Semiconducting Polymer Dots for Dual-Wavelength Differential Background-Suppressed Photoacoustic Imaging.

Photoacoustic imaging (PAI) can sensitively detect regions and substances with strong optical absorption, which means that diseased tissue can be imaged with high contrast in the presence of surrounding healthy tissue through the photoacoustic effect. However, its signal intensity and resolution may be limited by background signals generated by endogenous chromophores such as melanin and hemoglobin. A feasible method for practical application of this so-called background-suppressed PAI is still lacking. In this work, a dual-wavelength differential background noise-suppressed photoacoustic tomography is developed based on organic semiconducting polymer dots (Pdots). The Pdots have a strong absorption peak at 945 nm, and then the absorption decreases sharply with the increase of wavelength, and the absorption intensity drops to only about a quarter of the original value at 1050 nm. The present system significantly suppresses the strong background noise of blood through dual-wavelength differential PAI, enabling precise monitoring of the distribution information of theranostic agents in diseased tissues. The signal-to-noise ratio of the theranostic agent distribution map is increased by about 20 dB. This work provides a platform for real-time and accurate monitoring of tumors and drugs, which helps avoid damage to healthy tissue during treatment and has clinical significance in cancer treatment.

Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC.

INTRODUCTION: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. METHODS: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitive site sequencing (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. RESULTS: Considerable commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DHS-seq to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. CONCLUSIONS: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Synthesis and biological evaluation of folic acid-rotenol conjugate as a potent targeted anticancer prodrug.

Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative-rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential.

Proteomics: A new dimension to decode small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy. Conquering it will require deep insight into its biology. In this issue of Cell, Liu and colleagues describe proteomic and phosphoproteomic landscapes of resected SCLC tumors and illustrate the potential of this knowledge to identify new SCLC vulnerabilities.

Determining the association of insurance coverage and survival outcomes in patients with olfactory neuroblastoma utilizing machine learning.

KEY POINTS: We use machine learning to examine health insurance and mortality in olfactory neuroblastoma. Private insurance significantly improved survival even after adjusting for confounders. The regression model also found no statistical difference between Medicare and no insurance.

Health Insurance Coverage and Survival Outcomes among Nasopharyngeal Carcinoma Patients: A SEER Retrospective Analysis.

Objectives Insurance coverage plays a critical role in head and neck cancer care. This retrospective study examines how insurance coverage affects nasopharyngeal carcinoma (NPC) survival in the United States using the Surveillance, Epidemiology, and End Results (SEER) program database. Design, Setting, and Participants A total of 2,278 patients aged 20 to 64 years according to the International Classification of Diseases for Oncology (ICD-O) codes C11.0-C11.9 and ICD-O histology codes 8070-8078 and 8080-8083 between 2007 and 2016 were included and grouped into privately insured, Medicaid, and uninsured groups. Log-rank test and multivariable Cox's proportional hazard model were performed. Main Outcome Measures Tumor stage, age, sex, race, marital status, disease stage, year of diagnosis, median household county income, and disease-specific survival outcomes including cause of death were analyzed. Results Across all tumor stages, privately insured patients had a 59.0% lower mortality risk than uninsured patients (hazard ratio [HR]: 0.410, 95% confidence interval [CI]: [0.320, 0.526], p < 0.01). Medicaid patients were also estimated to have 19.0% lower mortality than uninsured patients (HR: 0.810, 95% CI: [0.626, 1.048], p = 0.108). Privately insured patients with regional and distant NPC had significantly better survival outcomes compared with uninsured individuals. Localized tumors did not show any association between survival and type of insurance coverage. Conclusion Privately insured individuals had significantly better survival outcomes than uninsured or Medicaid patients, a trend that was preserved after accounting for tumor grade, demographic and clinicopathologic factors. These results underscore the difference in survival outcomes when comparing privately insured to Medicaid/uninsured populations and warrant further investigation in efforts for health care reform.

In vivo photothermal therapy monitored by multi-position calibrated photoacoustic thermometer.

