Understanding SCLC heterogeneity and plasticity in cancer metastasis and chemotherapy resistance.

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases and features a strong predilection for early metastasis and extremely poor prognosis. Despite being highly sensitive to chemotherapy and/or radiotherapy initially, most SCLC patients develop therapeutic resistance within one year and die of distant metastases. Multiple studies have revealed the high heterogeneity and strong plasticity of SCLC associated with frequent metastases and early development of therapeutic resistance as well as poor clinical outcome. Importantly, different SCLC subtypes are associated with different therapeutic vulnerabilities, and the inflamed subtype tends to have the best response to immunotherapy, which highlights the importance of precision medicine in the clinic. Here, we review recent advances in SCLC heterogeneity and plasticity and their link to distant metastases and chemotherapy resistance. We hope that a better understanding of the molecular mechanisms underlying SCLC malignant progression will help to develop better intervention strategies for this deadly disease.

Probing the impact of the N3-substituted alkyl chain on the electronic environment of the cation and the anion for 1,3-dialkylimidazolium ionic liquids.

In this study, X-ray photoelectron spectroscopy is used to probe the impact of the N3-substituted alkyl group on the electronic environment of the cation and the anion by comparing two types of imidazolium cations, 1-alkyl-3-butylimidazolium and 1-alkyl-3-methylimidazolium. Due to the more intense inductive effect changing from methyl to butyl, the electronic environment of the cationic nitrogen can be significantly affected, which is reflected in a shift of N 1s binding energy. The magnitude of the binding energy shift is found to be more pronounced in the case of the less basic anion and inversely proportional to the basicity of the anion. The increase of the N3-substituted alkyl chain length can also influence the charge-transfer effect from the anion to the cation. This gives rise to a change in the electronic environment of the anion. Such an impact is found to be concentrated on the anion-based component bearing more negative point charges.

Kdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest.

Small cell lung carcinoma (SCLC) is one of the deadliest cancer types, with a 5-year survival rate less than 10%. Kdm1a/Lsd1 has recently been implicated as a potential therapeutic target for SCLC. However, the underlying molecular mechanism by which Kdm1a promotes the oncogenesis of SCLC has not been fully understood. Kdm1a is significantly elevated in most human SCLC specimens, whereas Rest, a tumor suppressor and neuronal repressive transcriptional factor, is typically inactivated. Knock-out of Kdm1a (Kdm1a-KO) in mouse SCLC cell lines resulted in the suppression of cell growth and soft agar colony formation. RNA-Seq analysis of the Kdm1a-KO cells revealed significant repression of a program of neuroendocrine signature genes, and conversely, a significant upregulation of a network of genes capable of inhibiting tumor cell growth. Rest was identified among the top 10 upregulated genes in Kdm1a-KO cells. The treatment of the SCLC cells with Kdm1a demethylase inhibitors resulted in a dramatic up-regulation of Rest similar to the extent of that in Kdm1a-KO cells. Importantly, accompanying the restored expression of the SCLC signature genes, knock-out of Rest in Kdm1a-KO cells rescued the restricted cell growth and soft agar colony formation. Taken together, these novel findings show that Kdm1a is a key transcriptional repressor of Rest, and that suppression of SCLC progression by the targeted inhibition of Kdm1a depends on the reactivation of Rest, suggesting a new strategy for effective SCLC treatment by targeting the Kdm1a/Rest molecular pathway.

NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition.

Metastasis is the major cause for high mortality of lung cancer with the underlying mechanisms poorly understood. The scaffolding protein neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) has been identified as a pro-metastasis gene in several types of cancers including melanoma and breast cancer. However, the exact role and related mechanism of NEDD9 in regulating lung cancer metastasis still remain largely unknown. Here, we demonstrate that NEDD9 knockdown significantly inhibits migration, invasion and metastasis of lung cancer cells in vitro and in vivo. The pro-metastasis role of Nedd9 in lung cancer is further supported by studies in mice models of spontaneous cancer metastasis. Moreover, we find that NEDD9 promotes lung cancer cell migration and invasion through the induction of epithelial-mesenchymal transition (EMT) potentially via focal adhesion kinase activation. More importantly, NEDD9 expression inversely correlates with E-cadherin expression in human lung cancer specimens, consistent with the findings from in vitro studies. Taken together, this study highlights that NEDD9 is an important mediator promotes lung cancer metastasis via EMT.

