Encapsulation of Hydrophobic-but-Not-Lipophilic Perfluoro Liquids Based on a Self-Assembled Double Emulsion Template via Solvent Evaporation Method.

The facile encapsulation of perfluoro liquids that are hydrophobic but not lipophilic into liposomes or microcapsules presents a significant challenge in the fields of biomedicine, dynamic optics, functional chemical applications, etc. This is due to their chemical inertness and physical immiscibility, particularly those with low boiling points. In this study, a novel strategy based on a double emulsion template via solvent evaporation is proposed after investigating the mechanism of three-phase emulsion systems. The perfluoro liquid droplets can be easily emulsified into a polymer solution as the second emulsion layer, where the polymer shell is formed during solvent evaporation in the continuum medium under proper processing controls. The morphology of particles is predictable and fits well with the linear model derived from Neumann's triangle in three-phase systems. Furthermore, a comprehensive study on the encapsulation of perfluoro ketone, which is widely used as a green fire extinguisher agent, is conducted as an example. The encapsulated perfluoro ketone showed instant thermal response upon heating while maintaining a good shelf life at room temperature. The remarkable fire suppression performance exhibited great potential for practical applications. This work offers more insight into the encapsulation of "naughty" perfluorinated chemicals and provides more possibilities for extended applications.

Effect of Selenium and Selenoproteins on Radiation Resistance.

With the advancement of radiological medicine and nuclear industry technology, radiation is increasingly used to diagnose human health disorders. However, large-scale nuclear leakage has heightened concerns about the impact on human organs and tissues. Selenium is an essential trace element that functions in the body mainly in the form of selenoproteins. Selenium and selenoproteins can protect against radiation by stimulating antioxidant actions, DNA repair functions, and immune enhancement. While studies on reducing radiation through antioxidants have been conducted for many years, the underlying mechanisms of selenium and selenoproteins as significant antioxidants in radiation damage mitigation remain incompletely understood. Therefore, this paper aims to provide new insights into developing safe and effective radiation protection agents by summarizing the anti-radiation mechanism of selenium and selenoproteins.

Hepatocyte-specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity.

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases.

Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity.

INTRODUCTION: Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined. OBJECTIVES: We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet. METHODS: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue. RESULTS: Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation. CONCLUSION: Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.

SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer.

Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.

Biomimetic MicroRNAs-Selenium-Nanocomposites for Targeted and Combined Hyperlipidemia Therapy.

Hyperlipidemia is considered as a high-risk factor for leading to coronary heart disease. MicroRNA-148a-3p (miR-148a-3p) inhibitor is a potential therapeutic target to bind low-density lipoprotein cholesterol receptors (LDLR) for decreasing the levels of low-density lipoprotein cholesterol in plasma. However, the therapeutic effects are not ideal in the clinical translation of nucleic acids treatment, owing to the short circulation time in vivo. Therefore, a platelet membrane (PM) cloaks Se nanoparticles (SeNPs) delivery system with chitosan (CS) modifies and miR-148a-3p inhibitors encapsulated is designed (PM/CS-SeNPs/miR). The PM/CS-SeNPs/miR shows a uniform shell-core structure with a particle size of ≈90 nm. Co-delivering miR-148a-3p inhibitors and Se effectively alleviate hyperlipidemia via LDLR pathway and Toll-Like Receptor 4 (TLR-4)/NF-κB signaling pathway, respectively. Furthermore, coated by PM, PM/CS-SeNPs/miR successfully prolong circulation time to 48 h in vivo and quickly target to liver with no toxicity. This dual combination therapy with miRNAs and Se based on nanoparticles targeted delivery presents a high-performance strategy for precise hyperlipidemia treatment.

SNP-based and haplotype-based genome-wide association on drug dependence in Han Chinese.

BACKGROUND: Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. METHODS: A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. RESULTS: Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. CONCLUSIONS: These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Stabilization by Chaperone GroEL in Biogenic Selenium Nanoparticles Produced from Bifidobacterium animalis H15 for the Treatment of DSS-Induced Colitis.