With the ability of monitoring both temperature and photothermal agents, the photoacoustic (PA) imaging is a promising guiding tool for the photothermal therapy (PTT). The calibration line which depicts the relative variation of PA amplitude with the temperature should be obtained before using PA thermometer. In existing study, a calibration line was generated based on the data from one spatial position, and used in the whole region of interesting (ROI). However, the generalization of this calibration line in ROI was not verified, especially for ROI with heterogeneous tissues. Moreover, the relationship between the distributions of photothermal agents and effective treatment area is not clear, hindering using photothermal agents' distribution to optimize the administration-therapy interval. In this study, the distribution of effective photothermal agents and temperature in subcutaneously transplanted tumor mouse models were continuously monitored by 3D photoacoustic/ ultrasonic dual-modality imaging in 8 h after administration. With multiple micro-temperature probes in tumor and surrounding normal tissue, the PA thermometer was calibrated and evaluated at multiple spatial positions for the first time. The generalization in homologous tissue and tissue specificity in heterogeneous tissues of the PA thermometer calibration line were verified. Our study not only validated the effectivity of PA thermometer by proving the generalization of calibration line, but also removes a major obstacle that prevents applying the PA thermometer to a heterogeneous tissues ROI. The positive correlation between the proportion of effective treatment area and the proportion of effective photothermal agent area in the tumor was observed. Since the latter can be monitored with fast PA imaging, PA imaging can be employed as a convenient tool for seeking optimal administration-treatment interval.

Comparison of Effectiveness and Safety in Treating Acute Acromioclavicular Joint Dislocation with Five Different Surgical Procedures: A Systematic Review and Network Meta-Analysis.

This network meta-analysis aims to evaluate the comparative effectiveness and safety of suture anchors (SA), tendon grafts (TG), hook plates (HP), Tight-Rope (TR), and EndoButton (EB) in the treatment of acute acromioclavicular joint (ACJ) dislocation. The Embase, PubMed, and Web of Science databases were searched from their inception date to June 3, 2022. Studies included all eligible randomized controlled trials (RCTs) and cohort studies with the comparison of five different fixation systems among SA, TG, HP, TR, and EB were identified. All studies were reviewed, performed data extraction, and assessed the risk of bias independently by two reviewers. The primary outcomes are Constant-Murley score (CMS) improvement for assessing clinical efficacy, and complications. The second outcomes are visual analog scale (VAS) for assessing pain relief and the coracoclavicular distance (CCD) for assessing postoperative joint reduction. Version 2 of the revised Cochrane risk of bias tool for randomized trials (RoB 2) and the risk of bias in nonrandomized studies of interventions (ROBINS-I) were used to assess the RCTs and non-randomized trials, respectively. The continuous outcomes were presented as mean differences (MD), and risk ratios (OR) were used for dichotomous outcomes, both with 95% confidence intervals (CI). Surface under the cumulative ranking curves (SUCRA) results were calculated to offer a ranking of each intervention. We identified 31 eligible trials, including 1687 patients in total. HP showed less CMS improvement than TR and EB in both the Network Meta-analysis (NMA) and pairwise meta-analysis. HP also showed less CMS improvement than SA in NMA. For pain relief, HP performed worse than TR both in pairwise meta-analysis and NMA. No significant differences were found for the measured value of CCD. Both TR and EB showed a lower incidence of complications than HP in pairwise meta-analysis. The rank of SUCRA for CMS improvement was as follows: SA, TR, EB, TG, and HP; for pain relief: TR, EB, TG, SA, and HP; for CCD: HP, TR, SA, EB, and TG. For complications, HP showed the highest rank, followed by TG, EB, TR, and SA. SA shows better clinical effectiveness and reliable safety in the treatment of acute ACJ dislocation. Although HP is the most widely used surgical option currently, it should be carefully taken into consideration for its high incidence of complications.

Cigarette Smoke Enhances the Malignant Phenotype of Esophageal Adenocarcinoma Cells by Disrupting a Repressive Regulatory Interaction Between miR-145 and LOXL2.