Degradation Behaviors of Polylactic Acid, Polyglycolic Acid, and Their Copolymer Films in Simulated Marine Environments.

Poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) are extensively studied biodegradable polymers. However, the degradation behavior of their copolymer, poly(lactic-co-glycolic acid) (PLGA), in marine environments has not yet been confirmed. In this study, the changes in macroscopic and microscopic morphology, thermal properties, aggregation, and chemical structure of PLA, PGA, PLGA-85, and PLGA-75 (with 85% and 75% LA content) in simulated marine environments were investigated. Results revealed that degradation occurred through hydrolysis of ester bonds, and the degradation rate of PGA was faster than that of PLA. The amorphous region degraded preferentially over the crystalline region, leading to cleavage-induced crystallization and decreased thermal stability of PLA, PLGA-85, and PLGA-75. The crystal structures of PLGAs were similar to those of PLA, and the higher GA content, the faster was the degradation rate. This study provides a deeper understanding of the seawater degradation behaviors of PLA, PGA, and their copolymers, and provides guidance for the preparation of materials with controllable degradation performance.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

[Fluorescent labeling of latent fingerprints with metallic ions modified ZnS/PAMAM nano-composites].

Abstract Effects of metallic ions, such as Zn2+ , Mn , Cd2+, Na+, K+, Ag, CuZ+ and PbZ, on the photoluminescence properties of ZnS(ZINC sulfide) QDs (quantum dots)/poly (amido amine) (PAMAM) dendrimer nanocomposites(NCs) with blue emission under the irradiation of UV light were studied. The results show that the effects of different metallic ions on the photoluminescence properties of the prepared ZnS QDs were different. Zn+ , Mn2+ and Cd2+ ions enhance the PL(photoluminescence) intensity; Na+ and K+ ions don't change the PL intensity obviously while Ag+, Cu2+ and Pb2+ quench it. Compared with ZnS/PAMAM NCs, fingerprints treated with ZnxCd1-x) S/PAMAM NCs emitted brighter blue light, the contrast between abstracts and fingerprints was more obvious, which shows good reference

Microcrystalline cellulose grafted hyperbranched polyester with roll comb structure for synergistic toughening and strengthening of microbial PHBV/bio-based polyester elastomer composites.

The brittle feature of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is the major challenge that strongly restricts its application at present. Successfully synthesized bio-based engineering polyester elastomers (BEPE) were combined with PHBV to create entirely bio-composites with the intention of toughening PHBV. Herein, the 2,2-Bis(hydroxymethyl)-propionic acid (DMPA) was grafted onto microcrystalline cellulose (MCC) and then further transformed into hyperbranched polyester structure via polycondensation. The modified MCC, named MCHBP, had plenty of terminal hydroxyl groups, which get dispersed between PHBV and BEPE. Besides, a large number of terminal hydroxyl groups of MCHBP can interact with the carbonyl groups of PHBV or BEPE in a wide range of hydrogen bonds, and subsequently increase the adhesion and stress transfer between the PHBV and BEPE. The tensile toughness and the elongation at break of the PHBV/BEPE composites with 0.5phr MCHBP were improved by 559.7 % and 221.8 % in comparison to those of PHBV/BEPE composites. Results also showed that MCHBP can play a heterogeneous nucleation effect on the crystallization of PHBV. Therefore, this research can address the current issue of biopolymers' weak mechanical qualities and may have uses in food packaging.

Characteristics of Shiga Toxin-Producing Escherichia coli Circulating in Asymptomatic Food Handlers.

