In Situ Monitoring and Tuning Multilayer Stacking of Polymer Lamellar Crystals in Solution with Aggregation-Induced Emission.

Many types of self-assembled 2D materials with fascinating morphologies and novel properties have been prepared and used in solution. However, it is still a challenge to monitor their in situ growth in solution and to control the number of layers in these materials. Here, we demonstrate that the aggregation-induced emission (AIE) effect can be applied for the in situ decoupled tracing of the lateral growth and multilayer stacking of polymer lamellar crystals in solution. Multilayer stacking considerably enhances the photoluminescence intensity of the AIE molecules sandwiched between two layers of lamellar crystals, which is 2.4 times that on the surface of monolayer crystals. Both variation of the self-seeding temperature of crystal seeds and addition of a trace amount of long polymer chains during growth can control multilayer lamellar stacking, which are applied to produce tunable fluorescent patterns for functional applications.

Preoperative Radiotherapy Does Not Change the Existing Treatment Paradigm in Stage III Breast Cancer.

INTRODUCTION: Radiotherapy (RT) plays an indispensable role in postoperative breast cancer treatment. This study aimed to assess the feasibility of preoperative RT for stage III breast cancer by comparing preoperative RT with postoperative RT in terms of overall survival (OS). METHODS: Based on the information in the Surveillance, Epidemiology, and End Results database from 2000 to 2018, patients with stage III breast cancer who had undergone radical surgery and RT were divided into two groups: a preoperative RT group and a postoperative RT group. OS was calculated using Kaplan-Meier analysis. The Cox proportional hazards model was used to evaluate independent factors associated with OS. Propensity score matching (PSM) was used to balance stratification factors. RESULTS: In total, 9,605 patients were enrolled, of whom 9,456 received postoperative RT and 149 received preoperative RT. After a median follow-up of 72 months, postoperative RT was found to be superior to preoperative RT in terms of OS (p < 0.000). Compared to the postoperative RT group, the preoperative RT group showed a significantly higher risk of overall mortality without PSM in univariate (OS: hazard ratio [HR] = 1.653, 95% confidence interval [CI]: 1.288-2.123, p < 0.000) and multivariate analyses (OS: HR = 1.409, 95% CI: 1.096-1.810, p = 0.007). After PSM, the OS of the postoperative RT group was superior to the OS in the preoperative RT group (p = 0.041). Compared with the postoperative RT group, the preoperative RT group showed a significantly higher risk of overall mortality without PSM in univariate (HR = 1.312, 95% CI: 1.010-1.704, p = 0.042) and multivariate analyses (HR = 1.466, 95% CI: 1.127-1.906, p = 0.004). CONCLUSION: Preoperative RT does not improve OS in patients with stage III breast cancer and has a worse prognosis. Preoperative RT has not changed the existing treatment paradigm in the current therapeutic context for patients with stage III breast cancer.

Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy.

OBJECTIVE: The present study aimed to evaluate the clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy (NAC). METHODS: Patients with HER2 negative breast cancer receiving NAC from January 2017 to December 2020 were enrolled in this study. The clinicopathological characteristics, response to NAC, evolution of HER2 and prognostic value were retrospectively analyzed. RESULTS: 410 patients were included. The proportion of HR positive disease in HER2-low cases was higher than in HER2-zero population (75.8 % vs. 65.8 %, P = 0.040). No statistical significant difference in pCR rate was observed between HER2-low and HER2-zero patients (33.8 % vs. 39.3 %, P = 0.290) when pCR was defined as ypTis/0ypN0. Exploratory analysis revealed that the pCR rate of HER2-low cases was significantly lower than HER2-zero patients in the entire population (19.8 % vs. 33.3 %, P = 0.004) and HR positive population (12.6 % vs. 29.9 %, P = 0.001) when pCR was defined as ypT0ypN0. The evolution rate of HER2 expression after NAC was 31.0 % in HER2-zero patients and 24.7 % in HER2-low patients. Compared with patients with HR positive disease, patients with TNBC had higher evolution rate of HER2 expression after NAC (37.7 % vs. 23.6 %). Significant association was observed between HER2 evolution with histology type and Ki-67 index in HER2-zero patients and with lymph node involvement, HR status and Ki-67 index in HER2-low patients. Prognostic impact of HER2 evolution was not observed. CONCLUSIONS: HR positive and HR negative HER2-low breast cancer exhibit different clinicopathological features, response to NAC and HER2 evolution after treatment.

