Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

GWAS meets TCGA to illuminate mechanisms of cancer predisposition.

Genome-wide association studies (GWASs) have unraveled a large number of cancer risk alleles. Understanding how these allelic variants predispose to disease is a major bottleneck confronting translational application. In this issue, Li and colleagues combine GWASs with The Cancer Genome Atlas (TCGA) to disambiguate the contributions of germline and somatic variants to tumorigenic gene expression programs. They find that close to half of the known risk alleles for estrogen receptor (ER)-positive breast cancer are expression quantitative trait loci (eQTLs) acting upon major determinants of gene expression in tumors.

Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.

Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells.

Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.

MASLD/MetALD and mortality in individuals with any cardio-metabolic risk factor: A population-based study with 26.7 years of follow-up.

BACKGROUND AND AIMS: A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the "MASLD/MetALD" and "no steatotic liver disease (SLD)" groups in individuals with any CMRF. APPROACH AND RESULTS: A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the "MASLD," "MetALD," and "no SLD" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the "MASLD" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the "no SLD" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4). CONCLUSIONS: In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes.

Association between dental diseases and oral hygiene care and the risk of vertebral fracture: a nationwide cohort study.

Periodontal disease and increased missing teeth were associated with incident vertebral fractures. In contrast, professional dental cleaning and frequent tooth brushing, was associated with a lower risk of vertebral fracture. Better oral hygiene care attenuated the risk associated with dental diseases. PURPOSE: To investigate the association between oral health and the risk of vertebral fractures. METHODS: We included 2,532,253 individuals aged ≥40 years who underwent the Korean National Health Insurance Service health examinations in 2008 and followed up until December 31, 2017. We performed multivariable Cox proportional hazard regression analyses to evaluate the association between dental diseases and oral hygiene care and the risk of vertebral fractures. RESULTS: Over the 9.3-year median follow-up, 1.46% (n = 36,857) experienced vertebral fractures. Individuals with dental diseases had a higher risk of vertebral fracture than those without (hazard ratio [HR] 1.04, 95% confidence interval [CI]: 1.02-1.07 for periodontal diseases; 1.02, 1.00-1.05 for dental caries; 1.12, 1.05-1.20 for ≥15 missing teeth). Good oral hygiene care was associated with a lower vertebral fracture risk (HR 0.89, 95% CI: 0.86-0.91 for ≥1 time/year [vs. <1 time/year] of professional dental cleaning; 0.90, 0.87-0.93 for ≥2 times/day [vs. 0-1 time/day] of toothbrushing). The combined dental diseases was significantly associated with an increased vertebral fracture risk, whereas combined oral hygiene care was associated with further risk reduction. Better oral hygiene care reduced vertebral fracture risk associated with dental diseases (all P <0.001). CONCLUSION: Periodontal disease, dental caries, and an increased number of missing teeth were independently associated with higher risks for vertebral fractures. Conversely, improved oral hygiene care, such as personal dental cleaning and frequent tooth brushing, may modify vertebral fracture risks associated with dental disease.

Admixture Mapping in African Americans Identifies New Risk Loci for HCV-Related Cirrhosis.

BACKGROUND & AIMS: Cirrhosis is the main predisposing condition for hepatocellular carcinoma. Host genetic risk factors have been reported for cirrhosis; however, whether there is a genetic contribution to racial disparities in cirrhosis requires further investigation. METHODS: We used an affected-only mapping by admixture linkage disequilibrium analysis to characterize the genetic risk of cirrhosis in 227 African American patients with cirrhosis genotyped at 19,804 ancestry-informative marker single nucleotide polymorphisms. We additionally performed analyses stratified by hepatitis C virus (HCV) infection status. To replicate our findings, we conducted a case-control analysis in an external study population (452 cases and 196 controls). RESULTS: The mean age of patients was 63.3 years and 98.2% were male. Risk factors for cirrhosis included HCV infection (83.7%) and alcohol abuse (56.4%). In the admixture mapping analysis, we found that European ancestry on chromosome 2q21.1 and African ancestry on chromosome 6p21.2 were associated with increased risk of cirrhosis in African Americans. In the fine-mapping analysis, we identified regions near POTEKP on 2q21.1 (P = .0001) and DNAH8 on 6p21.2 (P = .0017) that were associated with cirrhosis. As the admixture peaks in the HCV-positive patients were the same as those in the overall group, findings in the analysis are reflective of the HCV-positive group. In the replication analysis, the results on chromosome 2 were not significant after adjusting for multiple comparisons, and we could not replicate the results on chromosome 6. CONCLUSIONS: We used admixture mapping to identify novel genomic regions on 2q21.1 and 6p21.2 that may be associated with HCV-related cirrhosis risk in African Americans.

