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PURPOSE Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti–PD-L1 monoclonal antibody, in R/R ENKTL. METHODS Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee–assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Hairpin DNA containing split G-quadruplex at its terminus displayed tagging position-dependent horseradish peroxidase activity. In general, the hairpin DNA coupled with one GGG repeat at its 5’-terminus and three GGG repeats at its 3′-terminus demonstrated strong catalytic activity, while slight activity was observed after exchanging the position of split G-quadruplex sequence. Inspired by these observations, a novel colorimetric biosensor for nuclease activity assay was developed by selecting S1 nuclease as the model. Specifically, S1 nuclease cleaves the split G-quadruplex into mono- or oligonucleotide fragments, thereby suppressing the catalytic activity, accompanied by a color change from blue to colorless. Under optimum conditions, S1 nuclease was determined with a linear range from 1.60 to 17.6 U/mL and a detection limit of 1.458 U/mL. The constructed method was simple and did not require complex sequence design, expensive instrumentation, and probe labeling. Most importantly, this work facilitates a better understanding of the catalytic mechanism of the DNAzyme and provides an example of the practical application of G-quadruplex-based DNAzyme.

SummaryNeoliberal land reforms to increase economic development have important implications for biodiversity conservation. This paper investigates land reform in New Zealand’s South Island that divides leased state-owned stations (ranches) with private grazing leases into state-owned conservation land, private land owned by the former leaseholder and private land under protective covenant (similar to conservation easement). Conserved lands had less threatened vegetation, lower productivity, less proximity to towns and steeper slopes than privatized lands. Covenants on private land were more common in intermediate zones with moderate land-use productivity and slope. Lands identified with ecological or recreational ‘significant inherent values’ were more likely to shift into conserved or covenant status. Yet among lands with identified ecological values, higher-threat areas were more likely to be privatized than lower-threat areas. This paper makes two novel contributions: (1) quantitatively examining the role of scientific recommendations about significant inherent values in land reform outcomes; and (2) examining the use of conservation covenants on privatized land. To achieve biodiversity goals, it is critical to avoid or prevent the removal of land-use restrictions beyond protected areas.

The development of novel luminescent materials with multi-stimuli responsive and multi-functional properties is required. In this work, we designed and synthesized a novel AIE-based fluorenone derivative, MBPF. The donor–acceptor–donor (D–A–D) structure promoted the intermolecular hydrogen bonding capacity of the exposed oxygen atom in fluorenone. MBPF displayed three different aggregation morphologies: an amorphous floccule Y-MBPF with yellow-green luminescence, a block crystal O-MBPF with orange luminescence, and a needlelike crystal R-MBPF with red emission. They all exhibited reversible stimuli-response phase transitions to temperature and shear, accompanied by fluorescence switching. The orange crystal O-MBPF was also sensitive to isotropic hydrostatic pressure with prominent and contrasting luminescent conversion. Furthermore, we prepared MBPF nanocrystallites and encapsulated them with DSPE–PEG and the monoclonal antibody cetuximab (C225) to obtain MBPF-C225 NPs, which were biocompatible and photostable. They could be used for specific cancer cell imaging through receptor-mediated endocytosis.

This study aimed to explore the function of IFN-γ+ IL-17+ Th17 cells on fibrosis in systemic scleroderma (SSc). Blood and skin samples were collected from 20 SSc cases and 10 healthy individuals. The percentage of IFN-γ+ IL-17+ Th17 cells was detected using flow cytometry. The in vitro induction of IFN-γ+ IL-17+ Th17 cells was performed adopting PHA and rIL-12. Gene expression was detected via quantitative real-time polymerase chain reaction (qRT-PCR), whereas western blot analysis was adopted for protein analysis. The distribution of IFN-γ+ IL-17+ Th17 cells was significantly increased in SSc cases and positively correlated with SSc stages (P = .031), disease duration (P = .016), activity (P = .025) and skin scores (P < .001). In vitro, IFN-γ+ IL-17+ Th17 cells could promote the expressions of α-SMA and COL1A1, revealing increased fibroblasts' proliferation and enhanced collagen-secreting capacity. In addition, IL-21 expression was significantly increased in co-culture medium of IFN-γ+ IL-17+ Th17 cells and fibroblasts (P < .001). IL-21 neutralizer treatment resulted in the down-regulation of α-SMA and COL1A1. IL-21 was confirmed as an effector of IFN-γ+ IL-17+ Th17 cells in fibrosis process. The distribution of IFN-γ+ IL-17+ Th17 cells was significantly increased in SSc cases and positively correlated with disease activity. IFN-γ+ IL-17+ Th17 cells could promote fibroblast proliferation and enhance collagen-secreting ability via producing IL-21, thus contributing to fibrosis in SSc.