Brain metastasis in de novo stage IV breast cancer.

OBJECTIVES: Information of brain metastasis (BM) in de novo stage IV breast cancer is lacking, which is an unavoidable problem and dilemma in practice. Understanding the current situation is helpful for the clinical cognition and decision-making. METHODS: We retrospectively analyzed the clinical and survival information of de novo stage IV breast cancer with BM between 2015 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable logistic and Cox regression analyses were performed to identify predictors of BM and factors associated with all-cause mortality in de novo stage IV breast cancer, respectively. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. RESULTS: Our cohort consisted of 1366 patients with BM in de novo stage IV breast cancer, with an incidence of 8.38% in patients with metastatic disease to any distant site. Incidence was highest among patients with metastatic disease with HR-HER2+ (12.95%) and HR-HER2- (13.40%) subtypes. The higher the number of extracranial metastases, the higher the BM incidence. The median OS was 12.0 (95%CI: 10.426-13.574) months in BM group; it was longest in HR + HER2+ (19.0[95%CI: 11.793-26.207] months), and shortest in HR-HER2- (7.0 [95%CI:5.354-8.646] months). Marital status, subtype, and abundance of metastatic sites influenced morbidity and OS of BM in de novo stage IV breast cancer. CONCLUSIONS: Population-based estimates of the incidence and prognosis for patients with BM in de novo stage IV breast cancer were closely associated with subtype and metastatic burden. These findings may be helpful in developing diagnostic strategies, especially for brain screening.

BDE-47 Induces Immunotoxicity in RAW264.7 Macrophages through the Reactive Oxygen Species-Mediated Mitochondrial Apoptotic Pathway.

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2',4,4'-Tetrabrominated biphenyl ether (BDE-47) is the most biotoxic PBDE congener, and, in this study, we evaluated its toxicity toward RAW264.7 cells of mouse macrophages. The results show that exposure to BDE-47 led to a significant decrease in cell viability and a prominent increase in apoptosis. A decrease in mitochondrial membrane potential (MMP) and an increase in cytochrome C release and caspase cascade activation thus demonstrate that cell apoptosis induced by BDE-47 occurs via the mitochondrial pathway. In addition, BDE-47 inhibits phagocytosis in RAW264.7 cells, changes the related immune factor index, and causes immune function damage. Furthermore, we discovered a significant increase in the level of cellular reactive oxygen species (ROS), and the regulation of genes linked to oxidative stress was also demonstrated using transcriptome sequencing. The degree of apoptosis and immune function impairment caused by BDE-47 could be reversed after treatment with the antioxidant NAC and, conversely, exacerbated by treatment with the ROS-inducer BSO. These findings indicate that oxidative damage caused by BDE-47 is a critical event that leads to mitochondrial apoptosis in RAW264.7 macrophages, ultimately resulting in the suppression of immune function.

Retracted: Long noncoding RNA RHPN1-AS1, induced by KDM5B, is involved in breast cancer via sponging miR-6884-5p.

The above article, published online in Journal of Cellular Biochemistry on 31 January 2020 in Wiley Online Library (https://doi.org/10.1002/jcb.29645), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The authors asked to retract their article after substantial mistakes in experimental data were found, thus the results are considered to be invalid.

Theoretical study on the origin of the dual phosphorescence emission from organic aggregates at room temperature.

