Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

Effectiveness and safety of glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes: evidence from a retrospective real-world study.

Introduction: Global phase III clinical trials have shown superior hypoglycemic efficacy to insulin and other oral hypoglycemic agents. However, there is a scarcity of real-world data comparing different glucagon-like peptide 1 receptor agonist (GLP-1RA) directly. This study aimed to assess the safety and effectiveness of various GLP-1RA in treating type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify predictive factors for favorable treatment outcomes. Methods: This was a retrospective, single-center, real-world study. The changes in HbA1c, fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the percentage of participants who achieved HbA1c of <7%, 7%-8%, and ≥ 8% after GLP-1RA treatment was analyzed. The clinical factors that affect the effectiveness of GLP-1RA were analyzed. Results: At baseline, the 249 participants had a mean baseline HbA1c of 8.7 ± 1.1%. After at least three months of follow-up, the change in HbA1c was -0.89 ± 1.3% from baseline. Dulaglutide exerted a more significant hypoglycemic effect than immediate-release exenatide. The percentage of participants who achieved HbA1c<7% was substantial, from 6.0% at baseline to 28.9%. Average body weight decreased by 2.02 ± 3.8 kg compared to baseline. After GLP-1RA treatment, the reduction in SBP was 2.4 ± 7.1 mmHg from baseline. A shorter duration of diabetes and a higher baseline HbA1c level were more likely to achieve a good response in blood glucose reduction. Conclusions: This study provided real-world evidence showing that GLP-1RA significantly improved HbA1c, body weight, and SBP. The results can inform the decision-making about GLP-1RA treatment in daily clinical practice.

Association between phthalate exposure and obesity risk: A meta-analysis of observational studies.

According to epidemiological studies, phthalate exposure is associated with an increased risk of obesity in children and adults; however, these observations remain debatable. Therefore, we performed a systematic review and meta-analysis of the current literature to explore the effects of phthalate exposure on obesity. A systematic search was performed from inception to July 2022 in PubMed, EMBASE, Scopus, and Web of Science. Quality assessment was completed using criteria modified from Newcastle-Ottawa Scale (NOS) for the included studies. Meta-analysis showed that childhood exposure to MnBP, MBP, MEP, MiBP, and MECPP was positively correlated with obesity. In adults, MMP, MEP, and MiBP were positively correlated with adult abdominal obesity, while MEHHP, MECPP, and MCOP were positively correlated with adult general obesity. Subgroup analysis revealed that the positive correlation was particularly significant in women, as well as in Europe and the United States. Overall, a substantial association exists between phthalate exposure and obesity in children and adults. Sex and study site may provide limited sources of heterogeneity.

A Novel Aldisine Derivative Exhibits Potential Antitumor Effects by Targeting JAK/STAT3 Signaling.

The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors targeting JAK/STAT3 have enormous potential for cancer treatment. Herein, we modified aldisine derivatives by introducing the isothiouronium group, which can improve the antitumor activity of the compounds. We performed a high-throughput screen of 3157 compounds and identified compounds 11a, 11b, and 11c, which contain a pyrrole [2,3-c] azepine structure linked to an isothiouronium group through different lengths of carbon alkyl chains and significantly inhibited JAK/STAT3 activities. Further results showed that compound 11c exhibited the optimal antiproliferative activity and was a pan-JAKs inhibitor capable of inhibiting constitutive and IL-6-induced STAT3 activation. In addition, compound 11c influenced STAT3 downstream gene expression (Bcl-xl, C-Myc, and Cyclin D1) and induced the apoptosis of A549 and DU145 cells in a dose-dependent manner. The antitumor effects of 11c were further demonstrated in an in vivo subcutaneous tumor xenograft experiment with DU145 cells. Taken together, we designed and synthesized a novel small molecule JAKs inhibitor targeting the JAK/STAT3 signaling pathway, which has predicted therapeutic potential for JAK/STAT3 overactivated cancer treatment.

Tanshinone IIA Microemulsion Protects against Cerebral Ischemia Reperfusion Injury via Regulating H3K18ac and H4K8ac In Vivo and In Vitro.