Design of XS2 (X = W or Mo)-Decorated VS2 Hybrid Nano-Architectures with Abundant Active Edge Sites for High-Rate Asymmetric Supercapacitors and Hydrogen Evolution Reactions.

Two-dimensional layered transition metal dichalcogenides have emerged as promising materials for supercapacitors and hydrogen evolution reaction (HER) applications. Herein, the molybdenum sulfide (MoS2 )@vanadium sulfide (VS2 ) and tungsten sulfide (WS2 )@VS2  hybrid nano-architectures prepared via a facile one-step hydrothermal approach is reported. Hierarchical hybrids lead to rich exposed active edge sites, tuned porous nanopetals-decorated morphologies, and high intrinsic activity owing to the strong interfacial interaction between the two materials. Fabricated supercapacitors using MoS2 @VS2  and WS2 @VS2  electrodes exhibit high specific capacitances of 513 and 615 F g- 1 , respectively, at an applied current of 2.5 A g- 1  by the three-electrode configuration. The asymmetric device fabricated using WS2 @VS2  electrode exhibits a high specific capacitance of 222 F g- 1  at an applied current of 2.5 A g- 1  with the specific energy of 52 Wh kg- 1  at a specific power of 1 kW kg- 1 . For HER, the WS2 @VS2  catalyst shows noble characteristics with an overpotential of 56 mV to yield 10 mA cm- 2 , a Tafel slope of 39 mV dec-1 , and an exchange current density of 1.73 mA cm- 2 . In addition, density functional theory calculations are used to evaluate the durable heterostructure formation and adsorption of hydrogen atom on the various accessible sites of MoS2 @VS2  and WS2 @VS2  heterostructures.

Current trends and prospects in catalytic upgrading of lignocellulosic biomass feedstock into ultrapure biofuels.

Eco-friendly renewable energy sources have recommended as fossil fuel alternatives in recent years to reduce environmental pollution and meet future energy demands in various sectors. As the largest source of renewable energy in the world, lignocellulosic biomass has received considerable interest from the scientific community to advance the fabrication of biofuels and ultrafine value-added chemicals. For example, biomass obtained from agricultural wastes could catalytically convert into furan derivatives. Among furan derivatives, 5-hydroxymethylfurfural (HMF) and 2, 5-dimethylfuran (DMF) are considered the most useful molecules that can be transformed into desirable products such as fuels and fine chemicals. Because of its exceptional properties, e.g., water insolubility and high boiling point, DMF has studied as the ideal fuel in recent decades. Interestingly, HMF, a feedstock upgraded from biomass sources can easily hydrogenate to produce DMF. In the present review, the current state of the art and studies on the transformation of HMF into DMF using noble metals, non-noble metals, bimetallic catalysts, and their composites have discussed elaborately. In addition, comprehensive insights into the operating reaction conditions and the influence of employed support over the hydrogenation process have demonstrated.

Late-spring frost risk between 1959 and 2017 decreased in North America but increased in Europe and Asia.

Late-spring frosts (LSFs) affect the performance of plants and animals across the world's temperate and boreal zones, but despite their ecological and economic impact on agriculture and forestry, the geographic distribution and evolutionary impact of these frost events are poorly understood. Here, we analyze LSFs between 1959 and 2017 and the resistance strategies of Northern Hemisphere woody species to infer trees' adaptations for minimizing frost damage to their leaves and to forecast forest vulnerability under the ongoing changes in frost frequencies. Trait values on leaf-out and leaf-freezing resistance come from up to 1,500 temperate and boreal woody species cultivated in common gardens. We find that areas in which LSFs are common, such as eastern North America, harbor tree species with cautious (late-leafing) leaf-out strategies. Areas in which LSFs used to be unlikely, such as broad-leaved forests and shrublands in Europe and Asia, instead harbor opportunistic tree species (quickly reacting to warming air temperatures). LSFs in the latter regions are currently increasing, and given species' innate resistance strategies, we estimate that ∼35% of the European and ∼26% of the Asian temperate forest area, but only ∼10% of the North American, will experience increasing late-frost damage in the future. Our findings reveal region-specific changes in the spring-frost risk that can inform decision-making in land management, forestry, agriculture, and insurance policy.