Purely organic materials with dual room temperature phosphorescence (RTP) phenomenon were reported recently, but the underlying mechanism was still ambiguous. Herein, we revealed the source of dual RTP emission, taking CzDPS crystal as prototype, by using hybrid quantum mechanics and molecular mechanics (QM/MM) coupled with the thermal vibration correlation function rate theory. Theoretical calculations verified that the emission lifetimes are prolonged from 70 ms in the higher triplet state T2 to 216 ms in the lowest triplet state T1, which is well consistent with the increase of RTP lifetimes from 74 ms for the peak at 465 nm to 627 ms for the band at 565 nm. This is because the radiative and nonradiative decay rates are larger for T2 â†’ S0 than that of T1 â†’ S0, which was mainly contributed by the synergistic effect of the increase of spin-orbit coupling and excitation energy, as well as the decrease of reorganization energy. Moreover, the simulated RTP spectra agree well with the experimental ones, including the emission position and profiles. Therefore, the upper-lying triplet excited states are responsible for the dual RTP in CzDPS crystal. This work could contribute to further understanding on the multiple luminescence of organic aggregates.

HER2-low expression does not affect the clinical outcomes of metastatic breast cancer treated with CDK4/6 inhibitor: A real-world study.

Background: There is accumulating evidence support human epidermal growth factor receptor 2 (HER2)-low as a biologically distinct subtype of breast cancer. The present study was conducted to explore whether HER2-low expression will affect the clinical efficacy of cyclin-dependent kinase (CDK) 4/6 inhibitor for patients with hormone receptor (HR)-positive, HER-2 negative metastatic breast cancer. Methods: Patients with HR+/HER2- metastatic breast cancer who were treated with palbociclib from January 2019 to June 2021 were retrospectively analyzed based on real-world clinical practice. HER2-zero was defined as immunohistochemistry (IHC) 0, and HER2-low was defined as IHC 1+ or IHC 2+/fluorescence in situ hybridization (FISH) negative. The primary end point was progression free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival(OS) and safety. Results: 45 patients received palbociclib plus aromatase inhibitor (AI) or fulvestrant therapy, including 24 HER-2-zero and 21 HER-2-low patients. There were no statistically significant differences in clinicopathological characteristics between the two groups. No significant differences were observed in ORR (41.7% vs. 28.6%, P=0.360) and DCR (79.2% vs. 76.2%, P=0.811) between HER-2-zero and HER-2-low patients. And simultaneously, HER2-zero and HER2-low patients obtained similar median PFS (16.2m vs. 14.1m, P=0.263). The median OS was not reached. Neutropenia and leukopenia were the most common adverse events. Grade 3-4 adverse events(AEs) occurred in 58.3% and 57.1% of patients, respectively. Conclusions: HER2-low expression does not affect the clinical efficacy of palbociclib and our present study did not support incorporating HER2-low into systemic therapy decisions for patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitor.

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer.

Background: Antiangiogenic agents provides an optional treatment strategy for patients with metastatic breast cancer. The present study was conducted to evaluate the efficacy and safety of anlotinib as third-line or above therapy for patients with HER-2 negative metastatic breast cancer. Methods: Patients with HER-2 negative metastatic breast cancer who have failed from prior therapy and treated with anlotinib monotherapy or combined with chemotherapy or immunotherapy from June 2018 to December 2020 were retrospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: 47 patients with HER-2 negative metastatic breast cancer received anlotinib monotherapy or combination therapy as third-line or above therapy. In the general population, 10 patients achieved PR, 25 patients had SD and 12 patients had PD. The overall ORR and DCR were 21.3% and 74.5%, respectively. Subgroup analysis suggested that there were no statistically significant differences in ORR and DCR with respect to HR status (positive vs. negative), treatment programs (monotherapy vs. combination) and treatment type in combination group (chemotherapy vs. immunotherapy). The patients who did not received previously anti-angiogenesis therapy had superior DCR (84.8% vs. 50.0%, P=0.012). Median PFS and OS were 5.0 months (95% CI=4.3-5.7) and 21.0 (95% CI=14.9-27.1) months, respectively. The PFS (6.5m vs. 3.5m, P=0.042)and OS (28.2m vs. 12.6m, P=0.040) were better in HR positive patients than HR negative patients. And simultaneously, patients who received anlotinib combination therapy obtained better PFS (5.5m vs. 3.0m, P=0.045). The incidence of Grade 3-4 adverse events(AEs) was 31.9%. Conclusions: Anlotinib monotherapy or combination therapy provide a viable third-line or above therapeutic strategy in patients with HER-2 negative metastatic breast cancer, a median PFS of 5.0 months was obtained with well tolerated toxicity.