It has been demonstrated that thymine–guanine (T–G) mismatches in duplex DNA specifically coordinate with mercury ion (Hg2+), forming T–Hg2+–G base pairs. However, the binding performance of T–G mismatches with Hg2+ and its application in biosensors have been rarely reported so far. In this study, the binding between T–G mismatches and Hg2+ was investigated and efforts were made to systematical characterize the analytical performance of T–G mismatches in the determination of Hg2+ and glutathione (GSH), where the thymine–thymine (T–T) mismatches were used as the reference. In specific, Hg2+ induced the conformational change of the fluorescently labeled DNA (FDNA) consisted of seven T–T mismatches, resulting in the dissociation of FDNA with its complementary sequence labeled with a quencher, followed by the disappearance of the fluorescence resonance energy transfer (FRET). The experimental results suggest that the T–G mismatch showed faster signaling kinetics and high sensitivity in sensing Hg2+ with a limit of detection of 4.72 nM for Hg2+. Moreover, the platform based on the T–Hg2+–G structure was successfully applied to determine glutathione with a detection limit of 18.96 nM. These findings of this study may describe the interactions between Hg2+ and nucleobases and extend the applications of Hg2+–mediated base pairs.

A gold nanoparticle (AuNP)–based sensing strategy based on rapid reduction of Au(I→0) is proposed. As a proof-of-concept study, the proposed sensing principle is designed for simultaneous and colorimetric detection and discrimination of multiple proteins. In the presence of H2O2, the target proteins could reduce Au(I) (i.e. HAuCl2) to AuNPs with different sizes, shapes and dispersion/aggregation states, thus resulting in rapidly colorimetric identification of different proteins. The optical response (i.e. color) of AuNPs is found to be characteristic of a given protein. The color response patterns are characteristic for each protein and can be quantitatively differentiated by statistical techniques. The sensor array is capable of discriminating proteins at concentrations as low as 0.1 μg/mL with high accuracy. A linear relationship was observed between the total Euclidean distances and protein concentration, providing the potential for protein quantification using this sensor array. The limit of detection (LOD) for catalase (Cat) is 0.08 μg/mL. The good linear range (from 0 to 8 μg/mL) has been used for the quantitative assay of Cat. To show a potentially practical application, this method was used to detect and discriminate proteins in human urine and tear samples.

7501 Background: R/R ENKTL is a rare and aggressive type of non-Hodgkin’s lymphoma. Responses to chemotherapy after failure of prior asparaginase-based regimen were not durable with a median OS of < 7 months (mos) and 1-year OS rate of < 20% (Lim et al, Ann Oncol 2017; Bellei et al, Haematologica 2018). The only targeted therapy approved in China for R/R peripheral T cell lymphoma (ENKTL included) showed an ORR of 18.8% and a CR rate of 6.3% (Shi et al, Ann Oncol 2015). Here, we present the primary analysis from GEMSTONE-201, the largest registrational study reported to date to evaluate an anti-PD-L1 mAb in R/R ENKTL. Suge received breakthrough therapy designation from US FDA in 2021 for adult R/R ENKTL pts based on preliminary data of this study. Methods: Pts with ECOG PS of 0/1 and histologically confirmed ENKTL who failed prior asparaginase-based regimen were enrolled. Pts accepted suge at 1200 mg Q3W, iv, for up to 24 mos, until progression, death, or withdrawal from study. The primary endpoint was ORR (CR+PR) assessed by independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included investigator-assessed ORR, CR and PR rate, DoR assessed by IRRC and investigators, and safety. Results: As of the data cutoff date, Nov 10, 2021, 80 pts were enrolled and treated (median follow-up of 13.4 mos). Median age was 48 years (range 29-74); 64% were males; 74% had ECOG PS of 1 at baseline; 68% had stage IV disease; about half (49%) received ≥ 2 lines of prior systemic therapy. The median duration of treatment was 5.2 mos (range 0.7-37.4); 23 pts remained on treatment. Among the 78 evaluable pts as per IRRC, ORR was 46.2% (95% CI: 34.8%, 57.8%); 29 (37.2%) pts achieved CR; median DoR was not reached (NR); 12-mo DoR rate was 86%. Investigator’s assessments in 79 evaluable pts were consistent with IRRC results, i.e. ORR of 45.6% (95% CI: 34.3%, 57.2%), 24 (30.4%) pts with CR, and median DoR of NR. The 1- and 2-year OS rates were 68.6% and 54.6%, respectively; median OS was NR (range 0.9-37.2+ mos). Of all pts, 96% (n = 77) had at least one AE. The most common AEs were pyrexia and WBC decreased (n = 24 each, 30%). Grade ≥ 3 AEs occurred in 31 (39%) pts. Suge-related AEs occurred in 61 (76%) pts and were mostly (60%) Grade 1/2. The most common irAE assessed by sponsor was hypothyroidism (n = 13, 16%). SAEs occurred in 18 (23%) pts; 5 (6%) pts had suge-related SAEs which had all been resolved (1 with sequelae). Fatal AEs occurred in 5 (6%) pts and none were suge-related as assessed by investigators. Conclusions: Suge has demonstrated deep and durable anti-tumor activity in R/R ENKTL pts, with a high CR rate and a promising OS benefit trend comparing to historical data. Suge had a well-tolerated safety profile and no new safety signals were detected. Primary analysis indicates that suge could provide a new treatment option to R/R ENKTL pts. Clinical trial information: NCT03595657.