Although linked to esophageal carcinogenesis, the mechanisms by which cigarette smoke mediates initiation and progression of esophageal adenocarcinomas (EAC) have not been fully elucidated. In this study, immortalized esophageal epithelial cells and EAC cells (EACCs) were cultured with or without cigarette smoke condensate (CSC) under relevant exposure conditions. Endogenous levels of microRNA (miR)-145 and lysyl-likeoxidase 2 (LOXL2) were inversely correlated in EAC lines/tumors compared with that in immortalized cells/normal mucosa. The CSC repressed miR-145 and upregulated LOXL2 in immortalized esophageal epithelial cells and EACCs. Knockdown or constitutive overexpression of miR-145 activated or depleted LOXL2, respectively, which enhanced or reduced proliferation, invasion, and tumorigenicity of EACC, respectively. LOXL2 was identified as a novel target of miR-145 as well as a negative regulator of this miR in EAC lines/Barrett's epithelia. Mechanistically, CSC induced recruitment of SP1 to the LOXL2 promoter; LOXL2 upregulation coincided with LOXL2 enrichment and concomitant reduction of H3K4me3 levels within the promoter of miR143HG (host gene for miR-145). Mithramycin downregulated LOXL2 and restored miR-145 expression in EACC and abrogated LOXL2-mediated repression of miR-145 by CSC. These findings implicate cigarette smoke in the pathogenesis of EAC and demonstrate that oncogenic miR-145-LOXL2 axis dysregulation is potentially druggable for the treatment and possible prevention of these malignancies.

mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K-AKT-mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.

BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.

Small-cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promising targets in SCLC-N subtype tumors. IMPLICATIONS: Our findings suggest that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.

Kinematic alterations of the ankle in subjects with generalized joint hypermobility compared with the controls: A cross-sectional study.

INTRODUCTION: Generalized joint hypermobility (GJH) is a hereditary connective tissue disease in which the range of motion (ROM) of multiple joints exceeds the normal range, and the ROM varies with age, gender, and ethnicity. At present, the six-degree-of-freedom (6-DOF) of ankle kinematics among people with GJH have not been studied. To investigate the kinematic characteristics in the ankle during treadmill gait of university students with generalized joint hypermobility compared to normal participants. We hypothesized that compared to the participants in the control group, those with GJH would exhibit kinematic characteristics of poorer active motion stability in the ankle during treadmill gait. METHODS: Healthy university student volunteers aged 18-24 (excluding those with a history of ankle trauma, etc.) were recruited and divided into a control group (50 volunteers) and a GJH group (Beighton score ≥4, 50 volunteers). Data of the 6-DOF kinematics of ankle was collected using a 3D gait analysis system. Variables were evaluated using independent t-tests and Wilcoxon signed-rank tests. RESULTS: In the proximal/distal parameter, proximal displacement was significantly increased in the GJH group compared with the control group during 4-9% and 96-97% of the gait phase (loading response and terminal swing phase), with an increase of (0.1-0.2 cm, p < .05). Regarding the proximal/distal, internal/external, plantarflexion/dorsiflexion, and anterior/posterior parameters, the participants with GJH exhibited greater ROM than those in the control group throughout the gait cycle (0.24 ± 0.22 cm vs. 0.19 ± 0.15 cm, p = 0.047, 5.56 ± 2.90° vs. 4.48 ± 3.30°, p = .020, 23.05 ± 5.75° vs. 20.36 ± 4.91°, p < .001, 0.65 ± 0.30 cm vs. 0.55 ± 0.27 cm, p = .018). However, ROM of inversion/eversion translation was found to be decreased in the GJH group compared to the control group (8.92 ± 1.59° vs. 9.47 ± 1.37°, p = .009). In addition, there was no statistical difference between the GJH group and the control group in ROM of medial/lateral translation (0.05 ± 0.06 cm vs. 0.04 ± 0.05 cm, p = .131). CONCLUSION: Our results confirm that our hypothesis is not valid. Although there were a few differences in each gait parameter of the ankle between the GJH group and the control group, the difference was not significant. These results indicate that the presence of GJH has less effect on ankle kinematics and enhance our knowledge of the relationship between GJH and 6-DOF of ankle kinematics.