Clinical, Pathological Complete Response, and Prognosis Characteristics of HER2-Low Breast Cancer in the Neoadjuvant Chemotherapy Setting: A Retrospective Analysis.

BACKGROUND: The present study was conducted to evaluate the clinical, pathological response, and prognosis characteristics of human epidermal growth factor receptor 2 (HER2)-low breast cancer in the neoadjuvant chemotherapy setting. METHODS: Patients with HER2-negative breast cancer who received neoadjuvant chemotherapy from January 2017 to December 2019 were retrospectively analyzed. HER2-negative breast cancer was divided into two groups: HER2-zero (defined as immunohistochemistry [IHC] 0) and HER2-low (defined as IHC 1+, or IHC 2+ and fluorescence in-situ hybridization-negative. RESULTS: Overall, 314 patients with HER2-negative breast cancer were analyzed. The proportion of HER2-low patients with hormone receptor (HR)-positive disease was higher than in triple-negative breast cancer (TNBC; 75.3% vs. 63.2%, p = 0.032). In HR-positive breast cancer, HER2-low tumors presented less nodal involvement (p = 0.023) and earlier clinical stage (p = 0.015) compared with HER2-zero tumors; however, in TNBC, HER2-low patients had a later clinical stage (p = 0.028). With the pathological complete response (pCR) defined as ypTis/0ypN0, there was no difference in pCR rates among the entire cohort, HR-positive disease, and TNBC. However, with the pCR defined as ypT0ypN0, the pCR rate in HER2-low breast cancer was significantly lower than HER2-zero breast cancer in the entire cohort (24.3% vs. 36.4%, p = 0.032) and the HR-positive subgroup (18.7% vs. 32.1%, p = 0.035), but not for TNBC. Multivariate analysis demonstrated that HER2 status (low vs. zero) was an independent predictive factor for pCR (p = 0.013) in HR-positive breast cancer. There were no statistically significant differences in 3-year disease-free survival and overall survival between HER2-low and HER2-zero breast cancer among the entire cohort, HR-positive disease, and TNBC. CONCLUSIONS: HER2-low breast cancer exhibits specific clinical features and different response to treatment associated with HR status in the neoadjuvant chemotherapy setting.

Hypoxia-Activated Fluorescent Probe Based on Self-Immolative Block Copolymer.

This work reports a hypoxia-activated fluorescent probe for tumor imaging by using self-immolative block copolymer with azobenzene linkage. The water-soluble polymer composed of self-immolative building blocks shows no obvious fluorescence. Under the hypoxic microenvironment of tumor cells, the azobenzene is reduced by the overexpressed azoreductase, which will trigger a domino-like disassembly of the self-immolative polymer. The released building blocks from the self-immolative polymer emit strong fluorescence, which shows the potential application in tumor imaging.

Hypoxia-Triggered In Situ Self-Assembly of a Charge Switchable Azo Polymer with AIEgens for Tumor Imaging.

In recent years, stimuli-responsive in situ self-assembly fluorescent probes for tumor imaging, which leverage the advantage of efficient penetrability and satisfactory accumulation, have attracted much attention. In this work, we rationally integrate charge switchable azobenzene moiety and long wavelength aggregation-induced emission fluorogens (AIEgens) into one water-soluble polymer to construct the hypoxia-triggered in situ self-assembly fluorescent probe for tumor imaging. Due to the good water solubility and the quenching effect of azobenzene moiety, the AIEgens containing polymer showed no significant fluorescence. Under a tumor hypoxic environment, the enzymatic reduction of azobenzene triggered cationic quaternary ammonium converting into anionic carboxylate. Then self-assembly nanoparticles were obtained, driven by the electrostatic interaction between negatively charged carboxylate ion and positively charged AIEgens, which emitted a strong orange-red fluorescence.

lncRNA PCNAP1 predicts poor prognosis in breast cancer and promotes cancer metastasis via miR­340­5p­dependent upregulation of SOX4.

