fortified products with high bioavailability, better stability, and lower cost. It is also essential to develop newer processing technologies for more effective fortification. This review compared the iron supplementation strategies used to treat the highly iron-deficient population and the general public. We also reviewed the efficacy of functional (iron-rich) ingredients that can be incorporated into food materials to produce iron-fortified foods. The most commonly available foods, such as cereals, bakery products, dairy products, beverages, and condiments are still the best vehicles for iron fortification and delivery.Scope of reviewThe manuscript aims at providing a comprehensive review of the latest publications that cover three aspects: administration routes for iron supplementation, iron-rich ingredients used for iron supplementation, and iron-fortified foods.

Scutellaria barbata D. Don Inhibits the Main Proteases (Mpro and TMPRSS2) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, Mpro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of Mpro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or Mpro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting Mpro and TMPRSS2 protease activities.

Tianma Formula Alleviates Dementia via ACER2-Mediated Sphingolipid Signaling Pathway Involving Aß.

OBJECTIVE: To reveal the molecular mechanism of the antagonistic effect of traditional Chinese medicine Tianma formula (TF) on dementia including vascular dementia (VaD) and Alzheimer's disease (AD) and to provide a scientific basis for the study of traditional Chinese medicine for prevention and treatment of dementia. METHOD: The TF was derived from the concerted application of traditional Chinese medicine. We detected the pharmacological effect of TF in VaD rats. The molecular mechanism of TF was examined by APP/PS1 mice in vivo, Caenorhabditis elegans (C. elegans) in vitro, ELISA, pathological assay via HE staining, and transcriptome. Based on RNA-seq analysis in VaD rats, the differentially expressed genes (DEGs) were identified and then verified by quantitative PCR (qPCR) and ELISA. The molecular mechanisms of TF on dementia were further confirmed by network pharmacology and molecular docking finally. RESULTS: The Morris water maze showed that TF could improve the cognitive memory function of the VaD rats. The ELISA and histological analysis suggested that TF could protect the hippocampus via reducing tau and IL-6 levels and increasing SYN expression. Meanwhile, it could protect the neurological function by alleviating Aß deposition in APP/PS1 mice and C. elegans. In the RNA-seq analysis, 3 sphingolipid metabolism pathway-related genes, ADORA3, FCER1G, and ACER2, and another 5 nerve-related genes in 45 key DEGs were identified, so it indicated that the protection mechanism of TF was mainly associated with the sphingolipid metabolism pathway. In the qPCR assay, compared with the model group, the mRNA expressions of the 8 genes mentioned above were upregulated, and these results were consistent with RNA-seq. The protein and mRNA levels of ACER2 were also upregulated. Also, the results of network pharmacology analysis and molecular docking were consistent with those of RNA-seq analysis. CONCLUSION: TF alleviates dementia by reducing Aß deposition via the ACER2-mediated sphingolipid signaling pathway.

Gastrodin protects H9c2 cardiomyocytes against oxidative injury by ameliorating imbalanced mitochondrial dynamics and mitochondrial dysfunction.

Gastrodin (GAS) is the main bioactive component of Tianma, a traditional Chinese medicine widely used to treat neurological disorders as well as cardio- and cerebrovascular diseases. In the present study, the protective effects of GAS on H9c2 cells against ischemia-reperfusion (IR)-like injury were found to be related to decreasing of oxidative stress. Furthermore, GAS could protect H9c2 cells against oxidative injury induced by H2O2. Pretreatment of GAS at 20, 50, and 100 µM for 4 h significantly ameliorated the decrease in cell viability and increase in apoptosis of H9c2 cells treated with 400 µM H2O2 for 3 h. Furthermore, we showed that H2O2 treatment induced fragmentation of mitochondria and significant reduction in networks, footprint, and tubular length of mitochondria; H2O2 treatment strongly inhibited mitochondrial respiration; H2O2 treatment induced a decrease in the expression of mitochondrial fusion factors Mfn2 and Opa1, and increase in the expression of mitochondrial fission factor Fis1. All these alterations in H2O2-treated H9c2 cells could be ameliorated by GAS pretreatment. Moreover, we revealed that GAS pretreatment enhanced the nuclear translocation of Nrf2 under H2O2 treatment. Knockdown of Nrf2 expression abolished the protective effects of GAS on H2O2-treated H9c2 cells. Our results suggest that GAS may protect H9c2 cardiomycytes against oxidative injury via increasing the nuclear translocation of Nrf2, regulating mitochondrial dynamics, and maintaining the structure and functions of mitochondria.