Tanshinone IIA (TanIIA) has neuroprotective effects against cerebral ischemia reperfusion injury (CIRI), but its clinical application is limited due to poor water solubility and robust first pass elimination property. In this study, we developed microemulsion loaded with TanIIA (TanIIA ME) to break through these limitations, and explored the neuroprotective effect of TanIIA ME against CIRI and the epigenetic regulation mechanism of this neuroprotection. In vivo, middle cerebral artery occlusion (MCAO) models were treated with TanIIA ME and TanIIA solution or sodium valproate as a control. The effect of TanIIA ME on HDAC activity was determined by ELISA assay. In addition, we used primary hippocampal neurons to establish oxygen-glucose deprivation and reoxygenation (OGD/R) models. Lactate dehydrogenase (LDH) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed to investigate the neuroprotective efficacy of TanIIA ME. Subsequently, the expression of H3K18ac, H4K8ac, NMDAR1, caspase-3, and MAP-2 were investigated in MCAO or OGD/R models treated with TanIIA ME, TanIIA solution or sodium valproate. In vivo experimental results indicated that TanIIA ME significantly reduced neurological scores, infarction volume, and HDAC activity compared with TanIIA solution and MCAO group, accompanied by upregulation of H3K18ac, H4K8ac, and MAP-2 expression and downregulation of NMDAR1 and caspase-3 expression. Additionally, in OGD/R models, the results demonstrated that TanIIA ME treatment had a better neuroprotective effect along with increased H3K18ac, H4K8ac, and MAP-2 expression and decreased NMDAR1 and caspase-3 expression, compared with the other treatments except sodium valproate. Overall, TanIIA ME treatment exhibited superior efficacy in protecting against CIRI through mechanisms that might involve the inhibition of NMDAR1 and caspase-3 expression and the enhancement of MAP-2 expression by regulating histone H3K18 and H4K8 acetylation. Thus, TanIIA ME could be potentially used to develop a promising drug for the treatment of ischemic stroke.

Di(2-ethylhexyl) phthalate disturbs cholesterol metabolism through oxidative stress in rat liver.

Di(2-ethylhexyl) phthalate (DEHP) is widely used and has been implicated in hepatotoxicity, although the mechanism is unclear. Here, we investigated the effect of DEHP on hepatic cholesterol metabolism in SD rats exposed to 0 and 300 mg/kg/day DEHP for 12 weeks. An RNA-Seq analysis was performed to describe the hepatic responses to long-term DEHP exposure in combination with serological and oxidative stress parameter measurements. DEHP increased the serum levels of total cholesterol (TC), high-density lipoprotein (HDL), and alanine transaminase (ALT). Moreover, DEHP increased the content of malondialdehyde (MDA) and decreased antioxidant enzyme activities in the liver. Transcriptomic results revealed that DEHP dramatically changed the cholesterol metabolism pathway and oxidation-reduction process and depressed gene expression involved in cholesterol efflux and monooxygenase activity. Total antioxidant capacity (T-AOC) positively correlated with Abcg5 and Abcg8. Overall, this study showed the mechanisms underlying hepatotoxicity caused by DEHP, providing new insights into understanding DEHP poisoning.

[Study on Herpes Zoster Reactivation Induced by Arsenic in Patients with Acute Promyelocytic Leukemia].

OBJECTIVE: To investigate herpes zoster reactivation induced by arsenic in patients with acute promyelocytic leukemia (APL). METHODS: The clinical data of 212 patients with APL treated in the Department of Hematology of the First Affiliated Hospital of Xi'an Jiaotong University from 2008 to 2019 were retrospectively analyzed to observe the activation of varicella zoster virus induced by arsenic. Kaplan-Meier analysis, chi-square test, and boxplot were used to analyze and describe the cumulative dose of arsenic and the time from the beginning of arsenic treatment to the occurrence of herpes zoster. RESULTS: Excluding early death cases and early automatic discharge cases, 17 cases developed herpes zoster reactivation in 175 patients with APL treated with arsenic, and the cumulative median dose of arsenic was 6.2(2-12) mg/kg. Precise risk of reactivation of herpes zoster with 10 months in APL patients treated by arsenic was 9.7%. CONCLUSION: Arsenic treatment can induce high reactivation rate of herpes zoster virus.

Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC50 ranging from 1.11 to 2.80 µM on various cancer cell lines. Consistently, the 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 µM without significant change in the total STAT3 level. Moreover, 6e also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 µM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that 6e could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway.

Integrated metabolomics and transcriptomics reveal di(2-ethylhexyl) phthalate-induced mitochondrial dysfunction and glucose metabolism disorder through oxidative stress in rat liver.