The high metastatic rate of breast cancer is the significant cause of its poor prognosis. The long noncoding RNA (lncRNA) proliferating cell nuclear antigen pseudogene 1 (PCNAP1) plays important roles in the initiation and progression of cancers; however, its regulatory function and molecular mechanism in breast cancer metastasis remains unknown. Therefore, we investigated the roles of lncRNA PCNAP1 in breast cancer metastasis by modulating the microRNA (miR)­340­5p/SOX4 axis using quantitative real­time PCR, in vivo mouse models, nucleo­cytoplasmic separation, western blot analysis, scratch assays, Transwell assays, luciferase reporter assays and MS2­RIP, in vitro and in vivo. lncRNA PCNAP1 was found to be upregulated in human breast cancer tissues, and high lncRNA PCNAP1 levels predicted poor overall survival. Function assays showed that knockdown of lncRNA PCNAP1 suppressed the migration and invasion of breast cancer cells in vitro and in vivo. Mechanistically, lncRNA PCNAP1 functioned as a competing endogenous (ce)RNA for miR­340­5p to facilitate the expression of its target gene SRY­box transcription factor 4 (SOX4), promoting migration and invasion of breast cancer cells. Overall, we found that lncRNA PCNAP1 predicted a poor prognosis in breast cancer and promoted cancer metastasis via miR­340­5p­dependent upregulation of SOX4 expression. These results suggest that lncRNA PCNAP1 has potential as an alternative therapeutic target to suppress breast cancer metastasis.

In situ construction of a self-assembled AIE probe for tumor hypoxia imaging.

This communication reported a hypoxia-responsive fluorescent probe based on the in situ concept, which combines a water-soluble azobenzene containing copolymer with a carbamate linkage and an anionic water-soluble aggregation-induced emission fluorogen (AIEgen) tetraphenylethene (TPE). The water-soluble copolymer can be transformed into a protonated primary amine containing polymer by the reduction of the azo bond and through a 1,6-self elimination cascade reaction under hypoxic conditions. The transition of anionic TPE from the molecular dispersed state to the aggregation state induced by self-assembly with the cationic polymer would lead to an obvious increase in fluorescence according to the AIE characteristics.

Superhydrophobic lotus-leaf-like surface made from reduced graphene oxide through soft-lithographic duplication.

In this work, reduced graphene oxide (RGO) was used as a material to fabricate superhydrophobic lotus-leaf-like surfaces through soft-lithographic duplication. In the process, a polydimethylsiloxane (PDMS) stamp was prepared by replica molding against the surfaces of fresh lotus leaves that functioned as masters. A dispersion of octadecylamine-modified reduced graphene oxide (ODA-RGO) in tetrahydrofuran (THF) was used as "ink". The lotus-leaf-like surfaces were fabricated by microcontact printing on the solid substrates. The results showed that due to the good processibility of the ODA-RGO dispersion, the printed layers display papillary micro/nano-structures with high fidelity to the surfaces of lotus leaves. The RGO-based lotus-leaf-like surfaces possess superhydrophobic characteristics with a water contact angle larger than 160° and the contact angle hysteresis less than 5°. Due to the excellent chemical stability of the RGO sheets, as-prepared surfaces show remarkable superhydrophobic stability. The lotus-leaf-like surfaces maintain the superhydrophobicity after heating treatment at 150 °C for 24 h or being exposed to corrosive solutions with different pH values for 12 h. The present findings prove that the RGO-based material is an ideal candidate for fabrication of environment-durable lotus-leaf-like surfaces, which can be expected to have applications in different areas.

Strategies for Tumor Hypoxia Imaging Based on Aggregation-Induced Emission Fluorogens.