The Potential Inhibitory Effects of miR-19b on Ocular Inflammation are Mediated Upstream of the JAK/STAT Pathway in a Murine Model of Allergic Conjunctivitis.

Purpose: Thymic stromal lymphopoietin (TSLP) is a pro-allergic cytokine that initiates allergic inflammatory reaction between epithelial and dendritic cells (DCs). miR-19b was reported to suppress TSLP expression. The present study aimed to examine miR-19b expression, regulation, and function in allergic conjunctivitis (AC). Methods: A murine model of experimental AC was induced in BALB/c mice by short ragweed pollen. The serum, eye balls, conjunctiva, and cervical lymph nodes (CLN) were used for the study. Gene expression was determined by RT-PCR, whereas protein production and activation were evaluated by immunostaining, ELISA, and Western blotting. Results: In the murine AC model, miR-19b was aberrantly downregulated, whereas the levels of TSLP and p-STAT3, as well as the number of CD11c+ pSTAT3+ DCs were increased. Moreover, Th2 inflammatory cytokine expression was significantly increased. These severe phenotypes could be counteracted by either applying exogenous miR-19b mimic microRNAs or the JAK/STAT inhibitor CYT387. Moreover, overexpression of miR-19b repressed p-STAT3 expression and the number of CD11c+ cells in AC eye and CLN tissues. Conclusions: These findings suggested that miR-19b reduced ocular surface inflammation by inhibiting Stat3 signaling via TSLP downregulation in a murine AC model. Moreover, the present study further demonstrated the clinical potential of applying miR-19b and anti-JAK/STAT therapies in the treatment of AC.

Dielectric properties of carrots affected by ultrasound treatment in water and oil medium simulated systems.

The ultrasound treatment of vegetables can damage their tissue structure and release water and soluble solids altering the dielectric properties of the material. Changes in the dielectric properties will influence the microwave processing of ultrasound pretreated material. In order to investigate the effect of ultrasound pretreatment on dielectric properties, carrots were ultrasonicated in simulated water and oil systems. Microwave heating and microwave-assisted vacuum frying of carrot slices were also completed to explore the relation between dielectric properties of microwave pretreated samples and microwave absorption. Ultrasound of carrots in water simulated system showed that ε' and ε″ of carrots tended to decrease with the increase of ultrasonic power (from 480 W to 640 W) and time (from 10 min to 30 min). Ultrasound treatment of carrots in salt solutions increased ε' and ε″ of carrots. The combined pretreatment of microwave blanching with ultrasound in salt solutions increased ε″ (from 19.72 to 29.90). Conversely, in oil simulated system, the ε' and ε″ of carrots also decreased as the ultrasonication power and time increased. Besides, the dielectric properties decreased as the temperature of oil medium increased from 35 °C to 75 °C. With improved dielectric properties, the dehydration rate during frying of carrot increased due to the enhanced microwave absorption. Therefore, the combined pretreatment of microwave blanching with ultrasound in salt solutions largely improved the dielectric properties of carrots, and reducing the required time of microwave vacuum frying.

Novel technologies applied for recovery and value addition of high value compounds from plant byproducts: A review.