Inflammatory bowel diseases have a high rate of mortality and pose a serious threat to global public health. Selenium is an essential trace element, which has been shown to play important roles in redox control and antioxidant defense. Microorganisms play important roles in the reduction of toxic inorganic selenium (selenite and selenate) to less-toxic biogenic selenium nanoparticles (Bio-SeNPs), which have higher biocompatibility. In the present study, novel Bio-SeNPs with high stability were synthesized using probiotic Bifidobacterium animalis subsp. lactis H15, which was isolated from breastfed infant feces. The Bio-SeNPs with a size of 122 nm showed stability at various ionic strengths, temperatures, and in simulated gastrointestinal fluid, while chemosynthetic SeNPs underwent aggregation. The main surface protein in the Bio-SeNPs was identified as chaperone GroEL by liquid chromatography-tandem mass spectrometry. The overexpression and purification of GroEL demonstrated that GroEL controlled the assembly of Bio-SeNPs both in vitro and in vivo. In vivo, oral administration of Bio-SeNPs could alleviate dextran sulfate sodium-induced colitis by decreasing cell apoptosis, increasing antioxidant capacity and the number of proliferating cells, and improving the function of the intestinal mucosal barrier. In vitro experiments verified that Bio-SeNPs inhibited lipopolysaccharide-induced toll-like receptor 4/NF-κB signaling pathway activation. These results suggest that the Bio-SeNPs with high stability could have potential as a nutritional supplement for the treatment of colitis in nanomedicine applications.

Bifidobacterium animalis subsp. lactis A6 attenuates hippocampal damage and memory impairments in an ADHD rat model.

Attention deficit hyperactivity disorder (ADHD) is commonly accompanied by learning and memory deficits. This study aimed to demonstrate the effects of probiotic Bifidobacterium animalis subsp. lactis A6 (BAA6) on behaviour and memory function in spontaneously hypertensive rats (SHRs). The results showed that BAA6 treatment ameliorated spatial working memory deficits and inhibited hippocampal neuron loss in SHRs. The levels of neurotransmitters such as acetylcholine, dopamine, and norepinephrine, and the brain derived neurotrophic factor increased and that of glutamate decreased in the brain tissue of SHRs after BAA6 administration. Moreover, BAA6 reduced the levels of pro-inflammatory cytokines TNF-α and IL-1ß, and increased the levels of anti-inflammatory IL-10 and antioxidant glutathione in SHRs. 16S rRNA high-throughput sequencing showed that BAA6 treatment changed the gut microbiota composition. BAA6 promoted beneficial Lactobacillus, Romboutsia, Blautia, and Turicibacter, and decreased the enrichment of bacterial genera such as Dietzia, Sporosarcina, Brevibacterium, NK4A214_group, Atopostipes, and Facklamia negatively associated with neurotransmitter release and anti-inflammatory effects in SHRs. Together, these results suggested that BAA6 improved memory function by ameliorating hippocampal damage, abnormal neurotransmitter release and cerebral inflammation by reshaping the gut microbiota in SHRs. This study provides a scientific basis for the development and application of BAA6 as a promising dietary intervention to reduce the risk of ADHD.

Operando monitoring of dendrite formation in lithium metal batteries via ultrasensitive tilted fiber Bragg grating sensors.

Lithium (Li) dendrite growth significantly deteriorates the performance and shortens the operation life of lithium metal batteries. Capturing the intricate dynamics of surface localized and rapid mass transport at the electrolyte-electrode interface of lithium metal is essential for the understanding of the dendrite growth process, and the evaluation of the solutions mitigating the dendrite growth issue. Here we demonstrate an approach based on an ultrasensitive tilted fiber Bragg grating (TFBG) sensor which is inserted close to the electrode surface in a working lithium metal battery, without disturbing its operation. Thanks to the superfine optical resonances of the TFBG, in situ and rapid monitoring of mass transport kinetics and lithium dendrite growth at the nanoscale interface of lithium anodes have been achieved. Reliable correlations between the performance of different natural/artificial solid electrolyte interphases (SEIs) and the time-resolved optical responses have been observed and quantified, enabling us to link the nanoscale ion and SEI behavior with the macroscopic battery performance. This new operando tool will provide additional capabilities for parametrization of the batteries' electrochemistry and help identify the optimal interphases of lithium metal batteries to enhance battery performance and its safety.