Synthesis and in vitro cytotoxicity study of three di-organotin(IV) Schiff base di-acylhydrazone complexes.

Three di-organotin(IV) complexes have been synthesized by the reaction of Schiff base di-acylhydrazone ligands bis(5-chlorosalicylaldehyde) adipoylhydrazone and R2SnCl2 [R = Me (1), Ph (2), n-Bu (3)]. Structures of all complexes were characterized by 1H, 13C, 119Sn NMR, elemental analysis, IR and mass spectrometry. Experimental results showed that the symmetric diacylhydrazone ligands coordinate the tin atom in a hexadentate form, where the tin atom shows a penta-coordination, in a distorted triangular bipyramid geometry. Using MTT method, in vitro cytotoxicity of three complexes was determined against three cancer cell lines (A549, HeLa, HepG-2). Studies reveal that complex 3 showed the strongest cytotoxic activity among the three complexes, which may be correlated with the generation of intracellular reactive oxygen species. Uptake of complex 3 into cells and promotion of reactive oxygen species were visualized by confocal fluorescence imaging.

Biomimetic semiconducting polymer dots for highly specific NIR-II fluorescence imaging of glioma.

Glioma with very short medium survival time consists of 80% of primary malignant types of brain tumors. The unique microenvironment such as the existence of the blood-brain barrier (BBB) makes the glioma theranostics exhibit low sensitivity in diagnosis, a poor prognosis and low treatment efficacy. Therefore, the development of multifunctional nanoplatform that can cross BBB and target the glioma is essential for the high-sensitivity detection and ablation of cancer cells. In this study, C6 cell membrane-coated conjugated polymer dots (Pdots-C6) were constructed for targeted glioma tumor detection. As a new kind of biomimetic and biocompatible nanoprobes, Pdots-C6 preserve the complex biological functions of natural cell membranes while possessing physicochemical properties for NIR-II fluorescence imaging of glioma. After encapsulating C6 cell membrane on the surface of conjugated Pdots, Pdots-C6 exhibited the most favorable specific targeting capabilities in vitro and in vivo. In particular, this pilot study demonstrates that biomimetic nanoparticles offer a potential tool to enhance specific targeting to the brain, hence improving glioma tumor detection accuracy.

The effect of insulin and kruppel like factor 10 on osteoblasts in the dental implant osseointegration in diabetes mellitus patients.

Diabetes mellitus, metabolic disease, is characterized by chronic hyperglycemia. Patients with diabetes mellitus are susceptible to infection and therefore have a higher prevalence and progression rate of periodontal disease. We aimed to study the effect of insulin and kruppel like factor 10 (KLF10) on osteoblasts proliferation and differentiation, and expression of bone metabolism-related molecules and related signaling pathway molecules of AKT serine/threonine kinase 1 (AKT) and nuclear factor kappa B subunit 1 (NF-κB) through in vitro experiments, which can provide theoretical basis for the dental implant osseointegration in diabetic patients. The osteoblasts (hFOB 1.19 cells) were subdivided into KLF10 gene over expression group, KLF10 gene knockdown group, and KLF10 gene knockdown + insulin treatment group. CCK-8 and ELISA were, respectively, used for analysis of cell proliferation and differentiation. In vitro experiments were applied to detect the mRNA and protein expression of bone metabolism-related molecules, respectively. GSE178351 dataset and GSE156993 dataset were utilized to explore the expression of KLF10 in periodontitis. In osteoblasts, insulin treatment increased the expression of KLF10. Insulin and KLF10 could reduce the proliferation and differentiation of osteoblasts. Knockdown of KLF10 could increase the expression of bone metabolism-related molecules and activate AKT and NF-κB pathways, whereas insulin reversed this effect. KLF10 was up-regulated in both patients with periodontitis and type 2 diabetes mellitus with periodontitis. It is assumed that knockdown of KLF10 in insulin resistance may promote osteoblasts differentiation and dental implant osseointegration in diabetic patients.