Plant byproducts of food processing industry line are undervalued yet important resource. These byproducts contain large percentage of high value functional substances such as antioxidants, pectin, polyphenols and so on. Recently, many research studies concentrated on innovative technologies that promise to overcome such issues as time consuming, inefficiency, and low yield, among others, which exist in most conventional techniques. Consequently, to achieve the recovery of nutraceuticals from high added-value by-products, it is necessary to have more knowledge of these novel technologies and more importantly explore the possibility of application of these latest technologies to the recovery downstream processing. The present work will summarize state-of-the-art technological approaches concerning extraction, superfine and drying applied to plant food processing residues. Simultaneously, the application of the bioactive components originated from byproducts in food industry will also be reviewed.

Effects of garlic polysaccharide on alcoholic liver fibrosis and intestinal microflora in mice.

CONTEXT: Alcoholic liver fibrosis (ALF) is treatable and reversible consequence of liver disease. Intestinal microflora plays an important role in the progression of liver disease. Garlic (Allium sativum L. [Amaryllidaceae]) has been consumed as a traditional medicine to treat liver injury. OBJECTIVE: To investigate the effects of garlic polysaccharide (GP) on ALF and intestinal microflora in mice. MATERIALS AND METHODS: KM mice were orally administered with alcohol (56%, 6 mL/kg) for 30 d to establish ALF model, and divided into four groups together with control group (water only). Hugan tablet (60 mg/kg) or GP (250 and 150 mg/kg) were given 5 h after each dose of alcohol. Biochemical markers in serum and liver homogenate were determined with kits. Alteration of intestinal microflora, and protein expressions of TGF-ß1, TNF-α and decorin were detected. RESULTS: In GP-H group, ALT and AST decreased to 18.85 ± 4.71 U/L and 40.84 ± 7.89 U/L. MDA, TC, TG and LDL-C decreased to 2.32 ± 0.86 mmol/mg, 0.21 ± 0.12 mmol/L, 0.96 ± 0.31 mmol/L and 0.084 ± 0.027 mmol/L. SOD, GSH-Px and GSH increased to 118.32 ± 16.32 U/mg, 523.72 ± 64.20 U/mg and 0.56 ± 0.05 mg/g. Ratios of TGF-ß1 and TNF-α decreased to 0.608 ± 0.170 and 1.057 ± 0.058, decorin increased to 2.182 ± 0.129. Lachnospiraceae and Lactobacillus increased, Facklamia and Firmicutes decreased with GP pretreatment. DISCUSSION AND CONCLUSIONS: Intestinal microflora provides novel insight into the mechanisms of GP that may be used to treat ALF and intestinal microflora dysbiosis.

Heat conjugation of antibacterial agents from amino acids and plant oil.

Antimicrobial peptides are components of the innate immune systems in animals and plants as natural defense against pathogens. Critical issues like manufacturing costs have to be addressed before mass production of these peptides for agriculture or community sterilizations. Here, we report a cost-effective chemical synthesis method to produce antimicrobial cocktails, which was based on the heat conjugation of amino acids in the presence of phosphoric acid and plant oil at 150 °C. The conjugates showed potent biological activities against all tested bacteria including a multi-drug resistant Staphylococcus aureus strain Y5 and ampicillin resistant Pseudomonas aerugenosa ATCC9027 strain, demonstrating potential in agriculture, and prophylactic applications in hospital and community settings.

Protective effects of theasinensin A against carbon tetrachloride-induced liver injury in mice.