Shiga toxin-producing Escherichia coli (STEC) is a foodborne zoonotic pathogen that causes diarrhea, hemorrhagic colitis (HC), and hemolytic uremic syndrome (HUS) worldwide. Since the infection can be asymptomatic, the circulation of STEC in some asymptomatic carriers, especially in healthy-food-related professionals, is not yet well understood. In this study, a total of 3987 anal swab samples from asymptomatic food handlers were collected, and ten swabs recovered STEC strains (0.251%). Of the ten STEC isolates, seven serotypes and eight sequence types (ST) were determined using whole genome sequencing (WGS). Two stx1 subtypes (stx1a and stx1c) and four stx2 subtypes (stx2a, stx2b, stx2d, and stx2e) were detected. Seven different insertion sites were found in fourteen Stx prophages, and the dmsB and yfhL were the newly identified insertion sites. The ten strains showed the variable Stx transcription levels after the mitomycin C induction. The whole-genome phylogeny indicated that the strains from the asymptomatic food handlers were genetically distant from the strains of HUS patients. The STEC isolates circulating in asymptomatic carriers might pose a low potential to cause disease.

Substantial and efficient adsorption of heavy metal ions based on protein and polyvinyl alcohol nanofibers by electrospinning.

The adverse effects of heavy metal pollutants in wastewater have threatened human health in recent decades. Therefore, the development of absorbents for such pollutants is essential to overcome these problems. Electrospun nanofibers are often used for wastewater treatment owing to their high porosity and high specific surface area. Zein from plants and collagen from animals are vulnerable to moisture, which limits its broad application in practice. However fully biodegradable polyvinyl alcohol (PVA), which is soluble in water, can be mixed with protein individually to overcome the limitation. In this work, the two proteins described above and PVA were combined to prepare protein nanofibers by electrospinning technology, which could achieve adsorption of Cu2+. As the protein content increased, the adsorption properties of the obtained nanofibers for Cu2+ showed a rising and then decreasing trend, with the highest point at 50 % of protein content, especially the collagen nanofibers, which reached 24.62 mg/g. Both protein nanofibers reached adsorption equilibrium after 15 h, but overall, collagen nanofibers showed a superior adsorption performance for Cu2+ than that by zein nanofibers. In the process of Cu2+ adsorption by protein nanofibers, both physical and chemical effect existed, and the physical effect played the leading role.

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation.

Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

Correction to: Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis.

[This corrects the article DOI: 10.1093/nsr/nwab232.].

miR-375 is highly expressed and possibly transactivated by achaete-scute complex homolog 1 in small-cell lung cancer cells.

In this study, we identified five miRNAs highly expressed in the small-cell lung cancer (SCLC) cell line NCI-H209. Among them, the expression levels of miR-375 were dramatically elevated in all SCLC cell lines examined, coincident with the expression of the transcription factor achaete-scute complex homolog 1 (ASCL1). Moreover, miR-375 was upregulated and correlated with ASCL1 in the cell lines generated from mouse SCLC-like tumors as well. Dual-luciferase assays further showed that ASCL1 activated the expression of miR-375 by binding to the three E-box elements in the miR-375 promoter. These results imply a role of ASCL1 in SCLC via the upregulation of miR-375.

[Fluorescent labeling of latent fingerprints with PAMAM capped ZnS QDs].

Stable PAMAM (polyamidoamine) capped ZnS (zinc sulfide) QDs (quantum dots) were prepared and characterized with UV-Vis spectrum and PL(photoluminescence) emission spectrum on the base of coordination of Zn2+ ions with PAMAM dendrimers. The results show that Zn2+ ions coordinated with N atoms of PAMAM ligand and the saturated coordinating time is about 6 h; PAMAM capped ZnS QDs emitted strong blue light under the irradiation of UV light at the wavelength of 365 nm, and the PL emission peak is at about 500 nm. Finally, the prepared PAMAM capped ZnS QDs were applied in the fluorescent labeling of latent fingerprints on tinfoils; Latent fingerprints emitting strong blue light and were successfully detected with good resolving rate.

Tailoring compatibility and toughness of microbial poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/bio-based polyester elastomer blends by epoxy-terminated hyperbranched polyester.