The 0-3 Lead Zirconate-Titanate (PZT)/Polyvinyl-Butyral (PVB) Composite for Tactile Sensing.

In this study, a 0-3 piezoelectric composite based on lead zirconate-titanate (PZT)/polyvinyl-butyral (PVB) was fabricated and characterized for its potential application in tactile sensing. The 0-3 composite was developed to incorporate the advantages of both ceramic and polymer. The paste of 0-3 PZT-PVB composite was printed using a conventional screen-printing technique on alumina and mylar substrates. The thickness of the prepared composite was approximately 80 µm. After printing the top electrode of the silver paste, 10 kV/mm of DC field was applied at 25 °C, 120 °C, and 150 °C for 10 min to align the electric dipoles in the composite. The piezoelectric charge coefficient of d33 and the piezoelectric voltage coefficient of g33 were improved by increasing the temperature of the poling process. The maximum values of d33 and g33 were 14.3 pC/N and 44.2 mV·m/N, respectively, at 150 °C. The sensor's sensitivity to the impact force was measured by a ball drop test. The sensors showed a linear behavior in the output voltage with increasing impact force. The sensitivity of the sensor on the alumina and mylar substrates was 1.368 V/N and 0.815 V/N, respectively. The rising time of the sensor to the finger touch was 43 ms on the alumina substrate and 35 ms on the mylar substrate. Consequently, the high sensitivity and fast response time of the sensor make the 0-3 PZT-PVB composite a good candidate for tactile sensors.

Comparative performance of risk prediction models for hepatitis B-related hepatocellular carcinoma in the United States.

BACKGROUND & AIMS: Guidelines recommend hepatocellular carcinoma (HCC) surveillance in patients with chronic HBV infection. Several HCC risk prediction models are available to guide surveillance decisions, but their comparative performance remains unclear. METHODS: Using a retrospective cohort of patients with HBV treated with nucleos(t)ide analogues at 130 Veterans Administration facilities between 9/1/2008 and 12/31/2018, we calculated risk scores from 10 HCC risk prediction models (REACH-B, PAGE-B, m-PAGE-B, CU-HCC, HCC-RESCUE, CAMD, APA-B, REAL-B, AASL-HCC, RWS-HCC). We estimated the models' discrimination and calibration. We calculated HCC incidence in risk categories defined by the reported cut-offs for all models. RESULTS: Of 3,101 patients with HBV (32.2% with cirrhosis), 47.0% were treated with entecavir, 40.6% tenofovir, and 12.4% received both. During a median follow-up of 4.5 years, 113 patients developed HCC at an incidence of 0.75/100 person-years. AUC values for 3-year HCC risk were the highest for RWS-HCC, APA-B, REAL-B, and AASL-HCC (all >0.80). Of these, 3 (APA-B, RWS-HCC, REAL-B) incorporated alpha-fetoprotein. AUC values for the other models ranged from 0.73 for PAGE-B to 0.79 for CAMD and HCC-RESCUE. Of the 7 models with AUC >0.75, only APA-B was poorly calibrated. In total, 10-20% of the cohort was deemed low-risk based on the published cut-offs. None of the patients in the low-risk groups defined by PAGE-B, m-PAGE-B, AASL-HCC, and REAL-B developed HCC during the study timeframe. CONCLUSION: In this national cohort of US-based patients with HBV on antiviral treatment, most models performed well in predicting HCC risk. A low-risk group, in which no cases of HCC occurred within a 3-year timeframe, was identified by several models (PAGE-B, m-PAGE-B, CAMD, AASL-HCC, REAL-B). Further studies are warranted to examine whether these patients could be excluded from HCC surveillance. LAY SUMMARY: Risk prediction models for hepatocellular carcinoma (HCC) in patients infected with hepatitis B virus (HBV) could guide HCC surveillance decisions. In this large cohort of US-based patients receiving treatment for HBV, most published models discriminated between those who did or did not develop HCC, although the RWS-HCC, REAL-B, and AASL-HCC performed the best. If confirmed in future studies, these models could help identify a low-risk subset of patients on antiviral treatment who could be excluded from HCC surveillance.