Theasinensins have been identified as a major group of unique catechin dimers mainly found in oolong tea and black tea. Among several types of theasinensins, theasinensin A (TSA), an epigallocatechin gallate (EGCG) dimer with an R-biphenyl bond, is the most abundant theasinensin prevalent in oolong tea. Previous studies have reported that TSA exhibits antioxidative, anti-inflammatory and anti-cancer activities in vitro and in vivo. However, little is known about the hepatoprotective effect of TSA. Thus, the aim of this study was to investigate the inhibitory effect of TSA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. After intraperitoneal injection of CCl4 for eight weeks, histological lesions in the liver tissue and elevated serum levels of alanine aminotransferase and alkaline phosphatase were found in mice. Conversely, oral administration of TSA relieved CCl4-induced liver injury as well as ameliorated liver functions. Our immunohistochemical staining results revealed that collagen deposition was profoundly reduced due to supplementation with TSA. In addition, we also found that hepatic α-smooth muscle actin (α-SMA) and matrix metallopeptidase 9 (MMP-9) expression was suppressed through the inhibition of transforming growth factor ß (TGF-ß). Taken together, our current findings suggest that TSA may serve as a potent bioactive constituent from oolong tea that acts against liver fibrosis through the inhibition of hepatic stellate cell (HSC) activation.

[Association of serum vitamin D level with severity and treatment in children with Henoch-Schönlein purpura].

OBJECTIVE: To investigate the association of serum vitamin D [25-(OH)D3] level with the severity and treatment in children with Henoch-Schönlein purpura (HSP). METHODS: A total of 50 children with newly-diagnosed HSP between January and December, 2015 were enrolled as HSP group, and 49 healthy children were enrolled as control group. Fasting serum samples were collected, and ELISA was used to measure serum 25-(OH)D3 level. According to the serum 25-(OH)D3 level, the HSP group were further divided into normal group (>20 ng/mL) (n=9), insufficiency group (15-20 ng/mL) (n=15), deficiency group (≤15 ng/mL) (n=25), and severe deficiency group (≤5 ng/mL) (n=1). The general data, clinical manifestations, hormone therapy, course of disease before admission, and length of hospital stay were compared between groups. RESULTS: The HSP group had a significantly lower serum 25-(OH)D3 level than the control group (16±6 ng/mL vs 29±5 ng/mL; P<0.01). Compared with the normal and insufficiency groups, the deficiency and severe deficiency groups had significant increases in the incidence rate of renal involvement, rate of hormone application, and median length of hospital stay (P<0.05), while there was no significant difference in course of disease before admission (P>0.05). CONCLUSIONS: Children with HSP have a low serum 25-(OH)D3 level, and such children may have a high risk of renal involvement, a high rate of hormone application, and a prolonged length of hospital stay. However, further studies are needed to investigate whether vitamin D supplementation is helpful to the treatment of HSP and can shorten the course of disease in children with HSP.

Effect of flecainide on the extension and localization of complex fractionated electrogram during atrial fibrillation.

AIMS: Complex fractionated electrogram (CFE) ablation in addition to pulmonary vein isolation is an accepted strategy for the treatment of non-paroxysmal atrial fibrillation (AF). We sought to determine the effect of flecainide on the distribution and extension of CFE areas. METHODS: Twenty-three non-paroxysmal AF patients were enrolled in this prospective study. A first CFE map was obtained under baseline conditions by sampling 5 s of continuous recording from the distal electrodes of the ablation catheter. Intravenous flecainide (1 mg/kg) was administered over 10 min and followed by 30-min observation time. A second CFE map was obtained with the same modalities. CFE-mean values, CFE areas, and atrial electrogram amplitude were retrieved from the electro-anatomical mapping system (Ensite NavX). RESULTS: After flecainide administration, CFE-mean values increased (111.5 ± 55.3 vs. 132.3 ± 65.0 ms, p < 0.001) with a decrease of CFE area (32.9%) in all patients. Atrial electrogram amplitude decreased significantly (0.30 ± 0.31 vs. 0.25 ± 0.20 mV, p < 0.001). We observed 80.9% preservation of CFE areas. A CFE mean of 78 ms was the best cutoff for predicting stable CFE areas. CONCLUSIONS: Flecainide reduces the extension of CFE areas while preserving their spatial localization. A CFE-mean value <80 ms may be crucial to define and locate stable CFE areas.

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.