Hypoxia, as a crucial characteristic of cancer, has become an extremely significant direction for researchers to construct fluorescent probes for early diagnosis of tumors. Aggregation-induced emission fluorogens (AIEgens) possess many superior properties to those of conventional fluorophores due to aggregation-induced emission (AIE) features, such as a linear concentration-dependent increase in brightness, remarkable resistance to photobleaching, and the long-term tracking and imaging of cells. Constructing hypoxic response AIEgen-based probes will be very useful for the early diagnosis of tumors. Herein, several hypoxia-responsive probes based on AIEgens reported in the last three years are reported; these examples may lead to the construction of hypoxia-responsive AIE probes used for tumor hypoxia imaging in the future. In addition, typical, conventional hypoxia-responsive bioprobes are presented to further understand hypoxia-responsive fluorescent probes based on AIEgens.

Adsorption behavior of heavy metal ions from aqueous solution onto composite dextran-chitosan macromolecule resin adsorbent.

Dextran-chitosan (DC) macromolecule resin was synthesized by ultrasonic heating and applied to adsorb various heavy metal ions (Cu2+, Co2+, Ni2+, Pb2+, Cd2+). The morphology and structure of the samples were characterized by various testing methods. The effects of five factors on the adsorption properties were studied. The adsorption kinetics, thermodynamics and isotherm models were discussed theoretically. The results show that the adsorption of heavy metal ions by DC resin is a spontaneous single molecule chemical adsorption, and the adsorption capacities of DC resin for Cu2+, Co2+, Ni2+, Pb2+ and Cd2+ were 342 mg g-1, 232 mg g-1, 184 mg g-1, 395 mg g-1, and 269 mg g-1, respectively at 20 °C, pH = 7 and adsorbent dose is 0.01 g. In addition, DC resin adsorbent has good reusability.

Relationships between SNPs and prognosis of breast cancer and pathogenic mechanism.

BACKGROUND: Association between several single-nucleotide polymorphisms (SNPs) and breast cancer risk has been identified through genome-wide association studies (GWAS), but little is known about their significance in patients' prognosis. We screened SNPs which were related to the prognosis of breast cancer in Henan Han population, analyzed relevant genes by bioinformatics in database, and further constructed the genetic regulatory network involved in the pathogenesis of breast cancer. METHODS: We evaluated five SNPs in 232 cases of breast cancer at the Affiliated Tumor Hospital of Zhengzhou University. Relationships between five SNPs, clinical prognostic indicators, and disease-free survival (DFS) were evaluated by Kaplan-Meier analysis and Cox proportional hazards model. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of genes and Genome (KEGG) analysis were carried out to preliminarily establish genetic regulation network model of breast cancer. Bayesian algorithm was used to optimize the model. RESULTS: The multivariate Cox proportional hazards model confirmed that SNP rs3803662 (TOX3/TNRC9) had correlation with DFS independently. In the multivariate Cox proportional hazards model, compared with GA/AA, GG increased the recurrent risk of breast cancer (p = .021, hazard ratio [HR] = 2.914). GO analysis showed that the function of TOX3/TNRC9 included biological_process, molecular_function, and cellular_component. According to KEGG signaling pathway database, the map of breast cancer-related gene regulatory network was obtained. IGF-IGF1R-PI3K-Akt-mTOR-S6K was the best possible pathway for the differentiation of breast cancer cells in this network and ER-TOX3/TNRC9 was the best possible pathway for the survival of tumor cells in this network by Bayesian theorem optimization. CONCLUSIONS: SNP rs3803662 (TOX3/TNRC9) is an independent prognostic factor for breast cancer in Henan Han Population. ER-TOX3/TNRC9 is the best possible pathway involved in the pathogenesis of breast cancer.

"Turn-On" Activatable AIE Dots for Tumor Hypoxia Imaging.

A hypoxia-responsive fluorescence probe of amphiphilic PEGylated azobenzene caged tetraphenylethene (TPE) for tumor cell imaging is reported; it possesses excellent solubility in aqueous medium due to the easy formation of micelles by self-assembly. The fluorescence resonance energy transfer (FRET) process ensures that the fluorescence of the azobenene caged AIE fluorogen is quenched efficiently. When cultured with tumor cells, the azo-bond is reduced under hypoxia conditions and the fluorescence of AIE fluorogen recovers dramatically. Besides using UV light, NIR light can also be used as the excited light resource to generate the fluorescence due to the two-photon fluorescence imaging process.