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous pollutant that results in hepatotoxicity. However, an understanding of the systematic mechanism of hepatic injury caused by DEHP remains limited. Here, we performed a comprehensive metabolomics and transcriptomics analyses to describe hepatic responses of rats to long-term DEHP exposure and, together with pathology and functional injury of liver, systematically analyzed the pathogenesis and mechanisms of liver damage. SD rats were exposed to 0 and 600 mg/kg/day DEHP for 12 weeks. Thereafter, biochemical indicators and histopathological changes regarding liver function were detected. Metabolomics and transcriptomics profiles of rat liver samples were analyzed using a UPLC-MS/MS system and Illumina Hiseq 4000, respectively. DEHP induced hepatocyte structural alterations and edema, depressed monooxygenase activity, decreased antioxidant activities, aggravated oxidative damage, blocked the tricarboxylic acid cycle and respiratory chain, and disturbed glucose homeostasis in the liver. These findings indicate that reactive oxygen species play a major role in these events. Overall, this study systematically depicts the comprehensive mechanisms of long-term DEHP exposure to liver injury and highlights the power of metabolomics and transcriptomics platforms in the mechanistic understanding of xenobiotic hepatotoxicity.

An Investigation of the Cutting Strategy for the Machining of Polar Microstructures Used in Ultra-Precision Machining Optical Precision Measurement.

In this paper, an investigation of cutting strategy is presented for the optimization of machining parameters in the ultra-precision machining of polar microstructures, which are used for optical precision measurement. The critical machining parameters affecting the surface generation and surface quality in the machining of polar microstructures are studied. Hence, the critical ranges of machining parameters have been determined through a series of cutting simulations, as well as cutting experiments. First of all, the influence of field of view (FOV) is investigated. After that, theoretical modeling of polar microstructures is built to generate the simulated surface topography of polar microstructures. A feature point detection algorithm is built for image processing of polar microstructures. Hence, an experimental investigation of the influence of cutting tool geometry, depth of cut, and groove spacing of polar microstructures was conducted. There are transition points from which the patterns of surface generation of polar microstructures vary with the machining parameters. The optimization of machining parameters and determination of the optimized cutting strategy are undertaken in the ultra-precision machining of polar microstructures.

Cyclin G2 promotes the formation of smooth muscle cells derived foam cells in atherosclerosis via PP2A/NF-κB/LOX-1 pathway.

BACKGROUND: To investigate the role and underlying mechanism of cyclin G2 (G2-type cyclin) in the formation of vascular smooth muscle cells (VSMCs) derived foam cells. METHODS: The levels of α-SMA (alpha-SM-actin), p-NF-κB (phosphorylation nuclear transcription factors kappa B), and LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) were measured by immunohistochemistry and western blotting. The mouse aortic root smooth muscle cell line MOVAS was transfected to over-express cyclin G2, which were then stimulated with 80 µg/mL ox-LDL (oxidized low-density lipoprotein) to induce foam cell formation. DT-061 an activator of PP2A (protein phosphatase 2A) agonist was used to verify the role of PP2A in the process. RESULTS: Knocking out the Ccng2 gene in Apoe-/- mice alleviated aortic lipid plaque, foam cell formulation, ameliorative body weight, and LDL-cholesterol. We observed that the number of α-SMA positive cells was significantly decreased in Apoe-/-Ccng2-/- mice compared to Apoe-/- mice. Also, the protein levels of p-NF-κB and LOX-1 were markedly reduced in the aortic root of Apoe-/-Ccng2-/- mice. Upon stimulation with ox-LDL, upregulated cyclin G2 increased the intracellular lipid accumulation in MOVAS cells. Also, it suppressed the activity of PP2A but up-regulated LOX-1. Additionally, the cell nuclear translocation of p-NF-κB was increased. Interestingly, DT-061 intervention, re-activating the activity of PP2A, reduced the levels of nuclear p-NF-κB and LOX-1. This led to decreased lipid endocytosis reducing the formation of VSMCs- derived foam cells. CONCLUSIONS: Cyclin G2 increases the nuclear translocation of p-NF-κB by reducing the enzymatic activity of PP2A and upregulating LOX-1, thereby promotes the formation of VSMCs -derived foam cells in atherosclerosis.

Exploring the diagnostic value of photoacoustic imaging for breast cancer: the identification of regional photoacoustic signal differences of breast tumors.