Pharmacokinetic and pharmacodynamic studies of nicotine in rat brain: a simultaneous investigation of nicotine metabolites and the release of neurotransmitters in vivo.

Introduction: The body's ability to metabolize nicotine and the disposition of nicotine in the brain are important determinants of its exposure. Limited knowledge about the near real-time changes of neurochemicals during the brain nicotine metabolic process hinders the recognition of its multiple neuropharmacological effects. Methods: An online microdialysis coupled with UHPLC-HRMS/MS method for the in vivo multi-analysis of nicotine metabolites and several neurotransmitters in rat brain was developed. Whether the systemic modulation of metabolic enzyme CYP2B would modulate nicotine pharmacokinetics and local neurochemical effects was further investigated. Results: The dynamic profiles of over 10 nicotine metabolites and neurotransmitters were simultaneously obtained after a single injection of nicotine (2 mg·kg-1, i.p.) using the new method. Proadifen pretreatment (50 mg·kg-1·d-1, i.p., 4 days) caused significant inhibition of brain CYP2B1 activity. When exposed to nicotine, the brain C max of nicotine was 1.26 times higher and the levels of nicotine metabolites, nornicotine, and nicotine-N-oxide, were decreased by 85.3% and 34.4% in proadifen-pretreated rats. The higher level of brain nicotine induced a greater release of dopamine, serotonin, glutamate, and γ-amino-butyric acid in the nucleus accumbens. The concentrations of nicotine and dopamine were positively correlated, and the average levels of γ-amino-butyric acid and serotonin were 2.7 and 1.2 times higher, respectively, under the inhibition of nicotine metabolism. Discussion: These results demonstrated that inhibiting nicotine metabolism in rats can enhance the residence of brain nicotine and its local neurotransmitter effects. The metabolic activity of nicotine under different physiological conditions could regulate nicotine's bioavailability and its resulting pharmacology.

Detangling electrolyte chemical dynamics in lithium sulfur batteries by operando monitoring with optical resonance combs.

Challenges in enabling next-generation rechargeable batteries with lower cost, higher energy density, and longer cycling life stem not only from combining appropriate materials, but from optimally using cell components. One-size-fits-all approaches to operational cycling and monitoring are limited in improving sustainability if they cannot utilize and capture essential chemical dynamics and states of electrodes and electrolytes. Herein we describe and show how the use of tilted fiber Bragg grating (TFBG) sensors to track, via the monitoring of both temperature and refractive index metrics, electrolyte-electrode coupled changes that fundamentally control lithium sulfur batteries. Through quantitative sensing of the sulfur concentration in the electrolyte, we demonstrate that the nucleation pathway and crystallization of Li2S and sulfur govern the cycling performance. With this technique, a critical milestone is achieved, not only towards developing chemistry-wise cells (in terms of smart battery sensing leading to improved safety and health diagnostics), but further towards demonstrating that the coupling of sensing and cycling can revitalize known cell chemistries and break open new directions for their development.

Advances in the Study of Selenium-Enriched Probiotics: From the Inorganic Se into Se Nanoparticles.

Selenium (Se) is a momentous metallic element that plays an irreplaceable role in biochemical activities. Se deficiency remains a nutritional challenge across the world. Organic Se supplementation is the most effective treatment means for Se deficiency. Organic Se transformed from Se-enriched probiotics show outstanding excellent properties in antibacteria, anti-oxidation, anti-inflammation, and immunoregulation. Studying the influencing factors for Se enrichment capacity and enrichment mechanisms of Se-enriched probiotics is conducive to the exploit of more potent Se-enriched probiotics. Se-enriched probiotics transform inorganic Se into Se nanoparticles (SeNPs), which have been widely used in animal husbandry and biomedical field. In this paper, the novel development of Se-enriched probiotics is reviewed, and the bioactivities of SeNPs are assessed, so as to display their potential application prospects. The excellent role of SeNPs in anti-oxidation is summarized, and the mechanism by which SeNPs improve Se deficiency and boost animal health is explained.