Aim Recent studies have shown that anti-Ro52 antibody is associated with both interstitial lung disease (ILD) and the degree of disease severity in juvenile patients with dermatomyositis (DM). We found that more than half of adult patients with DM were positive for anti-Ro52 antibody. In this study, we analysed the correlation between anti-Ro52 antibody and ILD in adult patients with DM. Method Serum samples were collected from 153 adult inpatients with DM, at the First Medical Centre of PLA General Hospital, Beijing, China, who met the classification criteria of idiopathic inflammatory myopathies from March 1, 2016 to September 30, 2019. The patients were followed up to May 31, 2020. Immunoblotting was used to detect 16 types of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) from serum samples. High-resolution computed tomography (HRCT) was used to calculate the ILD score, and tumours were screened. Clinical data and HRCT scores were evaluated and analysed retrospectively. Results Our results showed that anti-Ro52 antibodies were the most commonly found antibodies in patients with DM, with a positive rate of 52.9%. Anti-Ro52, anti-aminoacyl-tRNA synthetase (anti-ARS), and anti-melanoma differentiation-related gene 5 (anti-MDA5) antibodies were found to be risk factors for ILD development. Anti-Ro52 antibodies had a strong predictive effect on ILD in patients with DM. Conclusion The occurrence of ILD is highly likely in patients with DM who are positive for the anti-Ro52 antibodies. Thus, anti-Ro52 antibodies is an independent risk factor for ILD in patients with DM.

We propose an aptamer-tethered DNA nanofirecracker probe that realizes molecular recognition-activatable disassembly of the DNA nanostructure for imaging of target molecules in living cells. The design principle offers a new paradigm to develop nucleic acid nanocircuits for live-cell study and manipulation.

Background Recent studies have shown that Ro-52 antibody is associated with interstitial lung disease(ILD) in children with dermatomyositis(DM) and with the degree of disease severity. Moreover, we found that 50% or more cases of adult patients with DM tested positive for antibody Ro-52. Here, we analyzed the correlation between antibody Ro-52 and ILD in inpatients with DM. Objective To explore the correlation between Ro-52 antibody and ILD of DM. Methods A total of 153 patients with DM were collected, who met the classification criteria of idiopathic inflammatory myositis. Immunoblotting was used to detect 16 myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) from patient serum samples. High-resolution computed tomography (HRCT) was used to calculate the ILD severity score, and the tumors were screened. The clinical data and CT scores were analyzed retrospectively. Results Our data showed that antibodies of Ro-52 and MDA5 were risk factors for ILD development in patients with DM. Antibody Ro-52 was the most commonly occurring (52.9%) antibody in DM patients. The presence of Ro-52 in DM patients strongly suggested the possibility for the occurrence of ILD (86.4%). The severity of Ro-52-positive cases was higher than that of the Ro-52-negative cases.Ro-52 may increase the incidence of ILD when combined with other antibodies of PM-Scl75, PM-Scl100, TIF1-𝛾,Mi-2β,and MDA5. Conclusions The occurrence of ILD is highly likely in patients with DM having the antibody Ro-52. Thus, Ro-52 is a risk factor for ILD in DM.

This study aimed to explore the function of IFN‐γ+IL‐17+Th17 cells on fibrosis in systemic scleroderma (SSc). Blood and skin samples were collected from 20 SSc cases and 10 healthy individuals. The percentage of IFN‐γ+IL‐17+Th17 cells was detected using flow cytometry. The in vitro induction of IFN‐γ+IL‐17+Th17 cells was performed adopting PHA and rIL‐12. Gene expression was detected via quantitative real‐time polymerase chain reaction (qRT‐PCR), whereas western blot analysis was adopted for protein analysis. The distribution of IFN‐γ+IL‐17+Th17 cells was significantly increased in SSc cases and positively correlated with SSc stages (P = .031), disease duration (P = .016), activity (P = .025) and skin scores (P