Comparative Effectiveness of Surveillance Colonoscopy Intervals on Colorectal Cancer Outcomes in a National Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND & AIMS: Surveillance colonoscopy is recommended to reduce colorectal cancer (CRC)-related morbidity and mortality in patients with inflammatory bowel disease (IBD). The comparative effectiveness of varying colonoscopy intervals on CRC outcomes among patients with IBD is unknown. METHODS: We performed a retrospective cohort study of patients with confirmed CRC within a cohort of 77,824 patients with IBD during 2000 to 2015 in the National Veterans Health Administration. We examined the association between colonoscopy surveillance intervals on CRC stage, treatment, or all-cause and cancer-specific mortality. The interval of colonoscopy prior to CRC diagnosis was categorized as those performed within <1 year, 1 to 3 years, 3 to 5 years, or none within 5 years. RESULTS: Among 566 patients with CRC-IBD, most (69.4%) did not have colonoscopy within 5 years prior to CRC diagnosis, whereas 9.7% had colonoscopy within 1 year prior to diagnosis, 17.7% within 1 to 3 years, and 3.1% between 3 and 5 years. Compared with no surveillance, colonoscopy within 1 year (adjusted odds ratio, 0.40; 95% confidence interval [CI], 0.20-0.82), and 1 to 3 years (adjusted odds ratio, 0.56; 95% CI, 0.32-0.98) were less likely to be diagnosed at late stage. Regardless of IBD type and duration, colonoscopy within 1 year was associated with a lower all-cause mortality (adjusted hazard ratio, 0.56; 95% CI, 0.36-0.88). CONCLUSIONS: In a national cohort of patients with CRC-IBD, colonoscopy within 3 years prior to CRC diagnosis was associated with early tumor stage at diagnosis, and colonoscopy within 1 year was associated with a reduced all-cause mortality compared with no colonoscopy. Our findings support colonoscopy intervals of 1 to 3 years in patients with IBD to reduce late-stage CRC and all-cause mortality.

Provider Attitudes Toward Risk-Based Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis in the United States.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy.

Reversible acetylation modulates p54nrb/NONO-mediated expression of the interleukin 8 gene.

The non-POU domain-containing octamer-binding protein (NONO, also referred to as p54nrb) is a multifunctional nuclear protein engaging in transcriptional regulation, mRNA splicing, nuclear retention of defective RNA, and DNA repair. Emerging evidence has demonstrated that p54nrb is subjected to various posttranslational modifications, including phosphorylation and methylation, which may be important regulators of its multifunction. However, among these modifications, direct evidence of p54nrb acetylation and its underlying mechanism remains unclear. In this study, we reported that lysine 371 of p54nrb was reversibly acetylated by the acetyltransferase general control non-depressible 5 (GCN5) and deacetylase sirtuin 1 (SIRT1), which was crucial for activity of p54nrb to inhibit interleukin-8 (IL-8) expression. Mechanistically, GCN5-mediated acetylation attenuates the recruitment of p54nrb on its core binding motif within the IL-8 gene promoter, preferentially increasing the expression of the IL-8 gene. In contrast, deacetylation by SIRT1 reverses this process. Altogether, our data suggest that reversible acetylation is an important switch for the multiple nuclear functions of p54nrb/NONO.

Unveiling the Redox Electrochemistry of MOF-Derived fcc-NiCo@GC Polyhedron as an Advanced Electrode Material for Boosting Specific Energy of the Supercapattery.

Metal organic frameworks (MOFs), which constitute a new class of porous organic-inorganic hybrid materials, have gained considerable attention in the fields of electrochemical energy storage and conversion devices owing to their open topological structures, large surface areas, tunable morphologies, and extreme redox activity. A synthesis protocol that comprises coprecipitation followed by controlled calcination processes to design a battery-type electrode is used. This electrode consists of three-dimensional (3D), ant cave-like polyhedrons of nickel-cobalt alloy on graphitic carbon (GC; NiCo@GC) nanostructures; trimesic acid is used as a potential MOF-linker. The developed NiCo@GC sample exhibits mesoporous characteristics with the maximum surface area of 94.08 m2 g-1 at 77 K. In addition, the redox activity at different sweep rates reveals the battery-type charge storage behavior of the NiCo@GC electrode; its three-electrode assembly provides 444 C g-1 specific capacity at 2 A g-1 with long-term capacity retention. The constructed supercapattery (SC) devices (i.e., AC//NiCo@GC) achieved capacity, specific energy, and specific power are 74.3 mAh g-1 , 39.5 Wh kg-1 , and 665 W kg-1 , respectively. Owing to its reasonable electrochemical characteristics, the prepared NiCo@GC material is a promising candidate for supercapattery electrodes for portable electronic devices.