Multi-pathway inducing ferroptosis by MnO2-based nanodrugs for targeted cancer therapy.

A multifunctional nanodrug (Tf-DHA-ASO-MnO2) based on manganese dioxide nanosheets was constructed by triple-dressing with transferrin, dihydroartemisinin, and antisense oligonucleotide sequences. Tf-DHA-ASO-MnO2 shows an effective targeted cancer therapy ability through the ferroptosis caused by the production of excessive lipid peroxides resulting from the combined effect of glutathione exhaustion, reactive oxygen species generation and down-regulation of glutathione peroxidase 4.

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.

Molecular Subtypes of Primary SCLC Tumors and Their Associations With Neuroendocrine and Therapeutic Markers.

INTRODUCTION: A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance. METHODS: We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3+ and CD8+ T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC. RESULTS: ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8+ T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8+ T-cells and a "desert" immunophenotype. CONCLUSIONS: We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.

Hookah Smoke Mediates Cancer-Associated Epigenomic and Transcriptomic Signatures in Human Respiratory Epithelial Cells.

INTRODUCTION: Although communal smoking of hookah by means of water pipes is perceived to be a safe alternative to cigarette smoking, the effects of hookah smoke in respiratory epithelia have not been well characterized. This study evaluated epigenomic and transcriptomic effects of hookah smoke relative to cigarette smoke in human respiratory epithelial cells. METHODS: Primary normal human small airway epithelial cells from three donors and cdk4 and hTERT-immortalized small airway epithelial cells and human bronchial epithelial cells were cultured for 5 days in normal media with or without cigarette smoke condensates (CSCs) or water pipe condensates (WPCs). Cell count, immunoblot, RNA sequencing, quantitative real-time reverse-transcriptase polymerase chain reaction, methylation-specific polymerase chain reaction, and quantitative chromatin immunoprecipitation techniques were used to compare effects of hookah and cigarette smoke on cell proliferation, global histone marks, gene expression, and promoter-related chromatin structure. RESULTS: CSC and WPC decreased global H4K16ac and H4K20me3 histone marks and mediated distinct and overlapping cancer-associated transcriptome signatures and pathway modulations that were cell line dependent and stratified across lung cancer cells in a histology-specific manner. Epiregulin encoding a master regulator of EGFR signaling that is overexpressed in lung cancers was up-regulated, whereas FILIP1L and ABI3BP encoding mediators of senescence that are repressed in lung cancers were down-regulated by CSC and WPC. Induction of epiregulin and repression of FILIP1L and ABI3BP by these condensates coincided with unique epigenetic alterations within the respective promoters. CONCLUSIONS: These findings support translational studies to ascertain if hookah-mediated epigenomic and transcriptomic alterations in cultured respiratory epithelia are detectable and clinically relevant in hookah smokers.

Second near-infrared photoactivatable biocompatible polymer nanoparticles for effective in vitro and in vivo cancer theranostics.

Photoacoustic imaging (PAI)-guided photothermal therapy (PTT) has drawn considerable attention due to the deeper tissue penetration and higher maximum permissible exposure. However, current phototheranostic agents are greatly restricted by weak absorption in the second near-infrared (NIR-II, 1000-1700 nm) window, long-term toxicity, and poor photostability. In this report, novel organic NIR-II conjugated polymer nanoparticles (CPNs) based on narrow bandgap donor-acceptor BDT-TBZ polymers were developed for effective cancer PAI and PTT. Characterization data confirmed the high photothermal conversion efficiency, good photostability, excellent PAI performance, and superior biocompatibility of as-obtained CPNs. In addition, in vitro and in vivo tests demonstrated the efficient PTT effect of CPNs in ablating cancer cells and inhibiting tumor growth under 1064 nm laser irradiation. More importantly, the CPNs exhibited rapid clearance capability through the biliary pathway and negligible systematic toxicity. Thus, this work provides a novel organic theranostic nanoplatform for NIR-II PAI-guided PTT, which advances the future clinical translation of biocompatible and metabolizable conjugated nanomaterials in cancer diagnosis and therapy.