Background and objectives Alopecia areata (AA) is an autoimmune disease characterized by T cell-mediated attack on the hair follicle. Although there are a wide range of therapies, the majority of them are not satisfactory due to side effects or limited efficacy. In this study, we sought to evaluate the efficacy, influence factors, and safety of 308-nm excimer lamp with minoxidil in the treatment of AA. Study design/materials and methods This was a prospective, single-blinded, self-control study, using 308-nm excimer lamp with minoxidil for the treatment of AA. One selected alopecia lesion was divided into the control and treated side. Topical minoxidil (2% solution) was used on both sides, but 308-nm excimer lamp was only added to the treated side. The primary endpoint was the discrepancy of hair growth on each side. Results A total of 38 patients (24 males and 14 females) with AA were enrolled in this study, and 34 of them (21 males and 13 females) completed the whole treatment. Thirty-two (94.2%) patients achieved clinical response, and 21 (44.1%) patients achieved with >50% hair regrowth on the treated side after a 12-week treatment. The hair number and diameter on the treated side had significantly increased compared with the control side with statistical differences. Hyperpigmentation and erythema occurred on the treated side of all the patients but they were considered tolerable. Patients of younger age or with smaller area of lesion had better effect. Conclusions The 308-nm excimer lamp with minoxidil therapy can be considered as an effective and safe treatment for single or multiple AA. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Background: Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin's lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients with relapsed or refractory (R/R) PTCL and ENKTCL are very poor. There is still a lack of effective treatment for these patients. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Liposome preparations have shown higher anti-tumor effect and lower toxicities due to modified drug release and particle shape. Mitoxantrone hydrochloride liposome (PLM60) was manufactured by Shijiazhuang Pharmaceutical Group Co., Ltd. (CSPC). High accumulation in tumor tissue was a key characteristic of PLM60 in our preclinical investigation. The pharmacokinetic parameters, especially half-life of PLM60 was prolonged significantly in phase Ⅰ trial. Phase II exploratory clinical trial showed promising results in R/R PTCL. Therefore, we conducted this pivotal registration phase II trial to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At the present time, this was the first clinical trial to assess PLM60 in treating R/R PTCL and ENKTCL worldwide. Methods : This was a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult patients with histologically confirmed PTCL (mainly peripheral T cell lymphoma, NOS, PTCL-NOS; angioimmunoblastic T-cell lymphoma, AITL; anaplastic large cell lymphoma, ALCL) after prior anthracyclines-based chemotherapy or ENKTCL failed from asparaginase-contained regimen, ECOG performance status ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion were recruited in this trial. Main exclusion criteria were patients with a cumulative dose of doxorubicin >360 mg/m2, known history of a clinically significant cardiac malfunction or uncontrollable cardiovascular diseases. PLM60 20mg/m2 was administered intravenously every 4 weeks. Treatment may continue for up to 6 cycles or until disease progression, or intolerable toxicity. The primary endpoint was objective response rate (ORR) based on Independent Review Committee (IRC) assessments according to Revised Response Criteria for Malignant Lymphoma (version 2007). Secondary endpoints included ORR based on assessment between investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Adverse events were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.03. This trial is registered at ClinicalTrials.gov (NCT03776279). Results: One hundred and eight eligible patients were treated in 26 institutions in China between April 26, 2018 and May 19, 2020. Patient characteristics are summarized in Table 1. 98 patients were evaluable for response. 44 patients (40.7%, 95% CI, 31.4-50.6%) achieved an objective response including 22 (20.4%) patients achieved CR based on IRC assessment (Figure 1a). ORR were 34.4% (11/32), 50.0% (13/26), 52.4% (11/21), 12.5% (2/16) , 53.8% (7/13) and the CR rates were 18.8% (6/32), 23.1% (6/26), 28.6% (6/21), 6.3% (1/16), 23.1% (3/13) for PTCL-NOS, AITL, NKTCL, ALCL ALK+/-, and other subtypes , respectively (Figure 2). The ORR for patients who received at least 2 cycles of treatment (N=90) was 60.0% (95% CI, 49.1-70.2%). The investigator-evaluated ORR for the whole cohort was 43.5% (95% CI, 34.0-53.4%) (Figure 1b). Median DCR of all patients was 77.8% (95% CI, 68.8-85.2%). The median DoR of the whole group was 9.8 (95% CI, 5.1-not evaluated) months. 77.3% (34/44) of patients achieved response had a DoR ≥3 months (Figure 3). Median PFS of the whole cohort was 6.7 (95% CI, 5.5-10.4) months, with a 6-month PFS rate of 55.3% (95% CI, 44.5-64.8%). Median OS of the whole group was 16.3 (95% CI, 10.7-not evaluated) months, with a 6-month OS rate of 74.9% (95% CI, 64.9-82.4%) (Figure 4a, 4b). All-grade treatment-emergent adverse events (TEAEs, >5%) are listed in Table 2. The most common toxicities of PLM60 were hematological toxicities. The most common grade ≥3 toxicities were leukocytopenia (50.0%) and neutropenia (45.4%). Conclusion: PLM60 monotherapy yielded promising results for patients with R/R PTCL and ENKTCL with moderate toxicities. Further investigation of combination therapy is warranted. Disclosures Xia: CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Xue:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Li:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment.