Impact of Molybdenum Dichalcogenides on the Active and Hole-Transport Layers for Perovskite Solar Cells, X-Ray Detectors, and Photodetectors.

The interface architectures of inorganic-organic halide perovskite-based devices play key roles in achieving high performances with these devices. Indeed, the perovskite layer is essential for synergistic interactions with the other practical modules of these devices, such as the hole-/electron-transfer layers. In this work, a heterostructure geometry comprising transition-metal dichalcogenides (TMDs) of molybdenum dichalcogenides (MoX2  = MoS2 , MoSe2 , and MoTe2 ) and perovskite- or hole-transfer layers is prepared to achieve improved device characteristics of perovskite solar cells (PSCs), X-ray detectors, and photodetectors. A superior efficiency of 11.36% is realized for the active layer with MoTe2 in the PSC device. Moreover, X-ray detectors using modulated MoTe2 nanostructures in the active layers achieve 296 nA cm-2 , 3.12 mA (Gy cm2 )-1 and 3.32 × 10-4 cm2 V-1 s-1 of collected current density, sensitivity, and mobility, respectively. The fabricated photodetector produces a high photoresponsivity of 956 mA W-1 for a visible light source, with an excellent external quantum efficiency of 160% for the perovskite layer containing MoSe2 nanostructures. Density functional theory calculations are made for pure and MoX2 doped perovskites' geometrical, density of states and optical properties variations evidently. Thus, the present study paves the way for using perovskite-based devices modified by TMDs to develop highly efficient semiconductor devices.

Gold(I)-Catalyzed Intramolecular Hydrothiophenylation of N-Thiophen-3-yl Alkynylamides for Accessing Thieno[3,2-b]pyridine-5(4H)-ones: Development of F-Actin Specific Fluorescent Probes.

Herein, we describe an original synthetic method for a series of fluorescent thieno[3,2-b]pyridine-5(4H)-one derivatives prepared via the gold(I)-catalyzed 6-endo-dig intramolecular hydrothiophenylation process involving N-thiophen-3-yl alkynylamides. The brightness was improved; emission could be tuned, and larger Stokes shifts were recorded. We also designed and synthesized the phalloidin-based fluorescent chemical probes KF-P1 and KF-P2 to realize fluorescent F-actin imaging.

Effect of the green synthesis of CuO plate-like nanoparticles on their photodegradation and antibacterial activities.

Green synthesis of copper oxide nanoparticles and its effects on photocatalytic dye degradation and antibacterial activities are reported. The synthesis of nanoparticles by green routes provides many advantages over chemical routes, including simplicity, cost-effectiveness, and fast processing route without using any costly or harmful chemicals. Tridax procumbense (coat buttons) plant root extract was used to synthesize copper oxide nanoparticles. The synthesized Tridax procumbense-copper oxide nanoparticles (TP-CuO NPs) were characterized by UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering spectroscopy (DLS), and X-ray diffraction (XRD) techniques. The synthesized TP-CuO NPs were applied for photocatalytic dye degradation and antibacterial activity studies. The TP-CuO NPs exhibited a maximum antibacterial activity at 500 µg mL-1 concentration against Staphylococcus aureus and E. coli showing inhibition zones of 7.5 mm and 7.2 mm, respectively. The photocatalytic ability of the TP-CuO was also tested against the textile dye Trypan blue (TB), and showed about 55% degradation after 48 h for 500 µg mL-1 CuO NP concentration, showing a concentration-dependent degradation efficiency. This is the first work on TP-derived CuO nanoparticles and their photocatalytic and antimicrobial applications. Overall, this study supports the superiority of green-synthesized TP-CuO NPs as photocatalytic and antimicrobial agents.

XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer.

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.