We examined 14 benign and 26 malignant breast nodules by a handheld dual-modal PA/US imaging system and analyzed the data using the quantitative and semi-quantitative method. The PA signal spatial density and PA scores of different regions of the benign and malignant nodules were compared, and the diagnostic performances of two diagnostic methods based on PA parameters were evaluated. For both quantitative and semi-quantitative results, significant differences in the distributions of PA signals in different regions of benign and malignant breast lesions were identified. The PA parameters showed good performance in diagnosing breast cancer, indicating the potential of PAI in clinical utilization.

[Synergistic Anti-tumor Mechanisms of Low-frequency Ultrasound-targeted Microbubble Destruction:Mechanisms and Application].

Ultrasound contrast agent microbubbles combined with low frequency ultrasound named as low-frequency ultrasound-targeted microbubble destruction technology has become an effective and non-invasive anti-tumor therapy for deep tumors.It can enhance the efficacies of chemotherapy,gene therapy,immunotherapy,and anti-angiogenic therapy by improving cell membrane permeability and destroying tumor neovasculature.It can be applied to sonodynamic therapy and realize multimodal synergistic therapy on the basis of nanoparticles,which increases the anti-tumor efficiency and offers a promising target therapy for tumors.

Bivariate Metal-Organic Frameworks with Tunable Spin-Crossover Properties.

In this work, pyrazine (A), aminopyrazine (B), quinoxaline (C), and 5,6,7,8-tetrahydroquinoxaline (D) have been screened out among a large number of pyrazine derivatives to construct Hofmann-type metal-organic frameworks (MOFs) Fe(L)[M(CN)4 ] (M=Pt, Pd) with similar 3D pillared-layer structures. X-ray single-crystal diffraction reveals that the alternate linkage between M and FeII ions through cyano bridges forms the 2D extended metal cyanide sheets, and ligands A-D acted as vertical columns to connect the 2D sheets to give 3D pillared-layer structures. Subsequently, a series of bivariate MOFs were constructed by pairwise combination of the four ligands A-D, which were confirmed by 1 H NMR, PXRD, FTIR, and Raman spectroscopy. The results demonstrated that ligand size and crystallization rate play a dominant role in constructing bivariate Hofmann-type MOFs. More importantly, the spin-crossover (SCO) properties of the bivariate MOFs can be finely tuned by adjusting the proportion of the two pillared ligands in the 3D Hofmann-type structures. Remarkably, the spin transition temperatures, Tc ↑ and Tc ↓ of Fe(A)x (B)1-x [Pt(CN)4 ] (x=0 to 1) can be adjusted from 239 to 254 K and from 248 to 284 K, respectively. Meanwhile, the width of the hysteresis loops can be widened from 9 to 30 K. Changing Pt to Pd, the hysteresis loops of Fe(A)x (B)1-x [Pd(CN)4 ] can be tuned from 9 (Tc ↑=215 K, Tc ↓=206 K) to 24 K (Tc ↑=300 K, Tc ↓=276 K). This research provides wider implications in the development of advanced bistable materials, especially in precisely regulating SCO properties.

High-frequency ultrasound features of basal cell carcinoma and its association with histological recurrence risk.

BACKGROUND: Due to advances in high-frequency ultrasound technology, it is easier to detect fine structures of skin lesions. The aim of this study was to examine the ultrasonographic features and use recurrence risk stratification to assess the diagnostic performance of pre-operative ultrasound examination of basal cell carcinoma (BCC). METHODS: This was a retrospective study. Forty-six BCC lesions underwent pre-operative ultrasound examination using 50- and 20-MHz probes. Ultrasonographic shape, margin, internal echoes, hyper-echoic spots, posterior echoes, and depth of the lesion were evaluated and correlated with the risk of recurrence based on histological features. RESULTS: Forty-two patients had 46 skin lesions in total. The high-risk (n = 6) and low-risk (n = 40) groups exhibited considerable overlap in the ultrasonographic manifestations and no significant difference in margin (χ = 3.231, P = 0.072), internal echo (χ = 1.592, P = 0.207), or posterior echo (P = 0.169). However, high-risk BCCs tended to be irregular in shape than low-risk lesions (χ = 4.313, P = 0.038). Both types presented hyper-echoic spots (χ = 1.850, P = 0.174). Additionally, 78% of low-risk lesions were confined to the dermis (31/40), and 100% of high-risk lesions infiltrated into the sub-cutaneous tissue, resulting in a significant difference between the two groups (χ = 10.951, P = 0.001). Ultrasound detected sub-clinical lesions in five patients. CONCLUSIONS: High-frequency ultrasound can provide important information for pre-operative evaluation of risk in BCC foci and reveal hidden lesions. The technique may play a crucial role in guiding therapeutic options for BCC.