Tight-controlling of the aspect ratios (ARs) and fine-tailoring of the crystallographic facets of gold nanorods (GNRs) are critical for their further applications in material, biological, and medical fields. However, the high-yield synthesis of GNRs with certain facets and ARs is still challenging because it requires grasping of various components and complicated interactions in the reaction system. Herein, we first report the pH-adjusting method to synthesize uniform and monodispersed GNRs in high yield with the (200) facet and fine-tuned their ARs within an optimal pH range. Through optimizing the experimental parameters, we found that the formation of GNRs was significantly influenced by the concentrations of silver ions and cetyltrimethylammonium bromide (CTAB). Based on the precise control over the quantity of silver ions and CTAB additives, we further optimized the pH in the buffer system. Under the optimized weakly acidic conditions (pH 5.5–7.0), HAuCl4 was reduced by NH2OH to form single-crystalline GNRs with a preferential growth along the [200] facet (i.e. [100] direction), which was supported by transmission electron microscopy (TEM) and X-ray diffraction (XRD). Interestingly, there was a linear relationship between the ARs and pH values over a narrow pH range of 5.5–6.5. The pH-dependent reducing ability of NH2OH enhanced with the increasing pH.

DNA-templated copper nanoclusters (CuNCs) have attracted extensive interest owing to their low cost, easy preparation, excellent optical properties and well biocompatibility, especially in the field of biosensor. However, exploration of DNA-templated CuNCs in biochemical application still suffer from the disadvantage of low sensitivity. Inspired by the report that dsDNA made up of poly adenine-thymine pair (polyAT) was a better template for fluorescent CuNcS, we reported herein for the first example to improve the CuNCs-based fluorescent assay platform, where alkaline phosphatase (ALP) was used as a model target. As a result, enhanced-assay for ALP was obtained (0.05 U/L), much lower than previously reported methods using CuNCs as probe. Meanwhile satisfying results were still obtained in the evaluation of the specificity and the detection of ALP in human serum, demonstrating its potential applications in clinical diagnosis. Notably, this research not only provides a novel and sensitive platform for ALP assay, but also plays an important guiding role in the design of biosensor using DNA-templated CuNCs.

Ke Xu,1 Bin Liu,2 Yegang Ma,1 Baojin Xu,3 Xiaojing Xing1 1Department of Thoracic Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 3General Surgery Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, People’s Republic of China Purpose: Zinc finger SWIM-type containing 5 (ZSWIM5) is a newly discovered protein, which contains a novel zinc-chelating domain SWIM (CxCxnCxH), and is predicted to interact with DNA or proteins. Currently, the knowledge of functions of ZSWIM5 remains limited. In this study, we aimed to elucidate the biological functions of ZSWIM5 and their mechanisms.Patients and methods: We detected the expression of ZSWIM5 in samples from 139 cases of non-small-cell lung cancer (NSCLC) patients and six cell lines using immunohistochemistry and Western blot. Moreover, we explored the biological functions of ZSWIM5 in lung cancer cells by siRNA interference and cDNA transfection of ZSWIM5.Results: The results showed that compared with adjacent non-tumor lung tissues, ZSWIM5 expression was significantly decreased in NSCLC tissues (P=0.0199) and that the ZSWIM5-positive rate in non-tumor tissues (76.67%) was notably higher than that in NSCLC tissues (40.29%). ZSWIM5 expression in human normal bronchial epithelial cells was also much higher than that in lung cancer lines (P

Bin Liu,1 Xiaojing Xing,1 Xiang Li,2 Qianxue Guo,1 Tonghong Xu,1 Ke Xu3 1Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, People’s Republic of China; 2Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, People’s Republic of China; 3Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, People’s Republic of China Purpose: Zinc finger protein 259 (ZNF259), also known as ZPR1, is a zinc finger-containing protein that can bind the intracellular tyrosine kinase domain of EGFR. At present, our knowledge on ZNF259 in cancers is limited. Here, we aimed to explore the biological functions of ZNF259 in breast cancer and reveal their mechanisms.Patients and methods: The expression of ZNF259 was measured in 133 cases of breast cancer by immunohistochemistry. The online database Kaplan–Meier (KM) Plotter Online Tool was used to analyze the relationship between ZNF259 expression and breast cancer patient survival prognosis. Plasmid transfection and small interfering RNA and inhibitor treatments were carried out to explore the functions of ZNF259 in breast cancer cell lines and its potential mechanism. Matrigel invasion and wound healing assays were performed to detect the invasion and migration ability of cancer cells. In addition, protein expressions in tissues and cells were determined by Western blotting.Results: ZNF259 expression was much higher in breast cancer cells than in the adjacent normal breast duct glandular epithelial cells (75.94% vs 7.52%, P