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is a type of promising bio-based thermoplastic for food packaging but find restricted industrial applications due to its brittleness and poor processability that is caused by its large spherulite sizes. In this study, for the purpose of toughening PHBV, bio-based engineering polyester elastomers (BEPE) were synthesized and blended with PHBV to prepare fully bio-based blends. In order to improve the compatibility and toughness of the BEPE/PHBV blends, epoxy-terminated hyperbranched polyesters (EHBP) were synthesized, which could be homogeneously dispersed into the PHBV/BEPE blends and improve the compatibility between the two phases of the matrix. The results showed that compared to those of the PHBV/BEPE blends, the elongation at break, impact strength and tensile toughness of the PHBV/BEPE blends with 3.0phr EHBP were enhanced by 134.2 %, 76.8 %, and 123.5 %, respectively. The crystallization study demonstrated the crystallization rate of PHBV/BEPE blends decreased due to the addition of EHBP. The reasons lied in that the addition of EHBP leads to chemical cross-linking between PHBV and BEPE. Meanwhile, the formation of hydrogen bonding, co-crystallization and chain entanglement increased the adhesion between PHBV and BEΡE, which generated the superior toughness of the blends.

Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer.

Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.

Rapid Multilateral and Integrated Public Health Response to a Cross-City Outbreak of Salmonella Enteritidis Infections Combining Analytical, Molecular, and Genomic Epidemiological Analysis.

On September 21, 2019, the Shenzhen and Dongguan Centers for Disease Control and Prevention received notification of a large cluster of suspected gastroenteritis involving primarily children who sought medical care at hospitals throughout two adjacent cities in China, Shenzhen, and Dongguan. A joint outbreak response was promptly initiated across jurisdictions in a concerted effort between clinical microbiologists, epidemiologists, and public health scientists. Concurrently, multiplex PCRs were used for rapid laboratory diagnosis of suspected cases; epidemiological investigations were conducted to identify the outbreak source, complemented by near real-time multicenter whole-genome analyses completed within 34 h. Epidemiological evidence indicated that all patients had consumed egg sandwiches served on September 20 as snacks to children and staff at a nursery in Dongguan, located near Shenzhen. Salmonella Enteritidis was isolated from case-patients, food handlers, kitchenware, and sandwiches with kitchen-made mayonnaise. Whole-genome single-nucleotide polymorphism (SNP)-based phylogenetic analysis demonstrated a well-supported cluster with pairwise distances of ≤1 SNP between genomes for outbreak-associated isolates, providing the definitive link between all samples. In comparison with historical isolates from the same geographical region, the minimum pairwise distance was >14 SNPs, suggesting a non-local outbreak source. Genomic source tracing revealed the possible transmission dynamics of a S. Enteritidis clone throughout a multi-provincial egg distribution network. The efficiency and scale with which multidisciplinary and integrated approaches were coordinated in this foodborne disease outbreak response was unprecedented in China, leading to the timely intervention of a large cross-jurisdiction Salmonella outbreak.

Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Small-cell lung cancer (SCLC) is a recalcitrant cancer characterized by high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using a Rb1 L/L /Trp53 L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as the SCLC metastasizing cell (SMC), which is progressively transitioned from the non-metastasizing NCAMloCD44hi cell (non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by the SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as the key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Efficient reproduction of cynomolgus monkey using pronuclear embryo transfer technique.

One of the technical bottlenecks in producing nonhuman primate models is that current assisted reproductive techniques, such as in vitro culture and frozen conservation of multicell-stage embryos, often result in poor embryo quality and subsequently lead to low birth rates. We investigated whether pronuclear embryo transfer can be used as an effective means for improving pregnancy and live birth rates of nonhuman primates. We collected 174 metaphase II oocytes by laparoscopy from 22 superovulated mature females and then fertilized these eggs using either in vitro fertilization or intracytoplasmic sperm injection, resulting in a 33.3% and a 50% fertilization rate, respectively. These 66 fertilized pronuclear-stage embryos were then tubally transferred to 30 recipients and led to 7 births and 1 abortion. Importantly, we observed that the highest live birth rate of approximately 64% was obtained when the transfer of pronuclear embryos was performed in the presence of new corpus luteum in the ovary of recipients between 24 h and 36 h after estradiol peak. Therefore, our experiments demonstrate that by matching the critical time window in the recipient's reproductive cycle for achieving optimal embryo-uterine synchrony, pronuclear embryo transfer technology can significantly improve the pregnancy rate and live birth of healthy baby monkeys. This efficient method should be valuable to the systematic efforts in construction of various transgenic primate disease models.