Building Smarter Aqueous Batteries.

Amidst the global trend of advancing renewable energies toward carbon neutrality, energy storage becomes increasingly critical due to the intermittency of renewables. As an alternative to lithium-ion batteries (LIBs), aqueous batteries have received growing attention for large-scale energy storage due to their economical and safe features. Despite the fruitful achievements at the material level, the reliability and lifetime of aqueous batteries are still far from satisfactory. Alike LIBs, integrating smartness is essential for more reliable and long-life aqueous batteries via operando monitoring and automatic response to extreme abuses. In this review, recent advances in sensing techniques and multifunctional battery-sensor systems together with self-healing methods in aqueous batteries is summarized. The significant role of artificial intelligence in designing and optimizing aqueous batteries with high efficiency is also highlighted. Ultimately, it is extrapolated toward the future and present the humble perspective for building smarter aqueous batteries.

Eucommia ulmoides polysaccharide modified nano-selenium effectively alleviated DSS-induced colitis through enhancing intestinal mucosal barrier function and antioxidant capacity.

Ulcerative colitis (UC) is currently the most common inflammatory bowel disease (IBD). Due to its diverse and complex causes, there is no cure at present, and researchers are constantly exploring new therapies. In recent years, nano-selenium particle(SeNP) has attracted wide attention due to excellent biological activities. Therefore, in this study, for the first time, we used a natural polysaccharide, Eucommia ulmoides polysaccharide (EUP), modified SeNP to get EUP-SeNP with a size of about 170 nm, and its effect on 3% dextran sulphate sodium (DSS) induced colitis was explored. Our results showed that colon intestinal histology, intestinal mucosal barrier, inflammatory cytokines and intestinal microbiome composition were changed after EUP-SeNP treatment in colitis mice. Specifically, it was also shown that oral treatment of EUP-SeNP could relieve the degree of DSS-induced colitis in mice by restoring weight loss, reducing disease activity index (DAI), enhancing colon antioxidant capacity and regulating intestinal microbiome composition. In addition, we verified the mechanism in intestinal epithelial cell lines, showing that EUP-SeNP inhibited LPS-induced activation of the TRL-4/NF-κB signaling pathway in intestinal epithelial cell lines. To some extend, our study provides therapeutic reference for the treatment of IBD.

The beneficial effects of commensal E. coli for colon epithelial cell recovery are related with Formyl peptide receptor 2 (Fpr2) in epithelial cells.

BACKGROUND: Formyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. Commensal E. coli is known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection between E. coli and Fpr2 in the recovery of colon epithelial cells. RESULTS: The deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes of E. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing. E. coli O22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated with E. coli O22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection with E. coli O22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived from E. coli O22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population of E. coli was observed to increase in the colons of Fpr2-/- mice with colitis. CONCLUSION: Commensal E. coli O22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products from E. coli induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increased E. coli population in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensal E. coli on colon epithelial cell recovery.

The effect of selenium on antioxidant system in aquaculture animals.

There will be generated some adverse conditions in the process of acquculture farming with the continuous improvement of the intensive degree of modern aquaculture, such as crowding stress, hypoxia, and malnutrition, which will easily lead to oxidative stress. Se is an effective antioxidant, participating and playing an important role in the antioxidant defense system of fish. This paper reviews the physiological functions of selenoproteins in resisting oxidative stress in aquatic animals, the mechanisms of different forms of Se in anti-oxidative stress in aquatic animals and the harmful effects of lower and higher levels of Se in aquaculture. To summarize the application and research progress of Se in oxidative stress in aquatic animals and provide scientific references for its application in anti-oxidative stress in aquaculture.

UHRF1/DNMT1-MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer.

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.