Cell mechanics plays an important role in regulating the physiological activities of cells. The advent of atomic force microscopy (AFM) provides a novel powerful instrument for quantifying the mechanics of single cells at the nanoscale. The applications of AFM in single-cell mechanical assays in the past decade have significantly contributed to the field of cell and molecular biology. However, current AFM-based cellular mechanical studies are commonly carried out with fixed measurement parameters, which provides limited information about the dynamic cellular mechanical behaviors in response to the variable external stimuli. In this work, we utilized AFM to investigate cellular viscoelasticity (portrayed as relaxation time) with varying measurement parameters, including ramp rate and surface dwell time, on both cell lines and primary cells. The experimental results show that the obtained cellular relaxation times are remarkably dependent on the parameter surface dwell time and ramp rate during measurements. Besides, the dependencies to the measurement parameters are variable for different types of cells, which can be potentially used to indicate cell states. The research improves our understanding of single-cell dynamic rheology and provides a novel idea for discriminating different types of cells by AFM-based cellular viscoelastic assays with varying measurement parameters.

Biglycan (BGN) is overexpressed in cancer stem cells of colon cancer and induces the activation of NF-κB pathway which contributes to the chemotherapy resistance of diverse cancer types. Therefore, we hypothesized that the overexpression of BGN also promoted the development of multiple drug resistance (MDR) in colon cancer via NF-κB pathway. The expression of BGN was bilaterally modulated in colon cancer cell lines HT-29 and SW-480 and the effect of treatments on the cell proliferation and resistance to 5-FU was assessed. Moreover, the role of NF-κB signaling in the BGN-mediated formation of MDR was further investigated by subjecting BGN-overexpressed SW-480 cells to the co-treatment of chemo-agents and NF-κB inhibitor, PDTC. The inhibition of BGN expression decreased the proliferation potential of HT-29 cells while the induction of BGN expression increased the potential of SW-480 cells. BGN knockdown increased HT-29 cells' sensitivity to 5-FU, represented by the lower colony number and higher apoptotic rate. To the contrary, BGN overexpression promoted the resistance of SW-480 cells to 5-FU. The effect of BGN modulation on colon cancer cells was associated with the changes in apoptosis and NF-κB pathways: BGN inhibition increased the expressions of pro-apoptosis indicators and suppressed NF-κB pathway activity while BGN overexpression had the opposite effect. It was also found that the BGN-mediated formation of MDR was impaired when NF-κB pathway was blocked. Findings outlined in the current study showed that BGN contributed to the formation of chemotherapy resistance in colon cancer cells by activating NF-κB signaling.

In this paper, we study a class of optimal dividend and investment problems assuming that the underlying reserve process follows the Sparre Andersen model, that is, the claim frequency is a “renewal” process, rather than a standard compound Poisson process. The main feature of such problems is that the underlying reserve dynamics, even in its simplest form, is no longer Markovian. By using the backward Markovization technique, we recast the problem in a Markovian framework with expanded dimension representing the time elapsed after the last claim, with which we investigate the regularity of the value function, and validate the dynamic programming principle. Furthermore, we show that the value function is the unique constrained viscosity solution to the associated HJB equation on a cylindrical domain on which the problem is well defined.

A new co-crystallized complex [Me2NH2]6[VIV12VV6O42][VON(CH2CH2O)3]·2H2O (1) based on mixed valence polyoxovanadate [VIV12VV6O42]6 − and a new mononuclear vanadium complex [VON(CH2CH2O)3] (2) were synthesized by controlling conditions of solvothermal synthesis and characterized by single crystal XRD, IR, XPS and EA, respectively. The compound 1 presents interesting antiferromagnetic interaction in solid state and luminescent property in aqueous solution.

Cobalt ferrite nanoparticles loaded on multiwalled carbon nanotube (MWCNT) magnetic hybrids have been demonstrated to be promising magnetic resonance imaging contrast agents and drug carriers. However, the hydrophobic, less biocompatible characteristics and low loading capacity for the drug hamper their wide biological applications. To solve the above problem, an alternative strategy is to coat the MWCNTs@CoFe

Psoriasis is a chronic inflammatory disease of the skin for which an effective treatment strategy remains to be developed. Characteristics of psoriasis include an altered differentiation of keratinocytes and hyperplasia of the skin. The present study aimed to investigate the role served by miR-520a in psoriasis. The results demonstrated that miR-520a inhibited the proliferation of HaCaT cells. miR-520a directly regulated the mRNA and protein expression of its target gene, protein kinase B (AKT). The siRNA silencing of AKT expression in these cells was also evaluated. miRNA-520a repressed the proliferation and mitotic entry of HaCaT cells, and promoted cell apoptosis. AKT silencing suppressed the proliferation of HaCaT cells. These results suggest that miRNA-520a regulates the survival of HaCaT cells by inhibiting AKT expression. miRNA-520a and AKT may therefore be novel targets for the treatment of patients with psoriasis.