Six-Transmembrane Epithelial Antigen of the Prostate-1 (STEAP-1)-Targeted Ultrasound Imaging Microbubble Improves Detection of Prostate Cancer In Vivo.

PURPOSE: To investigate the feasibility of the 6-transmembrane epithelial antigen of the prostate-1 (STEAP-1)-targeted microbubbles for enhancing ultrasound imaging of prostate tumors in the nude mouse xenograft models. METHODS: Contrast agents were established by conjugating biotinylated STEAP-1 monoclonal antibodies with streptavidin coated SonoVue microbubbles. Then, ordinary SonoVue (Bracco, Milan, Italy) microbubble and STEAP-1-targeted SonoVue microbubble were used, respectively, for contrast-enhanced sonography to detect prostate tumors in the nude mouse xenograft models. The characteristics, including peak intensity, time to peak, area under the curve, and mean transit time, were measured. RESULTS: The biological characteristics of STEAP-1-targeted SonoVue microbubbles were stable. STEAP-1-targeted SonoVue microbubbles can successfully conjugate to prostate cancer cell lines in vitro. Enhancement of ultrasound signal intensity was determined after injection of STEAP-1-targeted SonoVue microbubble, compared with ordinary SonoVue microbubble. Higher intensities of ultrasound signals in xenograft tumor of prostate cancer were associated with increased levels of STEAP-1 expression. CONCLUSION: Our results suggest that SonoVue microbubble carrying STEAP-1 monoclonal antibody could improve the ultrasound visualization of prostate cancer and identify the tumor more effectively in vivo. A prospective study is required to validate our finding in patients with prostate cancer.

Application of ultrasound in aggressive angiomyxoma: Eight case reports and review of literature.

Aggressive angiomyxoma (AAM) is a rare tumour that often occurs in soft tissues of the female genital tract. Eight cases of AAM are reported in this article, and the clinical features and ultrasound and magnetic resonance imaging (MRI) results of the eight cases are reviewed and summarized. The main complaints of all the patients were palpable and painless masses in the vulva or scrotum. The lesions were mainly located in the vulva, pelvis, and perineal region, with a large scope of involvement. The sonographic features of AAM were characteristic. On sonography, all of the masses were of irregular shape and showed hypoechogenicity, with a heterogeneous inner echotexture. Intratumoural and peritumoural blood flows were detected by colour Doppler imaging. On real-time ultrasonic imaging, prominent deformation of the lesions was observed by compressing the masses with the probe. Some special imaging features were also revealed, including a laminated or swirled appearance of inner echogenicity, and a finger-like or tongue-like growth pattern. On MRI imaging, the lesions showed intermediate-intensity signals and intermediate to high-intensity signals on TI-weighted and T2-weighted sequences. A rapid and uneven enhancement pattern was demonstrated. After the comparison of sonographic features with MRI and pathological findings, we found the relevance of the ultrasonographic characteristics with MRI and histological features of AAM. Ultrasound can be a valuable imaging method for the preoperative diagnosis, evaluation of scope, and follow-up of AAM.

Nanotechnology for Cancer Therapy Based on Chemotherapy.

Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.

Microwatts continuous-wave pumped second harmonic generation in few- and mono-layer GaSe.

We demonstrate the first achievement of continuous-wave (CW) pumped second harmonic generation (SHG) in few- and mono-layer gallium selenide (GaSe) flakes, which are coated on silicon photonic crystal (PC) cavities. Because of ultrahigh second order nonlinearity of the two-dimensional (2D) GaSe and localized resonant mode in the PC cavity, SHG's pump power is greatly reduced to microwatts. In a nine-layer GaSe coated PC cavity, while the optical power inside the GaSe flake is only 1.5% of that in the silicon PC slab, the SHG in GaSe is more than 650 times stronger than the third harmonic generation in silicon slab, indicating 2D GaSe's great potentials to strengthen nonlinear processes in silicon photonics. Our study opens up a new view to expand 2D materials' optoelectronic applications in nonlinear regime and chip-integrated active devices.

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells.

Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.