The different sized and shaped Au NPs have intrigued considerable attention, because they possess different surface plasma resonance (SPR) absorption bands and thus result in many colorimetric Au NP-based detection applications. In this article, four different sized and shaped Au NPs of nanodots/rods were prepared and characterized. The as-prepared Au NPs were modified by the negatively charged anions of [SCH2CO2]2− to investigate both the size and shape effects of modified Au NPs on colorimetric detection of Co2+ and the corresponding SPR absorption properties. The different-shaped Au NPs possess different SPR absorption properties. The Au nanorods appeared to be colorimetric sensitive for Co2+ sensing.

Radiotherapy in ovarian cancer frequently invokes resistance; this severely compromises its therapeutic effect and results in poor clinical prognosis. How to overcome the acquired resistance and re-sensitize tumors to radiation is the central question in this clinical setting. Cancer cell survival was evaluated using a clonogenic assay. The microRNA expression profile was analyzed using a microarray. Transcript expression was determined using real time PCR. The expression of protein was determined by immunoblotting. Transcription activation was measured using a luciferase reporter assay. Transcription factor binding was determined using ChIP-PCR. Xenograft model was established and exposed to radiation with the simultaneous administration of oleuropein. Tumor growth was monitored. We demonstrated that treatment of oleuropein-sensitized ovarian cells with radiation altered the microRNA expression profile. The endogenous expression of miR-299 was suppressed by a hypoxia inducible factor and relieved in response to oleuropein, which in turn suppressed HPSE1 expression and consequently led to increased sensitivity to radiation. Our data elucidates an unappreciated mechanism mediating radiotherapy resistance in ovarian cancer and exploits the potential synergistic effect of oleuropein with radiation, which warrants further clinical investigation.

Integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase, has been reported to be highly expressed in many human malignancies, including gastric cancer. However, the prognostic significance of ILK expression in gastric cancer remains to be elucidated. In the present study, ILK expression in 95 gastric tumor tissues and 30 adjacent non-cancerous gastric mucosa was evaluated by immunohistochemistry and correlated with clinicopathological characteristics and patients' outcome. The results showed that high ILK expression was observed in 47.4% (45/95) of gastric cancer tissues, but only in 20.0% (6/30) of adjacent gastric mucosa. Clinicopathological analysis indicated that high ILK expression was significantly associated with poor tumor differentiation (P=0.024), advanced TNM stage (P=0.006), tumor invasion (P=0.001), and lymph node metastasis (P=0.014). Kaplan-Meier survival curves demonstrated that patients with high ILK expression had substantially shorter overall survival that those with low ILK expression (P=0.043, log-rank test). Furthermore, Cox multivariate regression analysis identified ILK expression as an independent prognostic factor for overall survival of gastric cancer patients (hazard ratio, 1.95; 95% confidence interval, 1.02-3.13; P=0.026). In conclusion, our data suggest that ILK may contribute to the malignant progression of gastric cancer and serve as a novel prognostic indicator for gastric cancer patients.

4024 Background: Human epidermal growth receptor 2 (HER2) is considered as an oncogenic driver gene in gastric cancer (GC). Immunotherapy has been proven to be effective in GC patients. Previous studies indicated that patients harboring driver mutations were considered as poor candidate for immunotherapy. But the efficacy of immunotherapy for HER2 positive GC has not been defined. We therefore analyzed the immunogenicity of HER2 alterations in GC. Methods: Genomic profiling of DNA from 448 GC was performed using next-generation sequencing on 381 cancer associated genes. The expression of PD-L1 protein was evaluated in 192 GC with the use of an automated immunohistochemical assay (Ventana, SP263). Whole-exome sequencing, copy number variations, RNA-seq and clinical data of 443 GC from The Cancer Genome Altas (TCGA) were also analyzed to further evaluate the immunogenicity of HER2 alterations. TMB was defined as number of somatic non-synonymous mutations in coding regions. HER2 amplification in TCGA was defined as “2” derived from the copy-number analysis algorithms GISTIC. Results: HER2 alterations including amplification, missense and fusion were present in 19.2% (85/443) of TCGA cohort and 11.4% (51/448) of clinical cohort. 14.0% (62/443) of TCGA cohort and 6.0% (27/448) of clinical cohort harbored HER2 amplification. Higher TMB was observed in MSS/MSI-L patients carrying any HER2 alterations in TCGA cohort (P = 0.009). On the contrary, HER2 alterations did not show a higher neoantigen level and HER2 alterations were associated with decreased immunogenicity in terms of immune-related gene mRNA expression and immune infiltrates. In clinical cohort, HER2 alterations was also significantly associated with higher TMB (P = 0.001). Meanwhile, a trend of shrinking proportion of PD-L1 expression was observed in HER2 alteration subgroup (2/23, 8.7%) than HER2 wild-type subgroup (47/169, 27.8%, P = 0.071). Furthermore, HER2 amplification had significant positive associations with HRD score (P = 0.0169) in TCGA cohort which indicated an increased degree of genome instability. Conclusions: Although HER2 alterations in GC were associated with increased TMB, HER2 alterations exhibited poor immunogenicity. These findings indicated that HER2 alterations might confer resistance to immune monotherapy.

An in-situ reduction method has been reported to prepare gold nanoparticles (GNPs) of 40–110 nm by using the green reducing agents of proteins, which are activated by H2O2 and the superoxide anion ("Equation missing"). The protein of collagen turns HAuCl4 to the aqueous Au(I) ainions, which are further reduced by other proteins to be highly monodispersed and spherical GNPs of different sizes. The GNPs reduced by different proteins are found to be with the exposed {100} facets, the distinctive UV-vis absorption spectra and various colors (See Fig. 1). By means of extracting the color responses, such as red, green and blue (RGB) alterations, an in-situ reduction method-based multidimensional sensing platform is fabricated in the process of GNPs synthesis. Without further modification of GNPs, nine common proteins are found to be well detected and discriminated at different concentrations. Moreover, this sensing platform also demonstrates great potentials in qualitative and semiquantitative analysis on the individuals of these proteins with high sensitivity. Furthermore, the validation of this multidimensional sensing platform has been carried out by analysis on the spiked proteins in human urine and the target proteins in complex matrix (e.g. lysozyme in human tear).

Biglycan, an extracellular matrix protein, has been implicated in the oncogenesis and cancer development in various types of human cancer. The clinical significance of biglycan in colorectal cancer, however, remains unclear. In the present study, biglycan mRNA expression was analyzed in 110 samples (primary colorectal tumor and matched adjacent normal tissue) derived from 55 patients with colorectal cancer using quantitative real-time RT-PCR. The correlations between biglycan up-regulation and the clinicopathological data were also evaluated. We found that the up-regulation of biglycan occurred in 61.8% (34/55) of colorectal cancer tissues, and biglycan expression in colorectal cancer tissues was markedly higher than that in corresponding normal tissues (P = 0.0264). Moreover, statistical analysis displayed a significant correlation in biglycan up-regulation with poor tumor differentiation (P = 0.009), lymph node metastasis (P = 0.041), and distant metastasis (P = 0.036). However, there was no significant correlation between biglycan up-regulation and other clinicopathological factors (all P > 0.05). In conclusion, biglycan may be a potential marker for the malignancy of colorectal cancer.

Introduction Although immune dysfunction plays a role in the pathogenesis of systemic sclerosis (SSc), involvement of T helper 17 (Th17) and T regulatory (Treg) cells remains unclear. We aimed to investigate the presence of Th17 and Treg cells in SSc patients and the role of Th17 cells in collagen production in SSc fibroblasts. Methods We analyzed inflammatory cell profiles in the skin of 13 SSc patients by immunohistochemistry, the percentage of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) of 45 SSc patients and 24 healthy controls by flow cytometry, gene expression in PBMCs by real-time reverse transcription-polymerase chain reaction and interleukin-17 (IL-17) in sera and culture supernatants by enzyme-linked immunosorbent assay. We also investigated the effect of Th17 cell-derived IL-17 on fibroblast growth and collagen production. Results Infiltration of inflammatory cells including IL-17+ and Foxp3+ lymphocytes was detected in the skin of patients with early SSc. The percentages of circulating Th17 cells and IL-17 production were elevated in samples from patients with active SSc, whereas the percentage of circulating Treg cells was not affected. The number of Th17 cells was closely related to disease activity. IL-17 from SSc patients promoted fibroblast growth and collagen production, whereas IL-17 neutralizing antibody effectively blocked collagen production. Conclusion SSc progression might be linked to expansion of circulating Th17 cells and increased infiltration of IL-17+ cells in skin. Th17-derived IL-17 is involved in fibroblast growth and collagen production. IL-17 blocking antibody may be a useful tool for intervention in the fibrotic course of SSc.

Recent reports have demonstrated that endothelial cells are involved in vascular inflammatory injury in systemic sclerosis (SSc) and interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of SSC. However, little is known about the effects of IL-17A on endothelial cell inflammation in SSC. The aim of our study was to investigate the role of IL-17A in endothelial inflammation. Here, we showed that IL-17A mRNA and protein levels were augmented in the peripheral blood and more IL-17⁺ lymphocytes infiltrated in the perivascular areas in the involved skin of SSC patients. SSC patient serum induced chemokine and adhesion molecule expression in HUVECs, which was blocked by IL-17A neutralization. IL-17A alone induced chemokine and adhesion molecule expression and promoted T cell-HUVEC adhesion. Extracellular signal-regulated kinase (ERK) inhibition and IL-17A neutralization prominently inhibited chemokine and adhesion molecule expression and blocked T cell-HUVEC adhesion. IL-17A derived from SSC patient serum mediated endothelial cells inflammation by up-regulating chemokines and adhesion molecules, which was blocked by ERK inhibition. These data imply that ERK signal pathway might play a key role in the progression of endothelial injury induced by IL-17A in SSC.